We include a report on hepatitis D from this new meeting.

• Needs of neglected disease going unmet: a conference overview

A specialised conference on hepatitis Delta (D) took place on 25-26 September 2010, in Istanbul, Turkey. The conference was organised by the European Association for the Study of the Liver (EASL) and gathered together almost 200 health professionals.

This was the first conference on hepatitis D and for the first time the available information about the D virus was presented. Many aspects of Hepatitis D were highlighted: virology, pathogenesis, epidemiology, diagnosis and natural history, treatment, prevention and future development.

In 1977, Mario Rizzetto and colleagues described a novel antigen in the nucleus of hepatocytes derived from patients infected with HBV. Antibodies against the so-called ‘delta antigen’ were detected in patients with a particularly severe course of HBV infection. Subsequently, the hepatitis D virus (HDV) was identified as the infectious agent causing hepatitis in the presence of HBV infection. Thus, hepatitis D can occur only in individuals who are also infected with HBV, as HDV uses the hepatitis B surface antigen (HBsAg) as its envelope protein, which is essential for viral transmission. HDV infection can therefore occur as either a superinfection of chronic HBV infection or as simultaneous acute HBV and HDV coinfection.

Chronic HDV is by far the most dangerous hepatitis virus. It leads to more severe disease than hepatitis B mono-infection and more rapid rates of fibrosis progression. In HDV there is a relatively early decompensation. Hepatitis D patients are in a greater risk of developing a hepatocellular carcinoma. There are currently no established treatment options. Limited data suggest that hepatitis D is mainly an immune-mediated disease, at least in patients with HDV genotypes 1 and 2. Antiviral therapies should, therefore, aim to enhance anti-HDV immunity and reduce viraemia to confer long-term control of infection.

Comprehensive data on epidemiology of hepatitis D are missing. Nevertheless, 15–20 million people are estimated to have HDV globally. Other sources estimate 20-50 million people. However, this may still be an underestimation since epidemiology data from many areas where hepatitis B is highly prevalent are missing. Epidemiology of HDV is changing. In Europe, comprehensive data is available: 8—12% HBsAg positive patients were tested anti-HDV positive, most of the European HDV patients were born in highly endemic areas like Eastern Turkey, Eastern Europe, Central Asia, Africa, Southern America, Western Pacific. There is an urgent need for reliable data especially from highly endemic regions.
Even 30 years after discovery of HDV, its life cycle is not fully understood. The virus enters the hepatocyte via unknown receptor. The entry mechanisms of HBV and HDV are not fully described, but they are a therapeutic target for future antiviral drugs. Prenylation inhibitors are about to enter humans studies.

HDV has a great genetic variability. There are 8 genotypes and possibly several subclades, according to a French research by Emmanuel Gordien, who used 1116 samples for phylogenetic analysis collected between January 2001 and December 2009.The research showed that the distribution of clades is global.

Fig 1. Global epidemiology of HDV infection according to viral genotype

Source: Wedemeyer H and Manns MP. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat. Rev. Gastroenterol. Hepatol. (2010). doi:10.1038/nrgastro.2009.205.

Every individual who is HBsAg positive should be tested for anti-HDV IgG antibodies at least once. There is no evidence that direct testing for HDV RNA in the absence of anti-HDV antibodies is of any use because anti-HDV antibodies develop in every individual infected with HDV. A positive result for the presence of anti-HDV antibodies, however, does not necessarily indicate active hepatitis D; HDV RNA can disappear indicating recovery from HDV infection. In the long term, anti-HDV antibodies can disappear after recovery from infection. However, anti-HDV antibodies may persist for years, even when following HBsAg seroconversion or liver transplantation.

HDV infection should be confirmed by the detection of serum HDV RNA. If an individual tests positive for serum HDV RNA, subsequent evaluation including grading and staging of liver disease, surveillance for hepatocellular carcinoma and consideration for antiviral treatment is indicated. HDV RNA quantification is offered by some laboratories. However, similar to HCV, there is no evidence that serum HDV RNA levels correlate with any clinical marker of activity or stage of liver disease. Thus, HDV RNA quantification is only useful if antiviral treatment is indicated. Rules regarding the discontinuation of antiviral treatment depending on the level of HDV RNA decline are under evaluation.

Erhardt et al. have suggested that patients with less than a three log decline in serum HDV RNA levels after 24 weeks of treatment with PEG-IFN-alpha2b do not benefit from continued treatment. Similarly, Yurdaydin et al. showed that patients with HDV infection who achieve an SVR with conventional recombinant IFN-alpha usually show a decline in serum HDV RNA levels within the first 3–6 months of treatment compared with patients who are not able to clear HDV infection.

Prophylaxis against HDV is HBV vaccination and there remains a need for an HDV specific vaccine to protect HBsAg carriers in endemic areas or risk populations.

Coinfection with HDV and HIV is associated with higher replication markers of HDV and accelerated liver fibrosis progression. HIV-associated immunodeficiency favors viral replication escape, abrogating viral interference phenomena of hepatitis viruses. All viruses B, C and D may replicate in a given patient. Since the introduction of HAART in 1996, most HIV-positive people have experienced immune recovery and severe immunodeficiency is currently rare. The worst prognosis of viral hepatitis in this population has ameliorated in recent years. The wide use of oral antivirals with dual activity against HIV and HBV (tenofovir, 3TC, FTC), alone or in combination, provides a unique opportunity to explore their long-term effect on HDV in co-infected patients. (Soriano et al. AIDS 2005).

In the summary of his talk about EuroSIDA, Vincent Soriano said that the prevalence of anti-HDV in chronic HBsAg carriers in EuroSIDA is 12%. Up to 85% of these patients show HDV viremia. Overall patients with delta hepatitis show lower serum HBV-DNA levels than HBsAg+ carriers without delta hepatitis. However, in the subset of delta hepatitis patients with HBV-D, less inhibition of HBV replication was found. (Soriano et al, 2009).
The incidence and prevalence of delta hepatitis and HDV-related liver disease in the HIV population has dramatically declined since year 2006: HAART, broad HBV vaccination, decline in IDU, closer medical follow-up, no alcohol behavior, early diagnosis, proper follow-up of cirrhosis and other measures played its positive role.

HIV associated immunodeficiency is believed to be associated with a worsening in the natural history of chronic HDV, with evidence of increased replication markers (HDV-RNA levels and frequency of serum delta antigen recognition) and faster progression to the end stage liver disease. Early introduction of antiretroviral therapy might minimise these deleterious effects, by suppressing HIV replication and enhancing immune responses. Moreover, the use of potent anti-HBV agents with antiretroviral activity, such as tenofovir, has been associated with a steadily significant decline in serum HDV-RNA and amelioration of liver disease in a subset of HIV-positive patients with HDV, an observation, which requires further investigation (Sheldon et al, 2008). More recently, a small subset of HIV-HBV-HDV co-infected patients on long-term tenofovir/FTC therapy evolved to serum HBsAg clearance, which in all instances was preceded by a steadily decline in serum HBsAg titers. Serum HDV-RNA also became undetectable in these individuals. The question is whether the a cure for delta using nucleos(t)ide analogues was obtained.

Exposure to HCV preceding or following acquisition of HDV results in viral interference, which in most instances leads to replication of one virus and suppression of the other (Martin-Carbonero et al, 2007). It is HDV, which in most cases suppress HCV, which in general results in sustained clearance of HCV. In a subset of patients, however, and particularly in the presence of immunosupression (i.e. in HIV co-infection with low CD4 counts), replication of all viruses (HBV, HDV, HCV) may be recognised at all times points intermittently (Schaper et al, 2010).

Although treatment with pegylated interferon plus ribavirin may clear HCV in some of these triply or quadriply infected patients viremic for HCV, no sustained benefit is generally seen for hepatitis D following treatment discontinuation (Soriano et al, 2007).

The major challenges for hepatitis D are that it is a defective virus, its replication circle is unconventional and it is highly pathogenic (HDV causes the least common, but most severe form of chronic viral hepatitis, leading to cirrhosis in about 50-70% of the cases).

Despite been rare, because of the lack of an effective treatment and the severity of liver disease, chronic HDV is a serious health problem. Because of the paucity of the patients, most of the studies related to chronic HDV are inconclusive. Interferons and pegylated interferons may provide a 15 to 45% sustained virologic response. The replication strategy of delta virus is different from that of hepatitis B virus. Therefore, the nucleos(t)ide analoges, which are effectively used in the treatment of chronic hepatitis B, have no place in the treatment of CHD. These drugs may be beneficial only if they success a reduction in the level of HBsAg, which is required for the formation of the delta virion.

Lamivudine (3TC), which is commonly used to treat HBV (despite the risk of resistance), does not decrease the level of cccDNA or HBsAg. Therefore, it has no effect in the treatment of chronic HDV, either as a monotherapy or as a part of interferon combination. In a randomised study, improvement in necroinflammatory activity was found to be more significant in the combination group, comparing to interferon-treated patients. However, no significant improvement was observed in regards to fibrosis. The rate of sustained virologic response was statistically similar in combination therapy and interferon treated patients.

In recent years the most powerful antivirals have been shown to decrease the HBsAg titer and to achieve HBsAg loss. Some promising results are expected from the combination therapies of interferon with entecavir or tenofovir disoproxil fumarate (TDF). A case report described an HBsAg seroconversion after 10 month treatment of peginterferon alfa-2a plus TDF plus emtricitabine (FTC). Although  there are ongoing studies investigating the effectiveness of interferons, tenofovir and entecavir in HDV, there has been no published clinical study so far.

Based on the data of the reducing effect of adefovir dipivoxil on cccDNA and HBsAg titer, its combination with peginterferon alpha-2a was investigated (Wedemeyer et al, 2006). This study demonstrated no difference between peginterferon alpha-2a (PegIFN2a) and PegIFN2a+adefovir combination, in terms of HDV RNA negativity. However, HBsAg reduction was more pronounced in combination arm comparing to monotherapies.  40% of the patients in the combination arm achieved at least 1 log reduction of HBsAg level, while this figure is 5% in the PegIFN 2a-treated patients.

Ribavirin is effective against hepatitis C virus, and it has been shown experimentally to inhibit HDV genome replication in hepatocyte cultures. However, in a pilot study, including patients with chronic HDV, ribavirin monotherapy did not result in biochemical, virological or histologyical improvements (Garripoli A et al, 1994). Yet, ribavirin was tried in a combination with interferons in the treatment of CHD. In these trials, ribavirin combinations were not superior to interferon monotherapy. Two years duration of interferon plus ribavirin treatments (Kaymakoglu S et al, 2005; Gunzar F et al, 2005) and a 24-week peginterferon plus ribavirin combination (Niro G et al, 2006) achieved almost 20% sustained virologic response in patients with chronic HDV. Interferon and nucleos(t)ide combination therapies do not provide an additive or synergistic effect in the treatment of HDV. “However, the combinations with newer drugs are awaited with interest”, – said Doctor Akarca from Ege University Medical School, Izmir, Turkey.

Currently, the only option for treating HDV is IFN-a or pegIFN-alpha, resulting in moderate sustained virological response rates at long term and high dose application. Experimentally it has been shown that inhibitors of farnesyltransferase inhibit HDV secretion in mice by blocking farnesylation of the large HDAg. Some other specific approaches like the inhibition of the HDV-ribozyme or siRNA are feasible but far from entering the clinical stages. Thus there is a strong medical need to develop drugs that interfere with specific stages of HDV replication.

In a summary at the end of the conference, Dr Manns emphasised that there are many needs that concern us: improved awareness (Anti HDV in every HBsAg+ patient, standardised HDV RNA testing, increased funding for basic science, convincing governments to invest in research for HDV), promoting the importance of HDV infection to governments, foundations (Gates), EASL, AASLD, diagnostic companies, therapeutic companies. He also suggested the creation of International HDV Consortium (without formal membership, driven by projects, working on global database, collection of material (serum, DNA, tissue), and leading the interventional clinical trials).

A joint report from UNAIDS and Kaiser launched prior to the conference clearly and disturbingly showed that international donor funding, which now supports close to five million people on treatment, has leveled. This threatens to overturn the accumulated health benefits from the last ten years.

Flat-lined funding means treatment programmes will be closed to new patients and this will have a disastrous impact on HIV prevention.
Without treatment, not only is there little incentive to test, and an increase in AIDS and death, but also the beneficial impact that antiretroviral therapy has on the risk of transmission will be reduced.  And treatment is still likely to be more effective in preventing HIV than any other intervention.

This global crisis demands international support, and this involves funding. So while the US leads funding initiative, as the world’s richest country, it is just as important that other wealthy nations meet, for example, the commitments made at the G8 summit. The expense and investment in the conference itself, did not sit easily with the decision to hold the meeting in country that has not supported the Global Fund since 2002. Currently the Global Fund to Fight AIDS, TB and Malaria (GFATM) is faced with a $3 billion shortfall for 2010. Similarly, very few African nations have met their pledge in the Abuja Declaration 2001 to target at least 15% of GDP on healthcare.

The global demand for treatment challenges the concept of universal access using todays medications. Research into ARV drug delivery using nanotechnology is proceeding extremely slowly with only one abstract at this meeting, and yet this has the potential to address many obstacles to wider access. The volume of active ingredient is dramatically reduced with a nanoformulation requiring perhaps monthly dosing, both of which dramatical reduce costs.

This was a conference that highlighted access issues from a human rights perspective:

• The Vienna Declaration – is the official conference statement seeking to improve community health and safety by calling for the incorporation of scientific evidence into illicit drug policies (viennadeclaration.com).
• Many sessions addressed access to evidence-based harm reduction stategies including opioid substitution therapy (OST) and needle exchange progammes.
• Access to treatment to prevent mother-to-child transmission (PMTCT) – currently only 10–20% of HIV-positive women worldwide are able to access testing and treatment during pregnancy.
• The criminalisation of same sex relationships and discrimination against men and women whose sleep with partners of the same sex, highlighted most recently by extreme cases in Uganda, Malawi and Iran, was the focus of several sessions. .

In terms of medical and scientific research, there were a few important headline-grabbing studies and a good selection of interesting but preliminary research findings.

As with all meeting reports we include links to original abstracts and webcasts when available, and for this meeting we also start with a guide on how to navigate the conference website for other material.

Abstracts from the conference are published on the conference website:
http://www.aids2010.org/

As with previous IAS conferences, much of the conference material is available online and HTB reports include appropriate hyperlinks.

Locating the appropriate files, presentations, webcasts, transcriptions or even the basic abstracts is more challenging. Access is routed through the ‘Programme at a glance’ link on the conference homepage. This requires a free software plug-in called Silverlight, but an automatic download button should come up if you do not already have this installed.

Vienna Conference homepage

‘Programme at a glance’

The search facility requires selecting one of the seven options directly under the search bar ie to search the abstracts, you need to first click ‘abstract’ which when selected has the tiny white triangle in the red block turn to face down. Then search as you would normally by entering a keyword in the search box and clicking search. Results come up listed below.

The abstract books are available to download as free PDF files, but only for each day, so searching the whole conference requires repeating each search four times.

Download abstract books.

Although you can browse sessions by day and time, this is not so easy if you are looking for a specific session but don’t know when it was presented because there is not a programme that just shows the sessions. For example a search for ‘late breaker’ brings up no results whether searching ‘programme at a glance’, ‘abstracts’, or ‘oral sessions’.

If you find a session page, you then have to find and click the yellow ‘more info’ button at the bottom right of an empty box, and then you finally get to a page that makes sense. Don’t be entirely fooled. The ‘abstract’ links seems to work, but ‘slides with audio’ are not always available and the ‘powerpoint’ link doesn’t work at all. For presentation slides, scroll further down the page where slides that are available are listed under the ‘powerpoint presentations’ heading.

The audio works but you need to manually download the powerpoint slides to really follow the presentation.

To make things more confusing, some webcast presentations are provided by Kaiser Foundation on a different website.

http://globalhealth.kff.org/AIDS2010

These webcasts only show the presenter, with no slides and no easy links to slides. Although you often hear two different presentations simultaneously, this accurately captures the conference experience. Only a cloth curtain divided most session rooms, so the webcasts accurately reflect the conference atmosphere, including this difficulty.

Kaiser provide rough transcripts of the sessions that can be more useful with the slide set, than the webcast, though they are draft transcripts only.

Web access should be a leading priority for these conferences. The interface used by the Retrovirus (CROI) conference would be a much more useful model to use and would make this aspect of the meeting far more accessible, whether provided by IAS or Kaiser.

Even though majot HIV treatment conferences hardly cover IDU issues and the big news is that there is no news, the 18th International AIDS Conference proved me wrong.

The symposium, organised by The Lancet and entitled Global HIV epidemic among people who use drugs, was perhaps the single most important event tackling the topic during the last five or more years.

This session included seven state-of-the-art reviews, and a number of invited commentaries, all of which were published as a supplement to the Lancet, and which are free to access online (after intial free registration).

“Following the principle of “nothing about us without us,” each paper included the voices of people who use drugs. These include community participants and leaders from China, Ukraine, Thailand, Malaysia, and the USA. Invited commentaries include the Vienna Declaration, a call to decriminalise people who use drugs, and commentaries from high profile authors including state officials from Mexico who will discuss their country’s alternative approaches to the war on drugs, and commentaries on women and drug use, alcohol and HIV transmission in Africa. The series captures a ‘sea change’ in terms of the international response to HIV prevention and treatment among people who use drugs, a growing segment of the global HIV and AIDS epidemic that has been underappreciated for too long”.

All documents from the symposium are posted online.
http://pag.aids2010.org/session.aspx?s=155

These include all presentation slides and audio recording (including in Russian), as well as all PowerPoint presentations for download. Further to that, the Kaiser Family Foundation provides webcasts both in English and Russian, including transcripts of the talks.
http://globalhealth.kff.org/AIDS2010/July-20/The-Lancet-Series.aspx

Articles in The Lancet are also online. The site requires registration, but it is free for this particular issue.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60832-X/abstract

We recommend readers to view this symposium online, summaries are included below for some sessions.

Steffanie Strathdee from the University of California, San Diego, presented HIV and the risk environment among people who inject drugs: past, present, and projections for the future. [1]

The team systematically reviewed reports about determinants of HIV infection in injecting drug users from 2000 to 2009 and then modelled changes in risk environments in regions with severe HIV epidemics associated with IDU. The model clearly showed a heterogeneity in the number of HIV infections resulted from IDU and unprotected sexual intercourse. The estimations for 2010-2015 suggest that HIV prevalence can be reduced by 41% in Odessa (Ukraine), 43% in Karachi (Pakistan), and 30% in Nairobi (Kenya) through a 60% reduction of the unmet need of programmes for opioid substitution, needle exchange and provision of ARV.

The next presentation by Louisa Degenhardt was entitled HIV prevention for people who inject drugs: why individual, structural, and combination approaches are required. [2]

The researchers summarised evidence on the effectiveness of individual level approaches to prevention of HIV-infection, ie opioid substitution therapy, needle and syringe exchange programmes and ARV provision and afterwards modelled the effect of increased coverage and combination of the three approaches. The model shows that each intervention take individually will provide only modest reductions in HIV transmission, hence it is suggested that prevention needs high coverage and combined approaches. Some possible social and structural changes were also discussed.

Next three presentations were particularly topical . The first of those was by Daniel Wolfe on Treatment and care HIV-positive people who inject drugs: a review of barriers and ways forward. [3]

This presentation was based on a review of evidence for effectiveness, cost-effectiveness, and coverage of ARV for IDUs with a particular stress on low- and middle-income countries. Almost half of the IDUs living with HIV (47%) are concentrated in five countries-China, Russia, Ukraine, Vietnam and Malaysia. IDUs are 67% of the cumulative HIV cases in those countries, but only 25% of them receive ARV. For improvement of this situation, the writers suggest systemic and structural changes like integration of ARV provision with opioid substitution and TB treatment, increased peer engagement in treatment delivery and reform of harmful policies, ie. police use of drug user registries, detention of drug users, imprisonment for possession of drugs for personal use, etc.

Frederick Altice’s talk was entitled Medical, psychiatric and substance use co-morbidities among HIV-positive drug users: optimizing treatment and clinical outcomes. [4]

The presentation is of particular value, as it recognised that simultaneous clinical management of multiple comorbidities, that are more typical for HIV-positive IDUs than for the general HIV-positive population, might result in complex pharmacokinetic drug interactions that must be addressed accordingly. The article in The Lancet has several tables that will help medical professionals and treatment peer counsellors. Those tables present information on:

• Common legal and illegal drugs and their effect on HIV;
• Available pharmacological medication-assisted therapies used for treatment of substance-use disorders;
• Complications related to drug use in HIV–positive IDUs; and
• Common interactions between methadone and buprenorphine with treatment for HIV infection and other comorbidities.

The next presentation was on Amphetamine-group substances and HIV: what is to be done? by Grant Colfax. [5]

As amphetamine-group substances are used worldwide and are more prevalent than either cocaine or opioids, the researchers did a meta-analysis of randomised controlled studies of behavioural interventions for their use. 13 studies with a cumulative sample size of 1997 subjects met the inclusion criteria of the analysis. Overall, high intensity behavioural interventions were moderately effective. The researchers concluded that they: “Did not find conclusive evidence that behavioural interventions as a group are more effective than are passive or minimum treatment for reduction of amphetamine-group substance use or sexual risk behaviours.”

The topic of ‘People who use drugs, HIV, and human rights’ was also touched upon during the talk by Ralf Jurgens. [6]

He presented reports that clearly demonstrate a link between human rights abuses and vulnerability to HIV. These abuses include denial of harm reduction services, discriminatory access to ARV, abusive law enforcement practices, and coercion in the guise of treatment for drug dependence.

Finally, to set the scene for the general discussion that was particularly lively, there was a closing presentation by Chris Beyrer on ‘Galvanising a global response: a call to action for HIV and AIDS among people who use drugs’. [7]
According to the team of writers and based on the published work on HIV and in IDUs, the global burden of HIV infection in this group can be reduced.

The researchers identified synergies between biomedical science, public health, and human rights. Currently, only about 10% of the IDUs worldwide are reached with necessary services, hence the appalling state of HIV infection spread among the group. To change this situation will take commitment, advocacy, and political courage.

References:
1.     Strathdee S et al. HIV and the risk environment among people who inject drugs: past, present, and projections for the future. 18th International AIDS Conference. 18-23 July, 2010. Vienna. Symposium presentation TUSY0702
http://pag.aids2010.org/flash/?pid=100315
2.     Degenhardt L et al. HIV prevention for people who inject drugs: why individual, structural, and combination approaches are required. 18th International AIDS Conference. 18-23 July, 2010. Vienna. Symposium presentation TUSY0703
http://pag.aids2010.org/flash/?pid=100314
3.     Wolfe D et al. Treatment and care HIV-infected people who inject drugs: a review of barriers and ways forward 18th International AIDS Conference. 18-23 July, 2010. Vienna. Symposium presentation TUSY0704
http://pag.aids2010.org/flash/?pid=100315
4.     Altice F et al. Medical, psychiatric and substance use co-morbidities among HIV-infected drug users: optimizing treatment and clinical outcomes.18th International AIDS Conference. 18-23 July, 2010. Vienna. Symposium presentation TUSY0705
http://pag.aids2010.org/flash/?pid=100312
5.     Colfax G et al. Amphetamine-group substances and HIV: what is to be done? 18th International AIDS Conference. 18-23 July, 2010. Vienna. Symposium presentation TUSY0706
http://pag.aids2010.org/flash/?pid=100311
6.     Jurgens R et al. The topic of People who use drugs, HIV, and human rights. 18th International AIDS Conference. 18-23 July, 2010. Vienna. Symposium presentation TUSY0707
http://pag.aids2010.org/flash/?pid=100310
7.     Beyrer C et al. Galvanizing a global response: a call to action for HIV and AIDS among people who use drugs.18th International AIDS Conference. 18-23 July, 2010. Vienna. Symposium presentation TUSY0708
http://pag.aids2010.org/flash/?pid=100309

The Human T-lymphotropic virus-II (HTLV) is a human RNA retrovirus. It shares approximately 70% genomic homology (structural similarity) with HTLV-I.  Unlike HTLV-I, HTLV-II has not been clearly linked to any disease, but has been associated with several cases of myelopathy and tropical spastic paraparesis. HTLV-II infection has been predominantly detected in intravenous drug users (IDU) in urban areas of North America and some European countries, who often are coinfected with HIV-1. Subtype HTLV-IIa is the main circulating subtype in North America and Northern Europe while subtype HTLV-IIb is found in Southern Europe, especially in Italy and Spain.

Abad and colleagues looked into the epidemiology of the HTLV-II in Spain. They included 12 HTLV-II positive IDUs from Spain, coinfected with HIV-1 in the study. The researchers used proviral DNA extracted from participants’ peripheral blood mononuclear cells. The samples were sent for PCR. Amplified fragments from all Long terminal repeat (LTR) (389 bp),env (777 bp) and tax (993bp) regions were sequenced. The sequences were compared with HTLV-IIa prototype (Mo) and HTLV-IIb prototypes (G12 and NRA). Phylogenetic analysis was carried out together with reported sequences of all HTLV-II subtypes using the STLV-2 as an outgroup. One thousand bootstrap replicates were used to support the tree using the Unweighted Pair Group Method with Arithmetic Mean (UPGMA).

Sequence analysis confirmed that the samples studied belonged to HTLV-II subtype b. The regulatory elements were highly conserved for LTR, as well as functional domains for env and tax proteins.

The researchers concluded that HTLV-IIb remains the most frequent subtype in Spain. Besides, phylogenetic analysis showed that Spanish sequences shared many similarities with Portuguese and Italian ones. All of them obtained from intravenous drug users coinfected with HIV-1.

Ref: Abad M et al. HTLV-II molecular epidemiology from HIV-1-positive Spanish injecting drug users. 18th International AIDS Conference. 18-23 July, 2010. Vienna. Poster abstract CDC0388
http://pag.aids2010.org/Abstracts.aspx?AID=13142

Iran has a concentrated HIV epidemic among the IDU sub-population. As a result, a significant number of people who need ART are either IDU or ex-IDU. In some studies it has been demonstrated that IDUs benefit less from ART due to higher mortality or less adherence to treatment.

A team of researchers in Iran conducted a study to look more in-depth onto those previous assertions. In a historical cohort study the records of registered patients on ART were reviewed to determine their survival on treatment and its determinants. Data were gathered back to 2000 for 362 patients in nine provinces. Socio-demographic characteristics, drug use history, being on methadone maintenance treatment (MMT), CD4 count, the date of starting and discontinuation of treatment and its reason were all extracted. Non-adherence and mortality were analysed separately.

The data showed that one-year overall survival on treatment was 82%. Analysing non-adherence, being on MMT, being single or widowed and, and being a woman were factors with statistically significant effect on survival, not limited to the first year. Analysing mortality, current drug use, age (fifty and over) at the time of starting treatment, and lower levels of education were the determinants of a lower survival rate.

The study showed that IDU itself was associated with higher mortality than non-adherence, which is in accordance with other findings supporting the capability of IDUs to follow complex ART regimens; nevertheless, their other drug-related health problems have to be considered as well. On the other hand, MMT was associated with lower survival on ART due to non-adherence suggesting two main issues; possible not following the MMT guidelines completely and/or a possible drug interaction between methadone and ART, resulting in a lower methadone blood concentrations.

Ref: Taj M et al, Injecting drug use and ART: monitoring survival on treatment. 18th International AIDS Conference. 18-23 July, 2010. Vienna. Poster abstract CDC0945
http://pag.aids2010.org/Abstracts.aspx?AID=5831

It is hypothesised that the modulation of the dopaminergic pathway may underlie the exacerbation of HIV encephalopathy observed with opiate abuse. An important constituent of dopaminergic activities within the brain is a 32 kDa dopamine and adenosine 3´,5´-monophosphate-regulated phosphoprotein (DARPP-32) which is recognised to be critical to the pathogenesis of drug addiction. Genetic polymorphisms within Dopamine Transporter gene (DAT1) are associated with individual differences in DA (Dopamine) functioning that may contribute to varying degrees of neurocognitive impairment.

Mahajan S and colleagues researched whether DARPP-32 signaling pathway is the central molecular mechanism that integrates the neuropathogenic activities of both HIV-1 and opiate abuse and that examining DA-related genetic polymorphisms in these patients may provide insight into the susceptibility to and progression of HIV-associated neurocognitive disorders (HAND).

In order to do that, they obtained snap frozen human brain tissue samples (n=8/group) from National NeuroAIDS Tissue Consortium (NNTC) at autopsy from HIV-1 patients who abused/did not use opiates and who had varying degrees of HAND. Using real time QPCR and immunoblotting methods they examined the gene and protein expression levels of DARPP-32; genetic polymorphisms in the DAT1 gene, in the brain tissue samples and correlated the expression levels of these genes to the severity of neurocognitive impairment in these patients.

Data showed a significant increase in the total DARPP-32, Phosphothr34 DARPP-32 and DAT1 expression in HIV-1 patients who abused opiates and a significant positive correlation between expression levels of these genes and the severity of HAND.

The conclusion of the researchers was that a combination of HIV-1 and opiate abuse has an adverse impact on the dopaminergic system and contributes to significant neurocognitive impairments in HIV-1 patients who abuse drugs, confirming the role of the dopaminergic pathway in the pathogenesis of HAND.

Ref: Mahajan S et al, Dopaminergic signaling: a common neuropathogenic mechanism in the etiology of opiate addiction and Neuro-AIDS. 18th International AIDS Conference. 18-23 July, 2010. Vienna. Poster abstract CDA0007.
http://pag.aids2010.org/Abstracts.aspx?AID=4170

Even though cryopreservation is a common practice nowadays, because it allows both functional and phenotypic analyses, it may induce significant changes in the cell viability, in cytokine production and in the surface markers of peripheral blood mononuclear cells (PBMC), which may also alter the efficiency of T cell stimuli. This may be particularly true when the samples are obtained from IDUs, as IDU leads to chronic organism intoxication that causes a system-wide exhaustion and pathological changes of organs. It is unclear then how the PBMC of IDUs will be affected by cryopreservation.

Kukhareva P from the Biomedical Centre of St Petersburg (Russian Federation) reported on a project which main goal was to create standard operation procedures for IDUs PBMC isolation, cryopreservation and thawing.

She isolated PBMC by density gradient centrifugation on ficoll-paque and then followed the standard procedures for cryopreservation. For representation of surface markers and intracellular cytokines flow cytometric assay was used. To measure secretion of IFNγ in response to CMV stimulation she usedIntracelularcytokine staining (ICS).

Results clearly indicated that PBMC of IDUs can be stored at a concentration of 2,5 million/ml up to a month without a significant reduction in survival and number. Blood of drug users can be stored up to 7 hours before the isolation of the PBMC. Isolation on fikoll gradient and cryopreservation affect the composition of certain subpopulations of the PBMC of IDUs and healthy donors. Defrosted PBMC samples ofIDUs are suitable for assessing immune response with specific and nonspecific activation, therefore IDU does not affect the immunological characteristics of the PBMC in fresh and cryopreserved samples.

Ref: Kukhareva P, Characteristics of peripheral blood mononuclear cells of injecting drug users. 18th International AIDS Conference. 18-23 July, 2010. Vienna. Poster abstract CDB0062.
http://pag.aids2010.org/Abstracts.aspx?AID=12466

Studies have already demonstrated the possibility of post-injection pyoinflammatory complications (PIPIC) in HIV-infected IDUs consuming artificial drugs [1]. The most common complication registered is Staphylococci, however their methicillin-resistance has not been evaluated previously. To determine the role of MRS in various forms PIPIC, Popov A and colleagues carried out an antibiotic sensitivity testing in isolated strains of microorganisms.

The analysis of purulent specimens were studied according to standard bacteriological procedures. Susceptibility to antimicrobial agents was tested with the disk-diffusion method.

The study included 41 subjects (24 male and 17 female; age range 18-31). All of them were IDUs and had HIV-1-infection diagnosis in CDC II stage. Prevailing forms of PIPIC were abscesses (n = 33) and phlegmones (n = 8). 18 cultures of methicillin-resistant staphylococci were isolated. It included 14 cultures of methicillin-resistant S. aureus (MRSA) and 4 isolates of methicillin-resistant S. epidermidis (MRSE). All isolates of MRSA and MRSE retained sensitivity to vancomycin and linezolid.

The data obtained coincide with the general trend of the epidemic spread of MRSA and MRSE in out-of-hospital environment in immunocompetent persons. Empirical antibacterial therapy of PIPIC in HIV-infected IDUs should take into account the high frequency of MRSA and MRSE. This fact must provide a compulsory inclusion of glycopeptide or oxazolidinone antibiotics into the scheme of ethiotropic treatment.

Ref: Popov A, High frequency of methicillin-resistant staphylococci detection at post-injecting pyo-inflammatory complications in HIV-infected injecting drug users. 18th International AIDS Conference. 18-23 July, 2010. Vienna. Poster abstract CDB0091.
http://pag.aids2010.org/Abstracts.aspx?AID=4968

Of the 35,000 people who have received ART in Vietnam, more than half are current or former IDU. In the IDU subpopulation in the country, the prevalence of HIV-infection can reach up to 60% in certain areas. This situation requires a more in-depth understanding of the differences between IDU and non-IDU patients in treatment response, mortality and loss-to-follow-up.

Le and colleagues used the records of patients attending three adult clinics in provinces with high prevalence from August-September 2008. They included records of people who had started ART at least 6 months prior to that time point. Data were collected on reported drug use, gender, clinical stage, CD4 count, co-infection with viral hepatitis, TB, retention, and survival probability.

Of 1423 eligible people on ART, 1012 (71%) had recorded risk behaviors. Of these, 546 (54%) were IDU. Compared to non-IDU, IDU were more likely (p< 0.05) to be male (95% vs. 44%), coinfected with hepatitis B (16% vs. 12%) or hepatitis C (48% vs. 16%), in WHO clinical stage 3 or 4 (67% vs. 56%) and on TB treatment at ART initiation (15% vs. 6.7%). Median CD4 was significantly lower in IDU at baseline (75 cells/ml vs. 95), and at 6 (176 vs. 209) and 12 (217 vs. 250) months. Median increase in CD4 from baseline was lower in IDU at 6 (91 vs. 106) and 12 (128 vs.150) months. After a median of 16.5 months of follow up, 103 (19%) IDU died and 30 (5.5%) were lost-to-follow-up, significantly higher than non-IDU (8.6% and 2.2% respectively). Survival probability was lower (p< 0.05) in IDU than non-IDU after 6 (0.86 vs. 0.93) and 12 (0.79 vs. 0.91) months.

Based on these data, the researchers concluded that in this cohort immunological response was lower, and mortality and loss to follow up higher, among current and former IDU. Urgent interventions to initiate treatment earlier and improve treatment outcomes for IDU are warranted.

Ref: Le YN et al, Poorer antiretroviral therapy outcomes in HIV infected injecting drug users in Vietnam. 18th International AIDS Conference. 18-23 July, 2010. Vienna. Poster abstract CDB0136
http://pag.aids2010.org/Abstracts.aspx?AID=2416

Crystal methamphetamine (CM) use presents a significant threat to HIV prevention and treatment strategies. CM has been linked to sexual and parenteral risk behaviours and increased likelihood of HIV seroconversion, as well as poor adherence to antiretroviral therapy. In this study, the researchers examined the impact of CM injection on HIV RNA suppression among a prospective cohort of HIV-positive injection drug users (IDUs) initiating antiretroviral therapy. They used Cox regression to model factors that may affect the HIV RNA suppression, based on data obtained from HIV-positive IDUs who were community recruited into a prospective cohort study.

Between September 1996 and April 2008, 384 (54.2%) antiretroviral-naïve patients initiated HAART; 163 (42.5%) of whom were women. 36 (9.4%) reported CM injection at any time during follow-up. The analysis found CM injection to be negatively associated with viral load suppression (RH = 0.63 [95% CI: 0.40 - 0.98]; p = 0.039), even after adjustment for age, baseline CD4 cell count and viral load, heroin injection and cocaine injection.

These data indicate negative health outcomes associated with CM use among HIV-positive individuals. It is speculated that the psychopharmacological effects of CM may undermine antiretroviral treatment adherence.

Ref: Fairbairn N et al, Crystal methamphetamine injection predicts slower HIV RNA suppression among injection drug users. 18th International AIDS Conference. 18-23 July, 2010. Vienna. Oral Abstract Session MOAC04; MOAC0405
http://pag.aids2010.org/Abstracts.aspx?AID=13627

Injecting drug users comprise about 59% of all HIV positive people officially registered in Ukraine and only 7% of those were receiving ARV in 2009.
An the AIDS centre and two Drug Dependence clinics in Dnipropetrovsk region, the most affected in the country, implemented a comprehensive care model. The services provided on site included: Methadone Maintenance Therapy (MMT), HIV testing, CD4 count, viral load, TB testing; examination and counselling by infectious disease doctor, therapist, cardiologist, reproductive health professional, psychiatrist and also psychosocial support was provided.

The programme is being implemented with the financial support of Olena Franchuk ANTIAIDS Foundation and Elton John AIDS Foundation.
Overall, 428 patients (75% male, average age 35-42 years, average period of drugs use of 20 years) were enrolled since July 2008. The overall retention rate was 70%. 74% of all clients of the programme were HIV-positive. 80% of HIV positive clients received their CD4 test results, of which CD4 was below 350 cells in 58%.

Up to 2010, 50% of those met treatment eligibility criteria and started ARV and 40% were enrolled in preparation process to receive ARV. Undetectable viral loads were achieved in 85% of clients receiving ART after 6 months of treatment.
The results of the comprehensive care model clearly indicated that “integration of methadone maintenance therapy (MMT) and ARV is an important tool to enable access to life saving services for IDUs. Out of three clinical settings involved, the AIDS centre appeared to be better positioned to provide integrated MMT/ART services”, concluded the researcher.

Ref: Vlasenko L et al, Methadone based integrated care for IDUs in Dnipropetrovsk region of Ukraine. 18th International AIDS Conference. 18-23 July, 2010. Vienna. Poster Exhibition, D46, WEPE 0537
http://pag.aids2010.org/Abstracts.aspx?AID=14048

Depression is common among IDUs living with HIV and is associated with loss of social relationships, increased likelihood of risky behavior, and low-adherence to ARV treatment. Depression, however, often is considered as an insignificant problem, compared to other conditions that require urgent interventions and as a result of that majority of data on depression come from resource richer settings.

Li Y and colleagues looked into some key factors predicting depression in a resource poorer setting, namely Indonesia. Using a provider referral method, the team recruited and interviewed 142 IDUs receiving ARVs at three HIV clinics in Jakarta (n = 72) and two in Bali (n = 70). A structured questionnaire was used to collect participants’ demographic characteristics, history of drug use, treatment experiences, and social support.

Depressive symptoms were measured using a 9-item version of the Center for Epidemiologic Studies Depression Scale (CES-D).
92% of the participants were male, young (median age 30), and high school educated (90%). 33% (47) reported using alcohol frequently and/or at least one illicit substance in the past month, and 28% (40) were on methadone maintenance treatment. CES-D scores indicated that 28% (40) of participants were depressed. Multivariate analysis showed that depression was positively associated with recent substance use (OR: 4.6, p=0.003) and being on methadone (OR: 3.6, p=0.02). Older age (per year OR: 0.89, p=0.03), full-time employment (OR: 0.22, p=0.007), and living with parents (OR: 0.19, p=0.003) appeared to have a protective effect.

Ref: Li Y at al, Risk factors for depression among intravenous drug users (IDUs) receiving antiretroviral (ARV) treatment in Jakarta and Bali, Indonesia. 18th International AIDS Conference. 18-23 July, 2010. Vienna. Poster Exhibition D60, WEPE0720
http://pag.aids2010.org/Abstracts.aspx?AID=11385

In Bulgaria, the number of prisoners detained for drug-related crimes and drug use increased up to 10-12% of the total prison population after the 2004 amendment of the Penal Code which criminalised the “single dose” possession.

Since 2006, the Ministry of Health and Ministry of Justice jointly introduced the regular provision of anonymous HIV testing and counseling (T&C), in all 12 prisons and 2 detention centres. HIV T&C is provided by staff of public health institutions and NGOs in combination with HBV, HCV and syphilis testing, condom distribution and information materials. HIV-positive people in the penitentiary system are included in the HIV/AIDS patients monitoring system and receive regular follow-up and ARV treatment if needed. In 2009, out of total 9 270 prison population, anonymous HIV T&C was provided to 4,141 people, of who 805 reported history of injecting drug use (9% of total prison population). 27 HIV positive cases were newly diagnosed in IDUs.
In 2009, educational sessions on HIV/STIs prevention were introduced as additional service for 5 425 prisoners, again provided by the outside service providers.

The researchers concluded: “Introducing a comprehensive package of HIV services in prisons provided by outside service providers is effective in scaling-up access to HIV services and active HIV case finding in prisons, especially among IDUs”.

Ref: Varleva T et al, Effective strategy to scale-up HIV services among injecting drug users (IDUs) in prisons in Bulgaria. 18th International AIDS Conference. 18-23 July, 2010. Vienna. Poster abstract C54, WEPE0188
http://pag.aids2010.org/Abstracts.aspx?AID=16208

It is documented that initiation of ARV therapy often leads to overall weight gain, but patterns and predictors of weight change over time have seldom been examined.

Tang A et al recruited 100 male, ARV-naïve patients, in Hanoi, Vietnam for a longitudinal study of nutrition and HIV. Subjects started HAART within 2 weeks of their baseline visit. Using a repeated measures regression model they identified clinical and nutritional correlates of weight change over 2 consecutive 6-month intervals (INT1: pre-HAART to 6 months post-HAART, and INT2: 6 to 12 months post-HAART).

The mean age of participants in the study was 37±5 years and 48% reported recent illegal drug use at baseline. 81 subjects completed 6-month and 68 completed 12-month follow-up visits. 57% were started on AZT/3TC/efavirenz. Mean BMI was 19.1 kg/m2 at baseline. Mean weight gain was 3.1±4.8 kg in INT1 and 0.7±2.7 kg in INT2. Mean CD4 change was 65±98 cells/mm3 in INT1 and 26±100 cells/mm3 in INT2. In both intervals, greater increases in CD4 and presence of nausea were both statistically significantly associated with increased weight gain (p=0.03 for both). Diarrhoea at start of interval was associated with a weight change difference of 0.3 kg in INT1 and -7.7 kg in INT2 (p=.003 for interaction). Use of liquid supplements (e.g. Ensure or sweetened condensed milk) was associated with a weight change difference of 6.5 kg in INT1 and 0.9 kg INT2 (p=0.02 for interaction).

These results suggest that use of liquid supplements, especially during the first 6 months after the initiation of therapy may be a useful intervention.

Ref: Tang A et al, Predictors of weight gain in a cohort of HIV-positive injection drug users (IDUs) initiating antiretroviral (ARV) therapy in Hanoi, Vietnam. 18th International AIDS Conference. 18-23 July, 2010. Vienna. Poster exhibition MOPE0105
http://pag.aids2010.org/Abstracts.aspx?AID=11283

Drug users with asymptomatic chronic hepatitis C rarely have a liver biopsy to stage fibrosis. Instead, medical professionals use FIB-4, as it is a reliable, indirect marker for detecting liver fibrosis in patients with chronic hepatitis C. As many factors contribute to the progression of fibrosis and taking into account their possible differential effect, Muga A et al analysed demographic, clinical and laboratory data on FIB-4 elevations among young HCV monoinfected and HCV/HIV co-infected patients.

Participants were recruited in a unit for substance abuse treatment between 1994-2006. Socio-demographic, alcohol and drug histories and clinical characteristics were obtained trough hospital records and questionnaires. Blood samples for biochemistry, liver function tests, CD4 cell count, and serology for HIV and HCV infections were collected at admission. In order to analyse the possible predictors of FIB-4 increase, multivariate linear regression was used.

The study included 472 participants (83% male) who met the inclusion criteria. Median age of 31 years (IQR 27-35 years), median duration of injection drug use was 10 years (IQR: 5.5-15 years). Daily alcohol consumption was reported in 32% of patients and prevalence of HIV infection was 51.7% (244/472).

Median FIB-4 at admission was 0.9 (IQR 0.65- 1.46), significantly higher in the HCV/HIV co-infected patients (1.14; IQR 0.76- 1.87) than in the HCV mono-infected (0.75; IQR 0.56-1.11) (p< 0.001).

In multivariate analysis, alcohol consumption (p=0.034), lower total cholesterol (p=0.042), lower albumin (p< 0.001), higher GGT (p< 0.001) and longer duration of drug use remained independently associated with a FIB-4 increase among the HCV monoinfected patients. In the co-infected, lower CD4 cell count (p=0.006), higher total bilirubin (p< 0.001), lower albumin (p< 0.001) and longer duration of drug use (p< 0.001) were statistically significantly associated with FIB-4 increase.

The data suggests that both immunodeficiency as a result of HIV, but also alcohol consumption independently impact FIB-4 elevations of HIV/HCV coinfected and HCV monoinfected people. This as a result may lead to FIB-4 related liver fibrosis.

Ref: Muga A et al, Clinical and laboratory predictors of FIB-4 elevations in HCV moinofected and HCV/HIV co-infected patients. 18th International AIDS Conference. 18-23 July, 2010. Vienna. Poster exhibition MOPE 0172
http://pag.aids2010.org/Abstracts.aspx?AID=8499

Even though there are much data on the link between cortisol levels and depression in several populations, its response to stress has not been thoroughly examined. In a previous study, Ownby et al showed that cortisol response to stress was related to cognitive function in HIV-positive injecting drug users (IDUs). In the study presented at the IAC, the team evaluated the relation of HIV and IDU status and depressive symptoms to cortisol response to cold pressor stress.

Serum cortisol levels were assayed at baseline and at 10, 15, 30, and 50 minutes after cold pressor stress in 110 HIV-positive and 246 HIV-negative individuals. The relation of HIV and IDU status and depressive symptoms as reported on the Beck Depression Inventory (BDI) and symptoms of fatigue on the Profile of Mood States (POMS) to serum cortisol levels were evaluated via repeated measures ANCOVA.

The results showed that both HIV-positive and IDU-positive individuals had substantially higher levels of cortisol in response to cold pressor stress, although only the effect of IDU status was statistically significant (p=0.001). Depressive symptoms were significantly related to cortisol levels (p=0.002).

The researchers concluded: “Depression in HIV-infected individuals may be related to biological markers of stress. Stress management activities in HIV-positive individuals may be useful in reducing symptoms of depression”.

Ref: Ownby R et al, Cortisol response to stress in HIV+ IDUs is related to depression. 18th International AIDS Conference. 18-23 July, 2010. Vienna. Poster abstract WEPE0073
http://pag.aids2010.org/Abstracts.aspx?AID=11001

In this study, 1022 participants of the longitudinal ALIVE study (from Baltimore, MD) who reported cigarette smoking at baseline, who were HIV-positive, and who attended at least three additional semi-annual visits from 1988-2008 were evaluated via Kaplan-Meier estimates and discrete time proportional hazards models for the relative hazards for first reported attempt to quit tobacco smoking. The study is important, as heavy tobacco smoking among HIV-positive people, and in particular IDUs, is common globally.

Despite HAART-increased survival, smoking-related morbidity in HIV-positive people is increasing.

Thirty per cent of the participants were female and the median age at baseline was 35 years [IQR=30-40]. At study entry, 87% reported current injection drug use and 52% reported smoking 1 or greater packs/day. 292 people reported at least one attempt to quit smoking (cumulative smoking cessation incidence: 41/1,000 person-years [IQR=37-46]; median age at first quit attempt: 43 years [IQR=39-46]). In multivariate analysis, recent injection drug use cessation was associated with an increased likelihood of quitting smoking (RH=2.0, 95%CI: 1.6, 2.5). Virological response to ART (RH=0.70, 95%CI: 0.52, 0.93) and increasing CD4 levels (250-350 vs. < 250 RH=0.73, (95%CI: 0.56, 0.95); 350-500 vs. < 250 RH=0.69, (95%CI: 0.53, 0.89); >500 vs. < 250 RH=0.77, (95%CI: 0.61, 0.96)) were significantly associated with a decreased likelihood of quitting smoking, as were alcohol and marijuana use.

These results clearly show that despite increased interaction with healthcare providers, HIV-positive individuals successfully receiving ART therapy appear less likely to quit smoking. Hence, HIV care providers must increase evidence-based cessation interventions to further reduce morbidity among HIV-positive people.

Ref: Ambrose BK et al, The impact of injection drug use cessation and antiretroviral therapy on smoking cessation among HIV-infected injection drug users in Baltimore, MD 1988-2008. 18th International AIDS Conference. 18-23 July, 2010. Vienna. Poster abstract WEPE0496
http://pag.aids2010.org/Abstracts.aspx?AID=7695

• Raltegravir and darunavir pharmacokinetics in liver disease

The effect of TMC278 (25 mg once daily) on the pharmacokinetics and pharmacodynamics of methadone was studied in 13 HIV negative volunteers stable on methadone maintenance therapy (60-150 mg/day).  TMC278 decreased the AUC, Cmax and Cmin of active R-methadone by 16%, 14% and 22%, respectively. Decreases were also seen in the AUC (16%), Cmax (13%) and Cmin (21%) of inactive S-methadone.  Exposure of TMC278 in the presence of methadone was within the expected range. No signs of opiate withdrawal were observed.

Comment

Although no a-priori dose adjustment of methadone is required, clinical monitoring for withdrawal symptoms is recommended as some patients may require dose adjustment.

Ref: Crauwels HM et al. Pharmacokinetic interaction study between TMC278, a next-generation NNRTI and methadone. 11th PK Workshop, 7–9 April 2010, Sorrento, Italy. Abstract 33.

The pharmacokinetic profiles of darunavir and raltegravir were analysed in five HIV/HCV coinfected patients with moderate to severe liver disease. Based on the ultrasonographic and histological evaluation, two patients had HCV-related chronic active hepatitis, and three patients had a diagnosis of cirrhosis (Child Pugh stage B). Trough concentrations were determined 14 and 30 days after starting a raltegravir/darunavir containing regimen.

Mean raltegravir and darunavir trough concentrations in the hepatic impairment group was 637 (mean Ctrough in control group: 221±217 ng/ml) and 8519 ng/mL (mean Ctrough in control group: 3236±2183 ng/ml), respectively. In a sub-group analysis, patients with cirrhosis had higher mean raltegravir Ctrough than patients with active non cirrhotic hepatitis (665 vs 581 ng/mL). The mean darunavir Ctrough was consistently higher in cirrhotic than non cirrhotic patients (9820 vs 2016 ng/mL).

Comment

The data suggest special caution in the use of raltegravir, and especially of darunavir, in patients with moderate to severe liver impairment because of the risk of additionally increased toxicity.

Ref: Tommasi C et al. Raltegravir and darunavir plasma pharmacokinetic in HIV-1 infected patients with advanced liver disease.11th PK Workshop, 7–9 April, 2010, Sorrento, Italy. Abstract 10.

Introduction

The 17th Conference on Retroviruses and Opportunistic Infections (CROI), one of the most important annual HIV meetings, was held this year from 16-19 February. As with previous meetings, much of the conference is published online including all abstracts and webcasts of oral presentations including selected poster discussions.

Making this scientific content available without login or subscription is itself a significant achievement. It is a model for broadening access to medical research to a degree that is currently unmatched by any other meeting.

The webcasts this year include oral presentations, poster discussions, the opening lectures and the pre-meeting set of training workshops for young investigators.

The conference website also includes a searchable abstract database.

We encourage readers to view these lectures directly.

http://www.retroconference.org/2010/Abstracts/38289.htm

http://www.retroconference.org/2010/data/files/webcast_2010.htm

Lectures are also available as audio downloads and podcasts, which include slides as audiobooks.

The following reports from the conference are included in this issue of ARVs4IDUs:

• Hepatitis studies: IL28B genetics, HCV survival, FibroScan in acute HCV, MSM reinfection and responses to transplantation

• A significant transmission bottleneck among newly and recently HIV-positive IDU in St Petersburg, Russia

• Similar immunologic responses to modern HAART among IDU and non-IDU in a population setting

• Highly active antiretroviral therapy eliminates HIV epidemics in a network model of an Injecting Drug User community

Simon Collins, HIV i-Base

The following studies focused on aspects of hepatitis coinfection.

IL28 predict treatment response to IL28

Some of the most exciting coinfection studies included those elaborating on the recent association between genetic variations in the IL28B gene and both HCV pathogenesis and response rates to PEG-IFN and ribavirin treatment.

Andri Rauch from University Hospital Bern, introduced the HCV coinfection scientific session with an overview lecture of this research, most of which has become clearer within the last six months. [1]

Rauch detailed how several groups have independently screened the human genome for genetic variations associated with HCV immune response linked to spontaneous clearance or to explain the wide range of responses to HCV treatment: important as roughly 50% patients globally are unable to clear the virus. These studies consistently identified genetic variations in interleukin 28B (IL28B) as the strongest predictor of spontaneous clearance and treatment-related clearance, in both monoinfection and HIV/HCV coinfected individuals.

Rauch explained how IL28B on chromosome 19 encodes interferon-lambda, a type III interferon with antiviral activity mediated through the JAK-STAT pathway by inducing interferon-stimulated genes. Several single nucleotide polymorphisms (SNPs) might modulate function or expression of IL28B.

The correlation between allele frequency in different American ethnicities and treatment outcome was also detailed. The rs12979860 SNP is found in approximately 40%, 70% and 95% of those with African, European and Asian decent, which correlates with SVR rates of 25%, 55% ad 75%, respectively.

IFN-lambda is induced by IFN-alpha and encoded by IL28B, and is not known to play an important role though mechanism in yet to be determined. Phase 1b trials show a potential treatment, synergistic to IFN-alpha, but associated with fewer side effects including reduced fever, flu-like symptoms, neutropenia, bone marrow toxicity.

Together, these findings may enable greater understanding of individual response rates to current treatment, potentially developing management strategies based on genetic differences, and also, potential lead to new antiviral HCV treatments.

Julia di Iulio from University Hospital Lausanne and colleagues presented an analysis of the rs8099917 allele, linked to the Type II haplotype family, in a genome-wide association study involving 347 people with spontaneous HCV clearance and 1015 people with chronic HCV. This in turn lead to identification 21 SNPs, and then four potential causal SNPs closer to IL28B, that are associated with chronic HCV and that may be more likely to influence IL28B function or expression. [2]

Norma Rallon and colleagues from Madrid reported on the role of rs12979860 on treatment responses of 198 HIV/HCV coinfected patients (106 with SVR and 92 non-responders). Due to sampling issues, 164 patients were included in final analysis.

The SVR rate was significantly higher in patients with the CC alleles than in those with CT/TT alleles across all HCV genotypes (75% vs 38%, p<0.0001) and by genotype (G1: 65% vs 30%, p=0.001; G-3/4 83% vs 57%, p=0.02). In the multivariate analysis, the rs12979860 CC genotype was a strong predictor of SVR (OR 3.4; 95%CI 1.4–7.9; p=0.006), independent of other well-known predictors such as HCV genotype 3, baseline serum HCV-RNA <600,000 IU/mL and fibrosis <F3-F4.

Jacob Nattermann from the University of Bonn, and colleagues, reported slightly different results to other coinfection cohorts when they looked at whether IL28B SNP rs12979860 affected treatment outcome in 192 co-infected patients (74 acute and 118 chronic). Rates of sustained virological responses (SVR) were compared in patients carrying different genotypes. As comparison, 136 uninfected and 156 HCV mono-infected patients were included as control groups. [4]

IL28B genotype distribution did not differ significantly between the HIV (acute and chronic) and uninfected groups but monoinfected patients had a low rate of the protective C/C genotype (30% vs 41-47%).

While coinfected patients with the C/C genotype had significantly higher SVR rates than patients with C/T and T/T (58.1% vs 40.6%; p=0.041). This effect reached statistical significance only in HIV-positive patients with chronic (50% vs 29%; p=0.04) but not in those with acute (73.3% vs 60%; p=NS) HCV.

comment

In addition to the data in co-infected patients reviewed by Rauch, his group has also shown that, as in mono-infected patients, polymorphisms also determine spontaneous clearance rates.  The potential for a genetic mechanism to explain differences in spontaneous clearance and HCV treatment response rates by ethnicity is clearly important given the social aspects of HCV care globally. This suggests perhaps a more accurate marker with, or instead of, early treatment response rates, in order to identify people who risk only toxicity without any likely clinical benefit if they use treatment with pegylated interferon and ribavirin.

Clearly, before these tests are utilised in clinical pathways, we need further studies. Positive- and negative-predictive values for genotype results need to be highly predictive to ensure this is not used as a way to exclude some patients from treatment.  IL28 alayses are likely to be included in future treatment studies. Furthermore, there may be implications for the clinical utility of these tests to identify patients with a low likelihood of response to standard therapy who may be candidates for early treatment with specifically-targeted anti-HCV drugs.

Duration of infectious HCV survival in syringes

Elijah Paintsil and colleagues from Yale School of Medicine presented results of the impact that different gauge syringes and different temperatures has on the duration of HCV infectivity and therefore risk from residual blood. [5]

Syringes with low (2 uL) and high (32 uL) quantities of residual HCV-containing blood after full plunger depression, with 1-cc insulin syringe (permanently attached needle) and 1-cc tuberculin syringe (detachable needle), respectively. Syringes were either immediately tested for viable virus or stored at 4ºC, room temperature and 37ºC, for up to 56 days. Virus was recovered from stored syringes and tested for infectivity in cell culture using relative luciferase activity.

HCV infectivity was not detected in the small syringes beyond day one except for those stored at 4º where HCV remained viable in 5% of syringes up to day 7.

After 7 days of storage, 96% ± 7.5, 71%± 23.1, and 52% ± 20 of 32 uL syringes were HCV-positive at 4º, room temperature, and 37º, respectively. Viable virus was recovered from the 32 uL syringes up to day 56. In general, the infectivity of the recovered virus was inversely related to duration and temperature of storage.

Caution when interpreting FibroScan results from acute HCV infection

A study from the European NEAT coinfection group reported that liver stiffness was elevated during acute HCV infection, probably due to high levels of inflammation and short observation periods, and that early FibroScan results should therefore be interpreted with caution, rather than assume that greater stiffness are a marker of rapid progression. [6]

Fibrosis progression rate (FPR) was calculated dividing the difference in fibrosis units by the time of follow-up. The analysis included 28 HIV-positive men with acute HCV that become chronic (91% MSM sexual exposure risk), or if FibroScan prior to anti-HCV therapy was available. Plotting FPR over follow-up time revealed short observation times being strongly correlated with high fibrosis progression rates. No interaction of risk factors for cirrhosis or HAART exposure with follow-up time was observed.

The authors concluded: Calculated high fibrosis progression rates after acute HCV infection in HIV-positive individuals are probably influenced by short observation periods. Higher liver stiffness in the acute phase of HCV infection may be at least partially explained by higher inflammatory activity that has been shown to increase stiffness leading to overestimation of fibrosis. A linear model for fibrosis progression, as is currently applied in the setting of chronic HCV infection, should be used with caution in the setting of acute HCV infection.

HCV reinfection after spontaneous HCV clearance

A poster on acute HCV infection in HIV-positive MSM in Germany was interesting for two reasons. Firstly, 22% patients spontaneously cleared HCV, and secondly, a high rate of reinfection that was reported (5 patients: 17% of those with a spontaneous or treatment related SVR). [7]

Hans-Jürgen Stellbrink and colleagues reported on 46 cases of acute HCV in MSM since 2001, from an HIV cohort of >4,400 predominantly MSM. Incidence rates per 1000 PYFU increased steadily from 0.15 in 2001/02 to 2.48 in 2007/08. HCV was genotype 1, 2, 3 or 4 in 20 (43%), 1 (2%), 9 (20%) and 16 (35%) cases, respectively.

Of the 34 patients treated with peg-IFN/RBV, SVR was achieved in 20 (65% of the 31 subjects with follow-up after treatment), relapse occurred in 3 (10%), and primary non-response was observed in 8 (26%). Ten patients (22%/46) cleared HCV spontaneously, and 2 (4%) remain untreated with persistent infection.

Re-infection occurred in five individuals (17%) of those who cleared acute hepatitis C infection (three with different genotypes, 1 with the same, 1 with pending genotype). After primary infection with G3, one patient developed severe hepatitis upon second re-infection with G1; this patient cleared HCV all 3 times without therapy.

Of note, a 24% rate of spontaneous clearance was reported by Bradley Hare and colleagues in a group of 54 HIV-positive MSM in San Francisco and New York. This study also reported 100% response rates in patients who, having achieved undetectable HCV RNA at week 8 or 12, continued treatment with PEG-IFN only (dropping RBV) for the subsequent 12 weeks. [8]

People with haemophilia with HIV/HCV coinfection need earlier referral for liver transplant

Margaret Ragni and colleagues presented results of canditates for liver transplant from the US multicentre study in people coinfected with HIV/HCV, comparing outcomes in men with and without haemophilia. [9]

Of 100 HIV/HCV enrolled candidates, 33 (33%) underwent orthotopic liver transplantation (OLTX), including 8/16 (50.0%) with haemophilia and 25/84 (29.8%) without.

Men with haemophilia were less likely to still be alive, and more likely to have died before transplant (mainly related to sepsis or multi organ failure). Men with haemophilia reached transplant (OLTX) and MELD of 25 marginally faster than non-hemophilic subjects (p=0.09 and 0.06 respectively). Although younger (42 vs 48 years, p=0.004), there were no differences in BMI, CD4, detectable HIV RNA or detectable HCV VL, time to post-OLTX death, graft loss, and treated rejection or 3-year survival. See Table 1.

Table 1: Outcomes from liver transplant in men with and without haemophilia

The authors concluded that in HIV-positive men with hemophilia, “despite early acquisition of HCV, transplant outcomes appear to be similar to those in co-infected individuals without hemophilia. However, pre-transplant mortality appears higher among co-infected hemophilic men. Whether earlier intervention could reverse this finding is not known”.

comment

Although this was one of the few studies at CROI to mention management issues for people with haemophilia, these results should be interpreted cautiously. With only 16 haemophilia patients in the study who are, by definition, a highly selected group of long-term survivors, the researchers are unlikely to have been able to adjust for the likely differences between the two groups.

References

All references are to the 17th Conference on Retroviruses and Opportunistic Infections, 16-19 February 2010, San Francisco. Oral presentations are included in the webcast: Oral Abstracts and Scientific Overview: Hepatitis C: Transmission, Outcomes, and Treatment. 17th CROI, 2010. Friday 09.30am.

1. Rauch A. The interleukin 28B gene and HCV recovery. 17th CROI, 2010. Oral abstract 162.

http://www.retroconference.org/2010/Abstracts/39872.htm

2. di Iulio J et al. Association of IL28B haplotypes with chronic HCV infection in HIV/HCV co-infected individuals. 17th CROI, 2010. Oral abstract 163.

http://www.retroconference.org/2010/Abstracts/37377.htm

3. Rallon N et al. Strong association of a single nucleotide polymorphism located near the interleukin-28b gene with response to hepatitis C therapy in HIV/HCV co-infected patients. 17th CROI, 2010. Oral abstract 165LB.

http://www.retroconference.org/2010/Abstracts/39833.htm

4. Nattermann J et al. Genetic variation in IL28B and treatment-induced clearance of HCV in HCV/HIV co-infected patients. 17th CROI, 2010. Oral abstract 164.

http://www.retroconference.org/2010/Abstracts/39494.htm

5. Paintsil E et al. Survival of HCV in syringes: implication for HCV transmission among injection drug users. 17th CROI, 2010. Oral abstract 168.

http://www.retroconference.org/2010/Abstracts/38965.htm

6. Vogel M et al. Liver Fibrosis Progression after Acute HCV Infection in HIV+ Individuals. 17th CROI, 2010. Poster abstract 642.

http://www.retroconference.org/2010/Abstracts/38914.htm

7. Stellbrink H-J et al. Incidence, Genotype Distribution, and Prognosis of Sexually Transmitted Acute Hepatitis C in a Cohort of HIV-infected Patients. 17th CROI, 2010. Poster abstract 645.

http://www.retroconference.org/2010/Abstracts/38606.htm

8. Hare B et al. Kinetically Guided PEG Alfa-2a and RBV Therapy for HIV-+ Adults with Acute HCV Infection. 17th CROI, 2010. Poster abstract 639.

http://www.retroconference.org/2010/Abstracts/38114.htm

9. Ragni M et al. Outcomes in HIV/HCV Hemophilic vs Non-hemophilic Transplant Candidates. 17th CROI, 2010. Poster abstract 688.

http://www.retroconference.org/2010/Abstracts/39692.htm

Studies have shown that about 80% of the sexual transmission of HIV-1 subtype B and C is characterised by a genetic bottleneck, that is currently explained by low efficiency of virus penetration through mucosal layers and potential selective pressure at the sites of transmission in either the donor or the recipient.

Dukhovlinova and colleagues took a step further and looked whether and to what extent this phenomenon is present with the intravenous HIV-1 transmission. The researchers performed a single genome amplification (SGA) to analyse HIV-1 quasispecies in intravenous drug users (IDU) from St Petersburg, Russia and quantified the multiplicity of infection. The results of 17 IDUs from different cohorts in the city were analysed. Those were samples from people with acute, early and chronic infections. SGA followed by direct sequencing was used to determine the complexity of full-length env gene. A minimum of 20 single env amplicons for each patient was used to identify and to characterise the transmitted virus.

The recently infected IDU (n=13) had multiple viral variants in only 31% (4 of 13) of the subjects. Four chronically infected subjects had complex viral populations. All but one analysed HIV-1 strains belonged to the Eastern Europe lineage of subtype A. The viral strains in one sample represented the mixture of HIV-1 CRF06_cpx strains with its subsequent recombinant CRF-06_cpx/subtype A. No evidence of superinfection was discovered. All but 1 of the transmitted viruses was estimated to be CCR5-tropic based on the sequence of the V3 loop.

The researchers concluded that the ‘results suggest that infection in this cohort is most often initiated with the minimum infectious dose, i.e. a single virion, even in those subjects where parenteral transmission was the predominant risk’.

Ref: Dukhovlinova E et al. A significant transmission bottleneck among newly and recently HIV-1-infected IDU in St Petersburg, Russia. Poster abstract 477.

http://www.retroconference.org/2010/Abstracts/38528.htm

In this study the researchers examined the impact of IDU status and a series of clinical indicators on immunologic response. The treatment outcomes of treatment naïve adults (≥18 years old) initiating HAART after the year 2000 were assessed.

The clinical indicators used were:

1) Having <3 versus >3 CD4 count measurements in the first year of follow-up;

2) Having <3 versus >3 viral load measurements in the first year of follow-up;

3) Having a genotypic resistance testing done at baseline requested by the enrolling doctor in samples with viral load >250 copies/mL;

4) Having started therapy with <200 cells/mm3 CD4 cell count;

5) Having started on non-recommended HAART;

6) Having achieved viral suppression at 6 months since therapy initiation.

The model was adjusted for sex, age, CD4 cell count, viral load at baseline, and adherence to therapy during the first 6 months. Immunologic response was defined as the percent change in the 12-month CD4 cell count from the CD4 at baseline. Because the response was categorised as percent change >100%, percent change >0% and <100% and percent change <0%, a partial proportional odds model was used.

402 out of1633 (25%) of the people participating in the study reported IDU status. IDU were more likely to be female, younger, have adherence <95% during the first 6 months, <3 CD4 cell count and <3 viral load measurements during the first year on HAART, having started HAART with a CD4 cell count of 160 cells/mm3, and against all odds, being able to achieve suppression at 6 months since the initiation of HAART (P <0.01). The multivariate model (Table 2) estimated that IDU versus non-IDU immunologic responses did not differ significantly when stratified by the clinical indicators. Of note, as seen in the table, IDU and non-IDU had similar overall responses to HAART when stratified by adherence rates. This clearly indicates that a change in the general discourse on the benefits of HAART in the IDU population is necessary.

Table 2: Comparison of immunological and virological responses to ART between IDUs and non-IDUs based on level of adherence

Ref: Lima V et al. Similar Immunologic Responses to Modern HAART among IDU and Non-IDU in a Populational Setting. Poster abstract 516.

http://www.retroconference.org/2010/Abstracts/38235.htm

This model evaluates Highly Active Antiretroviral Therapy (HAART) as an intervention to reduce HIV incidence and prevalence in IDU communities. The model used is a network model based on a Mover-Stayer framework and on a previous cellular automaton model to evaluate HAART as prevention.

In the model, IDU are distinguished based on syringe-sharing behavior and HIV status, and exert social influence on peers, encouraging, or discouraging syringe sharing. HAART is applied at coverage levels of 0% to 100%, assuming complete adherence and no drug resistance, tracked HIV incidence, and prevalence to equilibrium. Community composition, needle sharing frequency (60/month), and initial HIV prevalence (31%) were derived from data on IDU enrolled in the Vancouver Injection Drug User Study (VIDUS). Published transmission rates for HIV disease stages were used. HAART, initiated after 5 years (Scenario 1), was combined with reduced risk behavior (Scenario 2), the latter repeated with HAART initiated after 1 year (Scenario 3).

Without intervention (Table 3), HIV spreads rapidly and reaches very high prevalence (90%) in the model. With increasing HAART coverage, HIV incidence and prevalence decrease for all scenarios, eventually reaching 0%. Without change in risk behavior (Scenario 1), HIV prevalence decreased gradually to 60% HAART coverage, dropping rapidly thereafter. Behavioral interventions (Scenarios 2 & 3) amplified HAART effects. At 40% to 50% HAART, both incidence and prevalence were reduced by about half. Above 80% coverage, the epidemic was effectively eliminated. Early HAART initiation showed little impact.

Table 3: Effect of HAART coverage on HIV incidence and prevalence in a network model of injecting drug users

Ref: Bastani P et al. Highly active antiretroviral therapy eliminates HIV epidemics in a network model of an Injecting Drug User community. Poster abstract 997.

http://www.retroconference.org/2010/Abstracts/38240.htm

• Increasing uptake of HAART in HIV-positive ongoing drug users

This study looked into the effect of HAART in a group of HIV infected patients infected through injecting drug use (IDUs) compared to patients infected via other routes. In the Danish HIV cohort study, patients who initiated HAART from 1 January 1997 to 31 December 2007 were identified. CD4+ cell counts and viral load were followed. For CD4+ cell counts, medians for the two groups were compared and for viral load the percentage of full viral suppression defined as <500 copies/mL.

The study included 3615 patients, representing 22,804 person years of observation. A total of 346 people (9.6%) were categorised as IDUs.

IDUs were diagnosed with a higher median CD4 cell count (IQR) [300 (170-480) vs 248 (109-418), p< 0.0001] but initiated HAART on average 125 (19-560) days after they were first eligible to treatment according to national guidelines, compared to non-IDUs who started after a median of 31 (5-158) days.

IDUs were more likely to receive a first regiment based on PIs compared to NNRTI based regiments for non-IDUs, and IDUs received more Trizivir. Importantly, more than half of IDUs had fully suppressed viraemia within the first 3 months of HAART.

Ref: Larsen M V et al. Efficacy of highly active antiretroviral treatment in HIV-1 positive injecting drug users – results from the Danish HIV cohort study. PE20.3/1

This study analysed the trends of antiretroviral therapy (ART) uptake among HIV-positive current drug users seeking substance abuse treatment in the HAART era at three hospitals in Barcelona, Spain, between 1997 and 2007. The results were divided into 3 periods (p) p1: 1997-1999; p2: 2000-2003; p3: 2004-2007), reflecting the evolution of HAART regimens over time.

In this analysis, 705 HIV-positive people were eligible (74.6% men); 299 were admitted in p1, 249 in p2 and 157 in p3. Mean age was 34 years, 94.7% had previous injection drug use (IDU) and 67.7% were current IDUs at admission. CD4 cell count was 399 cells/mm3 [IQR 203-632]. Lifetime prevalence of ART use was 59.4% (416/705), increasing from 48.1% in p1, to 64.6% in p2 and 72.6% in p3 (p<0.05). The prevalence of ART uptake at admission was 40.7%, increasing from 31.4% (p1) to 41.0% (p2) and 58.0% (p3) (p<0.05).

In multivariate logistic regression analysis, age, calendar period, and non-IDU were predictors of being in ART at admission. Among those taking ART, 21.6% were on suboptimal combinations, mostly during the first period. Overall, 44.6% of patients were on PI + NRTI-based regimens, 21.9% on NRTI + NNRTI-based regimens and 9.4% on triple NRTI-based regimens.

The researchers concluded that HAART uptake is steadily increasing in ongoing HIV-positive drug users. The continued “However, a remarkable percentage still remains ART-naïve despite immunosuppression. Interventions focused on the integration of both substance abuse and HIV/Aids treatment are necessary to increase survival in this population’.

Ref: Vallecillo G. et al. Increasing uptake of HAART in HIV + ongoing drug abusers. PE20.3/2

• General overview of the abstracts and presentations on HIV in IDUs

It is commendable that this conference is already organised as a regular event and focuses on a region that was not so high on the list of other major international HIV/AIDS events. It is also good that local researchers can show their concepts of science development and scientific agenda. Unfortunately, the quality of the majority of abstracts was not high and hardly any research breakthroughs were presented. The section on HIV treatment in IDUs illustrates this, though the same can be said for many mainstream HIV medical meetings.

While recognising that IDU is heavily political, especially in the Russian Federation, not allocating enough of time and attention to this topic is a particularly near-sighted, given that the main characteristic of the HIV population in the region is still IDU.

The following article is a general overview of three abstracts that I found of the more interest. Nevertheless, the community should insist on more research and better in terms of methodology research among the IDUs in the region.

Dolzhanskaya and colleagues analysed medical notes to study the attitude of doctors to providing narcological help and HAART assessed the situation with providing help with overdose in different countries from the region. It is well documented that educational programmes have small to insignificant effect in avoiding overdose, while naloxone, a medicinal product that helps people in overdose to recover from it, has the potential to have a major impact.

They found that many medical forms were not filled as required and that there was considerable amounts of missing data, especially on patients’ social background and their risk behavior. This may be due to either doctors not valuing this information to patients withholding information through concerns related to disclosure.

People who were registered with AIDS Centres and who are IDUs were hardly ever referred to, or visited, the Narcological Units. The lack of medical documentation for visits to TB Units or STI clinics also indicates that there is no clear idea about these patient needs, as well as perhaps little or no cooperation among the different institutions that are involved in provision of treatment, care and support for PLWHA.

A group of researchers from Armenia looked into the use of HAART and survival of HIV-positive IDUs in Armenia. [2]

Even though this topic has been researched on many occasions and in quite diverse settings and the results have been consistently good, it is commendable that now we have findings from the Caucasus too.

The study included 71 HIV-positive men using injecting drugs who were on first- or second-line ARV therapy (according to the National Guidelines of Armenia) and who were followed from February 2005 till May 2009. CD4 count, viral load and hepatitis B and C markers were recorded. Adherence was evaluated through a special computer programme that was created by the National AIDS Centre of Armenia.

During the study period, all people started therapy but 18 (25.3%) interrupted the treatment either because of complications (including side effects) or as a personal decision and 10 people consequently died. In this group, 62 (87%) of the participants had AIDS, 45 (63%) had hepatitis C and two (3%) had hepatitis B. One person had both hepatitis B and C. TB was registered in 46.5% patients.

All 10 people who died were staged as AIDS. Their average CD4 count was 93 cells/mm3. Nine had chronic hepatitis C and six had TB coinfection. It was postulated that two deaths were a result of drug overdose. Four people stopped ARVs as a result of complications (hepatotoxicity and anaemia), one gave up treatment as a personal decision, two died as a result of TB complications and one as a result of complictions from hepatitis C.

From the 33 (62%) people continuing therapy, 8 had adherence <95% and 25 >95%. Three people on therapy failed to reduce their viral load to undetectable, probably due to low adherence. In people continuing therapy, the average CD4 count increased to 245 cells/mm3.

Shonning and colleagues presented an abstract on the results of a study conducted by the Eurasion Harm Reduction Network in 2008. Shockingly, in 2006 from 3 555 568 registered IDUs, 9354 died of overdose. The researchers assessed the situation with providing help with overdose in different countries from the region. It is well documented that educational programmes have small to insignificant effect in avoiding overdose, while naloxone, a medicinal product that helps people in overdose to recover from it, has the potential to have a major impact.

The pilot programmes for distributing naloxone in Tajikistan and Russia showed that this is a viable option. The researchers suggest that if the existing harm reduction programmes are allowed to enhance access and start delivering naloxone to IDUs, their partners, relatives, etc, many unnecessary deaths from overdose will be avoided. Easy access to naloxone will also help with avoiding the psychological barriers to search help-fear of contacting the medical establishment and/or police or in cases logistics problems like late arrival of the ambulance.

References

Unless otherwise indicated, all references are to the book of abstracts of the conference.

1. Должанская Н и др. Анализ медицинской документации и изучение отношения врачей к оказанию наркологической помощи пациентам с ВИЧ-инфекцией и готовности к проведению совр. методов лечения (ВААРТ). Стр. 81

2. Мкртчян А и др. ВААРТ и выживаемость ВИЧ-инфицированных потребителей инъекционных наркотиков в Армении. Стр. 83

3. Шоннинг Ш. и др. Передозировка: основная причина предотвратимой смертности среди ЛЖВ.

• Efavirenz and substance use

• Atazanavir and tobacco or marijuana

• Darunavir/r and buprenorphine/naloxone

• Raltegravir and methadone

• NRTIs and buprenorphine

The efavirenz trough concentrations in 17 HIV+ subjects with substance related disorders (SRDs) and 20 HIV-positive subjects without SRDs were evaluated. The median efavirenz trough concentrations in the SRD groups were lower with tobacco (1.76 vs 2.295 ug/ml), alcohol (1.41 vs 2.25 ug/ml), marijuana (1.73 vs 2.24 ug/ml) and cocaine (1.92 vs 2.05mg/ml), but higher with opioids (2.41 vs 1.85 mg/ml). Only the differences with tobacco and alcohol were statistically significant. There was no significant relationship between SRD and antiviral response.

Ref: Meeting Report – 49th ICAAC, San Francisco, September 2009. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 2009.

http://www.hiv-druginteractions.org/data/NewsItem/79_ICAAC49.pdf

Atazanavir trough concentrations were evaluated in 32 HIV-positive subjects with substance-related disorders (SRDs) and 35 HIV-positive subjects without SRDs.

The median atazanavir concentrations in the SRD groups were lower with tobacco (0.314 vs 0.712 ug/ml), marijuana (0.238 vs 0.593 ug/ml), alcohol (0.534 vs 0.558 ug/ml), and opioids (0.325 vs 0.712 ug/ml), but higher with cocaine (0.768 vs 0.544 ug/ml).

Trough concentrations in the SRD group were below the therapeutic range in 36% of tobacco users and 50% of marijuana users. Only the differences with tobacco and marijuana were statistically significant. There was no significant direct effect of SRD on viral load or CD4 count.

Ref: Meeting Report – 49th ICAAC, San Francisco, September 2009. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 2009.

http://www.hiv-druginteractions.org/data/NewsItem/79_ICAAC49.pdf

The effect of darunavir/r (600/100mg twice daily for seven days) on the pharnacokinetics of buprenorphine was assessed in 17 HIV-negative subjects stable on buprenorphine/naloxone maintenance therapy (daily doses up to 24/6mg). There was no effect on buprenorphine AUC, Cmax or trough concentrations; however, norbuprenorphine Cmax increased by 36% and AUC increased by 46%.

No subject required dose adjustment of buprenorphine/naloxone.

Given the increase in norbuprenorphine concentrations, close clinical monitoring of patients is recommended.

Ref: Meeting Report – 49th ICAAC, San Francisco, September 2009. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 2009.

http://www.hiv-druginteractions.org/data/NewsItem/79_ICAAC49.pdf

The effect of raltegravir (400mg twice daily) on the pharnacokinetics of methadone were investigated in 12 HIV-negative subjects stable on methadone.

There was no change in either methadone AUC or Cmax in the presence of raltegravir and no dose adjustment is required.

Ref: Meeting Report – 49th ICAAC, San Francisco, September 2009. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 2009.

http://www.hiv-druginteractions.org/data/NewsItem/79_ICAAC49.pdf

The interaction between buprenorphine and didanosine, lamivudine and tenofovir was investigated in 27 HIV-negative buprenorphine/naloxone maintained subjects.

Data for didanosine and tenofovir were compared to values obtained from 20 control subjects not receiving buprenorphine; lamivudine was compared to control data.

No significant changes in buprenorphine pharmacokinetics were observed when coadministered with didanosine, lamivudine and tenofovir. When compared to controls, buprenorphine had no statistically significant effect on NRTI concentrations.

Ref: Meeting Report – 49th ICAAC, San Francisco, September 2009. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 2009.

http://www.hiv-druginteractions.org/data/NewsItem/79_ICAAC49.pdf

Introduction

The IAS conference did not have a lot of new research related to IDU, although one of the sessions did focus on IDU-related issues. We include the following reports in this issue:

• Influence of HIV infection on renal function among heroin users
• Risk of developing specific AIDS-defining illnesses in patients coinfected with HIV and HCV, with or without liver cirrhosis
• Response to first line antiretroviral therapy in patients with and without a history of IDU in Indonesia
• Screening, enrolment, and follow-up of IDUs in an HIV pre-exposure prophylaxis trial in Bangkok
• HIV, HCV and somatic comorbidity in a heroin maintenance centre in Switzerland – a case for an integrative medical approach to harm-reduction
• Performance of simple non-invasive scores to predict fibrosis in HIV/HCV co-infection in daily clinical practice
• Liver disease is associated with HIV/HCV co-infection and alcohol use among IDUs in Chennai, India
• Hunger and food insufficiency are independently correlated with unprotected sex among HIV-positive IDUs with and without HAART
• Drug and alcohol dependence special session

For the first time, webcasts of several sessions are available via the conference website together with searchable online abstracts and PDF files of many of the posters or presentations:

http://www.ias2009.org

The abstract database from the meeting is online at the same site.

An Italian study from the Sao Paolo Hospital in Milan looked into the correlation between the occurrence of different AIDS-defining illnesses (ADIs) and chronic HCV infection or HCV-related liver cirrhosis. [1]

There are few data concerning the risk of specific opportunistic diseases in patients with and without hepatitis C virus (HCV) infection.

The study was conducted in an Italian cohort of over 5000 HIV-positive patients, stratified into two groups: i) patients without HCV coinfection and with persistently normal aminotransferase levels and ii) patients with HCV coinfection. Coinfected patients were stratified according to liver cirrhosis. The incidence of new ADIs was calculated per 1000 person-years of follow-up by Poisson regression model and adjusted tor potential confounders.

The researchers observed 496 ADIs among 5397 patients over 25,105 person-years of follow-up, half of which were in coinfected patients. HCV coinfection was associated with an increased risk of developing an ADI (adjusted relative rate [ARR], 2.61; 95% confidence interval [CI], 1.88-3.61). Specific rates included, bacterial infection (ARR 3.15; 95%CI 1.76-5.67), HIV-related disease (ARR 2.68; 95%CI 1.03-6.97) and mycotic disease (ARR 3.87; 95%CI, 2.28-6.59), but not non-Hodgkin lymphoma (ARR, 0.88; 95% CI, 0.22-3.48).

HIV-monoinfected patients had a significantly lower rate of mycotic infection, bacterial infection, toxoplasmosis, and HIV-related ADI than among patients with HCV and cirrhosis. The risk among coinfected patients with cirrhosis was also greater than non-cirrhotic patients.

The researchers concluded that ‘HIV-related bacterial and mycotic infections are strongly associated with positive HCV serostatus and HCV-related cirrhosis’.

They strongly recommended that these data should be considered when deciding when to start antiretroviral therapy in HCV-coinfected individuals.

References:

D’Arminio Monforte et al. Risk of developing specific AIDS-defining illnesses in patients coinfected with HIV and hepatitis C virus with or without liver cirrhosis. Clin Infect Dis. 2009 Aug 15;49(4):612-22.

http://www.ncbi.nlm.nih.gov/pubmed/19591597

An Italian study from the Sao Paolo Hospital in Milan looked into the correlation between the occurrence of different AIDS-defining illnesses (ADIs) and chronic HCV infection or HCV-related liver cirrhosis. [1]

There are few data concerning the risk of specific opportunistic diseases in patients with and without hepatitis C virus (HCV) infection.

The study was conducted in an Italian cohort of over 5000 HIV-positive patients, stratified into two groups: i) patients without HCV coinfection and with persistently normal aminotransferase levels and ii) patients with HCV coinfection. Coinfected patients were stratified according to liver cirrhosis. The incidence of new ADIs was calculated per 1000 person-years of follow-up by Poisson regression model and adjusted tor potential confounders.

The researchers observed 496 ADIs among 5397 patients over 25,105 person-years of follow-up, half of which were in coinfected patients. HCV coinfection was associated with an increased risk of developing an ADI (adjusted relative rate [ARR], 2.61; 95% confidence interval [CI], 1.88-3.61). Specific rates included, bacterial infection (ARR 3.15; 95%CI 1.76-5.67), HIV-related disease (ARR 2.68; 95%CI 1.03-6.97) and mycotic disease (ARR 3.87; 95%CI, 2.28-6.59), but not non-Hodgkin lymphoma (ARR, 0.88; 95% CI, 0.22-3.48).

HIV-monoinfected patients had a significantly lower rate of mycotic infection, bacterial infection, toxoplasmosis, and HIV-related ADI than among patients with HCV and cirrhosis. The risk among coinfected patients with cirrhosis was also greater than non-cirrhotic patients.

The researchers concluded that ‘HIV-related bacterial and mycotic infections are strongly associated with positive HCV serostatus and HCV-related cirrhosis’.

They strongly recommended that these data should be considered when deciding when to start antiretroviral therapy in HCV-coinfected individuals.

References:

D’Arminio Monforte et al. Risk of developing specific AIDS-defining illnesses in patients coinfected with HIV and hepatitis C virus with or without liver cirrhosis. Clin Infect Dis. 2009 Aug 15;49(4):612-22.

http://www.ncbi.nlm.nih.gov/pubmed/19591597

This study from Indonesia, reported during the IAS Conference in Cape Town, looked at the response to first line HAART in IDU and non-IDU patients as injecting drug use (IDU) is often associated with lower uptake, retention and success of antiretroviral treatment (ART).

The participants were all registered as HIV-positive between 1996 and April 2008 in a referral hospital. Data before January 2007 was collected retrospectively from medical records, with prospective questionnaires and blood results used subsequently.

Of the 773 adult HIV patients, just over 80% had a history of IDU. These patients presented with a lower CD4-cell (median 33 vs. 84 cells/mm3) and a high prevalence of HCV-infection (88%). Uptake and adherence to ART, however, were not different between IDUs and non-IDUs. Importantly, IDUs and non-IDUs showed similar mortality and loss to follow-up (see Figure 1 below). After a median of 20 months ART, virologic failure was detected in approximately 12% of IDUs and 16% of non-IDUs (p=0.524).

These data are particularly important in the Indonesian setting, where IDU remains the main route and risk factor for infection.

Figure 1: Mortality and loss to follow up by IDU status

References:

R. Wisaksana et al. Response to first line antiretroviral therapy among HIV-infected patients with and without a history of injecting drug use in Indonesia. 5th IAS Conference, 19-22 July 2009, Cape Town. Abstract MOPEB060.

http://www.ias2009.org/pag/Abstracts.aspx?AID=3468

The Bangkok Tenofovir Study is an ongoing randomised, double-blind, placebo-controlled study using daily oral tenofovir to prevent HIV infection among injecting drug users (IDUs). Preliminary results on the trial status were presented at the IAS conference in Cape Town. [1]

The trial is being conducted in 17 Bangkok Metropolitan Administration drug treatment clinics. Eligible IDUs (n=2400) are randomised (1:1) to receive daily tenofovir 300mg or placebo. Participants choose follow-up either daily with directly observed taking of study drug (DOT) or monthly without DOT. HIV status and demographics are assessed at enrolment, blood chemistry and hematology for safety at enrolment and every 3 months, and HIV status and adherence every month.

Between 2005 and 2008, 3824 IDUs were screened and 2259 (59%) enrolled. Reasons for screen failure included HIV infection (10%), elevated ALT or AST (8%), and chronic Hepatitis B infection (6%). Median age of enrollees was 31 years (range, 20-59), 79% were male, and 87% had completed primary school or higher. Retainment was high with 85% of eligible participants completing the 12-month visit, 84% the 24-month visit, and 94% the 36-month visit. Participants reported taking study medication the day before 94% of monthly visits and 88% chose DOT follow-up.

The first efficacy and safety results are expected in 2010.

References:

Martin M et al. Screening, enrolment, and follow-up of injecting drug users in an HIV pre-exposure prophylaxis trial in Bangkok. 5th IAS Conference, 19-22 July 2009, Cape Town. Abstract WEPEC081.

http://www.ias2009.org/pag/Abstracts.aspx?AID=2200

As somatic diseases in IDU is not well investigated, the centre for heroin maintenance centre KODA in Bern, Switzerland compared the effectiveness of heroin maintenance therapy for criminal and socio-economic harm-reduction to evaluate the somatic health status of patients on heroin maintenance therapy and to assess the need for improving on-site somatic care.

The researchers performed a cross-sectional survey of all 201 IDU treated in KODA and developed a database containing medical, laboratory and epidemiological information.

Of the 201 patients (72% male, median age 40.5 years), 26 (13%) were HIV-positive and 17 were on antiretroviral treatment. Of 9 untreated patients, 3 would qualify for ART according to treatment guidelines. Three-quarters of patients (151/201) were coinfected with HCV. Plasma HCV-RNA results were available for 121 individuals. In 41 patients, no HCV-replication was found, suggesting a high spontaneous viral clearance rate of 27%. Of 80 patients with documented HCV-replication only 9 (9%) had formally been evaluated for interferon/ribavirin therapy, and 6 were treated (2 SVR, 3 non-responders and 1 patient currently on treatment).

Over 50% patients (113/201) had an additional somatic diagnosis: infection related (34%), pulmonary (24%), cardiovascular (22%), neurological (22%) and haematological (19%) disorders were the most prevalent. Only 16% patients (32/201) were regularly followed by a specialist in the field of somatic illnesses.

The researchers concluded that ‘In this hard to reach population somatic co-morbidities are difficult to manage within existing health care structures. However, they are likely to have an impact on long-term mortality. Improved on-site care for somatic illnesses should be included in heroin maintenance programmes’.

References:

M.C. Thurnheer et al. HIV, HCV and somatic co-morbidity in a heroin maintenance centre in Switzerland – a case for an integrative medical approach to harm-reduction.5th IAS Conference, 19-22 July 2009, Cape Town. Abstract CDC 071.

http://www.ias2009.org/pag/Abstracts.aspx?AID=2880

Liver biopsy is the current gold standard for diagnosis of liver fibrosis in majority settings. As an invasive procedure, many HIV-positive people have either postponed or even refused it, sometimes leading to delayed diagnosis monitoring and treatment.

Non-invasive tests to predict fibrosis in HIV/HCV coinfection have the potential to overcome some of the above-mentioned limitations. These include AST to platelet ratio index (APRI) and Forns index (FI) which have both been validated in coinfected patients. However, the diagnostic yield of these indexes outside validation studies might be lower. Based on this, the GRAFICO study group examined the value of APRI and FI to detect significant fibrosis in coinfected patients in real life conditions. [1]

The study was a cross-sectional evaluation of fibrosis and included 8490 subjects with detectable plasma HCV-RNA. Patients came from 95 Spanish hospitals. Data of the last visit were obtained. For patients who had undergone a liver biopsy within 24 months of the last visit (n=519), APRI and FI was measured by areas under the receiver-operating-characteristic curves (AUROC).

The diagnostic accuracy was tested by positive (PPV) and negative (NPV) predictive values.

Results showed that AUROC of APRI was 0.668 (95%CI 0.662-0.714) and of FI 0.665 (95%CI 0.619-0.712). The PPV of APRI was 79% and the NPV was 66%. The PPV of FI was 74% and the NPV 64%. Liver biopsy length was available and ≥15 mm in 120 individuals. In this group, the PPV of APRI and of FI was 85% and 81% respectively. Using these indices, 22% of patients could be spared from having a biopsy. Applying both models sequentially, 30% of patients could benefit from exclusion of biopsy, with a PPV of 83%.

These data show that the combined use of both indices to decide anti-HCV therapy may save a significant proportion of patients from LB in non-referral centres or centres with lower experience in performing liver biopsy.

Reference:

González-García J et al. Performance of simple non-invasive scores to predict fibrosis in HIV/HCV co-infection in daily clinical practise. 5th IAS Conference, 19-22 July 2009, Cape Town. Abstract WEPEB217.

http://www.ias2009.org/pag/Abstracts.aspx?AID=249

Few data on the effect of HIV and HCV coinfection in IDUs have been collected from developing countries. Treatment decisions have been made based on data from developed countries, where the possible risk factors may not necessarily reflect the situation in lower income settings.

A study from Mehta and colleagues addressed this by characterising liver disease prevalence associated with HIV/HCV in a cohort of IDUs in Chennai, India. [1]

During the study, a convenience sample of 1158 IDUs was recruited through community outreach (2005-06) who were then followed twice a year. In 2008, a liver panel and complete blood count were performed (n=463). AST to platelet ratio index (APRI) was used to estimate the prevalence of significant fibrosis (APRI>1.5). Prevalence ratios (PR) of significant fibrosis were calculated using Poisson regression analysis.

The median age of IDUs was 35 years, 21% were HIV-positive, 52% HCV-antigen positive (70% HCV RNA positive). 41% reported heavy alcohol use and 52% daily cannabis use. The prevalence of significant fibrosis was 7% overall. Group ratios by HIV and HCV status were: 4% HIV/HCV-negative; 3% HIV mono-infected (HCV RNA-); 11% HCV mono-infected (HCV RNA+); and 14% HIV/HCV co-infected (p< 0.001). In multivariate regression analysis, adjusted for age, years of injection, and drug/alcohol use, compared to HIV/HCV-uninfected people, those HCV RNA+ only (PR: 3.6) and those HIV/HCV co-infected (PR: 5.0) had significantly higher fibrosis prevalence; however, HIV+ (HCV RNA-) did not demonstrate a higher prevalence. Cumulative alcohol use over the previous three years was positively associated with fibrosis (PR: 7.4 for heavy use) and cumulative cannabis use was negatively associated with fibrosis (PR: 0.3 for daily use).

The results clearly show that there is an association of HIV/HCV co-infection with liver disease in a setting where HIV subtype C and HCV genotype 3a predominate. This may be a signal for policy makers and clinic managers to incorporate components of liver disease management in HIV treatment programmes in Chennai, India.

References:

Mehta SH et al. Sustained immunological response among HIV-infected patients enrolled in a cost-recovery programme in Chennai, India: an alternate approach to free rollout programs. 5th IAS Conference, 19-22 July 2009, Cape Town. Abstract TUPED082.

http://www.ias2009.org/pag/PosterExhibition.aspx

Shannon and colleagues presented a study that looked at food insufficiency and risk taking in Canada. [1]

Previously, the data on these issues have nearly always been collected from resource-limited settings. The researchers examined longitudinally the relationship between food insufficiency and unprotected sex among HIV-positive injection drug users (IDUs) both with and without HAART.

Longitudinal analyses were restricted to HIV-positive IDUs who completed baseline and at least one follow-up visit in the ACCESS cohort between 2005 and 2008. The participants relied mainly on food banks and shelters to obtain food and were housed only occasionally. A multivariate logistic model using generalised estimating equations (GEE) and a working correlation matrix to assess an independent relationship between food insufficiency (eg. going hungry due to insufficient access to food or money to acquire food) and unprotected sex (inconsistent condom use for vaginal/anal sex) was constructed.

Among 436 HIV-positive IDU, the median age was 42 years (IQR: 36-47) with 42% female. Food insufficiency over the follow-up period was reported by 67% of participants. In multivariate GEE, younger age (AOR 0.96; 95% CI 0.93-0.99), being married/cohabitating (AOR 4.56; 95%CI 3.01-6.87), and food insufficiency (AOR 2.68; 95%CI 1.49-4.82) independently correlated with unprotected sex among HIV-positive IDU (adjusting for binge drug use, HAART, RNA viral load suppression and other potential confounders).

These results indicate that improved access to free and low-cost food among HIV-positive IDU as a secondary prevention strategy, including interventions that account for the potential competing resource demands of acquiring drugs and food.

References:

Shannon K et al. Hunger and food insufficiency are independently correlated with unprotected sex among HIV+ injection drug users both on and not on HAART. 5th IAS Conference, 19-22 July 2009, Cape Town. Abstract WPDEC101.

http://www.ias2009.org/pag/Abstracts.aspx?AID=3310

It is commendable that the 5th IAS conference included a special session on IDU and dependence issues. It is unfortunate though that the session was poorly attended. Below is the report of the conference rapporteur Sinead Delany-Moretlwe.

The session highlighted the importance of treating drug addiction for HIV prevention. Advances in understanding brain metabolism, functional pathways and the expression of specific receptors have enhanced the understanding of the interactions between genes, biology and environment which can result in addiction in some people.

Methamphetamine use (MA) was shown to be strongly associated with an increased risk of HIV infection, and progression of HIV disease. Effective behavioural and medical intervention strategies are available to treat MA addiction, and this can be used either alone or in combination.

Data from a published meta-analysis of 20 studies in Africa was presented which showed a 57% increased risk of HIV acquisition among alcohol drinkers compared to non-drinkers after controlling for other factors. A crude dose response was observed with heavy drinkers having a greater risk of HIV acquisition than moderate drinkers. Interventions are needed to address the increased risk of HIV acquisition in alcohol users.

The achievements and challenges of delivering methadone substitution treatment (ST) programmes in Eastern Europe and Central Asia were presented. Some advances have been made in some countries to secure funding for ST programmes, to integrate ST programmes in HIV/TB treatment programmes, and to develop policies for the management of HIV in injecting drug users (IDU). However, significant social, political and regulatory obstacles to the acceptance and integration of ST programmes into general medical care still remain common.

This has lead to the abrupt closing and withdrawal of treatment programmes in several countries with severe consequences for the people in these programmes.

An evaluation from a supervised injecting facility (SIF) in Vancouver, Canada was also presented. In this programme reductions in public disorder and HIV risk behaviour were observed, with no increases in harmful behaviour such as increased initiation into drug use. Despite these successes there are political challenge to the expansion of this programme beyond the pilot phase, highlighting the stigma and lack of political will that many harm reduction programmes face, despite the evidence of success.

Throughout the session, strong arguments were made that addiction is a chronic disease, which should be managed as other chronic diseases. Treatment for drug addiction was seen as the best strategy for HIV prevention in drug using populations.

References:

Drug and alcohol dependence – new advances and ongoing challenges in HIV treatment and prevention. Tuesday 21July. Special Session TUSS3. http://www.ias2009.org/pag/PSession.aspx?s=2383

A PDF file of the abstract book from the Harm Reduction 2009 is now available to download free from the conference website.
The site also links to a searchable database of conference abstracts,

http://www.ihra.net/Thailand/ProgrammeAbstracts

The following transcript is the keynote closing address from the conference.

Sawa dee Kap. Good afternoon.

Distinguished, compassionate and determined fellow harm reduction advocates, let me first thank the organisers, and Professor Gerry Stimson in particular, for providing me the opportunity to make some reflections on the politics of harm reduction and the global response to HIV.

Five years ago this week I became the Executive Director of the International AIDS Society. It was just three months before the International AIDS Conference in Bangkok, and the IAS was about to relocate to Geneva and restructure its operations, staff and strategic vision. Needless to say, things were somewhat of a mess, and believe me, I was terrified, despite having worked in HIV for close to 15 years at the time.

On July 11, the conference opened in Bangkok, the first time the meeting had ever been held in South-East Asia. Close to 30,000 people had registered, and, as the Asian bird flu epidemic had only recently been contained, I sighed with relief that the conference

was not cancelled. I’m sure Gerry can relate that feeling to this week’s conference! Though bird flu was under control, the war against drug users in Thailand was not. It was estimated that thousands had been killed as part of then-Prime Minister Thaksin Shinawatra’s attempts to rid the country of drugs. The dead were mostly individual drug users and small-time dealers, certainly not the powerful mafia that control the production and distribution of illegal drugs in Thailand. They remained of course untouched.

At the opening session, Prime Minister Thaksin, former-UN Secretary General Kofi Annan, and, who could forget, Miss Universe, made strong commitments to the fight against AIDS. Dignitaries and celebrities were falling over themselves to say how much they cared.

And then it was time for the substantive part of the opening session – a global overview of HIV epidemiology and the current response, and a passionate call for humanity and harm reduction by one of Thailand’s bravest and strongest HIV-positive drug user activists Paisan Suwannawong. Paisan, if you are in the room today, I pay tribute to you. Inexplicably, the dignitaries, led by Prime Minister Thaksin, ceremoniously filed out of the stadium before the substantive discussions began. Paisan was left on the stage with a dwindling audience that, having seen all the dignitaries leave, thought the opening was over, and emptied the hall.

Needless to say, there was an outcry. Behind the scenes over the following days were angry meetings between the IAS and community leaders, and difficult meetings between the IAS and Thai government representatives. I realised that the IAS had made a mistake in allowing Paisan’s talk to be scheduled at the end of the programme, even though we did not know that the Prime Minister would leave early. I learned that it was not considered appropriate for a Thai Prime Minister to listen to a drug user. I learned a lot of things that week.

In the end, Paisan was given the opportunity to speak again, this time at the Closing Session, but the damage was done.

One of the many things I learned from that experience, that has been compounded over the past five years in the work I have done related to drug use, harm reduction and HIV, is the enormous fear that underpins the world’s approach to drugs, drug use and people who use drugs.

At the end of this year I will be leaving the IAS, after six IAS conferences and some dramatic progress in the response to HIV. I’d like to offer three observations I have made related to the response to HIV as it relates to drug use and harm reduction.

All three are about fear.

The person who uses drugs as “other”

My first observation is how all of us continue to talk about people who use drugs as “other”. We use terms like “drug abuser”, “drug user” and even “person who uses drugs” as if some of us do not use drugs. But which one of us does not use a drug that alters our mood, our consciousness of pain, our physical or emotional state? A joint, a dab of speed, a line of coke, a tab of ecstasy, a shot of heroin. Even the last three Presidents of the United States between them have admitted using some of these. A pint of beer, a glass of wine, a shot of whisky. A cigarette. A cup of coffee or tea. A pain relieving medication, an anti-depressant, a valium, a sleeping pill.

We are all people who use drugs. Our refusal to acknowledge this is all about our fear that “we” might become, or be seen as, one of “them”.

Throughout history human beings have been people who use drugs. We will always be people who use drugs. As human beings we strive to develop the knowledge and technologies to control our environment and to manage our circumstances. The drug user, the person who uses drugs, is not the “other”. She or he is you and me.

It seems to me that what we really need to focus on is the difference between drug use and drug addiction or dependency. Global drug policy continues to focus efforts primarily on the substances alone. This is wrong.

Of course, the harms associated with some drugs are worse than others. Sometimes these are due to the degree of addictiveness of a particular drug. But most of the harms are due to the way that a particular drug is acquired (for example in a dark back alley versus from a pharmacy) the way in which it is used (as a pill, for example, versus smoking, snorting or injecting), and, even more importantly, the way in which society treats people who use drugs. The vast majority of the horrific harms associated with drug use – crime, HIV and other infections, violence, incarceration, death – are clearly fuelled by the drug policies our governments pursue. It doesn’t take a rocket scientist to show that criminalizing drugs and drug use leads to a dramatic increase in drug-related crime, and that controlling and regulating the production and distribution of all drugs would go a long way towards reducing that crime.

If we are all people who use drugs then the critical questions seem to me to be:

• Why is it that some people who use drugs go on to have problematic drug use?
• How we can prevent that from happening?
• How we can help those that already have dependence problems? and
• How can we change the social and economic conditions that drive many people into drug dependence?

The reasons for drug use per se seem at least fairly well-characterised. We use drugs out of curiosity, to feel good, to feel better, to do better, or to manage physical, emotional or psychological pain. One might add to dance better, to have sex better, to relax more, to switch off, to switch on or to escape from the misery of social and economic deprivation. As to why some people go on to become drug dependent, the answers are less clear. There is some evidence, though still weak, that genetic factors, including the

effects of our environment on gene expression and function, may contribute to vulnerability. People with mental health problems are at greater risk for drug dependency. This is not surprising, considering the generally pathetic state of mental health services around the world that drive people to self-medicate, and the neglect of the poor and the marginalised. How and why some people become drug dependent and not others and how we can prevent drug dependency is an area that still requires much research. But no reason should be used to blame or belittle anyone who is drug-dependent.

So long as we continue to define the drug user as “other” and define the drug itself as the problem we will be trapped in our misguided and harm-inducing programmes and policies.

The wilful denial of evidence and the abuse of medical authority

My second observation relates to the wilful denial of evidence by policy makers throughout the world and the abuse of power by some members of the medical profession who support this denial.

The most obvious example of wilful denial of evidence is of course the fact that methadone remains illegal in Russia, thereby preventing the introduction of substitution therapy for people dependent on opioid drugs. The International AIDS Society has made the issue of access to methadone in Russia and throughout Eastern Europe and Central Asia a policy priority. Across the region, over 3.7 million people inject drugs, with over two million people injecting in Russia alone, the highest per capita in the world, with four times the overall global prevalence of injecting drug use. Close to 70% of all HIV infections in Russia are linked to injecting drug use, versus 30% globally outside of sub-Saharan Africa.

We all know that there are decades and decades of research showing that opioid substitution therapy is the most effective intervention to reduce injecting and prevent HV infection among people dependent on opioids, particularly if delivered as part of a comprehensive package of harm reduction interventions, including education and counseling, needle and syringe exchange programmes, provision of condoms, HIV diagnosis and treatment and TB and STI diagnosis and treatment.

But in Russia methadone remains illegal, and the Russian government maintains that there is no evidence that it works to prevent HIV infection or reduce the harms associated with injecting opioids. This denial of evidence is so profound that the government even dares to boldly distort the facts in international fora, such as at the high level meeting of the Commission on Narcotic Drugs in Vienna last month.

This kind of blatant and wilful denial of the evidence can only be based on deep-seated fear. Remember, this is a society steeped in denial due to fear. For decades the horrors of Stalin’s regime were denied by not only the Russian government but ordinary Russian citizens, until long after the death of Stalin, and despite the disappearance of tens of millions of people.

But this kind of denial of the evidence is by no means limited to Russia. Even in my own home country of Canada, a supposed bastion of democracy and human rights, there is a concerted and organised state-supported campaign to deny evidence related to harm reduction. For a number of years now a number of studies in the Downtown Eastside of Vancouver have struggled against the odds to scientifically determine the impacts of a number of harm reduction interventions, including a supervised injection site and heroin maintenance therapy. These studies have been dogged by government interference since their inception, including unwarranted attempts to shut trials down, spending of public funds on harm reduction-denialist organisations to write negatively about the trials, misrepresentation of the evidence of the studies’ results, and interference in the peer review process.

Fear drives the global war on drugs. Otherwise how could such clear evidence of the failure of the past ten years’ international drug policy be so blatantly denied? How could billions of dollars be wasted on a global anti-drugs programme that fuels violence, harms individuals, families and communities, strengthens organised crime and punishes sick people with prison sentences rather than providing them with the treatment, care and dignity that they need?

Fear also drives the abuse of people who use drugs by doctors and others in the medical system. In particular, I’m referring to the continuing use of forced detention and isolation, electro-shock therapy, forced participation in medical experiments and other abuses of people who use drugs that many of us might refer to as “torture”. Doctors who administer these abuses under the guise of “drug treatment” are not just wilfully denying the evidence, they are violating human rights and the Hippocratic Oath. And make no mistake, as a membership association of health care professionals and researchers working in HIV, the International AIDS Society abhors and condemns these unethical and inhumane practices.

Fear drives the denial of evidence. I have seen it in the denialists who claim that HIV does not cause AIDS and the denial of the evidence that antiretrovirals work to control HIV.

Fear can induce denial of any evidence we throw at it.

The need for common ground between the harm reduction and anti-drugs movements

My third and final observation relates to the seemingly vast gulf of irreconcilable differences between those of us advocating for harm reduction approaches to drug use and those in the anti-drugs movement.

Recently I visited the INSITE supervised injecting site in the Downtown Eastside of Vancouver. It was late afternoon, a very busy time at the centre. There was actually a queue of people outside the door over 15 people deep, each waiting impatiently for his or her chance to inject in one of the supervised cubicles inside. I spoke with a few individuals. These were not happy people. They were skinny, undernourished, bruised and cut, in tattered clothing, scared, twitchy, and desperate. There was a hint, a glimmer, of hope in the eyes of one or two, but not much. The road ahead for these people looked bleak to me. God knows how it looked to

them. Using the supervised injecting site was just one small but significant notch above sharing a needle and syringe in the alley up the road. Homeless and hungry, their lives pretty much devastated by the harms associated with drug use and the failure of the Canadian health and social systems. This is the reality of a supervised injecting site, an entry point to reduce harm amidst a sea of neglect.

To bridge the gap between the harm reduction and anti-drugs movement we harm reduction advocates must not be coy about the horrific problems that can be associated with drug use – their effects on the individual, the family, the community and humanity. Individuals in the anti-drugs movement are motivated too by their experience of the worst harms associated with drug use. Discussing these experiences openly and without prejudice could be the beginning of a common language we share. If we are not able to reach out to these groups and find common ground then our evidence will never overcome their fear.

Most importantly, our own fear that we might weaken the argument of our evidence that harm reduction works if we acknowledge and talk openly too much about the ugly side of drug dependency must also be overcome. If we let the chasm between us and the anti-drugs movement get too great then we will have to fight this battle far longer than necessary. We are not, after all, “pro-drug”, we are not “encouraging drug use”. We must reach out for dialogue consistently, with passion and compassion if we are to make further gains.

Conclusion

Next year, in July 2010, the International AIDS Conference will be held in Vienna, Austria. This will not be a repeat of the recent meeting in Vienna that has so angered us all. The conference will have a major focus on injecting drug use and human rights. There will be a special sub-focus on Eastern Europe and Central Asia, using Vienna in its historical role as a bridge between East and West. Let’s work together to ensure that Vienna in 2010 helps confront the fear that was rampant at the Commission on Narcotic Drugs in Vienna in 2009.

Fellow people who use drugs, let us all continue to dig deep within ourselves to face our own fears about the drugs we use, how we use them, how we can continue to be curious, to feel good, to feel better and to do better. Let us continue to consider how we can prevent or reduce any harm we might cause ourselves, our families, our communities and society. Let us stop HIV infection in people who use drugs and treat, care and support those that are living with HIV. Let us move towards a unified voice where public health and human rights are two sides of the same coin. Let us fight for a more just and equitable society for all people in all places.

Finally, let us continue to search for common ground with those who are not yet on what Michel Kazatchkine referred to earlier this week as “the right side of history”? Let us find the passion and compassion to talk to our so-called enemies, show them the way, and help them overcome their fear. Because as Nobel Laureate and human rights warrior Aung San Suu Kyi said:

“Fear is not the natural state of civilised people.”

Thank you.

Michel Kazatchkine

The Global Fund is the leading multilateral donor of harm-reduction initiatives-including methadone substitution, needle-exchange programmes and antiretroviral drug access-for IDUs worldwide. During his address to the conference, Kazatchkine said that drug use should be decriminalised to help curb the spread of HIV. “I am talking about decriminalisation of drug users,” he said, adding, “I am not talking about decriminalisation of drug trafficking, there should not be any misunderstanding. Drug users have been looked towards as criminals, they are arrested, harassed, they are imprisoned, they have no access to services, they are not respected in the very basic human rights perspective”.

Pratin Dharmarak, Thailand’s country representative for Population Services International, said that about 30% to 40% of the country’s estimated 200,000 IDUs are living with HIV. “Services for [IDUs have] been overlooked,” Pratin said. Thailand this year received $100 million from the Global Fund for HIV/AIDS efforts, some of which will be allocated to harm-reduction efforts among IDUs. However, because of next year’s funding shortfall, such programmes in the region likely will see reductions.

Source: kaisernetwork.org [21 April 2009]

http://www.kaisernetwork.org/daily_reports/rep_index.cfm?hint=1&DR_ID=58114

Taiwan’s HIV incidence declined to 1,752 new cases in 2008, compared with more than 3,300 in 2005 – nearly double the number recorded in 2004. Sheng Mou Hu, the country’s health minister at the time, said the success in reducing the number of new HIV cases can be attributed to the approach that “harm reduction should be based on human rights.”

The programme was launched in 2006 and includes elements like enhanced screening and monitoring of HIV-positive IDUs, a needle-exchange programme and methadone replacement initiatives. As a result, IDUs in Taiwan are presented to the public as “patients” who required medical attention rather than criminals.

Ton Smits, executive director of the Asian Harm Reduction Network, said, “No other country in Asia can match Taiwan’s achievement in launching and sustaining this harm reduction program.” He said that in most Asian countries, policies relating to drug control “are in direct conflict with HIV-related policy, undermining harm reduction programmes in the region.” He also noted that 3% of IDUs in Southeast Asia have access to harm reduction services and that such programmes are “facing a financial crisis,” with a 90% resource gap in 2009. Only 2% to 3% of all available resources for HIV/AIDS is spent on harm reduction strategies.

Some encouraging signs have been seen in other Asian countries – such as China, Malaysia, Thailand and Vietnam – that are beginning programmes similar to Taiwan’s that treat IDUs through public health approaches rather than law enforcement measures. IDUs still are listed as one of the most vulnerable groups in the region. According to IHRA, there are close to 16 million IDUs in 158 countries worldwide. Information released at the conference said that some estimates place the number of HIV-positive IDUs at three million, while others place it at more than 6.6 million.

Source: kaisernetwork.org [Apr 28, 2009]

http://www.kaisernetwork.org/daily_reports/rep_index.cfm?hint=1&DR_ID=58234

• Victory for maintaing the status quo

The High Level Segment (HLS) of the Commission on Narcotic Drugs (CND) ended mostly unobserved and unnoticed. The United Nations Office on Drugs and Crime (UNODC) is the operational arm of CND. In 1998, a UN General Assembly Special Session (UNGASS) on drugs was held in New York. Rallied by the slogan “A drug free world, we can do it”, the meeting set a number of targets to be achieved over the following 10 years. The March High Level Segment in Vienna was the culmination of a review of the last 10 years. The lead-up to the meeting saw the most rancorous debate ever experienced at a CND meeting. The HLS of CND culminated in the passing of a Political Resolution that was ostensibly achieved by consensus, but with 26 countries objecting to the omission of the words ‘harm’ and ‘reduction’ in paragraph 21 of the resolution, consensus was clearly a mockery.

The Political Declaration will be in place for the next decade. It is a non-binding document important in 2 ways. Without harm reduction being named in the Political Declaration, no approach is identified for working with active drug users, and there is no serious intent to include the views of drug users in the development of global drug policy. Preventing people from starting drug use, helping people end their drug use, and reintegrating them into mainstream society appear in the document, but absent is the most important population: people who use drugs. Secondly, many countries, the majority from the developing and transitioning world, are drafting national drug plans. The Political Declaration can serve as a blueprint for national governments, but with harm reduction ‘delegitimised’ by its omission, harm reduction practice and philosophy will remain absent from national plans also.

Many governments argued vociferously for inclusion of harm reduction in the Political Declaration but were opposed and undermined by the United States in collusion with Russia and Japan. However, the United States made one major concession by reversing its longstanding opposition to needle exchange. The US government has finally accepted the abundant science that needle exchange is an effective intervention to stop the spread of blood-borne HIV among drug injectors. This appears to be one area where the new administration refuses to play politics with people’s lives. During his election campaign, President Obama publicly endorsed the removal of the congressional ban preventing the use of federal funds to support needle exchange*. In a February 12, 2009 letter signed by US Ambassador Geoffrey Pyatt to the presiding Chair of the UNODC meeting in Vienna.

However, needle exchange does not appear in the Political Declaration.

In making its position known, the United States issued a statement supporting needle exchange but objecting to harm reduction on the grounds that the term is ambiguous. There was no corollary complaint that anti-corruption, drug prevention or drug treatment are also ill-defined in the Political Declaration. One can only be suspicious that this was a purely political manoeuvre.

Ten years ago, demand reduction was the controversial issue. This year it was accepted that demand for drugs needs to be addressed on par with the supply of drugs. Perhaps in ten years time, people who use drugs and harm reduction will also be accepted on an equal footing.

References:

http://www.whitehouse.gov/agenda/civil_rights/

Links:

http://www.ungassondrugs.org/

FAQ on the 2009 review of the 1998 UNGASS:

http://www.harmreduction.org/article.php?id=876

* In a historic move, the U.S. House of Representatives voted on July 24 to remove a 21 year old ban that has restricted the use of federal funds being used to support needle exchange programs. However the Senate retained the complete ban in its version of the budget. The possible removal of ban also has implications for U.S. support of needle exchange programmes in other countries. The vote was a surprise to some who had despaired after President Obama failed to remove language retaining the ban in the 2010 budget he submitted to Congress. The White House also removed President Obama’s campaign support for removing the ban from its website. In reality though, the win was thanks to the relentless efforts of harm reduction advocates in the United States, who worked district by district to mobilize constituents to lobby their representative.

Though the House of Representatives vote is a promising first step, the battle is not over. The ban contains a problematic provision prohibiting federal dollars from being used to fund programmes that operate within 1,000 feet of schools, daycare centers, universities, pools, parks and video arcades. While, on the face of it this may sound innocuous, in many districts, particularly in urban areas, this would stop needle exchange programmes from operating where services are needed most.

U.S.-based advocates are working to convince Congressional members to remove this provision when the bill goes to “conference” – the time when the House and Senate meet to iron out differences between the two versions of the bill, something that will likely happen in late 2009. Until that time, the ban remains in place.

Abstracts and webcasts can be accessed via the conference website at the following link: http://www.retroconference.org

The following reports from the conference are included in this issue of ARV4IDUs:

• Waning of virological benefits following directly administered ART among drug users: results from a randomised, controlled trial
• Effect of substance abuse on ART pharmacokinetics
• HIV among IDU in Almaty, Kazhakstan: driving forces and implications for HIV treatment – a personal view

The study had a very innovative and interesting design. It was a community-based, prospective, randomised controlled trial of 6 months of DAART compared with self-administered therapy.

The primary endpoint was the proportion of participants with a virological suppression after 6 months post intervention, defined as achieving either a ≥1.0 log reduction from baseline or HIV-1 RNA <400 copies/mL. Secondary endpoints included change in CD4 count.

The DAART group (n=88) was more likely to have a virological success (70.5% vs 54.7%, p=0.02), mean reduction in HIV-1 RNA level (-1.16 vs -0.29 log copies/mL; p=0.03) and a change in CD4 count (+58 vs –24 cells/mm3; p=0.002).

After further 6 months, however, when all subjects received HAART as self-administered therapy, the DAART (n=82) and self-administered therapy (n=52) arms did not differ on virological success (DAART 58% vs self-administered therapy 56%, p=0.64), mean reduction in viral load (–0.79 vs –0.31 log copies/mL, p=0.53), nor mean change in CD4 lymphocyte count (+60 vs –15 cells/mm3, p=0.12). Statistically, in the multivariate analysis, only high levels of social support significantly predicted virological success.

Researchers suggest that “a longer DAART duration or incorporation of self-efficacy or social support components, which may provide durability to this otherwise effective intervention” may be necessary to improve the clinical outcomes among HIV-positive IDUs.

References:
Smith-Rohrberg Maru D et al. Waning of Virological Benefits following Directly Administered ART among Drug Users: Results from a Randomised, Controlled Trial. 16th CROI, 2009, Montreal. Abstract 579.
http://www.retroconference.org/2009/Abstracts/35670.htm

This study looked at a group of 275 patients, 47% of whom were active users of at least one substance (heroin 2%; cocaine 7%; marijuana 13%; tobacco 43%; alcohol 22%; prescription opioids 14%). It was found that a significantly higher proportion of substance users had antiretroviral trough concentrations below the therapeutic range (23% vs 9%, p=0.048). The proportion of patients with an unfavourable treatment outcome (HIV RNA >75 copies/ml) was significantly higher in the substance user group than in the non-user group (40% vs 28%, p=0.044). However, when adjusted for race, substance abuse was no longer associated with virological response.

References:

Ma Q, et al. Comparison of ART pharmacokinetics and clinical monitoring parameters in HIV-infected patients with and without substance abuse. 16th CROI, Montreal, 2009. Abstract 698.

http://www.retroconference.org/2009/Abstracts/35802.htm

I’m taking you to a different part of the world, to Kazakhstan in Central Asia. Before I begin, I want to say that there are not much data in the region and I worked very hard to get data to present at this conference, although I have been working there for almost 6 years. As you see from this map, Kazakhstan is in Central Asia and it has borders with China, Russia, other Central Asian countries and with Afghanistan, which produces the drugs I’m going to talk about. Kazakhstan has 15 million people and a territory of 2.7 million kilometers. It’s really the largest country in central Asia and in fact is the 9th largest country in the world. What I’ll be doing in this presentation, I’ll talk about HIV epidemic in Kazakhstan and I’ll highlight two cities, Almaty and Temirtau, greatly affected by the HIV epidemic. I’ll talk about the forces that drive the HIV epidemic in Central Asia and specifically Kazakhstan and finally, I’d like to talk about what needs to be done in the region to deal with the epidemic.

Let me begin by saying that Kazakhstan as a country has a relatively low prevalence rate of HIV, however, in the past several years, Kazakhstan has been experiencing a very high incidence of HIV and is one of the fastest growing epidemics of HIV in the world. As you see from this figure, the rate of HIV in 2002 was 0.05% and in 2007 is greater than 1%. The number of people living with HIV in Kazakhstan as of 2007 is 12,000. However, it’s tripled since 2001. As you see in this figure, every year, there are more and more cases of HIV in Kazakhstan and I’d like you to pay attention to 2005, when there were less than 1000 cases and it’s doubled in 2007 as you see here 1979 cases. The good news about Kazakhstan is the increased number of people who are tested for HIV. If you look at 2005, there were less than 1 million people tested for HIV. In 2007, 12% of the population (1.8 million) in Kazakhstan have been tested for HIV. Recent data shows that the number is closer to 2 million.

It says that there are 350 people who’ve died from AIDS but the estimates vary; elsewhere it says 600 people have died from AIDS. What I’d like to focus on is drug use. As you see from this figure, drug use accounts for more than 73% of HIV cases in Kazakhstan. According to data, there are 53,000 individuals registered to be DU. But this number is in fact not true. It’s estimated that there are 120-200,000 drug users in Kazakhstan, and it’s further estimated that the rate of HIV varies between 1-4% of the population.

When you talk about Almaty, the former capital of Kazakhstan, affected greatly by HIV as well as Temirtau, in the north of Central Asia and it’s a factory city. Almaty has 1.3 million people, has 8,000 registered drug users and has an estimated 30,000 drug users not only registered but total. There are HIV drug users around 1,500 and the rate of HIV among drug users is 5%. Temirtau has 170,000 people, 650 registered drug users (4700 estimated RDU), HIV+ drug users is 1677 and the rate of HIV among drug users is 19%.

Here I’d like to share with you the prevalence rate of HIV among drug users in Kazakhstan, both in Almaty and Temirtau. As you see in this figure, the rate of HIV in country in 2005 was 3.4% and in 2007 it became 3.9%. And if you look at Almaty, it started at 2.1% in 2005 and moved to 5% in 2007. In Temirtau in 2005, as you see here, it was 17% and moved to 19.3% I don’t know what happened in 2006.

Prevalence rate of syphilis among DU is quite high in K, A, and T. AS you see here, the country prevalence rate of syphilis is 11%, in Almaty 8.2% and Temirtau 12%x percent. Also the prevalence rate of HCV among drug users is quite high. In the country, that rate is 66%, 77.1% in Almaty and 76% in Temirtau. Coinfection. Kazakhstan has the highest incidence of TB in the world (CDC 2008), especially for multi-drug resistance. In 2007, the incidence rate was 132 per 100,000 and TB mortality rate was 18.2 per 100,000. 14% of all new cases are MDR (CDC 2006). I’d like to share with you data showing that coinfection is low but more research needs to be done about this issue. As you see from this figure, there are 220,904 TB patients, among whom the HIV coinfection rate is .5% Among 9379 HIV+ patients, coinfection rate is 11%. The data doesn’t reflect what’s happening because TB is a serious issue in Kazakhstan. TB and HIV coinfection rate likely to rise as drug use continues; coinfection requires immediate attention.

Here it shows that access to ARV started in 2005. According to recent data showing that in 2005, 25% of people who needed treatment received it. In 2006 it increased to 31%. In 2007, 41% of those who needed treatment received it. There is a debate around this data and there is another story that the percentage is a lot lower than what I’ve presented here. Overall, 422 people received treatment for HIV in 2007 (Republican AIDS Center), also data showing that 50% of those treated are drug users (205) and national data showing that adherence to treatment showing between 50-70%. I would like to also comment on this data, I looked hard to find this data because adherence, or definitions to adherence, are not well defined. For this kind of data, adherence means that someone stayed in treatment for one year (UNAIDS 2008).
Now I want to move to talk about the forces that drive the HIV epidemic among drug users in Kazakhstan:

• Availability of drugs that come from Afghanistan
• Drug trafficking in Central Asia and particularly in Kazakhstan.
• Limited access and barriers to drug treatment as well as to HIV prevention

Drugs come to Kazakhstan from 10 different routes from Afghanistan. Drugs get easily to the region and is heavily affecting the HIV epidemic in the region. I want to give you a sense of what I mean; if you look at this figure, you see that in 2007, 93% of global drugs comes from Afghanistan and 50% traffick through Central Asia and heavily through Kazakhstan. If you look at this figure and this sad story, in 2001, 12% of global drugs came from Afghanistan whereas you see here in this figure of 2007, 93%. If also you look at opium production in metric tons, you’ll see that in 2007, 8200 metric tones of opium produced; compare it even with 2005, it was 4100 metric tons. And you see how the region is affected by drugs. This is another way to give you a sense of the opium cultivation in Afghanistan. In 2007, almost 200,000 hectares were cultivated of opium; this represents a 17% increase even from the previous year (if you look at the data, it tells you a story of what’s happening in the region). Also, data that was really fascinated with the findings; it is estimated that 100-120 tons of drugs was trafficked through Kazakhstan in 2006. Usually, 11% of drug trafficked through the country stays in Kazakhstan, which means it is estimated that 10-12 tons of drugs remain in Kazakhstan and used by the people there.

Another reason I want to talk about why we still see the HIV epidemic increasing among drug users. There is a low number of needle exchange programmes in the region. Overall, 146 in the whole country but most are housed in medical facilities where IDU don’t feel comfortable going; they’re stigmatised, not respected, not treated well. Only 29% of IDUs in Kazakhstan attend needle exchange programs. There are other problems in SEPs that prevent people from going there. SEP have difficulty obtaining a regular supply of syringes and there is no formal protocol for syringe collection in those programs. Sadly, there is limited distribution of HIV prevention services, even condoms, you don’t see them in needle exchange programs.

Drug users really have one option, which is to go to detoxification. No drug rehabilitation, no substation therapy, very limited access to HIV prevention. One other thing we need to understand when we talk about the epidemic among drug users is that DU are repeatedly subjected to arrest by the police and forced to go to detoxification unit. If you look at the number of prisoners who are drug users in Kazakhstan, it has been increasing tremendously. There is data showing that of the 100,000 prisoners in Kazakhstan, 60% are drug users. Another thing we need to look at in context of HIV prevention is that drug users are required to register. Anyone who has attended drug treatment or arrested must register. Registrations lead to restrictions in employment and prevent them from accessing any kind of treatment. Also, there is harsh penalties for possession of very small amount of drugs. Recently, I was talking to a drug user serving a 3-year prison sentence for carrying less than 1 gram of heroin.

So what do we need to do to deal with this huge, growing epidemic in the region? Clearly, there is a need to increase drug treatment programs. We need to focus on substitution therapies and promote 12-step programs. I met with some drug users recently who are really looking forward to starting 12 step programmes because they believe in the concept that it can help them to stay health. Also, there’s a need to increase the number of needle exchange programmes and make them accessible to drug users in the country and ENSURE distribution of condoms and other HIV prevention services. It is sad to see how drug users in the country would like to get access to condoms and no access to condoms, even in NEP where we expect drug users to have access to them.

Adherence to treatment – there’s so much to be done! As I presented earlier, I personally do not believe much in the numbers I presented. I would say that a lot of research should focus on understanding access to treatment as well as adherence to treatment. We talk about scaling up HIV prevention and this is a place where we really need to focus on prevention strategies like peer education and psychosocial HIV prevention strategies. Given that the epidemic is a concentrated one among drug users and clearly, the transmission from DU to their sexual partners is huge, I would like to recommend – and I have been talking about – this approach of working with the couples. It’s very important to come up with HIV prevention intervention that addresses the couple as a unit and focus prevention on that unit; concurrently develop interventions for sex workers. Another issue I’d like to focus on, and needs to be done immediately in Kazakhstan, is the elimination of the registration of drug users. I mentioned earlier that registration is a HUGE barrier that will prevent drug users from accessing treatment. Secondly, eliminate the punitive approaches used by the police against drug users. One point I’d like to make is the need to scale up HIV prevention in prison. Prisoners are in and out; the HIV prevention strategies in prisons are very rare, almost nothing is happening in prisons for drug users.

And I want to mention something I don’t have here, when I was looking at how the epidemic is concentrated in Kazakhstan, among which population and you see all the research that it’s limited – it’s about drug users, about sex workers (60,000 and 2/3 are drug users and no treatment and no approach to HIV prevention for this population) and the third group that I was looking for data on is men who have sex with men. According to the data from K, there is 100,000 MSM – when I was looking at the rate of HIV among this population, the response was 0 percent prevalence. A lot needs to be done not only in scaling up research and treatment but also research to better understand precisely what’s happening in the region.

References:
El-Bassel N and Terikbeyeva A. HIV among IDU in Almaty, Kazhakstan: driving forces and implications for HIV treatment. 16th CROI, 2009, Montreal. Abstract 60. http://www.retroconference.org/2009/Abstracts/36541.htm

This presentation is available online as a webcast as part of the symposium: A Tale of 4 Cities held on Monday 9 February 2009, 4pm. http://www.retroconference.org/2009/data/files/webcast.htm

Introduction

The International AIDS Conferences are held every two years, and alternate between a developed and a developing country. Approximately 25,000 people attend and over 4,500 research studies are presented.

This year the conference had very few new scientific advances in terms of new drugs or treatment strategies, but it did have a few controversial studies. These large conferences focus more on epidemiology, prevention, policy, access to treatment and issues relating to social exclusion (drug users, sex workers, MSM, gay men, young people, sexual violence, women’s rights, etc). These issues are covered in tracks C, D and E of the programme. Tracks A and B cover basic science and clinical science respectively.

Conference abstracts (reduced summaries of each study) are all available online, as are many of the powerpoint slides, web casts, transcriptions and daily ‘rapporteur’ summaries. Abstracts are accessed via the online conference programme. At the bottom of each daily programme (you need to scroll right down to find the abstract session) is a link to the searchable database.

As it is difficult to find, this is the direct URL for the posters
http://www.aids2008.org/Pag/PosterExhibition.aspx?presType=PE&D=04&S=621

For the programme
http://www.aids2008.org/Pag/PAG.aspx

This i-Base report includes references to a range of studies – from major presentations and large studies, to overview summaries and to examples of single posters. It is not meant to cover everything that happened, but to give an overview of some of the key themes.

Hyperlinks are either directly to the abstracts or to appropriate programme pages that include further links to abstracts, powerpoint slides or webcasts and abstracts.

A summary of the transcription from the talk is included below – but better still, get to a broadband internet connection and watch it first-hand.

Plenery Session, Day 2:
http://www.aids2008.org/Pag/PSession.aspx?s=32

Adeeba Kamarulzaman

I started life as an AIDS physician, and I still am, and every day I am confronted with patients such as this.

This is an x-ray of a 35-year old man with extensive TB who presented to me approximately three months ago, in severe respiratory failure and metabolic derangement. We were unable to do anything for him, and within two days of admission, he passed away.

This is just one example of a patient who succumbed who, because of the failure of the Malaysian government to implement harm reduction measures 20 years ago.

Many of you see similar patients daily because at the recent estimation, there are approximately 11 million injecting drug users around the world, of whom more than 3.3 million are infected with HIV, and even more infected with hepatitis C virus. We know that outside the sub-Saharan Africa, 30% of HIV infections are due to injecting drug use and in Asia, the region I live, and in Central and in Eastern Europe, injecting drug use is the main drivers of the HIV epidemic.

The situation is even worse in prisons where the prevalence of HIV is more than 4 to 10 times the general community. And we know that prisons are an incubator that makes transmission of HIV and other infectious diseases, particularly tuberculosis, a lot worse. In the words of my colleague, Rick Altice, prison is like a semi-permeable membrane which with prisoners going in and out to the community, the HIV and other infections that occur within prison, then go out into the community and back into the prisons as the prisoners come back into the system.

Drug users do not live in isolation. This complex diagram from Bangladesh showing the social and sexual network of injecting drug users shows how injecting drug use can quickly fuel the HIV epidemic within the HIV community and eventually into the general community.

Now, we know that drug use is a chronic and relapsing disease for many years, the argument for or against harm reduction to prevent HIV transmission should be long over.

Extensive, scientific evidence for the effectiveness of opiate substitution therapy and needle exchange therapy have been done over the last 20 years. Review after review, including two reviews by the Institute of Medicine in the U.S. have shown the effectiveness of harm reduction measures. Immediate action needs to be taken to slow the spread of HIV amongst injection drug users using multiple approaches, as was the conclusion of the review by the Institute of Medicine in 2006.

WHO and UNAIDS have also endorsed harm reduction in their policy briefs since 2005. Yet, out of the 158 countries that have injecting drug use, only 77 countries have implemented needle exchange. Even fewer countries have opiate substitution treatment with less than a million people globally receiving opiate substitution therapy.

So what is stopping us? Unfortunately, in the last few decades, criminalisation of drug use and law enforcement have taken over the health issues of drug use. Dominance of law enforcement over health takes over harm reduction, and moral and religious frameworks are linked to prohibition. Treatment, when it is available, is often geared towards abstinence and a drug-free environment.

Conflicting policies coming from the UN organisations often sends countries confused messages. The UNGASS on AIDS in 2005 emphasised the importance of “ensuring wide-range prevention programs and commodities, including condoms and sterile injecting equipment, and harm reduction, if it is related to drug use”. However, in Vienna, the UNGASS on drugs has said, since the Vienna Convention in 1988, to “establish stricter obligations to criminalise all aspects of cultivation and production, distribution and possession of illicit drugs”. No wonder many countries are confused.

A large percentage of countries report laws, regulations and policies that present obstacles to services for injecting. Recent reports for UNAIDS show that, especially in countries that need it most, there are many, many countries with laws that prohibit harm reduction.

The presence of laws that criminalise drug use, not only prevent access to much needed harm reduction measures, but most often, also leads to outright abuse of human rights. A recent raid in Cambodia led to many people, including non-drug users and children, being behind bars.

Funding for effective HIV prevention including harm reduction measures is abysmal, highlighted by a recent UNAIDS report from the recent Global AIDS update. Even in countries that have embraced harm reduction, the National Drug Policy funding goes mostly towards enforcement. In the Canadian Federal National Anti-drug strategy, funding for harm reduction is a mere 2% compared to 70% for enforcement.

I am moving on to treatment—opiate substitution treatment. The WHO says that medicines that satisfy the priority of healthcare needs of the population are criteria for medicines to be included into the essential medicines list. And they are selected with due regard to disease prevalence, evidence on efficacy and safety and comparative cost effectiveness. They are intended to be available at all times in adequate amounts.

Methadone and buprenorphine were listed in this list in 2005. However, in many countries, these two drugs, which are essential components of the harm reduction program, remain illegal, or unavailable. A report in the New York Times (on 22 July 2008) describes how Russia, up until now, does not make methadone available for its severe heroin problem.

In most instances, evidence-based treatment is put aside for treatment based on incarceration and punitive actions (which have no evidence base), as can be seen in pictures here from Malaysia, Russia, and Myanmar.

All is not bad. There has been progress, including in my own country where the government allowed for the implementation of harm reduction programs, including opiate substitution therapy and needle exchange. Since 2005, we have more than 22,000 drug users on opiate substitution therapy, 11 needle exchange sites (including seven that are funded by the government) with more than a million needles and syringes distributed up to June 2008. More recently, we have also introduced pre-release prison methadone programmes in our prison system.

In China, the roll-out for harm reduction is very fast, as only the Chinese could do, with 88,000 people on methadone maintenance therapy, and 50,000 injecting drug users receiving needle syringe services, as of October 2007.

In the Islamic Republic of Iran, there are now 600 addiction clinics including 132 methadone clinics. Between 100,000 to 130,000 people are on methadone maintenance therapy, including a very large number of prisoners. More recently, they have even introduced automatic vending machines offering sterile syringes and condoms.

At this point I would like to take a minute of my presentation to appeal to the Government of the Islamic Republic of Iran to release Arash and Kamiar Alaei from custody and the charges that have been brought upon them.

I have met the brothers on many occasions and had the opportunity to visit your beautiful country as a Faculty member of the HIV/TB training course for the region that they organised. It was through the inspiration that was gained by the visit to your country that the Malaysian Prison Department has implemented opiate substitution therapy in the Malaysian prison system. As a fellow Muslim, I appeal to the leaders of the Islamic Republic of Iran, in the name of Allah the Most Merciful and Compassionate, to release these brothers immediately.

If access to opiate substitution therapy and needle syringe programs is problematic, excess to antiretroviral therapy is equally abysmal. A review conducted by the WHO European region, showed, for example, that 83% of the HIV reported cases in Eastern Europe are injecting drug users, but only 24% of people on HAART are injecting drug users. These kinds of statistics are seen in many, many regions of the world, including Asia.

Why is this? Barriers to access can be sociopolitical, social marginalisation and the continued criminalisation and stigma and discrimination of drug users. Individual barriers including fear of side effects, psychiatric illness, homelessness, lack of trust, addiction and addiction related instability and ask the medical community equally at fault with our own perceptions and prejudice against drug users.

In an ideal world, we would like to see the integration of HIV treatment with opiate substitution therapy, tuberculosis, hepatitis C, and mental illness. Unfortunately, these kinds of services only occur in very, very select sites around the world.

If we continue to reject harm reduction it will be at a huge cost. For instance, in the US, where harm reduction is widely rejected at home, but also in countries where it financially supports health programmes.

In the US, 25-33% of injecting drug users are HIV-positive. In contrast, in Australia, where harm reduction was adopted in the early 80’s, this figure is only 3-6%.

We need to stop arguing about the merits of harm reduction and just do it. We need to expand coverage in countries where this is currently not a priority. We need to raise funding for health measures at the same level as law enforcement. We need to harmonise public security and health policies, and lastly we need to integrate prevention and treatment services. We need to do all this based on science, public health and human rights.

Now ladies and gentlemen, while we sit here and argue, and while we sit here and collect statistics of drug users becoming infected with HIV and hepatitis C, I would like to share with you something that I think brings home to all of us that drug users are people like you and me. They are somebody’s son, somebody’s brother, somebody’s daughter. This is a documentary that was done by the BBC more than 15 years ago, but the messages that it brings, I think is relevant until today.

The video shows the anguish of this mother over her son’s drug addiction. Thank you.

Several oral presentations on IDU issues relating to treatment were included in a symposium on IDU and global responses.

Eric Goosby from University of Califaornia, San Francisco provided an evidence-based review of clinical treatment considerations for IDU, including ARVs as effective and life saving treatments, that recognised drug addiction as a chronic progressive relapsing condition and a treatable medical problem. [1]

Factors driving the importance of this emphasis on IDUs include drug use being the globally the second most prevalent risk behavior associated with HIV transmission, later stage of presentation of IDUs to medical services, co-morbidities, and adherence difficulties associated with active psychoactive substance use and untreated co-morbid mental illness. He also stated that IDUs in western countries have high rates of HIV risk behaviors with 90% sexually active in previous year, 20% reporting having sex with >5 sexual partners and low rates of condom use (9% to 34%).

Unique aspects of management of care include recognising existing prejudices from the medical system and social and legal differences especially when they over lap with prison populations.

Medical Schools do not always emphasise the complex medical and psychosocial aspects of the HIV-positive IDU, where relapse rates for addiction are high at >75-97%. Empathy, and a nonjudgmental approach are critical in obtaining a comprehensive and accurate personal and treatment history. Understanding that the addiction may involve multiple substances makes history taking more complex, but this is important because the use of stimulants and alcohol are associated with increased sexual activity.

Specific history should include substances used, route of administration over time (IV, sc/IV, intranasal, inhaled, oral, anal, other), pattern of use (amount, frequency, most recent use, needle sharing), treatment history, both outpatient and inpatient.

Medical complications of substance use include needle-induced (viral, bacterial, fungal infections, peripheral vascular disease); drug-induced (overdose, withdrawal, organ-specific complications e.g.,nephropathy due to heroin, cardiac ischemia due to cocaine, gastrointestinal, cardiac and neurologic disease due to alcohol); and major coinfections (TB. HBV, HCV and other STIs). Social complications include unemployment, family disruption, legal problems and homelessness.

Many effective risk reduction strategies already have a strong evidence base. These include: syringe exchange programs; opiate substitution therapy (OST) (methadone/buprenorphine maintenance which all have better outcomes when combined with cognitive behavioral therapy, motivational enhancement techniques or contingency management); peer-driven interventions; community outreach; risk reduction counseling; and diagnosis and treatment of mental illness. Methadone for example can reduce injecting drug use by 40% and use of shared equipment by 75%.

It is important to have a versatile and opportunistic approach which, for the most part, should come from the patients’ preference and that ‘one single approach does not always apply to the medical presentation’. Sometimes reducing drug use is more important that treating any psychiatric condition and sometimes vice versa, though both need to be addressed in order to optimise treatment of HIV or other illnesses.

The presentation then outlined management of a range of OIs and coinfections, all generally more prevalent in HIV-positive IDUs including bacterial Infections (>4 times higher than HIV-negative IDUs), TB (IDU increased risk and HIV worsens outcome), hepatitis (common and higher risk in IDU), STIs, HTLV-1 and 2, cancer (more aggressive), before reviewing approaches to HIV treatment. The presentation also included an overview of interactions between methadone and ARVs and other medications that is summarised in Table 1.

Table 1: ARV interactions with methadone

ADD TABLE

The presentation concluded with three summary points relating to provider-patient interactions:

• The physician/provider attitude related to drug abuse is critical to the development of a trusting relationship.
• Providers who openly diminish the needs, complaints, requests of addicted patients are most often excluded from decisions that impact the patients ability to maintain adherence or enter care.
• Despite multiple and repeated documentation of the efficacy of drug treatment programs, care givers and politicians often view treatment programs as ineffective.

Principles to enhance physician-patient relationship include: mutual respect (educating the patient about HIV and addiction, recognising the effects of continued drug use, the impact on adherence, and transmission. Providers need to acknowledge that patients can benefit from drug treatment and HIV treatment.

References
This presentation was part of a symposium on issues important to a global response relating to injecting drug use: Injecting Drug Use and Infectious Diseases: Implications for the Global HIV/AIDS Response (An IAS/IDSA Partnership). Symposium TUSY06.
http://www.aids2008.org/Pag/PSession.aspx?s=18

1. Eric Goosby. Comprehensive care for injecting drug users: Syringe exchange, methadone and HIV care and treatment. Abstract TUSY0601.

Another talk in the IDU symposium was given by Frederick Altice from Yale University and looked at management of staphylococcal infections among IDUs. [1]

As an introduction, Professor Altice emphasied that skin and soft tissue infections are the leading cause for emergency room visits and hospitalisations for IDUs, with S aureus & S pyogenes the most common pathogens. [2] S aureus nasal carriage occurs in ~20% of people and associated with development of community- and nosocomial-acquired S aureus infections. [3, 4] IDUs have a higher rate of S aureus colonisation than the general population and is associated with subsequent infections in IDUs, [3, 4, 5]

An overview of risk factors and the relationship to HIV was summarised from a published paper form 2002. [6]

Skin and soft tissue infections (SSTIs) among IDUs include local (cellulitis & abscesses) and necrotising (complicated abscesses, necrotising fasciitis, pyomyositis, myonecrosis) infections. They are related to local tissue trauma as a direct effect of injecting drugs, tissue ischemia and inoculation of bacteria.

A recent study identified several potentially modifiable risk factors for SSTIs in injection drug users. The practice of injection directly into skin or muscle when veins are no longer accessible (“skin-popping”) is the strongest risk factor for abscess, followed by use of dirty needles and injection of a mixture of heroin and cocaine (“speedball”). The practice of drawing blood into the syringe before injection drug intravenously, known as “booting,” seems to be a risk factor in those who do not engage in skin-popping. The only protective factor identified was cleaning skin with alcohol before injection. Women may be at greater risk for SSTIs, presumably because they may have greater difficulty in accessing their veins.

The mechanism by which infection is established probably relates to tissue trauma, direct effect of drugs, tissue ischemia, and inoculation of bacteria. As a result of repeated injections into a single site, skin and surrounding tissue are damaged, develop local ischemia and necrosis, and become susceptible to infection. The drugs and diluents themselves may compound the tissue injury by causing vasospasm and thrombosis. Cocaine, in particular, has been associated with these complications.

Infecting organisms may come from the skin surface, contaminated needles, or saliva when the injection needle is licked or tablets are crushed between teeth before injection. Although one study suggested the drug itself might be the source of infecting bacteria, most other studies failed to establish this association. A recent outbreak of a clonal strain of group A streptococcus in Switzerland may have been caused by contaminated drug containers or by contaminated cocaine, but investigators were unable to prove that either was definitely the source.

Infection with HIV has been recognised as a risk factor by some but not all investigators. Immune disorders may contribute to injection drug users’ predisposition to infection. Recent evidence for the expression of opiate receptors on immune cells, specifically receptors for morphine and the metabolites of heroin, support a connection between opiates and immune function. Opiates suppress several T-cell functions important for cell-mediated immunity and also inhibit phagocytosis, chemotaxis, and killing by polymorphonuclear neutrophil leukocytes (PMNs) and macrophages in humans. This impairment of phagocytosis and killing may be an important additional cause for the frequency with which injection drug users present with SSTIs caused by common bacterial pathogens.

Invasive infections among IDUs (most commonly is S aureus > Strep > GNRs) usually include bacteremia from local source (lungs, SSTIs), endocarditis and osteomyelitis. Endocarditis more likely to be right-sided among IDUs than among non-IDUs and duration of antibiotics is prolonged though shorter duration may be possible for right-sided infections.

MRSA has increased significantly in North America, accounting for 0ver 40% of ICU infection. When hospital-acquired (h-MRSA) it is plasmid-mediated, not associated with toxin production, associated with recent hospitalisation and use of antibiotics and highly resistant to most oral antibiotics, except linezolid. By contrast, when community-acquired (c-MRSA) it is chromosomally-mediated, associated with toxin production (Panton-Valentine leukocidin) and person-to-person transmission that is not associated with traditional risk factors [IDUs, sexual contact and crowding - ie athletes, prisoners, homeless shelters, day care centers). It also remains sensitive to many oral antibiotics (TMP/SMZ, tetracycline, etc).

Staphylococcal colonisation among IDUs is also increasing. A survey in 2000 to detect methicillin-resistant Staphylococcus aureus (MRSA) colonisation in Vancouver downtown east side injection drug users (IDUs) revealed an MRSA nasal colonisation incidence of 7.4%. This is a follow-up study to determine the current prevalence of MRSA colonisation and to further characterise the isolates and risk factors for colonisation. S. aureus was isolated from 119 of 301 (39.5%) samples; three (2.5%) participants had both methicillin-sensitive S. aureus (MSSA) and MRSA, resulting in 122 isolates. Of these, 54.1% were MSSA and 45.9% were MRSA, with an overall MRSA rate of 18.6%. USA-300 (CMRSA-10) accounted for 75% of all MRSA isolates; 25% were USA-500 (CMRSA-5). The antibiograms of USA-300 compared to USA-500 isolates showed 100% versus 7.1% susceptibility to tri- methoprim-sulfamethoxazole (TMP-SMX) and 54.8% versus 7.1% susceptibility to clindamycin. MRSA nasal colonisation in this population has increased significantly within the last 6 years, with USA-300 replacing the previous strain. Most of these strains are PVL positive, and all were susceptible to TMP-SMX.

In a 2001 analysis of a methadone (MM) and heroin (HM) maintenance programme in Basel, nasal carriage higher in MM (43%) than in HM (23%) patients. There was difference in recent or remote hospitalisation, MM subjects were more likely to have used antibiotics in previous month (12% vs 4%), to be HIV-positive (20% vs 6%) and have no IDU (34% vs 0%). In multivariate analysis, enrolled in MM was the only significant (AOR 2.27) correlate of S aureus colonization. No MRSA was isolated but subsequent studies have demonstrated MRSA transmission between drug users and introduction of new MRSA strains. [6]

A recent (2008) case-controlled study of 60 hospitalised opioid dependent (OD) and 60 non-drug users in Egypt, reported that colonization was higher in drug vs. non-drug users (30% vs 10%), an increased risk associated with duration of drug use and use of non-prescription antibiotics and that 58% of active MRSA infections associated with colonisation. [7]

MRSA colonisation persists for years, despite treatment of infection. contact precautions and isolation of wounds are recommended but universal screening, isolation and eradication of the carrier state remain controversial.

In summary, the following five points were outlined.

• IDUs exist on all continents and are more likely to be colonised with S aureus.
• Morbidity and mortality related to S Aureus infections is greater among IDUs.
• Colonisation with S aureus, including MRSA, is associated with increased risk for infection.
• Infection can be reduced with skin cleaning and sterile syringes.
• MRSA prevalence is variable but growing in different regions of the world, thus requiring increased surveillance to guide clinical practice.

References
This presentation was part of a symposium on issues important to a global response relating to injecting drug use: Injecting Drug Use and Infectious Diseases: Implications for the Global HIV/AIDS Response (An IAS/IDSA Partnership). Symposium TUSY06.
http://www.aids2008.org/Pag/PSession.aspx?s=18

1. Frederick Altice. Staph infections in intravenous drug users. Abstract TUSY0603.
2. Palepu A et al. Hospital utilization and costs in a cohort of injection drug users. CMAJ August 21, 2001; 165 (4).
http://www.cmaj.ca/cgi/content/abstract/165/4/415
3. Kluytmans J et al. Nasal carriage of Staphylococcus aureus: epidemiology, underlying mechanisms, and associated risks. Clin Microbiol Rev. 1997;10:505-20. [PMID: 9227864]
4. von Eiff C et al, Nasal Carriage as a Source of Staphylococcus aureus Bacteremia. NEJM 2001 Volume 344:11-16. (4 January 2001).
http://content.nejm.org/cgi/content/abstract/344/1/11?ck=nck
5. Bassetti et al. Staphylococcus aureus infections in injection drug users: risk factors and prevention strategies. Infection 2004 Jun;32(3):163-9.
http://www.ncbi.nlm.nih.gov/pubmed/15188077
6. Fleisch F et al. Transregional spread of a single clone of methicillin–resistant Staphylococcus aureus between groups of drug users in Switzerland. Infection, 2005.
http://www.springerlink.com/content/n8205g8169770204/
7. El-Sharif A, Ashour HM. Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) colonization and infection in intravenous and inhalational opiate drug abusers. Exp Biol Med, 2008 Jul;233(7):874-80.
http://www.ncbi.nlm.nih.gov/pubmed/18445771

Jens Lundgren from the INSIGHT research group presented an analysis of nucleoside toxicity and cardiovascular disease from the SMART treatment interruption study. [1]

This issue was one of the most discussed clinical topics of the meeting as GSK also presented an analysis from their trial database. [3]

In February 2008, the D:A:D study showed an increased risk of cardiovascular risk from current or recent use of abacavir – a finding that was unexpected and challenging for people skeptical of a cohort study identifying a new effect with an as yet unexplained mechanism. [4]

Cautious reactions to the D:A:D results looked for validation from other studies which were not allayed by GSK’s more limited dataset, originally published as a letter to the Lancet. [5]

The SMART researchers analysed patients in the continuous treatment arm of SMART, by use of NRTIs relating to the previous D:A:D findings: using abacavir (but not ddI) n=1019, using ddI (but not abacavir) n=643, and other NRTI combinations with netheir abacavir nor ddI (n=2882). Baseline characteristics of these three groups were similar, including common cardiovascular risks (~4% prior CVD, 40% current smokers, 35% ischemic abnormalities and 7% diabetic). Lipid lowering drugs and blood pressure medications were each used by just under 20% of patients. 15% patients had >5 cardiovascular risk factors.

In multivariate analyses adjusting for CVD risk factors, all four categories of cardiovascular disease defined by the group showed increased hazard ratios (HR) for abacavir compared to other NRTIs (see Table 1).

Table 1: Adjusted HR of cardiovascular event with abacavir use vs. other NRTIs in SMART

Importantly, the results were similar when patients receiving tenofovir were used as reference group and when the approximate 10% of patients with events in both D:A:D and SMART databases were excluded from the analysis.

The SMART study also showed a strong association between elevated levels of some inflammation biomarkers with levels of viral load rebound and risk of serious event. In this analysis, patients using abacavir had D-dimer and IL-6 that were 27% and 16% higher at study baseline than patients in the reference group using other NRTIs (both p=0.07).

These levels could have been higher for reasons unrelated to abacavir use and will need to be examined in a study looking prospectively at changes in these biomarkers in patients starting abacavir. Interestingly, the HEAT study from GSK reported reductions in hs-CRP and IL-6 in both the abacavir/3TC and tenofovir/FTC over 48 and 96 weeks with no differences seen between the two arms. [2]

Similar to D:A:D, the clinical significance from abacavir use was greatest in patients with the highest underlying cardiovascular risk factors. Those patients with five or greater cardiovascular risks or ischemic abnormalities on ECG showed three-fold increased risk from using abacavir compared to other NRTIs (both HR 3.1).

Earlier in the conference, GSK, reported that their retrospective meta analysis from 54 phase 2 and 3 abacavir registrational studies did not find an association between cardiovascular events and either abacavir or non-abacavir use. [3]

While this was important from a regulatory perspective – any safety signal requires a company to look at their own dataset – the limitations of both this database and the presented analysis were unlikely to resolve the concerns highlighted by D:A:D and SMART.

Of the 54 trials, only 13 were randomised for abacavir use, 33 included abacavir in background regimens and 8 did not include abacavir. Just over 14,000 adults and 500 children were included. Events were identified by a search for cardiovascular-related events and rates in naïve and experienced patients were calculated per 1000 person years.

No differences were seen in the relative rates by abacavir use for any cardiovascular event (RR=0.59; 0.35-1.01; p-value=0.055) or any MI (RR=0.863; 0.40-1.86; p=0.706).

Myocardial infarctions (MI) were only identified in 16 patients using abacavir (10 using non-PI and 6 on PI-containing regimens. Of the 11 MIs in the non-abacavir group, all used PI-based regimens except for one patient using an NNRTI-based combination.

Several limitations were raised concerning this data. Firstly, that there were too few events to have statistical power to detect an association either way. Many cardiovascular risks were not recorded at baseline, including smoking status, hypertension, HDL and LDL. Patient numbers were much lower (~7000 and 4500 PYFU in the abacavir and non-abacavir groups), and importantly median follow-up time was less than one year.

By comparison, D:A:D included 33,000 patients who needed to be followed for seven years (160,000 PYFU) until there was sufficient power to make associations to a single-drug effect.

Secondly, patients in clinical trials are and were generally younger, healthier, with lower cardiovascular risks. Interestingly, GSK did not present an analysis relating to the comparator regimens used in these studies, which were PI-based, and therefore already carried a higher risk of CVD.

comment

The significance of these results from the SMART study, which are already published as a fast track paper in the 12 September edition of AIDS [6], is that they support the earlier D:A:D findings in two ways. They report a similar association between current or recent abacavir use and cardiovascular disease; and they found that the clinical impact was most significant in patients with highest underlying CVD risk.

BHIVA guidelines have, for several years, included the recommendation to routinely assess CVD risk using Framingham calculators on first diagnosis, prior to starting treatment and annually thereafter. Taken together, the D:A:D and SMART results suggest that for patients at the highest CVD risk (>20% 10-year Framingham), abacavir only be used when alternative options are not available.

References
1. Lundgren J, Neuhaus J, Babiker et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the SMART study. Late breaker abstract THAB0305.
http://www.aids2008.org/Pag/Abstracts.aspx?SID=291&AID=16113
2. Smith K, et al. Similarity in efficacy and safety of abacavir/lamivudine (ABC/3TC) compared to tenofovir/emtricitabine (TDF/FTC) in combination with QD lopinavir/ritonavir (LPV/r) over 96 weeks in the HEAT Study. 17th IAC Mexico City, 2008. Poster LBPE1138.
http://www.aids2008.org/Pag/Abstracts.aspx?AID=15873
3. Cutrell A et al. Is abacavir (ABC)-containing combination antiretroviral therapy (CART) associated with myocardial infarction (MI)? No association identified in pooled summary of 54 clinical trials. Oral abstract WEAB0106.
http://www.aids2008.org/Pag/PSession.aspx?s=264
4. D:A:D Study Group, Sabin CA et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. 2008 Apr 26;371:1417-26.
5. Cutrell A et al. Abacavir and the potential risk of myocardial infarction. The Lancet. 2008 Apr 26;371:1413. 6. Lundgren et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS 2008, 22:F17-24.

They classified IDU into: (i) former; (ii) DTP (drug treatment program); (iii) DTP with ongoing IDU; or (iv) current drug use without DTP.

Of 8,660 patients, 6091 were never IDU, 1080 former, 741 DTP, 607 DTP with ongoing, and 141 current IDU without DTP.

The odds ratios of being on ART, interrupting ART, and having a viral load below limit of detection, detailed in Table 1 were adjusted for calendar year, sex, age, AIDS, and CD4 count.

Self reported adherence correlated with drug use behaviour, but not to the extent expected. Approximate adherence rates within the previous month were 79%, 70%, 70% 60% and 55% in non-IDU; former IDU; DTP; DTP with ongoing injection behaviour; and current IDU respectively.

Table 1: Odds ratios by IDU definitions compared to non-IDU patients

ADD TABLE

Importantly, the likelihood of being on ART and virological outcome were comparable between never- and former-IDU. In contrast, the results differed between the different IDU categories. Former IDU and persons in a DTP were more likely on ART and had an improved virological outcome compared with people currently injecting drugs with or without DTP.

Ref:
Huber M et al. Adherence to antiretroviral treatment (ART) of HIV-infected persons with or without injection drug use (IDU) or in a drug addiction treatment program: the Swiss HIV cohort study. Abstract TUPE0206
http://www.aids2008.org/Pag/Abstracts.aspx?AID=5706

The poster explained how the clinic in Thuy Nguyen established a comprehensive network model supporting PLHA and other marginalized communities including IDUs. The network gets involvement of self-help groups of PLHA, community health care workers, empathy clubs, local and INGO who are implementing projects in the area. Many of the patients accessing treatment services at the clinic are IDUs. Services include home visits, treatment adherence, ARV information, HIV/AIDS education, drug use. They also create community awareness on HIV/AIDS/Drugs use to reduce stigma and discrimination and provide peer support. The supporting network receives feedbacks from patients about the services of the clinic. Within a span of 10 months the network referred 100 patients and supported both ART and OI treatment.

This model helps reduce rate of lost to follow up and ART treatment failure and the network is planned to expand to involve groups such as Women’s Union, Youth Union and family members to provide this key factor for treatment success, especially IDUs.

Ref:
Hang NT, Thangsing C. Success in access to ART treatment for IDUs through PLHA network and community participation, Vietnam. Abstract MOPE0160.
http://www.aids2008.org/Pag/Abstracts.aspx?AID=10514

Provincial and local authorities with support from the Clinton Foundation have implemented HIV treatment in 11 sites since July 2005. Cumulatively 2315 patients were on ARVs with 4335 additional people followed in care by November 2007.

An integrated services approach links hospital-based clinics with community outreach/peer support centres that follow patients in clinic and out in their communities. Linkages with methadone maintenance, needle exchanges, and TB control programs extend the net of services to enter and retain IDUs in care. Extension of HIV treatment into enclosed settings has begun to ensure continuity of ARVs and re-entry into community-based medical care upon release. A model decentralising care from hospital clinics to township and village levels has been piloted with lines for consultation, referral and oversight by HIV-trained clinicians. Retention in care, and treatment benefit documented by CD4 and viral load, show good results.

Next steps are to expand capacities for patient follow-up at village level and access to care in enclosed settings.

Ref:
Wang Y et al. Scaling up comprehensive HIV treatment for injection drug using populations in Yunnan Province. Abstract CDB0248.
http://www.aids2008.org/Pag/Abstracts.aspx?AID=14468

The number of patients on ART in 76 program counties in the 7 program provinces increased from 89 at baseline to 12,495, with a higher than the national average growth rate. The highest growth rate was witnessed in Yunnan where the number of patients on ART increased from 6 at baseline to 5616, with an average quarterly growth rate of 0.6. Since the launch of the program, the ART service network has expanded considerably, covering PLWHA in both program and non-program counties.

PLWHA were mainly infected through injecting drug use.

Ref:
Zheng H. Analysis of progress in antiretroviral therapy (ART) in seven program provinces of China Global Fund Round 4/China-UK AIDS program. Abstract CDB0311.
http://www.aids2008.org/Pag/Abstracts.aspx?AID=10360

Three initial Trust Points (TPs) during 2000-2003 providing harm reduction services (mostly needle exchange) were scaled up to 10 TPS in 2004 to provide more comprehensive HIV prevention and Harm Reduction services.

To evaluate the programme, 100 IDUs were interviewed about accessability, availability, variety and quality of services provided; the effectiveness of those services and the satisfaction of the survey participants.

70% were satisfied with services, especially needle and syringes exchange, psychological support and referral to HIV testing. 30% of survey participants did not find Voluntary Counseling and Testing (VCT) available in TP and 20% were not satisfied by the fact of being referred to AIDS centre for testing part of the VCT, anticipating its availability in TP. 50% got information about substitution treatment from TPs and 30 were referred to substitution treatment.

The study concluded that while many IDUs are satisfied with services rendered in TPs, further improvement for provision of more comprehensive services including the complete VCT available in TPs is essential.

Ref:
Makhkamov M. Trust points as an effective approach to scale up HIV prevention among injecting drug users. Abstract CDB0334.
http://www.aids2008.org/Pag/Abstracts.aspx?AID=4470

A poster reported on two research projects on accessibility of ARV treatment for drug users.

One research project from 2007 focused on low quality of drug dependence treatment as an impediment to users’ access to ART. Documentation was carried out in four Russian cities and included interviews with 60 IDUs, over a dozen of whom were living with HIV and AIDS. The other study is an ongoing monitoring of access to hepatitis C, HIV and tuberculosis treatment in 20 Russian regions.

The research revealed: problems with procurement and distribution of ART in Russia; a lack of important diagnostic tests; lack of treatment for opportunistic infections; and discriminatory attitudes by health care providers that have in effect denied treatment to drug users in need. They reported lack of clear government support for harm reduction programmes proven to reduce HIV infections among IDUs, insufficient engagement of harm reduction programs in ART provision, inadequate information about HIV at government health care facilities; and lack of coordination between HIV, drug dependence, and tuberculosis clinics.

They also reported that after the findings of the research report were publicised, a new activist group emerged in St. Petersburg that will advocate for improving access to ARV therapy and high-quality medical care for drug users living with HIV.

Ref:
Ovchinnikova M and Lohman D. Drug treatment in the age of HIV/AIDS in Russia. Abstract WEPE0094.
http://www.aids2008.org/Pag/Abstracts.aspx?AID=10929

This prospective cohort study (from August 2005 to July 2007) of 856 male IDUs in Thai Nguyen province, all of whom injected heroin, and 23% were HIV-positive. Median age was 32 (range 18-59).

During 689 person-years of follow up, 43 injectors died (26% were drug overdose deaths). The overall mortality rate was 6% per year, and was significantly higher (p<0.001) among HIV-positive IDUs (14%/year) than among HIV-negatives (4%/year). In multivariate analyses, injecting benzodiazepines in addition to heroin during the 3-month period prior to enrollment increased the hazard of overdose deaths by 4.9 times (95% CI = 1.3-17.9) compared to heroin injection alone.

For non-overdose deaths, IDUs who were HIV-positive at enrollment had a 20% increase in the hazard of deaths (HR = 1.2, 95% CI = 1.1-1.4) compared to HIV-negative IDUs, and a history of tuberculosis increased the hazard by 2.2 times (95% CI = 1.4-3.5).

The study concluded that the observed death rate was high and that IDUs should be informed of the risk of fatal overdose associated with injecting benzodiazepines. Increased access to effective tuberculosis treatment and antiretroviral therapy may help reduce premature deaths among the drug users.

Ref:
Quan VM et al. Premature deaths among Vietnamese injection drug users: predictors and prevention. Abstract MOPO0247.
http://www.aids2008.org/Pag/Abstracts.aspx?AID=9931

Of 1158 IDUs recruited between April 2005 and May 2006, 293 (25%) were HIV-positive. 70 deaths were observed over 2168 person-years (PY) of follow-up (Incidence Rate [IR]: 3.2; 95%CI: 2.5 – 4.1). The risk of mortality among HIV positive IDUs (IR: 5.7 per 100 PY) was more than twice that of negative IDUs (IR: 2.3 per 100 PY).

This association persisted after adjustment for age, hepatitis C virus status, injection frequency, types of drugs injected, alcohol use, and incarceration. The leading causes of mortality in both HIV negative and positive IDUs were overdose (n=19), tuberculosis (n=12) and accident/trauma-related (n=9). Death rates from overdose and tuberculosis were higher in HIV positive than negative IDUs, though not statistically significant. Only 4 deaths in HIV positive IDUs were identified as being AIDS-related (IR: 0.7 per 100 PY).

Ref:
Solomon SS et al. High incidence of mortality in a cohort of HIV positive and negative injection drug users in Chennai, India. Abstract MOPO0244.
http://www.aids2008.org/Pag/Abstracts.aspx?AID=8338

Mean age at enrolment was 40.8 years, 150 (74%) were males, 107 (52%) were Aboriginal, and all were current or previous injection drug users.

There were 65 deaths for a cumulative mortality of 34.6% (annual mortality rate of 5.3%). Mean age at time of death was 42.5 years (44.1 yrs for males, 37.9 yrs for females). The cause of death was HIV-related in 36 (55%) cases, including AIDS without a specific pathological diagnosis (17); community-acquired pneumonia (5), tuberculosis (3), cryptococcal meningitis (2), mycobacterium avium-complex (2), lymphoma (2), PCP pneumonia (2), PML (2), and Kaposi’s Sarcoma (1). The 29 (45%) deaths not directly HIV-related included end-stage liver disease (9), drug overdose (6), cardiovascular disease (6), stroke (2), suicide (2), chronic lung disease (1), endocarditis (1), cancer (1), and undetermined (1). At the time of death, the mean CD4 count was 198 cells/mm3 and 23% had a plasma viral load less than 50 copies/ml.

The researchers concluded that despite HAART, mortality rates remained extremely high. In addition to a wide range of HIV related opportunistic infections, non-HIV related events accounted for nearly half of the deaths. Renewed efforts are needed to engage drug users in HIV care and address the social, environmental and addiction-related factors that contribute to these preventable and pre-mature deaths.

Ref:
Sadr A et al. Causes of mortality among injection drug users enrolled in an antiretroviral program in Vancouver, Canada. MOPO0253.
http://www.aids2008.org/Pag/Abstracts.aspx?AID=7351

The Action and Integration project is designed to promote the development of local, community based actions on HIV/AIDS in Central and Eastern Europe.

The November seminar targeted primarily people directly involved in the provision of HIV treatment and care to injecting drug users (IDUs) such as NGOs, activists, representatives of the drug users’community, and people living with HIV/AIDS from the new Member States and accession countries of the European Union. The purpose was to share experience and learn more about delivering treatment to IDUs. Targeting IDUs in Central and Eastern Europe is based on evidence that injecting drug use represents one of the major transmission routes of HIV in the region.

Today, the question of HIV care for IDUs in the Region is less a matter of financial resources than one of delivery.

Scientific evidence demonstrates that treatment outcomes for IDUs can be as good as the outcomes for other patients if appropriate services are provided.

The seminar gave East and Central European participants the opportunity to exchange best practices in the region and neighbouring Europe in order to overcome barriers faced by IDUs with HIV.

Other relevant issues were pointed out to raise awareness on the importance of integrating adequate TB and Hepatitis care as well as the provision of substitution therapy services with antiretroviral therapy (ART) services.

Eastern Europe is the home of 1.6 million people living with HIV (PLWH) and up to 2.8 million injecting drug users (IDUs). The region suffers from a heterogeneous dynamic. In the Czech Republic, Hungary, Slovakia and Slovenia, the predominant mode of transmission is sexual (heterosexual) intercourse even though there have been increases in the number of new cases reported among men who have sex with men. In Romania, most HIV infections took place among children who are now adolescents and young adults and recently HIV cases are reported to be acquired through heterosexual intercourse.

In Eastern Europe and Central Asia, the predominant transmission route for HIV infection is the sharing of injecting equipment. However, there is evidence of increasing heterosexual transmission. 64-85% of cumulative registered HIV cases with known transmission routes in Azerbaijan, Belarus, Estonia, Latvia, Lithuania, Moldova, Russia and Ukraine occurred among IDUs.

These figures suffice to demonstrate that harm reduction measures targeting IDUs need to be scaled-up in the region. There is also a need to improve both access to and the quality of health and social services (based on a non-discriminatory approach).

A number of studies were carried out to monitor current access to services including antiretroviral therapy (ART). The European and Central Asian governments signed the Dublin Declaration and thus committed themselves to eliminate inequality in treatment provision and to ensure equal universal access to ART for all people in need by 2005. It is worrying to observe that the region is far behind schedule.

Central European countries, like Western European countries, report good access to ART (defined as 75% and higher treatment coverage of the estimated number of people in need of ART) in 2004.

Eastern Europe and Central Asia have the second lowest coverage of antiretroviral therapy in the world. However, the region has seen significant increases in funding available for access to ART and significant expansion of access to ART within the last few years.

Despite this progress, access to ART for IDUs remains disproportionately low in the region overall.

Russia and Ukraine, where most of HIV-positive IDUs live, show low coverage and are rolling out antiretroviral therapy programmes, with ambitious plans to provide therapy to 60% (inRussia) and 55% (in Ukraine) of people in need by 2008.

The Baltic countries with fast developing upper-middle income economies, relatively small populations and with injecting drug use-driven HIV epidemics continue to experience problems with delivery of ART to IDUs.

A number of social and physical barriers are still in place. The impact of stigma cannot be underestimated. IDUs living with HIV face dual stigma associated with both injecting drug use and positive HIV status.

Low levels of knowledge about ART and misconceptions about treatment for IDUs is also one of the key barriers to treatment. In particular, the knowledge of ART needs to be improved in low prevalence countries. Myths or incomplete information about side effects, interactions with illicit drugs and interactions with opioid substitution treatment (OST) often discourage treatment uptake.

Patient’s education is thus recognized as a key facilitator of treatment adherence. Some interesting programmes for patient’s education have been piloted such as “patient schools” but are often challenged to find sustainable funding. Adequate education of health care staff is essential in order to improve access to treatment and care for IDUs.

This annual conference is one of the most important annual scientific meetings.

Abstracts for the meeting are online as soon as the conference opens, and many of the most important oral abstract sessions and overview sessions are posted as webcasts within a day or so. We encourage readers to go directly to the source for many of these sessions:

http://www.retroconference.org

A non-technical summary of general news from the conference, covering 25 studies and presentations in 12 key areas, is available from the i-Base website.

While there were few studies relating to ARV4IDUs several studies on coinfection were interesting:

• MELD score predictive of pre-transplant mortality in HIV/HCV coinfected patients
• Does abacavir decrease SVR rates with HCV treatment?
• No effect of interferon maintenance therapy on fibrosis progression in non-responders

Aruna Subramanian from Johns Hopkins University looked at determining incidence, cause, and time to pre-transplant mortality in transplant candidates compared to HIV-negative patients in a prospective cohort study at 20 US sites, with particular reference to the MELD score.

The MELD score (Model for End Stage Liver Disease) incorporates creatinine, bilirubin and INR checked at the same visit. MELD is validated as predictor of mortality in HIV-negative patients. It is used as a basis for organ allocation, so that sick patients get earlier access to transplant.

Patient in this study needed to fulfil local criteria to be included on a transplant list, with CD4 count of >100 cells/mm3 within 16 weeks of transplant (>200 if a recent OI), and to have undetectable viral load (except in cases when ART was discontinued due to hepatotoxicity, and a resistance profile indicated that HIV suppression post transplant would be likely. Clinical follow-up was at least every three months from joining the list until transplant.

Each case was matched (by age, gender, race, time of listing and HCV coinfection) with up to five controls, and compared by time to death, transplant and reaching MELD >25.

During follow-up the cohort included 167 HIV-positive patients (51% were not transplanted, 14% died and 35% received a transplant) and 792 controls (41% not transplanted, 11% died and 48% transplanted).

Median baseline CD4 was lower in patients who died compared to those who received a transplant (median 237 vs 315, p=0.01). There was no difference in the percentage with undetectable viral load, use of PI-based treatment or percent with HCV coinfection.

Cause of death pre-transplant were broadly similar in the HIV-positive vs control group, including sepsis (25% vs 20%), multi-organ failure (17% vs 26%), GI haemorrhage (13% vs 6%), other causes (29% vs 27%), and unknown (17% vs 20%).

Comparative time to death was similar in cases and controls, as was time to transplantation and to elevated MELD >25.

However, in multivariate model baseline MELD score showed the strongest risk (HR=21.8 95% CI 6.3, 75.7, p<0.0001). CD4 count <200 had only borderline significance (HR 2.6, 95%CI 0.98, 6.9, p=0.05), and viral load was not predictive.

The researchers concluded that low CD4 count at time of listing may be predictive of greater risk of death, but that after controlling for CD4 and viral load. MELD had excellent predictive value for pre-transplant mortality, and should be used routinely for patients with cirrhosis to help guide decisions for early transplant referral.

The group plans to develop a scoring method that incorporates CD4 count and MELD to predict mortality that could be validated for all patients, not just at transplant listing, and to determine optimum CD4 count for transplantation, and to determine any relationship between MELD score and post-transplant outcomes (which limited data indicate may be poorer in coinfected patients).

An online MELD calculator is available

http://www.unos.org/resources/MeldPeldCalculator.asp?index=98

Transplant study for people with HIV

http://hivtransplant.com

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These results should not be a surprise as MELD is well validated for assessing liver failure. MELD is used by European and US transplant centres, The post-transplant data are very important, because MELD score at the time of transplant may be an accurate indicator of post-transplant survival.

There are clearly concerns that ‘standard’ criteria for listing urgency may not apply for HIV-positive patients due to faster risk of progression and re-thinking listing priorities in this group of patients may be important. It is re-assuring that ‘standard’ MELD criteria still apply.

Ref Subramanian A et al MELD is the best predictor of pre-transplant mortality in HIV-infected liver transplant candidates. Oral abstract 64.

http://www.retroconference.org/2008/Abstracts/31927.htm

This oral presentation is available to view online from the conference website (Monday 4 February).

Three studies from Spain reported on the relationship between nucleoside/tide analogues and response to HCV treatment. [1, 2, 3] Last year at CROI, a poster from French researchers reported that abacavir use was significantly associated with poorer outcome to HCV treatment, through a possible intracellular competition between abacavir and ribavirin. [4]

Jose Mira and colleagues from Hospital University de Valme, Seville presented a retrospective analysis comparing sustained virological response (SVR) rates among HIV/HCV-co-infected patients treated with peg-IFN plus ribavirin, who were taking a NRTI backbone consisting of either abacavir + 3TC or tenofovir + 3TC/FTC. [1]

In an intention-to-treat analysis, sustained virological response (SVR) was seen in 20/70 (29%) individuals receiving abacavir and 83/186 (45%) patients using tenofovir, (p=0.02). NRTI backbone containing TDF was an independent predictor of SVR in the multivariate analysis (adj odds ratio, 95%CI: 2.6; 1.05 to 6.9); p=0.03).

HCV genotype 2 or 3, baseline LDL cholesterol levels ≥100 mg/dL, lower baseline plasma HCV viral load and undetectable baseline HIV viral load also predicted SVR. The association between abacavir use and lower SVR rate was mainly seen in patients with plasma HCV viral load >600,000 IU/mL, HCV genotype 1 or 4 and in patients who received lower doses of ribavirin. (those less likely to respond to HCV treatment)

Of patients using a daily dose of ribavirin of less than 13.2 mg/kg, 3 (20%) of those under abacavir vs 22 (52%) under tenofovir achieved SVR (p = 0.03), whereas the rates were 31% and 38% (p = 0.4), respectively, in those receiving RBV dose higher than 13.2 mg/kg.

A second retrospective cohort analysis, from Juan J Gonzalez-Garcia and colleagues from the GESIDA 50/06 Study Group looked at all HIV/HCV coinfected patients treated for HCV while on HAART between January 2003 and November 2005 from 35 sites. [2]

Patients were categorised in 2 groups:  tenofovir, used with 3TC or FTC (n = 238); and non-tenofovir (n = 481) that included patients using AZT + 3TC (n =265), d4T + 3TC (n = 164), or abacavir + 3TC (n =52). They excluded patients receiving ddI or tenofovir with AZT/d4T or abacavir from the analysis.

The two groups were well matched in baseline characteristics except for a lower CD4 cell count mean (535 vs 601; p=0.003), exposure to more HAART regimens (7.2 vs 5.7; p <0.001), and a higher mean GOT/GPT quotient (0.84 vs 0.77; p=0.04). Safety analysis revealed no differences between the groups in relation to death, hepatic decompensation and interruption of HCV treatment due to side effects.

Ribavirin dose-reductions were more frequent in non-tenofovir treated patients (12.8 vs 19.5%; p=0.03), particularly in patients treated with AZT (23.2%; p = 0.003). No significant differences were found in the SVR among patients in the tenofovir and non-tenofovir groups, by ITT analysis (45% vs 39%; p= 0.12).

In a multivariate analysis, adjusting for HCV genotype, HCV viral load <500,000 IU/mL, baseline HIV viral load <50 copies/mL, GOT/GPT quotient, and alcohol intake >50 g/day, SVR was positively associated with use of tenofovir (OR 1.70 95%CI 1.05 to 2.77, p=0.03) and negatively associated with use of AZT, related to anaemia (OR 0.60, 95%CI 0.37 to 0.99, p=0.05), detailed in the Table 1.

Table 1: Odds ratios of SVR by nucleoside backbone

*including patients with AZT+3TC+ABC

The study concluded that the use of TDF + 3TC/FTC was associated with an improved response to peg-IFN plus ribavirin, and that, as shown in previous studies, AZT is associated with a worse tolerability and effectiveness.

In the third study, Ana Moreno and colleagues from Hospital Ramon y Cajal, Madrid looked at use of abacavir or tenofovir in 174 HIV/HCV coinfected patients starting their first cycle of peg-IFN plus weight-adjusted ribavirin. Approximately half the patients used Pegysys and half used PegIntron [3]

Most subjects were male (76%), prior intravenous drug users (87%), with a median age of 40 years (28 to 63). The median duration of HCV infection was 21 years, and 102 (59%) had HCV-genotype 1 or 4. 82% were on HAART (49% PI, 32% NNRTI, and 18% triple-nuke). Tenofovir was used in 69 (48%), abacavir in 56 (39%). The mean ribavirin dosage was 14.7+2.4 mg/kg/day.

Baseline CD4 count, and HCV viral load were 513 cells/mm3 and 5.8 log IU/mL respectively, and two-thirds patients entered the study with undetectable HIV viral load.

SVR was reported in 79/174 (45%) patients. After each adjusted regression analysis however, neither abacavir (p = 0.59), tenofovir (p = 0.92), nor triple NRTI use (p = 0.12) had any significant effect on SVR.

By multivariate analysis, HCV genotype 1 or 4 (OR 7.8, 95%CI 2.6 to 22.93, p = 0.0001), and higher baseline HCV RNA levels (OR 3.5, 95%CI 1.7 to 7.3, p = 0.001) or fibrosis scoring (OR 1.7, 95%CI 1.2 to 2.6, p=0.003) remained independently associated with failure to achieve SVR.

The researchers concluded that in their cohort, use of abacavir, tenofovir or triple nucleosides di not significantly influence the rate of SVR in patients receiving peg-IFN + weight-adjusted-RBV.

comment

The first study from Mira et al. is a merger of data from Madrid and Seville. The data from Madrid were already presented at IAS and AASLD 2007 with similar findings. The study from Moreno et al. is considerably smaller which may explain the negative finding for abacavir.

The GESIDA cohort took a different route by including abacavir in the group of AZT, ddI and d4T – all of which are known to have toxicities limiting treatment efficacy in coinfected patients.

In summary, these data are no surprise and do not tell us much about abacavir.

References
1. Mira J, et al. Efficacy of pegylated interferon + ribavirin treatment in HIV/HCV-co-infected patients receiving abacavir + lamivudine or tenofovir + either lamivudine or emtricitabine as nucleoside analogue Backbone.15th CROI, Boston 2008. Abstract 1074.
http://www.retroconference.org/2008/Abstracts/30917.htm
2. Gonzalez-Garcia J, et al. The use of TDF+ 3TC/ FTC is associated with an improved response to pegylated interferon + ribavirin in HIV/HCV-co-infected patients receiving HAART: the Gesida 50/06 study. 15th CROI, Boston 2008. Abstract 1076.
http://www.retroconference.org/2008/Abstracts/32077.htm
3. Moreno A, et al. Does the choice of NRTI have a significant influence on the outcome of peg-IFN plus Ribavirin among HIV/HCV-co-infected Patients? 15th CROI, Boston 2008. Abstract 1075.
http://www.retroconference.org/2008/Abstracts/32710.htm
4. Bani-Sadr F et al. Factors associated with virological non-response to peg-interferon + ribavirin therapy in HIV/HCV co-infected patients: the role of abacavir. 14th CROI, Los Angeles, 2007. Abstract 897.
http://www.retroconference.org/2007/Abstracts/28572.htm

One aspect of HCV management that is informed by little data, is whether continued treatment of virologic non-responders with maintenance peg-IFN therapy can reduce the rate of clinical HCV progression.

This question was addressed in a study presented by Kenneth Sherman and colleagues in a multicentered US study that treated a mixed group of 329 patients (68% naïve and 32% refractory to previous treatment) with peg-IFN-alpha-2a plus weight-based ribavirin for 12-18 weeks. Median age was 48 years; 83% male; 43% white, 37% black, non-Hispanic and 15% Hispanic; baseline median HCV viral load was 6.6 log IU; CD4 was 498 cells/mm3; 74% had HIV RNA <50 copies/mL.

Early virologic response (EVR) was defined as achieving undetectable HCV viral load (<600 IU) or 2-log drop at week 12. Patients without an EVR received biopsy and were randomised to peg-IFN 180ug alone or observation for 72 weeks.

Liver biopsies obtained at start and end of therapy were blinded, and read by a single pathologist. The study design required 134 subjects to show whether maintenance treatment produced 0.18 unit/year reduction in the rate of Metavir fibrosis progression.

EVR was observed in 55.6% patients (95%CI 50 to 61%; ITT analysis) and was strongly associated with expected factors (gender, race, degree of fibrosis, AST, absolute neutrophil and heamoglobin levels.

86 patients without EVR were then randomised to peg-IFN vs observation. Median entry Metavir score was 2; 28% had advanced fibrosis (F3, F4).

However, lack of fibrosis progression in both groups, lead to DSMB-recommended early closure of the study, when 62 patients had completed 72 weeks of follow-up, only 45 of who had paired biopsy results for this analysis (24 in the IFN, 21 in observation arm).

Compared to the expected rate of 0.18 units/year, median fibrosis change was 0.0 (Q1,Q3: 0.0, 0.69) in the maintenance groups and 0.0 units/year (Q1,Q3: –0.69, 0.61) in the control group.

The authors concluded that, in contrast to recent reports, this randomised controlled trial failed to identify significant change in hepatic fibrosis among untreated non-early virologic responses over 72 weeks. They also commented that weight-based ribavirin achieved higher levels of EVR (55.6% vs. 41%) than the ACTG 5071 study, which used lower doses of ribavirin, and that race (Causaian>Hispanic>Black) appears to be an important independent factor in early virologic response.

comment

Right from the early registration studies for interferon and ribavirin, investigators had noted a slight reduction in hepatic fibrosis scores and also decreases in activity/inflammation, which drives fibrosis in patients who did not have a virological response to therapy. A question that had been asked was does this therapy have an anti-fibrotic effect over and above its anti-viral effect?

This phenomenon was recently explored in the HALT-C study (AASLD 2007, De Bisceglie et al), where HCV mono-infected patients with Child-Pugh A cirrhosis and previous non-response, were randomised to continue pegIFN-alpha 2a at half-dose (90mg) or placebo over 3.5 years. The end-points were death, de-compensation, HCC or an increase in fibrosis by two points. The results, presented by the authors at AASLD, suggested that for all individual end-points, there was no significant difference between the pegIFN arm and the placebo arm, thus suggesting that in clinical terms, pegIFN maintenance therapy did not prevent progression in cirrhotic patients.

This study, also called the SLAM-C study, included HIV/HCV co-infected patients, 15% of whom had cirrhosis.  After a lead in period of treatment with pegIFN and weight-based ribavirin, patients with no EVR were randomised to maintenance therapy with pegIFN 180mcgs/week or no therapy. Liver biopsies were evaluated after 72 weeks. There was no fibrosis progression in either arm. However, there was a greater reduction in inflammatory scores in patients on pegIFN arm. Clearly this begs the question of whether maintenance therapy will help reduce fibrosis progression in non-virological responders. From this study, evidently not, although these were small numbers, therapy and follow-up was only for 72 weeks and that these patients had good CD4 counts and well-controlled HIV disease, and were therefore likely to have slow progression of HCV related fibrosis.

Taking HALT-C and SLAM-C results into account, current evidence does not support pegIFN maintenance in patients with no virological response.

Ref
Sherman K, et al. Sustained Long-term Antiviral Maintenance with Pegylated Interferon in HCV/HIV-co-infected Patients: Early Viral Response and Effect on Fibrosis in Treated and Control Subjects.15th CROI, Boston 2008. Abstract 59.
http://www.retroconference.org/2008/Abstracts/31871.htm

Over 5,000 delegates from 133 countries registered for the meeting this year. For attendees from Europe, Africa and the US, the distance and cost probably limited attendance to the meeting. For those lucky enough to be able to attend, the meeting included a wealth of new data in many aspects of HIV research, with 978 abstracts were accepted for oral or poster presentation. For our coverage of new drugs, treatment strategies, paediatric care, mother to child transmission and prevention studies, please see coverage in HIV Treatment Bulletin.

It is also important and encouraging to see that the IAS has invested sufficient resources to ensure high quality internet access to the most important aspects of the meeting. Web casts are available for many plenary and oral presentations, including the late breaker sessions and including the questions and panel discussions afterwards. Most of these studies have links to the powerpoint slides and an email link to the main author. Additionally, MP3 audio recordings and transcriptions for many of the sessions are also online.

Reports particularly addressing ARV4IDUs included in this issue of ARV4IDUs are:

• Trends and predictors of HIV-associated risk behaviors among injecting drug users participating in an HIV prevention trial, Bangkok
• Harm reduction in Iran: a tale of two viruses
• HBV or HCV coinfection produced higher risk from treatment interruptions: drug holidays and hepatitis don’t mix

As with all reports and summaries, readers are encouraged to go directly to the source material for more detail:

http://www.ias2007.org

Other online sessions of interest for ARV4IDU include:

Global responses to HIV prevention among injection drug users
http://www.ias2007.org/pag/PSession.aspx?s=53

The intersection of biomedical and social aspects of prevention
http://www.ias2007.org/pag/PSession.aspx?s=8

Unless stated otherwise, references are to the Abstracts and Programme from the 4th International AIDS Society Conference on HIV Treatment and Pathogenesis (4th IAS), Sydney, 2007, and these are already posted to the conference website.

The Bangkok Tenofovir Study, an HIV prevention trial conducted at 17 drug treatment clinics in Thailand, is investigating safety and efficacy of tenofovir to prevent HIV in injection drug users (IDUs). The tenofovir study group is comprised of Thailand’s Ministry of Public Health, Bangkok’s Metropolitan Administration, The U.S. Department of Health and Human Services, and Centers for Disease Control. At this year’s IAS meeting in Sydney, Vanichseni and colleagues presented data on predictors of risk-taking, and actual risk behavior among 1,455 study participants.

Study participants are given a prevention package, which includes counseling on risk reduction, access to HIV counseling and testing, treatment for sexually transmitted infections (STIs), condoms, bleach and methadone. However, syringes were not provided through the study. When asked, Dr. Vanichseni said that it was illegal to do so in Bangkok. Thai advocates say that this would not be illegal (see comment).

Data on risk-taking were collected at enrollment, and then at 3, 6, 9 and 12 months (see Table 1. Baseline characteristics and risk behavior in the Bangkok tenofovir study). Participants were asked if they had injected drugs in the last three months, and if they had injected with used needles or syringes, via audio computer-assisted self-interview. Investigators looked at predictors of injecting drugs and needle sharing. Injection drug use was associated with being male, over 26 years of age, and an educational level above primary school, but there were no statistically significant predictors of sharing injection equipment.

Syringe sharing decreased significantly among study participants, from 17% to a remarkably consistent rate of 3%, where it remained at month 18. However, there was no information provided on where study participants obtained their own syringes. Injection drug use decreased significantly during the first three months of the study, from 62% to 17%, but then, it almost doubled by month 18 (to 32%). Oddly, the presentation did not include seroconversion data.

Table 1. Baseline characteristics and risk behavior in the Bangkok tenofovir study

ADD TABLE

Hopefully, in the future, if tenofovir turns out to be an effective intervention, it will be a part of more comprehensive HIV prevention and treatment initiatives for Thai drug users. These should include education, easy access to clean syringes, condoms, and opiate substitution therapy with methadone or buprenorphine, in the context of comprehensive health care.

comment

Activists were bitterly disappointed that their comprehensive care package for study volunteers—which included syringe distribution, working with the police on HIV and harm reduction, and educating drug users, health care providers and members of the community about why it is important to hand out needles—was rejected by the people running the trial.

“Since the beginning of the study, activists from Thailand’s National Network of People Living with HIV (TNP+), the Thai Drug Users Network (TDN), and representatives from other community-based AIDS and human rights organizations tried to be involved in the design and implementation of this study, but we were excluded from a working partnership with the people running the trial,” says Karyn Kaplan, Director of Policy and Development at Thai Treatment Action Group (TTAG).

The study’s principal investigator, and other US and Thai researchers “patently refused to provide syringes,” according to Kaplan. “The Americans said that it was illegal to use government funds for syringe distribution and the Thai investigators expressed concern that giving out syringes is illegal in Thailand—but this is untrue; providing medical devices for health promotion is not illegal in Thailand. We offered to set up on-site provision of needles by a third party—(Medecins Sans Frontieres, MSF), but they still refused.”

Community representation was provided by “a hand-picked advisory board, comprised of one drug user from each methadone center where the study was being conducted. These are people who do not know about research and were thus unable to contribute; they wound up being tokenised, while activists who wanted to create a long-term system to support drug user health in the context of the trial were excluded. This is outrageous, given that there is nothing in place for Thailand’s drug users, among whom HIV prevalence has remained stable at 50%. Harm reduction is virtually non-existent in Thailand. Nothing has been done to date to reduce the burden of HIV in IDUs—except letting people die untreated.”

Unaddressed ethical violations have led Kaplan and her colleagues, AIDS advocates from the Center for AIDS Rights, Thai Drug Users’ Network, and others, to take their case to the National Human Rights Commission. “Coercion is a major issue, due to inappropriate use of clinic staff as trial staff. We know that many people in the trial feel uncomfortable talking to the trial staff, since they are the very same people who provide them with their methadone. It is easy to tell people what you think they want to hear. Former clinic clients have reported getting phone calls from clinic nurses, begging them to come back, and join the trial even though they were no longer on methadone or injecting drugs. Therefore, we question the validity of the data.”

Ref: Vanichseni S, Martin M, Suntharasamai P, et al. Trends and predictors of HIV-associated risk behaviors among injecting drug users participating in an HIV prevention trial, Bangkok. 4th International AIDS Society Conference. 22-25 July, 2007. Sydney, Australia. Abstract MOAC201.

At the 4th International AIDS Society conference, Dr. Seyed Abbas Motevalian and colleagues reported on HIV prevalence and risk behavior among injection drug users (IDUs) imprisoned in Iran, measures instituted to decrease HIV transmission among incarcerated IDUs, and recommendations for preventing new HIV infections. [1]

The Islamic Republic of Iran has a population of 7.5 million. Approximately 70,000 are HIV-positive. An estimated two million Iranians use drugs; 200,000 of them by injection. In fact, injection drug use with shared equipment is a predominant mode of HIV transmission, accounting for 67% of notified cases, as of June 2007. Hepatitis C virus is also prevalent among Tehran’s injection drug users (IDUs), according to research from Zamani and colleagues. They assessed HIV and HCV prevalence among more than 200 IDUs, recruited from a drop in-center, adjoining streets and local parks in Shoosh, a poor area heavily populated by drug users. Overall, 23.2% were HIV-positive, and 52% were anti-HCV positive; 9.4% were HIV/HCV coinfected. [2, 3]

Each year, more than 500,000 people are imprisoned in Iran; almost half of them are serving time for drug-related crimes. High prevalence of HIV and hepatitis C among inmates, lack of access to condoms, tattooing with shared, unsterilised equipment the availability of drugs—albeit at high cost—and scarcity of injection devices make prisons a hotbed for new HIV and HCV infections. There is ample opportunity for preventing new HIV and HCV infections among prisoners. In fact, in their community-based sampling, Zamani and colleagues reported that HIV prevalence was significantly higher among IDUs who shared injection equipment while imprisoned (36%, versus 20% for IDUs who did not share), and that duration, and number of incarcerations are associated with both HIV and HCV. [2, 3]

In 2003, Motevalian and colleagues took a close look at risks for, and prevalence of HIV among 700 male IDUs in Tehran’s Quezel Hesar prison, grouping them by duration of incarceration (just entered vs. imprisoned for more than one week). After giving consent, prisoners were tested for HIV, and asked about injection drug use, both in and out of prison, and sexual behavior with female partners (see Table 1. HIV status, injection drug use history, and sexual behavior of IDUs imprisoned in Iran).

Table 1. HIV status, injection drug use history, and sexual behavior of IDUs imprisoned in Iran

ADD TABLE

HIV prevalence was lowest among new entrants with no prior incarceration (6%, vs. >20% among long-term inmates). During incarceration, 6% of new prisoners, and 21% of longer-term prisoners started injecting drugs, many with hand-made equipment. Among both new and long-term IDU prisoners, HIV infection was associated with:

• Lower level of education;
• Longer imprisonment;
• Younger age at initiation of IDU;
• Injection drug use in prison;
• Frequency and duration of injection drug use;
• Sharing injection equipment;
• Use of hand-made injection equipment;
• Having a tattoo.

Unfortunately, prisons provide condoms “on demand” only. There are no condom distribution programs for the 45,000 annual “carnal visits” between inmates and their wives. Prisoners were not asked about same-sex partners, either prior to, or during incarceration. However, Zamani and colleagues reported that eight percent (16/207) of male IDUs had same-sex partners, and recommended that Iran’s health authorities “…address same-gender sexual practices of IDUs, and. start identifying appropriate sexual risk reduction strategies, while avoiding further stigmatisation due to their same-gender sexual activity.”

Clearly, there are ample opportunities for HIV prevention in correctional facilities. Fortunately, results from this—and other similar studies—have been used as a “strong advocacy tool…translated to some strong actions in the country,” according to Dr. Motevalian. By 2005, HIV education was provided to an estimated 300,000 prisoners. During the same year, 4,500 inmates received methadone. By 2006, methadone was available to 10,000 prisoners (approximately 20% of incarcerated IDUs). Guidelines for syringe distribution in prisons have been approved by the Iranian judicial system; implementation is expected soon.

Dr. Motevalian closed by stating that more action is necessary to prevent HIV transmission among IDUs, their partners and children drug use, specifically: decriminalising drug use, distributing condoms for carnal visits, and creating programs for sex workers and partners of IDUs.

References

1. Motevalian SA, Farhoodi B, Motamedi M, et al. Prevalence of HIV and risky behaviors among injecting drug users of a prison in Tehran. 4th International AIDS Society Conference. 22-25 July, 2007. Sydney, Australia. Abstract MOAC203.
2. Zamani S, Kihara M, Gouya MM et al. High prevalence of HIV infection associated with incarceration among community-based injecting drug users in Tehran, Iran. J Acquir Immune Defic Syndr. 2006 Jul;42(3):342-6. PMID: 16639351.
http://www.jaids.com (free full text available online)
3. Zamani S, Ichikawa S, Nassirimanesh B et al. Prevalence and correlates of hepatitis C virus infection among injecting drug users in Tehran. Int J Drug Policy. 2007 Oct;18(5):359-63. PMID: 17854723. http://www.ijdp.org/article/PIIS0955395907000424/fulltext

SMART, the trial comparing continuous antiretroviral therapy with CD4-count-guided drug breaks, started with the hypothesis that drug holidays would lower the risk of antiretroviral side effects without threatening progression of HIV infection [1]. But it ended with a trove of data showing that treatment lulls pose a substantial risk of HIV progression while making a host of non-AIDS complications more likely.

At the February 2007 Conference on Retroviruses and Opportunistic Infections, SMART statistician Andrew Phillips reported that CD4-guided treatment breaks heightened chances of heart disease, possibly because steady antiretroviral therapy exerts an overall positive effects on risk factors [2].

At the 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention, SMART investigators served up results of fresh analyses showing that:

• Interrupting antiretrovirals proved “particularly unsafe” for people with hepatitis B or C virus (HBV or HCV) infection [3].
• SMART enrollees coinfected with HBV had to restart antiretrovirals more often than those without HBV [4].

SMART signed up 5472 mostly treatment-experienced people and assigned 2752 to keep taking antiretrovirals, regardless of CD4 count and 2720 to defer treatment until their CD4s tumbled below 250, then to resume or start therapy, only to stop again when CD4s climbed back above 350 [1]. The trial came to an abrupt end in January 2006, after an average 16 months of follow-up, when investigators found a 2.6 times higher risk of opportunistic disease or death as well as higher risks of heart, liver, and kidney disease in the drug-holiday group.

Two SMART substudies showed that CD4-guided treatment breaks may be a particularly bad idea for people coinfected with HBV or HCV [3,4]. Analysis of 922 SMART enrollees coinfected with HBV and/or HCV found that they accounted for about half of all non-AIDS deaths during the study, even though coinfected people made up only 17% of the whole cohort [3].

Defining chronic HBV as a positive test for hepatitis B surface antigen for more than 6 months and chronic HCV as positive for HCV antibody, the SMART team counted 922 coinfected people in the whole cohort (16.8%) and analyzed 467 in the drug-break group and 446 in the steady-therapy group. Equivalent proportions in both study arms had HBV only (n = 110), HCV only (n = 798), or both HBV and HCV (n = 14). In the coinfected subgroups, nadir (lowest-ever) CD4 count and CD4s at study entry were also equivalent in the two groups (median nadir 257 in the treatment-interruption group and 250 in the steady-therapy group; median entry CD4s 598 in the interruption group and 567 in the steady group). About two thirds of coinfected SMART enrollees had a viral load under 400 copies and about one quarter had AIDS.

When SMART ended, risk of opportunistic disease or death proved nearly identical in treatment interrupters with and without HBV or HCV coinfection. Coinfected people who took drug holidays had a 2.58 times higher risk of opportunistic disease or death than people who stayed on therapy. Among SMART enrollees without HBV or HCV, that risk was 2.57 times higher in the drug-holiday group.

Risk of death from a nonopportunistic disease proved 3.9 times higher in coinfected break takers than in the HIV-only drug-break group, and 3.5 times higher in the coinfected steady-therapy group than in the HIV-only steady-treatment group. SMART statisticians figured that this higher risk of non-AIDS deaths in coinfected people entirely accounted for the overall 2-fold higher risk of opportunistic disease or death in coinfected versus noncoinfected enrollees. The overall risk of a non-AIDS death was more than 3.5 times higher in coinfected people than in people without hepatitis virus coinfection (Table 1).

Table 1. AIDS and non-AIDS death rates with and without hepatitis coinfection

But hepatitis itself did not explain the higher non-AIDS death risk in HBV/HCV-coinfected people. In the coinfected group death rates per 100 person-years measured about 0.2 for liver disease, 0.3 for kidney disease, and 0.5 for non-AIDS cancers and substance abuse.

SMART investigators concluded that because the risk of non-AIDS deaths runs so much higher in HBV/HCV-coinfected people, “the strategy of antiretroviral therapy interruption is particularly unsafe in these patients.”

Using the same definitions of chronic HBV and HCV infection, another SMART team discovered that HBV coinfection by itself made restarting antiretrovirals more likely in treatment interrupters [4]. This analysis focused on 2669 study participants, all of them randomized to take CD4-guided drug breaks. Median baseline CD4 count measured 560 in 65 people coinfected with HBV, 608 in 402 people with HCV, and 595 in 2202 infected only with HIV. Respective nadir CD4 counts stood at 207, 265, and 250. Similar proportions in all three groups were taking tenofovir, emtricitabine (FTC), and/or 3TC.

In the average 16 months of follow-up, 63.1% of study participants in the HBV group had to resume therapy, compared with 45.5% in the HCV group and 39.2% in the group without HBV or HCV. Median CD4 counts when treatment resumed were similar in the three groups – 233 with HBV, 240 with HCV, and 232 with neither hepatitis virus. A multifactorial analysis pinpointed seven factors that independently made treatment resumption more or less likely, including HBV coinfection, which raised the risk by two thirds (Table 2). HCV coinfection had no impact on the need to restart therapy.

Hepatic flares or restarting antiretrovirals at higher CD4 counts did not explain the higher resumption rate in people with HBV. Rather, SMART statisticians reckoned that HBV-coinfected people had to resume treatment more because their CD4 counts plunged faster than those of other people when they took drug breaks. While 24.4% in the HBV group who resumed treatment did so because of a speedy CD4 drop, 21.6% without hepatitis and 16.4% with HCV restarted therapy for that reason.

Table 2. Independent predictors of need to restart therapy in SMART

This article is part of a longer report on the SMART trial

http://www.natap.org

See also:

HCV/HBV Coinfected at Greater Risk in SMART

http://www.natap.org/2007/IAS/IAS_58.htm

Higher rate of HAART reinitiation among HIV-HBV coinfected patients in the episodic arm of the SMART study

http://www.natap.org/2007/IAS/IAS_57.htm

References

1. The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283-2296.

http://www.nejm.org/doi/full/10.1056/NEJMoa062360?ck=nck

2. Phillips A, Carr A, Neuhaus J, et al. Interruption of ART and risk of cardiovascular disease: findings from SMART. 14th Conference on Retroviruses and Opportunistic Infections. February 25-28, 2007. Los Angeles. Abstract 41.

3. Tedaldi E, Puoti M, Neuhaus J, et al. Opportunistic disease and mortality in patients co-infected with hepatitis C virus (HCV) and/or hepatitis B virus (HBV) in the SMART (Strategic Management of Antiretroviral Therapy) study. 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention. July 22-25, 2007. Sydney. Abstract TUAB203.

http://www.ias2007.org/pag/Abstracts.aspx?SID=68&AID=3450

4. Dore G, Soriano V, Neuhaus J, et al. Higher rate of antiretroviral therapy reinitiation among HIV-HBV coinfected patients in the episodic therapy arm of the SMART study. 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention. July 22-25, 2007. Sydney. Abstract TUAB204.

http://www.ias2007.org/pag/Abstracts.aspx?SID=68&AID=4389

• Scaling up ART for people who use drugs: the Brazilian story

The International Harm Reduction Association (IHRA) 18th International Conference on the Reduction of Drug Related Harm took place in May 2007 in Warsaw, Poland. The five-day event was attended by over 1,200 people from over 80 countries (a record high number of countries). There were around 90 sessions (containing around 300 oral presentations and 300 poster presentations) covering a wide range of topics including illicit drugs, alcohol, tobacco, sex work, HIV/AIDS, young people, and prisons. The speakers at the meeting included major international organisations and donors (such as UNAIDS and the World Bank), and leading academics, advocates and practitioners from around the world.

For more information on the conference including links to opening and closing speeches and rapporteur summaries, see:
http://www.ihra.net/June2007

At the 18th International Conference to Reduce Drug-Related Harm, Dr Monica Malta discussed Brazil’s response to the HIV epidemic, and to recent trends in drug use among HIV positive Brazilians.

HIV epidemiology and treatment in Brazil

According to a UNAIDS estimate, 620,000 Brazilian adults and children are living with HIV/AIDS. Brazil was the first developing-world country to provide universal access to HIV treatment, beginning with prophylaxis and treatment for opportunistic infections in 1988, followed by AZT in 1991. Antiretroviral therapy has been provided free of charge since 1996. As of 2007, 180,000 HIV-positive Brazilians are receiving ART.

At least 20% of Brazil’s estimated 800,000 injection drug users (IDUs) are HIV-positive. [1, 2]

Brazil is the largest provider of HIV care and treatment to people who use drugs in the developing world; 30,000 are receiving ART. [3]

HIV and cocaine: the problem and the response

More than 90% of the world’s cocaine is produced in Latin America, and it is widely available in Brazil. Injection drug use in Brazil has decreased; people have switched to smoking crack and snorting cocaine. Several studies have reported that crack cocaine use is associated with high-risk sex, and HIV seropositivity in Brazil. [4, 5, 6, 7]

Since injection drug use has become less common, providing care and treatment for HIV-positive cocaine users has emerged as a key challenge in Brazil. In response, The Pan-American Health Organization (PAHO) and the Brazilian Ministry of Health created a task force to develop guidelines for management of HIV-positive cocaine users, in collaboration with clinicians, researchers, staff from non-governmental organizations and community members. The guidelines were widely distributed, and discussed during a series of meetings with local governments, health care providers, community members and NGO staff. Skills-building workshops were created to support their implementation.

Drug use and adherence to ART

Concerns about poor adherence to ART among drug users were repeatedly raised during guidelines meetings. Dr Malta conducted a comprehensive review of studies on adherence among current and former drug users (Table 1), to address these concerns. She reported adherence rates that ranged from 44-85%. In contrast, an analysis of adherence rates in resource-rich and resource-poor countries from Mills and colleagues reported an overall adherence rate in resource-rich countries of 54.7%, versus 77.1% in resource-poor countries. [8]

How much is enough?

With antiretroviral therapy, an adherence rate of >95% is generally considered necessary to suppress HIV RNA and avoid development of resistance. However, the correlation between adherence and resistance may differ by class of antiretroviral agent. For example, Bangsberg studied adherence and response to ART in the REACH cohort (Research on Access To Care), a group of homeless adults, 65% of whom had a history of injection drug use. A majority of those receiving a non-nucleoside analog (NNRTI)-based regimen achieved an HIV RNA of <400 copies/mL, despite adherence rates as low as 53% (range, 53-100%). In contrast, an adherence rate of >95% was necessary to achieve HIV RNA of <400 copies/mL for protease inhibitor-based regimens. [9]

Conclusion

Dr Malta summarised the key lessons learned:

• Drug users can adhere to ART
• If the regimen is sufficiently potent, viral suppression can be achieved with adherence rates of <95%
• Adherence rates among HIV-positive cocaine users increase when they have access to psycho-social support and drug treatment with their medical care
• HIV treatment should not be withheld from people who use drugs, regardless of concomitant diagnoses, such as psychiatric disorders and hepatitis C coinfection.

Brazilian HIV-positive drug users still face several barriers to effective HIV care and treatment. There is no substitution treatment for cocaine. Health care professionals require training to work with people who are using drugs. Lack of resources for comprehensive services, and social problems—racism, poverty, and stigma— continue to limit access.

However, the situation for HIV-positive drug users in Brazil is changing. In Dr Malta’s words, “It is possible to scale up ART and maintain the necessary adherence levels in developing country settings and among HIV-positive drug users. Improved access to HIV treatment is an essential step of any valid attempt to curb the AIDS epidemic, and needs to be faced as a human rights priority. No one should be left behind…”

Table 1. Adherence to ART among people who use drugs and alcohol

Adapted from Dr Monica Malta (abstract 949) Ten Years of universal access to HIV treatment: Learning from the Brazilian Experience. 18th International Conference to Reduce Drug Related Harm. Warsaw, Poland. May 13-17th, 2007.

ADD TABLE

Sources for Table 1:

Altice FL, Mostashari F, Friedland GH. Trust and the acceptance of and adherence to antiretroviral therapy. J Acquir Immune Defic Syndr. 2001 Sep 1;28(1):47-58.

Pradier C, Carrieri P, Bentz L, et al. Impact of short-term adherence on virological and immunological success of HAART: a case study among French HIV-infected IDUs. Int J STD AIDS. 2001 May;12(5):324-8.

Bouhnik AD, Chesney M, Carrieri P, et al; MANIF 2000 Study Group. Nonadherence among HIV-infected injecting drug users: the impact of social instability. J Acquir Immune Defic Syndr. 2002 Dec 15;31 Suppl 3:S149-53.

Carrieri MP, Chesney MA, Spire B, et al. MANIF Study Group. Failure to maintain adherence to HAART in a cohort of French HIV-positive injecting drug users. Int J Behav Med. 2003;10(1):1-14.

Palepu A, Tyndall M, Yip B, O’Shaughnessy MV, Hogg RS, Montaner JS. Impaired virologic response to highly active antiretroviral therapy associated with ongoing injection drug use. J Acquir Immune Defic Syndr. 2003 Apr 15;32(5):522-6.

Wagner G. Placebo practice trials: the best predictor of adherence readiness for HAART among drug users? HIV Clin Trials. 2003 Jul-Aug;4(4):269-81.

Wood E, Montaner JS, Yip B, et al. Adherence and plasma HIV RNA responses to highly active antiretroviral therapy among HIV-1 infected injection drug users. CMAJ. 2003 Sep 30;169(7):656-61.

Altice FL, Mezger JA, Hodges J, et al. Developing a directly administered antiretroviral therapy intervention for HIV-infected drug users: implications for program replication. Clin Infect Dis. 2004 Jun 1;38 Suppl 5:S376-87.

Palepu A, Horton NJ, Tibbetts N, Meli S, Samet JH. Uptake and adherence to highly active antiretroviral therapy among HIV-infected people with alcohol and other substance use problems: the impact of substance abuse treatment. Addiction. 2004 Mar;99(3):361-8.

Bouhnik AD, Préau M, Vincent E, et al; MANIF 2000 Study Group. Depression and clinical progression in HIV-infected drug users treated with highly active antiretroviral therapy. Antivir Ther. 2005;10(1):53-61.

References
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2. Aceijas C, Friedman SR, Cooper HL, Wiessing L, Stimson GV, Hickman M. Estimates of injecting drug users at the national and local level in developing and transitional countries, and gender and age distribution. Sex Transm Infect. 2006 Jun;82 Suppl 3:iii10-17.
3. Aceijas C, Oppenheimer E, Stimson GV, Ashcroft RE, Matic S, Hickman M. Antiretroviral treatment for injecting drug users in developing and transitional countries 1 year before the end of the “Treating 3 million by 2005. Making it happen. The WHO strategy” (“3 by 5”). Addiction. 2006 Sep;101(9):1246-53.
4. de Azevedo RC, Botega NJ, Guimarães LA. Crack users, sexual behavior and risk of HIV infection. Rev Bras Psiquiatr. 2007 Mar;29(1):26-30.
5. Dunn J, Laranjeira RR. HIV-risk behaviour among non-heroin using cocaine injectors and non-injectors in São Paulo, Brazil. AIDS Care. 2000 Aug;12(4):471-81.
6. Leukefeld CG, Pechansky F, Martin SS, et al. Tailoring an HIV-prevention intervention for cocaine injectors and crack users in Porto Alegre, Brazil. AIDS Care. 2005 Jun;17 Suppl 1:S77-87.
7. Pechansky F, Woody G, Inciardi J, et al. HIV seroprevalence among drug users: an analysis of selected variables based on 10 years of data collection in Porto Alegre, Brazil. Drug Alcohol Depend. 2006 Apr;82 Supplement 1:S109-13.
8. Mills EJ, Nachega JB, Buchan I, et al. Adherence to antiretroviral therapy in sub-Saharan Africa and North America: a meta-analysis. JAMA. 2006 Aug 9;296(6):679-90.
9. Bangsberg DR. Less than 95% adherence to nonnucleoside reverse-transcriptase inhibitor therapy can lead to viral suppression. Clin Infect Dis. 2006 Oct 1;43(7):939-41.

Introduction

This annual HIV conference is one of the most important conferences.

Included below are a selection of reports relating to IDU-interest research.

Unless stated otherwise, references are to the Programme and Abstracts for the 14th Conference on Retrovirus and Opportunistic Infections, available online.

Webcasts (including slides) and podcasts are also available on the site:

http://www.retroconference.org

The CROI website has made all key lectures and oral presentations available online, and includes online searchable free access to the abstracts from the meeting, and posts an increasing proportion of poster abstracts online in PDF format (though this is still only for a minority of the posters).

This broad access means that it is easy to see important trial results and overview lectures directly – this is better that through a community or medical journalist – and the questions and discussion at the end of each session are also included in these web presentations.

We encourage readers to find a few hours to follow some of this important material first hand.

IDU-related reports from this meeting, although adding little to current knowledge, include:

• Low rates of HCV treatment among eligible injection drug users;
• Effect of HCV and HIV on mortality among injecting drug users;
• HIV-positive IDU co-infected with HCV are at increased risk of hepatitis related death in the HAART era, compared with IDU with HCV monoinfection;
• Long-term effectiveness of isoniazid prophylaxis on TB incidence in a cohort of IDU;
• The dynamics of HCV transmission among injection drug users in St. Petersburg;
• “Founder effect” among HIV-positive IDU in Karachi, Pakistan.

These studies highlight the paucity of new research at this important HIV meeting, especially in the context of a burning need to improve access to, and quality of care for IDUs and coinfected people.

The study enrolled 332 subjects (172 HIV/HCV co-infected; 158 HCV mono-infected). HIV-co-infected IDU were younger (41 to <44 years) and were more likely to be African American (90% to >74%), have a monthly income >$500 (52% to >23%) than those with HCV alone. The investigators reported no difference in the prevalence of mental illness (~64%), alcohol use (~20%), or interest in receiving HCV treatment (~93%).

Table 1: Characteristics of HIV/HCV patients

ADD TABLE

Of the treatment-eligible IDU, about 40% initiated HCV therapy, defined as at least pegINF injection (31/75 HIV/HCV, 41%; 27/80 HCV, 36%).

The investigators concluded: “While approximately 50% of HIV/HCV-co-infected IDU were ineligible for HCV treatment, most (~80%) of HCV-mono-infected IDU were treatment-eligible. Despite the removal of financial and geographic barriers, only around 40% of treatment-eligible IDU initiated HCV treatment. Strategies are needed to increase HCV treatment uptake among IDU.”

comment

A paper from Mehta and colleagues (also at Hopkins) that came out last year, looking at access to HCV care and treatment among coinfected people is worth reading in this context.

Ref: Sulkowski M, Mehta S, Moore R et al. Low rates of HCV therapy among treatment-eligible injection drug users with and without HIV Co-infection. 14th CROI, 2007, Los Angeles. Poster abstract 947.

The investigators found, of 2069 participants, 721 were both HCV and HIV-negative (HCV–/HIV–), 962 were HCV-positive and HIV-negative (HCV+/HIV–), 33 were HCV negative and HIV-positive (HCV–/HIV+), and 353 were HCV and HIV-positive (HCV+/HIV+).

Among the 82 reported deaths, they found the two most common causes were HIV (25.6%) and unnatural causes (19.5%). The natural cause mortality rate was 15.5 deaths/1000 person-years overall (n = 66).

Table 1: Overall mortality by HIV and HCV status.

ADD TABLE

For HCV–/HIV+ and HCV+/HIV– subjects, mortality attributed to HIV and HCV was 15.2 and 2.0 deaths/1000 person-years. In HCV+/HIV+ subjects, mortality attributed to HIV and HCV were 25.6 and 1.3 deaths/1000 person-years. Overall, natural cause mortality was associated with HIV infection (adjusted HR 5.3, 3.0 to 9.7, p<0.001), age (HR 1.8/10-year increase, 1.3 to 2.4, p <0.001) and aboriginal ethnicity (HR 1.7, 0.96 to 3.0, p = 0.07), and not associated with HCV infection (HR 1.0, 0.50 to 2.0, p = 0.99).

The investigators concluded that mortality rates in IDUs were high in this analysis, and HIV infection gave a 5-fold increase in risk of mortality. They noted that due to the timing of the HCV epidemic in this population, there has been little impact of HCV on mortality to date. “They wrote “Without programmes to treat HCV in this group, we expect a significant increase in mortality attributable to HCV infection.”

Ref: Grebely J, Raffa J, Conway B et al. Effect of hepatitis C virus and HIV infections on mortality among illicit drug users. 14th CROI, 2007, Los Angeles. Poster Abstract 922.

The study population consisted of 1276 IDU from a cohort started in 1985. Blood samples collected for HIV testing at 4- to 6-monthly visits was retrospectively tested for HCV.

The investigators found serological groups at study entry were: 19% HCV+/HIV+, 43% HCV+/HIV–, 1% HCV–/HIV+, 36% HCV–/HIV–. During follow-up, 272 IDU died. Overall, mortality risk decreased for most causes of death in the HAART era (defined as after 1997), but the risk was not the same across the groups. For the HIV+/HCV+ IDU group, the risk of death from AIDS decreased significantly (CHR 0.37, 95%CI 0.19 to 0.72), whereas the risk of hepatitis or liver-related death did not change over time (CHR 0.87, 95%CI 0.21 to 3.58). In the HCV+/HIV– and HCV–/HIV– IDU groups, no significant changes in the risks of death were observed.

When comparing the risks of death among serologic groups, they found in the HAART era that the HCV+/HIV+ IDU group had a significantly higher risk of hepatitis or liver-related death than the HCV+/HIV– IDU group (CHR 7.15, 95%CI 1.98 to 25.8). Increased risks of dying from non-natural and natural causes of death were also found. No major differences were observed between the HCV–/HIV– and HCV+/HIV– IDU groups.

The investigators concluded that the risk of dying from HCV-related causes among HCV/HIV-co-infected IDU, has not increased after the introduction of HAART. But they found that compared to the HCV+/HIV– IDU group, HCV/HIV-co-infected IDU remained at increased risk of hepatitis and liver-related death after 1997, suggesting that HIV co-infection continues to accelerate HCV disease progression. They wrote: “Efforts should be made to establish effective HCV treatment in HCV/HIV-co-infected persons.”

Ref: Prins M, Smit C, van den Berg C et al. HCV/HIV-co-infected drug users are at increased risk of dying from hepatitis-related death in the HAART era, compared with HCV-mono-infected drug users. 14th CROI, 2007, Los Angeles. Poster Abstract 923.

This cohort includes >2000 IDU in Baltimore, 35% of whom were HIV-positive at baseline. TST and IPT were offered to all ALIVE participants from 1990 to 1998. TB incidence was measured in 3 periods:  pre-purified protein derivative (PPD) era (1988-1990), PPD era (1990-1998), and post-PPD era (1998-2004). Incidence rate ratios compared TB incidences among eras.

The investigators found out of a group of 753 HIV-positive participants, 651 (86%) had a TST ; 103 (16%) had a positive result (>5 mm); 65 (60%) started IPT; and 40 (62%) completed 6 months. Of the1264 HIV-negative participants, 1105 (87%) had a TST; 435 (39%) had a positive result (>10 mm); 246 (56%) started IPT; and 133 (54%) completed 6 months. In total, 32% of those with a positive TST completed 6 months of IPT.

In this study 30 TB cases were diagnosed over 28,750 person-years:  IR = 1.04/1000 person-years in HIV-negative; IR = 2.66/1000 person-years among the HIV-positive population. The investigators reported TB incidence in the post-PPD-era for the overall cohort was half that seen in the PPD-era (IRR = 0.44, 95%CI 0.19 to 1.04), but they found no significant difference between eras in the HIV-positive population (2.04 vs 3.14/1000 person-years; IR = 0.64, 95%CI 0.27 to 1.58).

Both overall and amongst the HIV-positive participants, TB incidence among those who never received IPT was greater than those who started IPT; no cases were detected for those who received 6 months of IPT. Among the HIV-positive participants the investigators found body mass index <21 (RH = 3.1, p <0.01) and CD4 <200 (RH = 9.6, p <0.01) to be most predictive of TB. ART use had no association with risk of TB.

The investigators reported that a significant long-term reduction in TB incidence was observed in a cohort of IDU with a high HIV prevalence after an 8-year strategy of TST/IPT, but no change was seen in the HIV-positive subset. They noted that IPT was highly effective for those who completed it, but only 32% of TST-positive patients completed. “Broader use of IPT in HIVIDU could substantially decrease TB incidence.” They wrote.

Ref: Jonathan Golub, J Astemborski, M Ahmed et al. Long-term effectiveness of isoniazid preventive therapy on TB Incidence in a cohort of injection drug users. 14th CROI, 2007. Los Angeles. Abstract 851.

The investigators reported that sequences from 77 people studied showed 3 main genotypes (3a, 1a, and 1b) circulating in the study population, with a majority of genotype 3a (62%). Genotypes 1b and 1a were 21% and 17%, respectively.

Of the total, 67/77 samples belonged to 11 recruitment chains of productive seeds or chains with more than 2 people; 4 chains with 6, 4, 2, and 3 people (excluding seeds) had a single genotype (3a); 4 chains with 7, 11, 5, and 4 members (excluding seeds) had multiple genotypes with >50% of them belonging to 3a; 3 chains with 13, 4, and 2 members (excluding seeds) contained discordant genotypes in variable amounts.

They concluded that these data suggest that molecular epidemiological tools could provide data to support or refute transmission within social networks that are exploited in assembling respondent-driven sampling study populations.

They wrote: “The ability of respondent-driven sampling to capture transmission patterns for prevalent infections appears limited, but the two data sets combined could provide a more robust exploration of incident transmissions of infectious diseases like HCV and HIV.”

Ref: Paintsil E, Abdala N, Niccolai L et al. The dynamics of HCV transmission among injection drug users in St. Petersburg, Russia: Sexual Transmission and Acquisition of HIV Cooperative Agreement Program. 14th CROI, 2007, Los Angeles. Abstract 131.

Mohammad Rai and co-workers reported findings from a study to determine whether an HIV outbreak among a community of 15 IDU in Karachi was from a single source.

Viral DNA was extracted from blood samples collected between January and December 2004. Sequence alignment of the nef gene from HIV-1-positive patients from Pakistan indicated that the HIV-1 strains differed from the strains circulating in neighbouring India, and were genetically closer to HIV-1 subtype A strains from Senegal, Uganda, and Kenya. Additionally, phylogenetic analysis of the complete nef gene sequence revealed highly congruent topologies, using the neighbour-joining method. The HIV-1 strains from Pakistan formed a monophyletic group.

The investigators wrote: “Our data suggest that the HIV-1 sequences circulating among IDU in Karachi, Pakistan, belong to only 1 HIV subtype, subtype A. Moreover, the intra-sequence identity of 98% indicates a founder effect.”

The noted that these data contrast with a previous observation demonstrating presence of multiple HIV-1 subtypes among overseas contract workers.

They concluded: “The HIV-1 epidemic in Pakistan is shifting from imported cases, such as among the overseas contract workers, to the spread of HIV among local high-risk behavior populations. More prevention and control studies are urgently warranted to curtail the spread of HIV in Pakistan.”

Ref: Rai M, Nerurkar V, Yanagihara R et al. Founder effect among HIV-1-infected Injection drug users in Karachi, Pakistan. 14th CROI, 2007, Los Angeles. Poster Abstract 241.