A report in the 24 September 2008 online edition of the Lancet estimates that about 3 million injecting drug users worldwide could be HIV-positive.

Bradley Mathers and co-authors, on behalf of the 2007 Reference Group to the UN on HIV and Injecting Drug Use, performed a literature search of peer reviewed and non-peer reviewed “grey” literature databases. Requests were also made to UN agencies and other international experts.

The authors considered 200 countries and the review revealed documented drug use in 148 of these. They reviewed 11,022 documents and noted that reports were only available for a small number of countries in the Caribbean (6/15) and sub-Saharan Africa (13/47).

They found that prevalence estimates of injecting drug use could be made for 61 countries representing 77% of the total population worldwide aged 15-64 years.

Extrapolated estimates from this review suggested that 15.9 million (range 11.0-21.2 million) people worldwide could be injecting drug users.

They found the largest numbers of injecting drug users in China, the USA and Russia with midpoint prevalence estimates of 12%, 16% and 37% respectively.

HIV prevalence among injecting drug users was 20–40% in five countries and was greater than 40% in another nine (they noted that areas of particular concern are countries in southeast Asia, eastern Europe, and Latin America). China, Russia, and the USA all had midpoint estimates of HIV prevalence in these populations of over 10%.

The authors estimated that worldwide about 3 million (range 0.8-6.6 million) people might be HIV positive.

They explain that the study has many limitations, not least that data from which to extrapolate prevalence estimates are inconsistent and populations typically hard to access.

They write: “People who inject drugs have the right to enjoy the highest standard of health attainable. There is a clear mandate to invest in HIV prevention activities such as needle and syringe programmes and opioid substitution treatment and to provide treatment and care for those who are living with HIV/AIDS.”

Ref:
Mathers BM, Degenhardt L, Phillips B et al. Global epidemiology of injecting drug use and HIV among people who inject drugs: a systematic review. The Lancet. Published online September 24, 2008.

A study by Angela Dean from the University of Queensland and colleagues in the journal European Psychiatry has reported similar improvements in depression in patients using either methadone (MM) and buprenorphine (BM) as opiod substitution therapy (OST). [1]

This is important because this benefit of OST is not widely understood, or reported for methadone, and because early studies of buprenorphine emphasized it’s antidepressant effect as a potential advantage.

This was a sub-study of a much larger trial. [2] The authors studied the antidepressant affects in 54 patients who were part of a randomised controlled trial (with additional matched placebo) of daily 30mg MM syrup vs 4mg BM sublingual tablets in 405 heroin-dependent patients seeking opioid maintenance treatment. Doses were individually titrated based on patient assessment to optimise response.

Daily dosing occurred for 6 weeks, after which alternate day dosing began. Those on buprenorphine received double their previous daily dose (or increased to the maximum permitted dose of 32 mg) on alternate days and placebo on interposed days. Methadone patients received a corresponding increase in their placebo buprenorphine tablets to maintain the blind.

Baseline demographics included approximately 60% men, 40% women; age 30; 6-7 years heroin use (with a wide range); and 70-80% prior treatment for opiate dependence.

Depression was measured using the self-report Beck Depression Inventory (BDI) at baseline and after 3 months. Symptoms of depression significantly improved in both treatment groups over the study period (p<0.001) with no differences between groups (p=0.83). Neither previous duration of heroin use, nor dose levels of either drug were related to results on the depression score. These results are detailed in Table 1.

Table 1: Depression score results

ADD TABLE

With patients in the methadone group, a higher baseline depressive symptoms predicted higher symptoms at 3 months (p<0.01) and there was a significant relationship between adherence (as % of doses taken in last 30 days) and BDI at 3 months (p<0.05). Neither factor was significant for the buprenorphine group (p=0.38 and p=0.58 respectively).

The 9% of the study group using antidepressants had a smaller improvement in BDI scores but a modest but significant relationship between BDI scores and heroin use over the previous month.

This study therefore found no differential benefits of buprenorphine vs methadone on depressive symptoms. The high levels of depressive symptoms at treatment entry and subsequent improvement over time in both groups are consistent with other research. [3, 4]

However the authors also noted that given the small sample size, the power to detect group differences is low, and that that larger samples would be required in future studies. Other factors that could have impacted on the results, included differences in dosing and under-reporting of antidepressant use.

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Questions:

This is from 2004 – have other larger studies reported on this, or confirmed the findings?

Did the authors republish later when all 147 subjects had both baseline and 3 months – ie increasing the study power?

Double blind studies with methadone and buprenorphine are very difficult to do.

Certainly the antidepressant effect of methadone and buprenorphine are well recognised clinically, but few studies are designed study to document the effect. This study was designed to show that the antidepressant impact of buprenorphine may be an advantage over methadone, but by comparing both drugs in a randomised placebo-controlled study, the methadone effect was also clearly identified.

The cause-effect relationship is complicated. Clearly OST has an antidepressant effect, but is it the medication, or is it the cessation of all those psychosocial negative impacts of chaotic heroin use and the benefits of achieving some control over you life which is the antidepressant effect?

Alternatively it may just be the cessation of the rapid up-and-down cycles associated with regular heroin use. Maybe repeated low-grade withdrawal is a depressant, and preventing it, a powerful antidepressant?

Many questions, few answers.

References

1. Dean AJ et al. Depressive symptoms during buprenorphine vs. methadone maintenance: findings from a randomised, controlled trial in opioid dependence. Short communication. European Psychiatry 19 (2004) 510–513.
2. Mattick RP et al. Buprenorphine versus methadone maintenance therapy: a randomized doubleblind trial with 405 opioid-dependent patients. Addiction 2003;98:441–52.
3. Rounsaville BJ et al. Diagnosis and symptoms of depression in opiate addicts: course and relationship to treatment outcome. Arch Gen Psych 1982; 39:151–6.
4. Strain EC et al. Early treatment time course of depressive symptoms in opiate addicts. J Nerv Ment Dis 1991;179: 215–21.

Vincent Sorriano and colleagues from the EuroSIDA cohort published an analysis in the November edition of JID of HCV genotype, viraemia and rates of spontaneous HCV clearance in HIV-positive patient in Europe and Argentina. [1]

All HCV antibody-positive (Ab+) patients the cohort with stored samples were tested for serum HCV RNA and viraemic patients were genotyped.

Of 1940 HCV Ab+ patients, 1496 (77%) were serum HCV RNA positive. Injection drug users (IDUs) were less likely to have spontaneously cleared HCV than were homosexual men (20% vs. 39%; adjusted odds ratio [OR], 0.36 [95% confidence interval {CI}, 0.24–0.53]), whereas patients positive for hepatitis B surface antigen (HBsAg) were more likely to have spontaneously cleared HCV than were those negative for HBsAg (43% vs. 21%; OR, 2.91 [95% CI, 1.94–4.38]).

Of patients with HCV viremia, 786 (53%) carried HCV genotype 1, and 53 (4%), 440 (29%), and 217 (15%) carried HCV genotype 2, 3, and 4, respectively. Higher HCV RNA levels were associated with a greater chance of being infected with HCV genotype 1 (OR, 1.60 per 1 log higher [95% CI, 1.36–1.88]).

The authors concluded that “more than three-quarters of the HCV Ab+ HIV-positive patients in EuroSIDA showed active HCV replication. Viremia was more frequent in IDUs and, conversely, was less common in HBsAg-positive patients. Of the patients with HCV viremia analyzed, 53% were found to carry HCV genotype 1, and this genotype was associated with greater serum HCV RNA levels.

An editorial comment by Raffaele Bruno and Paolo Sacchi pointed out that the high (25%) clearance rate should to be done by repeatedly using a more-sensitive test, such as a transcription-mediated amplification, rather than using single time point RNA. [2]

They explained that “In the absence of HIV infection, spontaneous HCV clearance occurs in 20% of patients. Spontaneous HCV clearance, which seldom occurs >12 months after primary infection, is less likely in men, people of black race, chronic carriers of HBV, and probably those who become infected after early childhood. Clearance of HCV does not convey immunity, because new exposure can result in reinfection. The rate of spontaneous clearance may be 2-fold higher (40%) in IDUs who clear their primary infection in the absence of HIV coinfection. Nonetheless, the majority of HCV reinfections become chronic, as seen in persons with hemophilia who used contaminated plasma derivatives before 1983. Mehta et al noted that, compared with primary infection, clearance of HCV reinfection increased among HIV-negative but not HIV-positive IDUs. [3]

“Given their low rate of spontaneous clearance and poor response rates, preservation of immune function with early antiretroviral treatment may be the best way to avoid a poor outcome of liver disease in HIV-positive patients. Further study of this strategy is warranted.”

References

1. Vincent Soriano V et al for the EuroSIDA Study Group. Spontaneous Viral Clearance, Viral Load, and Genotype Distribution of Hepatitis C Virus (HCV) in HIV-Infected Patients with Anti-HCV Antibodies in Europe. JID 2008;198:1337–1344.
http://www.journals.uchicago.edu/doi/abs/10.1086/592171
2. Raffaele Bruno and Paolo Sacchi. Spontaneous Hepatitis C Virus Clearance in HIV-Infected Patients: New Insights for Improving Management. Editorial commentary. JID 2008;198:1262–1264.
http://www.journals.uchicago.edu/doi/full/10.1086/592173
3. Mehta SH, Cox A, Hoover DR, et al. Protection against persistence of hepatitis C. Lancet 2002; 359:1478–83.

A very useful and timely epidemiology review of research papers on global HIV and IDU by the Reference Group to the UN on HIV and Injecting Drug Use was published in September in the Lancet. [1]

In a systematic search of peer-reviewed, internet, and grey literature databases; and data requests were made to UN agencies and international experts, over 11,000 documents were reviewed, graded, and catalogued.

Injecting drug use was identified in 148 countries but data for the extent of injecting drug use was absent for many countries in Africa, the Middle East, and Latin America. The presence of HIV infection among injectors had been reported in 120 of these countries. Prevalence estimates of injecting drug use could be ascertained for 61 countries, containing 77% of the world’s total population aged 15–64 years. Extrapolated estimates suggest that 15·9 million (range 11·0–21·2 million) people might inject drugs worldwide; the largest numbers of injectors were found in China, the USA, and Russia, where mid-estimates of HIV prevalence among injectors were 12%, 16%, and 37%, respectively. HIV prevalence among injecting drug users was 20–40% in five countries and over 40% in nine.

The researchers estimated that, worldwide, about 3 million (range 0·8–6·6 million) people who inject drugs might be HIV positive.

The authors concluded “The number of countries in which the injection of drugs has been reported has increased over the last decade. The high prevalence of HIV among many populations of injecting drug users represents a substantial global health challenge. However, existing data are far from adequate, in both quality and quantity, particularly in view of the increasing importance of injecting drug use as a mode of HIV transmission in many regions”.

In a separate editorial comment, Kamvar Arasteh and Don Des Jarlais from the Beth Israel Medical Center, New York, highlights the importance of the disturbing trends observed in the article for Asia and eastern Europe. [2]

In China, with the largest estimated population of injecting drug users and an HIV prevalence of 12% in users, HIV infections have been rising. In Vietnam, the prevalence of injecting drug use is estimated at 0·25% with an HIV prevalence of 34%. In Malaysia, the prevalence of injecting drug use is 1·3% with an HIV prevalence of more than 10%.

These estimates reveal large gaps between the numbers of IDUs who access prevention services and HIV testing. In 2007, less than half of IDUs in China had received an HIV test in the previous 12 months and knew their status, only a third reported using a condom during their last sexual intercourse, and only 40% reported using sterile injection equipment the last time they injected.

They concluded that “if HIV-prevention efforts are implemented on a large scale when prevalence is low in injecting drug users, it is possible to avert larger HIV epidemics. Thus it should be an imperative—for both resource-constrained countries and international donors—to implement large-scale evidence-based programmes for HIV prevention wherever there is an indication of a problem with the development of injecting drug use.”

References

1. Mathers BM et al for the 2007 Reference Group to the UN on HIV and Injecting Drug Use. Global epidemiology of injecting drug use and HIV among people who inject drugs: a systematic review . The Lancet DOI:10.1016/S0140-6736(08)61311-2. (Early publication 24 September 2008).
2. Arasteh K. Injecting drug use, HIV, and what to do about it. Comment. The Lancet DOI:10.1016/S0140-6736(08)61312-4. (Early publication 24 September 2008).

Four to six years after starting anti-HIV treatment, higher rates of AIDS and mortality were seen in injection drug users and in those who had had AIDS-defining events or CD4 cell counts less than 25 cells/mm3 before starting therapy. The study, conducted by the Antiretroviral Therapy Cohort Collaboration, was published in the December 15th issue of the Journal of Acquired Immune Deficiency Syndromes. [1]

Previous studies have found that rates of AIDS-related illness and death are higher in people who begin antiretroviral therapy with lower CD4 cell counts. Poorer response has also been found in injection drug users (IDUs) compared to other patients. However, most studies to date have looked at response over relatively short time periods. In this study, the Antiretroviral Therapy Cohort Collaboration (an international alliance of investigators from sixteen cohort studies of people with HIV [2]) analysed data from 20,379 HIV-positive adults who had been on anti-HIV drugs for up to six years.

Participating cohorts were included if they had enrolled at least 100 treatment-naïve patients, 16 years of age or older, who had begun treatment with a combination of at least three antiretroviral agents. People with baseline viral loads less than 1000 copies/ml were excluded as possibly not treatment-naïve. This yielded a total of 20,379 patients from twelve European and North American cohorts. Baseline characteristics were as follows: median age, 36; median CD4 cell count 224 cells/mm3; median month of therapy initiation, February 1999. Before treatment initiation, 2737 patients (23%) had already had a diagnosis of AIDS; 3231 (16%) were presumed infected due to IDU. Of the initial regimens, 66% were NRTI/PI, 24% NRTI/NNRTI, 7% NRTI only, 2% triple-class; and 2% other (NRTI-sparing, or including T-20). The majority of participants (88%) began on a three-drug regimen.

Over a total of 61,798 person-years of follow-up, 1844 participants developed at least one AIDS-defining event, and 1005 died. AIDS-defining events and deaths were analysed by: baseline CD4 cell count (<25, 25 to 49, 50 to 99, 100 to 199, 200 to 349, and >350 cells/mm3), baseline viral load(<100,000 or ≥100,000 copies/mL), presumed mode of transmission (IDU or other), and AIDS diagnosis before baseline (yes or no). Consistent with previous studies, lower baseline CD4 cell counts were consistently the strongest predictor of poorer outcomes. The effect was strongest for the lowest baseline counts, and tended to decline with length of time on therapy for all strata of CD4 count. Beginning therapy at a baseline CD4 cell count between 200 and 349 continued to show a benefit until the four-year mark. Compared to those beginning at >350 cells/mm3 (the comparator group), the hazard ratio for progression to AIDS at one to two years on therapy was 1.5 (95% confidence interval [CI]: 1.0 to 2.3), 1.4 at two to three years (95% CI: 1.0 to 2.1), and 1.0 at four to six years (95% CI: 0.6 to 2.0). For each time period, hazard ratios were progressively higher for each lower CD4 stratum. For baseline CD4 counts <25 cells/ mm3, the hazard ratio for developing AIDS was 3.7 at one to two years (95% CI: 2.2 to 6.1), 2.4 at two to four years (95% CI: 1.5 to 3.8), and 2.3 at four to six years (95% CI: 1.0 to 2.3). At four to six years, the hazard ratio for mortality was 2.5 (95% CI: 1.2 to 5.5) for baseline CD4 counts <25 cells/ mm3.

For people presumed infected through IDU, at four to six years on HAART, the hazard ratio for AIDS was 1.6 (95% CI: 0.8 to 3.0) and the hazard ratio for mortality was higher at 3.5 (95% CI: 2.2 to 5.5). Note that cause of death was not analysed and was not necessarily directly due to HIV; mortalities due to hepatitis-related liver disease, overdose, trauma and other causes were not excluded. Mortality rates were still lower than would be expected in the absence of anti-HIV therapy. Diagnosis of AIDS before the initiation of anti-HIV treatment also continued to predict AIDS-defining events at four to six years, with a hazard ratio of 2.3 (95% CI: 1.2 to 4.4); the predictive value for mortality ceased to be significant. HIV viral load (greater than, or less than, 100,000 copies/ml) was not a significant predictor of progression or death at any time point. The study was limited by declining numbers of patients in follow-up after longer periods on antiretroviral treatment. At the end of the fourth year of anti-HIV therapy, 6838 participants were still being followed (23% of the original cohort); only 791 (4%) were followed for more than six years. As most original patients were still being followed up at the time of analysis, the researchers “do not believe that informative censoring is likely to be an important source of bias.”

However, results may have been confounded by socioeconomic and other factors which caused people to begin treatment late in the course of HIV progression. Larger hazard ratios for mortality than for development of AIDS were seen in several groups, which may be evidence of such confounding. Also, race and ethnicity were not included in the analysis due to lack of sufficient data. The researchers concluded that “rates of AIDS and death were persistently higher in patients infected [through injection drug use]”, and that “although the prognostic value of baseline CD4 count and a prior AIDS diagnosis declined with time, patients who were severely immunodeficient when they started therapy experienced higher rates of AIDS and death up to 6 years later.” They believe these results may “strengthen the case for screening for HIV, because delaying treatment… has long-term disadvantages.”

Source: aidsmap.com
http://www.aidsmap.com/en/news/8ACEB690-26EB-4583-BF14-A4353CE335EC.asp

References:
1. Antiretroviral Therapy Cohort Collaboration. Importance of baseline prognostic factors with increasing time since initiation of highly active antiretroviral therapy: collaborative analysis of cohorts of HIV-1–infected patients. J Acquir Immune Defic Syndr 46 (5):607-615, 2007.
2. http://www.art-cohort-collaboration.org/