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.

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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”.

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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

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

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

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.

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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

HIV and hepatitis C are prevalent among current and former injection drug users (IDUs). For years, activists have been protesting the exclusion of people who use drugs from clinical trials of novel agents for HIV and hepatitis C. Excluding high prevalence populations from all research of new treatments is unacceptable, unless there is a compelling safety reason to do so.

Recently, exclusion criteria have become slightly less restrictive in some cases, leaving the investigator holding the bag, as it were. He or she is empowered to decide whether a person’s drug and/or alcohol use, dependence or abuse will interfere with the ability to participate in a trial—or if it could endanger study volunteers.

In theory, this is progress, but in practice, the impact is limited. Concerns about adherence and drug-drug interactions need to be addressed. Regular attendance at clinic visits may be a good indicator for the ability to participate in a clinical trial, rather than whether or not a person is using drugs and/or alcohol. Drug and alcohol use, dependence and abuse are not the same, and should be assessed with validated, easy-to-use tools such as the AUDIT-C. It may be possible to identify drug-drug interactions by in vitro studies—and if not, a safe way to gather this information must be determined.

Some drug-and alcohol-related exclusion criteria have become gospel, although the information they are based on may be limited or outdated. These have rendered drug and alcohol users ineligible for approved treatments and interventions, as well as clinical trials. Here are two examples:

• Early HCV treatment trials, using interferon monotherapy, reported poorer outcomes among people who drank before or during HCV treatment versus non-drinkers. [1, 2, 3] Hence, many doctors are unwilling to treat drinkers for hepatitis C, despite newer information, and more effective HCV treatment. Two recent studies, which used interferon plus ribiavirin), reported that people who drank prior to, or during HCV treatment responded as well as non-drinkers. [4, 5]
• Although recent alcohol and/or drug use is considered a “relative” contraindication for liver transplantation in the United States, candidates with a history of substance abuse must be abstinent for six months before they are put on the waiting list. [6] This delay may be fatal for some people ,since the chronic shortage of donor organs may mean a long wait. However, a recent study did not find any difference in survival of liver transplant recipients who resumed substance use versus those who remained abstinent after transplantation. [7]

HIV and hepatitis C trials for people who use drugs

The following listing of studies that are currently recruiting-or soon to open is compiled from:

http://clinicaltrials.gov

Unless listed under “international”, these trials are in the United States.

Listing these trials is not an endorsement or comment on either the research or trial design.

International

• Adolescent Drug and HIV Prevention in South Africa
• Methadone Maintenance & HIV Risk in Ukraine
• Naltrexone and Adrenergic Agents to Reduce Heroin Use in Heroin Addicts
• Project HERMITAGE: HIV Prevention in Hospitalized Russian Drinkers
• Addiction Treatment in Russia: Oral vs. Naltrexone Implant
• Hepatitis C Among Opioid addicts in Opioid maintenance Treatment in Zurich, Switzerland (HepCOP)

Prevention/Drug Treatment (HIV status not specified unless noted)

• Computer-Assisted HIV Prevention for Young Drug Users
• Treatment of Heroin and Cocaine With Methadone Maintenance and Contingency Management Users
• Drug Treatment Combined With Drug and Risk Reduction Counseling in the Prevention of HIV Infection Among Injection Drug Users (HIV negative)

Prisoners

• Prison Buprenorphine
• Effectiveness of Opiate Replacement Therapy Administered Prior to Release From a Correctional Facility – 1
• Buprenorphine Maintenance for Opioid-Addicted Persons in Jail and Post-Release (males only)
• Hepatitis C (HIV status not specified unless noted)
• A Video-Based HCV Curriculum for Drug Users
• Improving Hepatitis C Treatment in Injection Drug Users
• Study of the Effects of Motivational Enhancement Therapy on Alcohol Use in Chronic Hepatitis C Patients
• Treatment of Acute Hepatitis C Virus Infection With Pegylated Interferon in Injection Drug Users (for HIV-negative people only)

HIV Positive Women

• Brief Therapy Intervention for Heavy/Hazardous Drinking in HIV-Positive Women

HIV Positive or At-Risk Men

• Mirtazapine to Reduce Methamphetamine Use Among MSM With High-Risk HIV Behaviors
• Aripiprazole Treatment for Methamphetamine Dependence Among High-Risk MSM
• Acceptability of Pharmacologic Treatment for Methamphetamine Dependence Among MSM
• Behavior Change and Maintenance Intervention for HIV+ MSM Methamphetamine Users
• 12 Week Group Therapy Intervention for HIV+ Methamphetamine Users and Deliver It Within an HIV/AIDS Primary Care Setting.
• Behavioral Therapy Development for Methamphetamine Abuse
• Addressing Young Men’s Substance Use and HIV Risk

HIV-Positive: Women and Men

• Comparison of HIV Clinic-Based Treatment With Buprenorphine Versus Referred Care in Heroin-Dependent Participants
• Buprenorphine and Integrated HIV Care Evaluation
• Directly Administered HIV Therapy in Methadone Clinics
• Skills Based Counseling for Adherence and Depression in HIV+ Methadone Patients – 1
• The Effects of Nutritional Supplementation and Drug Abuse on HIV
• Pharmacotherapy for HIV+ Stimulant Dependent Individuals
• The CORE Buprenorphine Project – An HIV Primary Care Program Demonstration
• Buprenorphine HIV Care Integration Project

References
1. Mochida S, Ohnishi K, Matsuo S, Kakihara K, Fujiwara K. Effect of alcohol intake on the efficacy of interferon therapy in patients with chronic hepatitis C as evaluated by multivariate logistic regression analysis. Alcohol Clin Exp Res. 1996 Dec;20(9 Suppl):371A-377A.
2. Ohnishi K, Matsuo S, Matsutani K, et al. Interferon therapy for chronic hepatitis C in habitual drinkers: comparison with chronichepatitis C in infrequent drinkers. Am J Gastroenterol. 1996 Jul;91(7):1374-9.
3. Okazaki T, Yoshihara H, Suzuki K, et al. Efficacy of interferon therapy in patients with chronic hepatitis C. Comparison between non-drinkers and drinkers. Scand J Gastroenterol. 1994 Nov;29(11):1039-43.
4. Anand BS, Currie S, Dieperink E, et al; VA-HCV-001 Study Group. Alcohol use and treatment of hepatitis C virus: results of a national multicenter study. Gastroenterology. 2006 May;130(6):1607-16.
5. Schaefer M, Schmidt F, Folwaczny C, et al. Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups. Hepatology. 2003 Feb;37(2):443-51.
6. Lucey MR, Brown KA, Everson GT, et.al. Minimal Criteria for Placement of Adults on the Liver Transplant Waiting List: A Report of a National Conference Organized by the American Society of Transplant Physicians and the American Association for the Study of Liver Diseases. Liver Transpl Surg. 1997 Nov;3(6):628-37.
7. Nickels M, Jain A, Sharma R, et al. Polysubstance abuse in liver transplant patients and its impact on survival outcome. Exp Clin Transplant. 2007 Dec;5(2):680-5.

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

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.

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.