16th Conference on retroviruses and opportunistic infections, Montreal, Canada, 8-11 February 2009.

As the dawn of specifically targeted anti-hepatitis C therapy (STAT-C) approaches, in a timely symposium Professor Alan Perelson [1] reviewed mathematical modelling data on the emergence of resistant HCV and the future of HCV antiviral therapy with combination therapies and the possibility of avoiding pegylated interferons and ribavirin. Based on approaches that take into account preexisting mutations, viral turnover, antiviral efficacy and emergence of mutations he predicted that it would require drugs or drug combinations with a high barrier to mutation to avoid the pitfalls of resistant HCV emerging. We await with interest the first studies in HIV co-infected patients, but in the first instance, cocktails will need additional pegylated interferon and ribavirin and treatment combinations with STAT-Cs alone are some way away.

EPIDEMIOLOGY

The epidemic of acute hepatitis C (HCV) in HIV-positive men who have sex with men (MSM) continues to smoulder across Europe. Dr Jade Ghosn and colleagues [2] presented data from the French National Institute for Public Health Surveillance, which has been collecting samples and data on acute HCV-infected HIV-positive patients since 2006. Of 32 patients with available specimens, half were infected with genotype 4d virus. Sequence analysis suggested that all of these viruses segregated in a single cluster similar to the previously described sexually transmitted cluster from 2001 to 2003. In a study from a single centre in Amsterdam [3], there was evidence of a year-on-year increase in new cases of acute HCV through to 2008. In New York, however, Dr Sarah Fishman and colleagues [4] presented data that suggested there was higher condom use, but patients acquiring acute HCV reported more sharing of drug-smoking and injecting implements. These studies highlight the fact that the overriding priority needs to be vociferous public health messages surrounding the risks of acute HCV and the need to ensure that these messages are getting through if we are going to curb this epidemic successfully.

NATURAL HISTORY OF HCV AND LIVER DISEASE

Professor Rockstroh and colleagues from the EUROSIDA cohort [5] examined the effect of HCV genotypes and HCV viral loads on risk of death and specifically liver-related death. In this large cohort of over 2000 patients co-infected with HIV/HCV, HCV viral loads in excess of 500,000 iu/l at entry were independently associated with overall mortality and liver-related mortality after adjusting for a number of demographic and HIV-related variables. Moreover, genotype 3 infections were associated with a significantly lower incidence of liver-related mortality when compared to genotype 1 infection. This is in variance with monoinfected cohorts where HCV viral loads and genotypes have only been of significance in predicting response to therapy. Some of this difference could be explained by the rapid progression of fibrosis in co-infected patients and the ability to detect significant differences in clinical end-points. The support for early use of HAART in this group of patients was further strengthened by Dr Andri Rauch from the Swiss HIV Cohort [6] who shed important light on longitudinal restoration of HCV-specific T-cell responses and HCV viral loads in HCV-co-infected patients starting on combination antiretroviral therapy (CART). CART had a beneficial effect in terms of restoring CD4 responses to HCV core peptides, and after a transient increase in HCV viral loads in the first year after starting treatment was followed by a significant reduction in HCV viral loads. However, not all CART is beneficial. Dr Barreiro and colleagues from Madrid [7] examined factors associated with a significant progression of hepatic fibrosis, as assessed by transient elastography measurements at least 18 months apart, and showed significant association with HCV co-infection, glucose levels and body mass index, and didanosine use. Clearly the metabolic effects of some CART agents may have a detrimental effect on liver fibrosis progression. This was also noted in data from another multi-centre study from Spain [8] showing an association between insulin resistance and advanced hepatic fibrosis.

MANAGEMENT OF HCV AND HBV 

Whilst the promise of STAT-Cs in co-infected patients is yet to materialise, strategies to try and improve responses to pegylated interferon and ribavirin continue to be explored with vigour. Professor Chung presented data from step 3 of the SLAM-C study [9], which examined the sustained virological response (SVR) to a total of 72 weeks of pegylated interferon and weight-based ribavirin in those patients achieving an early virological response (EVR). In this study, 65% of patients were able to tolerate 72 weeks of therapy, and 51% overall in an intent-to-treat analysis achieved SVR. Of those achieving a complete EVR (undetectable HCVRNA at week 12), 62% achieved an SVR. Of the difficult-to-treat genotype 1 and 4 patients, 42% achieved an SVR. These data suggest that prolonged therapy is reasonably well tolerated and may well achieve responses akin to monoinfected patients especially in patients achieving a complete EVR. The importance of viral kinetics in determining the length of therapy was also highlighted by Dr Querada and colleagues from Madrid who, in a retrospective analysis, demonstrated that longer duration of HCV-RNA to below the limits of detection was an important independent predictor of SVR [10]. Dr Morella and colleagues [11] suggest that even with 13mg/kg of ribavirin some patients may be under-dosed and that plasma ribavirin trough levels at week 4 may be of benefit in adjusting doses and that a trough level of less than 2.5[micro]g/ml is an independent predictor of relapse. The controversy surrounding the clinical significance of the possible intracellular interaction between abacavir and ribavirin phosphorylation continues. Dr Amorosa [12] from Philadelphia presented data on a cohort of 212 patients on CART treated with pegylated interferon and ribavirin. In this group, 35% were on abacavir containing CART and no significant association between abacavir use and EVR or SVR was demonstrated.

Following on from the revelation that entecavir may have anti-HIV activity and may jeopardise the future use of lamivudine against HIV, interest is now focused on telbivudine and its potential use in patients not requiring CART. Dr Low from London presented a case report [13] of a patient achieving an undetectable HIV-RNA whilst on adefovir and telbivudine. Withdrawal of telbivudine led to a rebound of the HIV viraemia, which was re-suppressed after a further short re-introduction of telbivudine. No specific HIVRT mutations have been identified to date. Dr Avila and colleagues from Novartis [14], however, showed no in vitro anti-HIV activity of telbivudine, at concentrations well above treatment levels, against a number of laboratory and clinical HIV-1 isolates representing a range of subtypes and drug-resistant HIV-1 isolates using a highly sensitive phenotypic assay. This was in contrast to activity demonstrated by control groups using efavirenz and entecavir. This begs the question whether the anti-HIV activity seen in the London case demonstrates an immune modulation effect of the anti-HBV activity of adefovir and telbivudine restoring anti-HIV immune responses in the patient.

The long-term success of tenofovir against HBV was once again demonstrated by Dr Lacombe and colleagues from Paris [15]. In a 3-year follow-up study of 165 patients treated with tenofovir, over 95% of patients attained an undetectable HBV-DNA. The L217R RT polymorphism was demonstrated to emerge in three 'blippers' and pre-existed at baseline in both rebounders. Phenotypic assays and longer follow-up are needed to further characterise the true virological and clinical effects of this and other RT polymorphisms. In the meantime, tenofovir appears to be a viable and durable long-term treatment option for HBV in HIV co-infected patients.

END-STAGE LIVER DISEASE (ESLD) AND LIVER TRANSPLANTATION

As liver transplantation in HIV-positive patients becomes a reality, there were a number of important presentations on the outcomes of patients with ESLD pre- and post-transplantation. Dr Montes presented data from the GESIDA cohort in Spain [16] examining factors associated with survival, transplantation or occurrence of HCC in 284 patients with compensated cirrhosis followed for a median time of 34 months. CART and Child-Pugh A/B stages were significantly associated with better survival. In a single-centre retrospective study from Madrid, Dr Moreno [17] examined factors associated with survival in over 200 patients on a transplant waiting list, comparing HIV-positive and HIV-negative patients. HIV-positive patients had higher MELD scores and significantly higher mortality on the waiting list compared to HIV-negative patients. This suggests that HIV-positive patients with ESLD are being referred late for transplantation.

Professor Miro and colleagues from Spain also presented a case-control study looking at 5-year survival of HIV/HCV co-infected liver transplant recipients compared to matched HCV monoinfected transplant recipients [18]. Patient and graft survival had begun to diverge by 3 years post-transplant, with increased graft loss and mortality in HIV/HCV co-infected patients. By 5 years post-transplant there was more than 50% mortality in HIV/HCV co-infected patients. This is in keeping with previous data from Miami, London and Paris where this high morbidity and mortality in HCV/HIV co-infected patients has also been noted, much of it associated with aggressive HCV recurrence. Protocols for aggressive and effective management of HCV pre- and post-transplant are urgently needed for this group of patients.

NON-VIRAL LIVER DISEASE

More data emerged this year on non-viral liver disease in HIV-positive patients. Dr Perez-Camacho used transient elastometry with a liver stiffness cut-off of 7.2 KpA to identify patients with significant hepatic fibrosis and examined factors associated with this [19]. Didanosine, abacavir and alcohol use were all associated with a significant risk of developing hepatic stiffness. In a retrospective analysis of 2445 patients in the Swiss HIV Cohort study, Dr Kovari [20] demonstrated that prolonged antiretroviral therapy, high body mass index and high alcohol use were associated with chronic ALT elevation in non-HCV/HBV HIV-infected patients. Whether the associations and abnormalities demonstrated in both these cohorts will translate into clinically significant liver-related morbidity and mortality in the future is yet unknown, but merits close observation and further study.

CONCLUSION

This year's meeting once again highlighted the importance of liver disease in the care and management of HIV-positive patients. As we move towards long-term care of our patients, the issues pertaining to acute and chronic viral hepatitis co-infections, non-viral liver disease, ESLD and transplantation will continue to demand attention from clinicians and investigators in the field.

REFERENCES

All abstracts were presented at the 16th Conference on Retroviruses and Opportunistic Infections, Montreal, Canada, 8-11 February 2009.

[1.] Perelson A. New insights into the viral dynamics of HCV infection: can virologic cure be achieved without interferon and ribavirin? Abstr. 62.

[2.] Ghosn J, Larsen C, Piroth L et al. Evidence of ongoing epidemic sexual transmission of HCV (2006 to 2007) among HIV-1-infected men who have sex with men: France. Abstr. 800.

[3.] Van Den Berk G, Blok W, Barends H et al. Rapid rise of acute HCV cases among HIV-1-infected men who have sex with men, Amsterdam. Abstr. 804.

[4.] Fishman S, Childs K, Dieterich D et al. Age and risky behaviours of HIV-infected men with acute HCV infection in New York City are similar but not identical to those in a European outbreak. Abstr. 801.

[5.] Rockstroh J, Peters L, Soriano V et al. High HCV is associated with an increased mortality in HIV/HCV-co-infected individuals. Abstr. 101.

[6.] Rohrbach J, Harcourt G, Gandiere S et al. Successful ART is associated with increasing HCV-specific T cell responses. Abstr. 105.

[7.] Barreiro P, Fernandez-Montero JV, Labarga P et al. Progression of liver fibrosis in a large cohort of HIV patients over 4 years: emerging contribution of antiretrovirals and metabolic abnormalities. Abstr. 747.

[8.] Merchante N, Santos-Gil ID, Rivero A et al. Insulin resistance and liver stiffness: a new guest in liver disease progression? Abstr. 827.

[9.] Chung R, Umbleja T, Butt A et al. SLAM-C (ACTG A5178): role of early virologic response in extended therapy with Peg-interferon and weight-based ribavirin in HCV/HIV co-infection. Abstr. 103LB.

[10.] Querada C, Ferrere F, Moreno A et al. Duration of viral HCV suppression as a predictor of sustained virological response in HIV/HCV co-infected patients treated with pegylated-interferon + ribavirin. Abstr. 840.

[11.] Morello J, Rodriguez-Novoa S, Barreiro P et al. Ribavirin plasma levels at week 4 predicts hepatitis C virus relapse in HIV/HCV co-infected patients treated for hepatitis C. Abstr. 842.

[12.] Amorosa V, Slim J, Mounzer K et al. Abacavir use not associated with lack of virologic response in ARV-treated HIV/HCV co-infected patients receiving pegylated interferon and ribavirin. Abstr. 850.

[13.] Low E, Cox A, Atkins M and Nelson M. Telbivudine has activity against HIV. Abstr. 813a.

[14.] Avila C, Karwowska S, Lai C and Evans T. Telbivudine has no in vitro activity against laboratory and clinical HIV-1, including 5 clades and drug-resistant clinical isolates. Abstr. 813b.

[15.] Lacombe K, Gozlan J, Boyd A et al. HIV blippers and rebounders under treatment with tenofovir in HIV/HBV co-infection. Abstr. 100.

[16.] Montes ML, Pascual J, Lopez-Dieguez M et al. Survival of HIV/HCV co-infected patients with compensated liver cirrhosis: effect of HCV therapy. Abstr. 106.

[17.] Moreno A, Barcena R, Del Campo S et al. Effect of HIV co-infection on the outcome of viral cirrhosis liver transplant candidates on the waiting list at a reference center from 2001 to 2008. Abstr. 835.

[18.] Miro J, Montejo M, Castells L et al. 5-year survival of HCV/HIV co-infected transplant recipients: a case/control study. Abstr. 833.

[19.] Perez-Camacho I, Merchante N, Camacho A et al. Abnormal liver stiffness assessed by transient hepatic elastometry in HIV-infected patients without hepatitis B or C virus co-infection: prevalence and related factors. Abstr. 749.

[20.] Kovari H, Ledergerber B, Battegay M et al. Prolonged ART and risk for chronic elevation of alanine aminotransferase in HIV-infected persons without HBV or HCV co-infections. Abstr. 750.

Report by S Bhagani, Department of Infectious Diseases and HIV Medicine, Royal Free Hospital, London. Email: [e-mail]