Important note: Information in this article was accurate in March 2004. The state of the art may have changed since the publication date. 
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Hepatitis C was a prominent topic at the 11th CROI. The meeting started off with a plenary session by Charles Rice of Rockefeller University [Abstract 8]. Overall, advancement in the study of HCV drugs and vaccines has been hampered by issues such as difficulty with viral cultivation in the laboratory and limited animal models. New antivirals under investigation include the NS3-4A protease inhibitors and NS5B polymerase inhibitors. However, significant cardiotoxicity has led researchers to search for other cellular targets for treatment. Progress in the development of an HCV vaccine is slow due to the high incidence of chronic infection, the possibility of re-infection, as well as the multiple genotypes and rapid molecular evolution of the hepatitis C virus. On the other hand, given the demonstrated viral clearance on treatment and the progress made in developing subunit vaccines to prevent chronic infection, there is reason to hope that vaccine development will be more advanced by the 12th CROI.
Dr. Rice’s talk served as an excellent prelude to the rest of the meeting, where the hepatitis data presented were both positive (treatment trends in HIV/HCV coinfected patients) and sobering (con-tinued increases in mortality secondary to advanced liver disease).
Three treatment trials were presented which had treatment arms that included pegylated interferon (PEG-IFN) in various doses with or without ribavirin; all were compared to standard interferon plus ribavirin [Chung, et al. Abstract 110; Dietrich, et al. Abstract 112; and Perronne, et al. Abstract 117LB]. The treatment arms and results of these trials are presented in the table, p 9. In these studies, nearly 80% of patients were male and white, and 60% had genotype 1 virus. Liver disease and HIV disease were relatively mild, and no patients with advanced HIV or decompensated liver disease were included in any of the studies. Overall, treatment responses were better than expected, but sustained virologic response, particularly for genotype 1, was far worse than in HCV-monoinfected patients. Response rates for all genotypes combined varied from 41% to 49% at end of treatment, but decreased to 26% to 40% by 6 months following the completion of therapy, the time when sustained virologic response is defined. Treatment discon-tinuation rates varied from 12% to 39%, although most treatment discontinuation was due to lack of response, not adverse effects. Future studies will need to be performed that include more women, African-Americans, and those with more advanced HIV disease. In addition, data were presented from ACTG A5071 demonstrating that failure to achieve a 2 log10 decrease in HCV RNA by 12 weeks had a negative predictive value of 100% for achieving sustained virologic response [Chung, et al. Abstract 110]. This has important implications in identifying patients who are unlikely to benefit from long term HCV treatment.
Several groups presented data on organ transplantation. Roland and colleagues presented combined data from UC San Francisco on 10 liver and 15 kidney transplants [Abstract 826]. At a median of 480 days, 90% of liver and 93% of kidney transplant patients were alive. Recurrent HCV was noted in two liver recipients, and one liver recipient required re-transplant-ation due to a small-for-size graft. With anti-rejection treatment, all patients experienced a decrease in CD4 count, and three new opportunistic infections (OIs) occurred post-operatively, but there were no recurrences of OIs that had occurred prior to transplant. Rufi presented data on 21 orthotopic liver transplants from Spain that had been performed since January 2002 [Abstract 827]. Seventy-five percent of liver recipients suffered from HCV recurrence and were treated with PEG-INF and ribavirin. In addition, 38% suffered from acute rejection. Teicher presented data on 11 French liver transplant patients, with a 27% mortality rate [Abstract 828]. Of note, there were no opportunistic illnesses in the post-operative period; however, HCV replication resumed quickly in all patients, and seven patients reinitiated PEG-INF and ribavirin.
Previous data have suggested faster progression of HCV in those coinfected with HIV. Liver biopsy is often indicated for disease staging and determination of the need for treatment, but biopsy can have significant associated morbidity. Mehta and colleagues proposed an alternative measure of assessing fibrosis severity using a panel of potential fibrosis markers, including hyaluronic acid, AST, and albumin [Abstract 809]. Patients with albumin >3.5 g/dL, AST <60 IU/L, and hyaluronic acid >40 ng/mL exhibited low rates of medium-to-advanced fibrosis. Longitudinal studies using serial measurements are needed to determine whether these serum markers may be used to follow patients at low risk of progression to fibrosis in place of or in conjunction with liver biopsies.
Wilson and colleagues performed paired liver biopsies on a cohort of injection drug users and demonstrated that fibrosis progression did not appear to occur any faster in HIV positive patients than in HIV negative patients, with an increase in fibrosis scores of approximately 0.11 units/year (Modified Histologic Activity Index fibrosis scores with range 1-6) [Abstract 815]. A non-significant trend was seen toward increased risk of fibrosis progression in those on HAART.
While current recommendations include hepatitis A vaccination for HCV-infected patients, Weissman and colleagues demon-strated that the efficiency of this vaccination is dramatically reduced in a study of 278 HIV-infected patients [Abstract 830]. They demonstrated a response rate of 49% compared to 100% in HIV negative controls. Risk factors for non-response included male gender and CD4 <200 cells/mm3 at the time of vaccination. However, CD4 nadir did not predict response.
Consistent with last year’s abstracts, several groups presented data on increased liver-related mortality in HIV-infected cohorts from the United States and Europe. Data from New York City demonstrated that liver-related mortality among HIV-infected individuals increased significantly from 0.3% to 4% between 1993-2003 [Schlanger K, et al. Abstract 797]. Hispanics and injection drug users had increased risk of HCV-related mortality compared to blacks, whites, and non-drug users. Salmon presented data from France that demonstrated increased mortality in HIV/HCV- and HIV/HBV-coinfected patients compared to HIV-monoinfected patients [Abstract 798]. End-stage liver disease (ESLD) was a more common cause of death than OIs in HCV-infected patients (31% vs 29%; statistical significance not reported). Patients infected with all three viruses (HIV, HBV, and HCV) had the highest rates of ESLD morality (44%). Of note, nearly 50% of the patients who died of ESLD had a CD4 count >200 cells/mm3, suggesting that they were in fact not overtly immunocompromised. The EuroSIDA cohort found nearly identical results, with increased ESLD mortality in HIV/HBV- and HIV/HCV-coinfected patients [Abstract 799]. Unlike HCV, HBV was associated with an increased risk of all cause mortality as well. Of note, there were no virologic or immunologic differences between coinfected patients and HIV-monoinfected patients.
In conclusion, while encouraging treatment data were presented at CROI, including data suggesting improved sustained virologic responses with the new PEG-INFs, the reality of more liver-related deaths, and the lack of progress in HCV vaccine development was sobering.
In addition, the limited data on liver transplants in HIV/HCV-coinfected patients demonstrated that early mortality from transplantation is relatively low; however there were high rates of HCV recurrence requiring treatment.
| Table: Summary of HCV Treatment in Trials of HIV/HCV Coinfected Patients Using Pegylated Interferon | |||||
| Abstract | 110, 112, 117 N=67-286 |
110 N=67 |
112 N=286 |
112 N=286 |
117 N=205 |
| Treatment | IFN 3-6 MU TIW + RBV 600-1,000 mg/d |
PEG α-2a 180 µcg qwk + RBV 600-100 mg/d |
PEG α-2a 180 µcg qwk | PEG α-2a 180 µcg qwk + RBV 800 mg/d | PEG α-2b 1.5 µcg/kg qwk + RBV 800 mg/d |
| Duration (weeks) | 48 | 48 | 48 | 48 | 48 |
| Male | 81% | — | 82% | 80% | 74% |
| White | 78% | — | 79% | 80% | — |
| Mean Age (years) | 40 | — | 40 | 40 | 40 |
| Genotype 1 | 60% | — | 61% | 61% | 58%* |
| Tx Discontinuations | 39% | 12% | 31% | 25% | 40% |
| HCV Outcomes | |||||
| End of Treatment Response Overall | 12% to 14% | 41% | 33% | 49% | — |
| Genotype 1 | — | 29% | 21% | 38% | — |
| Non-Genotype 1 | — | 80% | 57% | 64% | — |
| Sustained Virologic Response Overall | 8% to 31% | 27% | 20% | 40% | 26% |
| Genotype 1 | 7% | 14% | 14% | 29% | 11% |
| Non-Genotype 1 | 20% | 73% | 36% | 62% | 43% |
| ** Genotypes 1 + 4 | |||||
References:
ACTG A5071 [Chung, et al. Abstract 110]
APRICOT [Dietrich, et al. Abstract 112]
ANRS HC02-RIBAVIC [Perronne, et al. Abstract 117LB]
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JH20040304
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