Co-Infection at the 2008 Retrovirus Conference
Liver Fibrosis, Hep C Treatment, and the Role of ART
This year's Conference on Retroviruses and Opportunistic Infections (CROI), held February 3-6 in Boston, featured numerous reports on hepatitis C virus (HCV) co-infection in people with HIV.
Liver Fibrosis Progression
Past research has shown that HIV/HCV co-infected individuals tend to experience more rapid liver disease progression than HIV-negative people with HCV alone, though there is conflicting data about whether this is true for co-infected patients with well-controlled HIV disease and well-preserved immune function. Most presentations at CROI supported faster progression -- with the notable exception of the SLAM-C study described below in the treatment section.
Juan Macias and colleagues (Abstract 1055) assessed fibrosis progression in 83 HIV/HCV co-infected patients in Spain who underwent paired liver biopsies separated by at least one year; those with pre-existing cirrhosis were excluded. Most were on HAART and 76% had undetectable HIV viral load. About half received interferon-based therapy, and half of these achieved an end-of-treatment response. Between the two biopsies, 16% experienced fibrosis regression by one or more stages, 43% had no change, and 41% progressed by at least one stage -- higher than the rate for HIV-negative hepatitis C patients. Co-infected individuals who responded to anti-HCV treatment, however, had a lower risk of progression.
More disturbing data came from a study (Abstract 1050) suggesting that people who are already HIV-positive when they contract HCV may experience unusually rapid liver disease progression. At last year's CROI, Daniel Fierer and colleagues from New York's Mt. Sinai School of Medicine reported that four out of five HIV-positive men infected with HCV for six months or less already had moderate fibrosis. This year, they presented further data showing that among 11 HIV-positive men with acute hepatitis C who underwent liver biopsies, nine already had stage F2 (moderate) and one had stage F1 (mild) fibrosis, for an average fibrosis progression rate of 4.5 units per year. The researchers concluded that HIV-positive people with acute HCV showed progression rates "far in excess of other settings of HCV infection."
These findings are a concern given recent outbreaks of apparently sexually transmitted HCV among mostly HIV-positive men who have sex with men in several cities in Europe and Australia. British researchers (Abstract 61LB) reported results from a viral genetic analysis showing that the re-appearance of HCV infection observed in several HIV-positive men was due to re-infection -- indicating continued unprotected sex -- rather than late relapse.
Another research team from Mt. Sinai (Abstract 57) revealed a possible mechanism for accelerated fibrosis in HIV/HCV co-infected individuals, demonstrating in a laboratory study that HIV enters and actively replicates within hepatic stellate cells, a type of support cell in the liver that produces collagen and other scar tissue proteins responsible for fibrosis.
Response to Hepatitis C Treatment
Along with accelerated liver disease progression, HIV/HCV co-infected people also typically respond less well to treatment with pegylated interferon alpha plus ribavirin. When treatment works, however, it can slow or halt fibrosis progression, according to the Spanish GESIDA 3603 study (Abstract 60). Investigators looked at about 700 co-infected patients with well-controlled HIV disease overall (median CD4 count of 544 cells/mm3). Six months after finishing treatment with pegylated interferon (Pegasys or PegIntron) or the older conventional interferon plus ribavirin, 14% with hard-to-treat HCV genotypes 1 or 4 and 46% with genotypes 2 or 3 achieved sustained virological response (SVR), or continued undetectable HCV viral load. After 20 months of follow-up, sustained responders were about nine times less likely than non-responders to develop liver cancer, progress to decompensated liver disease, or require a liver transplant.
Two other research teams looked at treatment of acute hepatitis C in HIV-positive individuals. A team of British, French, and German investigators (Abstract 1071) studied HIV-positive men involved in the previously mentioned acute hepatitis C outbreaks. Among 101 men who started treatment with pegylated interferon with or without ribavirin within 6 months after HCV infection, 64% achieved SVR, and response did not differ based on HCV genotype. In a related study, researchers with the Australian Trial in Acute Hepatitis C (Abstract 1070) found that rapid virological response at week 4 predicted which patients would go on to achieve SVR; however, co-infected individuals were slightly less likely to achieve rapid response than those with HCV alone (39% vs. 49%).
Given that many people do not respond to standard combination hepatitis C treatment, researchers have studied whether long-term interferon maintenance monotherapy might reduce the risk of liver complications even without HCV clearance. Kenneth Sherman and colleagues (Abstract 59) presented results from the SLAM-C study (ACTG 5178), which included 329 HIV/HCV co-infected participants with mostly well-controlled HIV disease (median CD4 cell count 498 cells/mm3). Participants first received combination treatment with 180 mcg once-weekly Pegasys plus 1,000-1,200 mg/day ribavirin. The 86 patients (44%) who did not achieve early virological response at 12 weeks were randomly assigned to either continue on Pegasys maintenance monotherapy at the same dose or undergo observation without further treatment for 72 weeks. An interim analysis of paired liver biopsies from 45 participants who completed follow-up showed that there was no significant change in fibrosis in either the Pegasys maintenance arm or the untreated observation arm. But the maintenance arm (which was halted in April 2007 due to lack of efficacy) was unable to demonstrate any benefit because the fibrosis progression rate in the untreated group was so unexpectedly low -- in contrast to the aforementioned research indicating that co-infected individuals tend to experience rapid progression.
Role of Antiretroviral Therapy
Several conference presentations looked at the role of antiretroviral therapy in HIV/HCV co-infected people. Assessing risk factors for fibrosis progression in 323 co-infected Spanish patients, Ana Moreno and colleagues (Abstract 1056) found that neither exposure to non-nucleoside reverse transcriptase inhibitors (NNRTIs) nor to protease inhibitors (PIs) were associated with advanced fibrosis or cirrhosis; however, those who used PIs tended to have a higher fibrosis progression rate.
Other studies suggested that choice of nucleoside reverse transcriptase inhibitors (NRTIs) may influence response to hepatitis C treatment. A retrospective analysis by researchers with the GESIDA 50/06 study (Abstract 1076) showed that patients who used tenofovir (Viread) as part of their HAART regimen were significantly more likely to achieve SVR with pegylated interferon plus ribavirin than those who used AZT (Retrovir, zidovudine), d4T (Zerit), or abacavir (Ziagen). Those who used AZT, by contrast, had a 40% lower sustained response rate, attributable to adverse events such as anemia. Another Spanish study (Abstract 1074) revealed that co-infected patients taking abacavir plus 3TC (Epivir) were less likely to achieve SVR than those using tenofovir plus 3TC or emtricitabine (Emtriva; also in the Truvada and Atripla combination pills), which they suggested may be due to a negative interaction between abacavir and ribavirin.
Finally, research with the large EuroSIDA study (Abstract 1069) presented encouraging data showing that HCV co-infection does not appear to impair CD4 cell recovery on antiretroviral therapy, which conflicts with some prior studies. Similarly, other researchers (Abstracts 1029, 1030, and 1031) reported that hepatitis B virus co-infection does not have a detrimental effect on virological or immunological response to HAART.
Liz Highleyman (firstname.lastname@example.org) is a freelance medical writer based in San Francisco.
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