Tracy Swan is the Coinfection Project Director for the New York-based Treatment Action Group
The HCV-HIV International Panel, a group of medical experts in HIV and HCV, has released new recommendations for the care of HIV/HCV co-infected patients. The panel has updated its 2002 recommendations to include new information on both viruses and their treatment. The new recommendations are framed around nine questions addressing current controversies about the natural history of HIV in co-infected persons, the use of liver biopsy, HCV treatment and side effect management, antiretroviral hepatotoxicity and liver transplantation.
Since HCV genotypes 1 and 4 do not respond as well to treatment as genotypes 2 and 3, those with HCV-1 and HCV-4 may prefer to delay therapy until more effective drugs become available. The panel recommends a liver biopsy for these individuals. HCV therapy may be delayed in genotypes 1 and 4 if no fibrosis is present. For those with minimal fibrosis who do not want HCV treatment, the panel recommends repeat biopsies every two to three years.
Although HIV accelerates HCV disease progression, the effect of HCV on HIV disease progression is unclear. Although some studies suggest that HCV co-infection may accelerate HIV disease progression, other large clinical and epidemiological studies have not identified HCV co-infection as a co-factor for HIV disease progression. Given what is known about the natural history of HCV in HIV-positive persons, the panel takes an aggressive stance on HCV treatment.
Treatment
The panel considers all HIV-positive persons with detectable HCV RNA as candidates for HCV treatment. Those eligible for HCV treatment should have persistently elevated alanine aminotransferase (ALT) levels, a CD4 cell count above 350 cells/mm3, and HIV RNA below 50,000 copies/ml. Those with persistently normal ALT should be treated for HCV only if they have fibrosis, or through a clinical trial if they do not have fibrosis. In those with CD4 cell counts below 350 CD4 cells/3, treatment should be “prescribed cautiously” as the likelihood of clearing hepatitis C (known as a sustained virologic response) is significantly greater among persons with CD4 cell counts above 350 cells/mm3. HCV treatment is not recommended for those with CD4 cell counts below 200 cells/mm3, due to low response rates and because interferon may increase the risk of developing opportunistic infections in this population. The panel recommends HCV treatment for individuals with compensated cirrhosis, but not for those with prior hepatic decompensation due to the risk of serious side effects. For these individuals, the panel recommended liver transplantation rather than HCV treatment .
The panel considers “illegal drug use” as a contraindication for HCV treatment, despite The National Institute of Health’s 2002 Consensus Statement on the Management of Hepatitis C, which recommended HCV treatment for active injection be considered “on a case-by-case basis.” The panel also considers a history of severe neuropsychiatric conditions as a contraindication for HCV treatment because of the potential for serious neuropsychiatric side effects from interferon.
Combination therapy with pegylated interferon plus ribavirin is the regimen of choice for HCV treatment in co-infected persons. Sustained virologic response rates to HCV treatment are less frequent among co-infected persons than in those with HCV alone, and tolerability is poor; dropout rates during clinical trials of HCV therapy range from 6-32%. The panel recommends discontinuing HCV treatment for those who do not have either a 2-log drop or undetectable HCV RNA after twelve weeks of therapy, as they are unlikely to clear hepatitis C. For early virologic responders, the panel recommended research on extending HCV treatment (>6 months in genotypes 2 and 3; >12 months in genotypes 1 and 4) to see if the sustained virologic response rate will increase.
Side-effect management
Adherence contributes to successful HCV therapy, thus proper side effect management is crucial for maintaining treatment. Treatment candidates should be given information about side effects and management strategies before initiation of HCV treatment. For example, patients need to know that significant but reversible decreases in the CD4 cell count (but usually not CD4 cell percentages) often occur during HCV treatment. Pegylated interferon may cause neutropenia, which can be managed by dose reduction or granulocyte colony-stimulating factor. Ribavirin may bring on anaemia, which can be managed by dose reduction or recombinant erythropoietin. Since higher doses of ribavirin have been associated with sustained virologic responses, management of anaemia with recombinant erythropoietin may be preferable to dose reductions. Interferon-induced depression should be treated promptly if symptoms appear.
Interactions between antiretroviral therapy and HCV therapy may be minimised by selection of antiretroviral therapy and frequent monitoring for toxicities. In those with advanced liver fibrosis, ribavirin and didanosine have been associated with hepatic decompensations, some deadly; hence this combination is contraindicated for cirrhotics. In general, ribavirin should not be used in combination with didanosine, as it increases didanosine levels, thereby increasing toxicity and the risk for development of lactic acidosis and pancreatitis. The combination of stavudine and ribavirin has been associated with lactic acidosis as well, albeit less frequently. Patients taking didanosine or stavudine with ribavirin need to be aware of the symptoms of lactic acidosis; their serum lactate and amylase levels should be monitored frequently. Use of stavudine with ribavirin has been associated with weight loss that looks similar to lipoatrophy. Because zidovudine cases anemia, haemoglobin levels should be monitored closely during the first six weeks of HCV treatment.
Since co-infected persons are at greater risk for developing antiretroviral-related hepatotoxicity, their HIV drugs should be selected carefully whether or not they are on concomitant HCV therapy. In particular, nevirapine and full-dose ritonavir have been associated with hepatoxicity. Liver enzymes should be monitored more frequently among users of these drugs. Antiretroviral therapy should be discontinued if grade 4 elevations (greater than ten times the upper limit of normal) in ALT levels or symptoms of hepatotoxicity develop.
Immune reconstitution resulting from antiretroviral therapy may cause elevations in liver enzymes, especially in those with low baseline CD4 cell counts and high baseline HIV RNA levels. As long as grade 4 elevations in ALT levels do not develop, antiretroviral therapy may be continued; usually liver enzyme elevations resolve.
A new section on liver transplantation appears in the updated recommendations. Because one-year survival among HIV-positive liver recipients is comparable to HIV-negative liver recipients (92% vs. 87.9%, respectively), HIV infection should no longer be considered as an absolute contraindication for transplantation. HIV-positive transplant candidates should have CD4 cell counts greater than 100 cells/mm3 and HIV RNA levels below 200 copies/ml or the potential to achieve undetectable HIV RNA after transplantation.
A multidisciplinary approach to pre-and post-transplant care of HIV-positive patients is necessary, as care and treatment for co-infected liver transplant recipients are medically and psychologically complex. Interactions between immunosuppressive agents and certain antiretrovirals warrant therapeutic drug monitoring.
Since HCV almost always recurs after transplantation, the panel recommends initiation of HCV treatment as soon as possible after transplantation, and research of pre-emptive HCV therapy prior to transplantation. The shortage of donor livers remains problematic, especially for co-infected persons, who appear to have poorer survival while listed for transplantation. Strategies to shorten the wait for liver transplantation in HIV-positive candidates need exploration.
Further information on this website
Soriano V et al. Care of patients with hepatitis C and HIV co-infection. AIDS 18: 1 —12, 2004.
National Institutes of Health Consensus Development Conference Statement. Management of Hepatitis C: 2002. Final statement September 12th, 2002. (accessed on 1/18/04)