An international panel of experts has issued revised guidelines for the management of HIV/HCV co-infection, reflecting new data that have become available since the previous recommendations were issued in 2004. The updated guidelines were published in the May 31st edition of AIDS.
As background, the authors noted that an estimated one-third of HIV-positive individuals have chronic hepatitis C, progression to end-stage liver disease occurs more rapidly in co-infected patients, and decompensated cirrhosis is a major causes of hospitalisation and death in this population.
The panel issued recommendations in 11 areas:
- Management of patients with persistently normal aminotransferases
- Assessment of liver fibrosis
- Predictors of response to anti-HCV therapy
- Optimal dosing of pegylated interferon and ribavirin
- Optimal duration of anti-HCV therapy
- Treatment of non-responders and relapsers
- Care of co-infected patients with end-stage liver disease
- Treatment of acute HCV infection in HIV-positive individuals
- Management of patients with multiple hepatitis viruses
- Interactions between anti-HCV medications and antiretroviral agents
- Hepatotoxicity of antiretroviral drugs
Predicting treatment response
The panel reviewed various factors that predict response to hepatitis C therapy, most of which - age, sex, race, body mass index, HCV viral load, HCV genotype, degree of fibrosis or steatosis - are the same for co-infected and HCV mono-infected individuals.
However, some additional factors appear to be associated with poor response in co-infected patients, including lower CD4 cell count and higher HIV viral load. Insulin resistance is of particular concern, given its association with certain antiretroviral drugs.
In both co-infected and HCV mono-infected patients, the best predictor of sustained virological response (SVR) is rapid virological response (RVR), or undetectable HCV RNA at week four of therapy.
Conversely, patients who do not achieve at least a 2 log10 reduction in HCV RNA by week twelve, or who still have detectable HCV RNA at week 24, are unlikely to achieve SVR, and should be advised to stop treatment.
Optimal doses and duration of therapy
Since HIV/HCV co-infected patients respond less well to anti-HCV therapy compared with HCV mono-infected individuals, good adherence and adequate doses and duration of therapy are necessary to obtain the best possible treatment outcomes.
Adequate exposure to ribavirin is “crucial to maximise responses to anti-HCV therapy,” the panel wrote, concluding that weight-based dosing (1000 mg/day if Retrovir) “should be avoided.”
Higher doses of pegylated interferon have been studied in co-infected patients, but so far results are inconclusive. Therefore, the panel recommended the same standard doses used for HCV mono-infected patients: 180 mcg/week of pegylated interferon alfa-2a (Pegasys) or 1.5 mcg/kg/week of pegylated interferon alfa-2b (PegIntron).
The authors continued to recommend 48 weeks of therapy for co-infected patients regardless of genotype. However, they allowed that 24 weeks may be adequate for patients with genotypes 2 or 3, whilst slow responders with genotypes 1 or 4 “might benefit from extended (60-72 weeks) courses of therapy.”
Treatment of acute hepatitis C
The panel called attention to recent outbreaks of acute, apparently sexually transmitted HCV infection among mostly HIV-positive gay and bisexual men in several cities in the U.K. and Europe.
Whilst 25–30% of HIV-negative individuals with acute HCV experience spontaneous viral clearance, HIV-positive individuals are more likely to develop chronic hepatitis C. For this reason, “early therapeutic intervention in acute HCV infection is particularly indicated in patients with HIV disease.”
The authors recommended that HIV-positive individuals with acute HCV should be treated for 24 weeks with pegylated interferon plus weight-based ribavirin, after waiting twelve weeks to allow for the possibility of spontaneous HCV clearance without treatment.
Non-responders and relapsers
A growing number of co-infected patients have already been treated with interferon-based therapies without achieving SVR, but re-treatment of co-infected non-responders and relapsers has not yet been adequately studied.
Co-infected patients who previously received suboptimal therapy (conventional interferon, short treatment durations, low ribavirin doses, interferon monotherapy, premature discontinuation due to side effects) may be re-treated with the best current standard therapy.
The authors noted that SVR is uncommon in prior true non-responders and relapsers to optimal therapy, but added that even failed therapy or long-term interferon maintenance monotherapy may help slow liver disease progression.
They also suggested that investigational agents - including novel types of interferon and directly targeted antiviral agents such as HCV protease and polymerase inhibitors - may offer improved outcomes.
“Trials exploring the efficacy and safety of these drugs in co-infected patients should be prioritised, without waiting for the final results of phase III trials conducted in HCV mono-infected individuals,” they wrote.
Antiretroviral therapy and hepatotoxicity
Finally, the panel discussed interactions between anti-HCV and anti-HIV drugs and hepatotoxicity of antiretroviral therapy.
Both ddI (Videx) and ribavirin can cause lactic acidosis, pancreatitis, and decompensated cirrhosis; therefore, this combination “should never be used.” Since AZT can cause the same blood deficiencies as ribavirin (anaemia) and interferon (neutropenia), the panel recommended that AZT should be “avoided when possible.”
The panel noted that various antiretroviral drugs affect the liver in different ways. Certain nucleoside analogues, notably ddI and d4T (Zerit), can cause mitochondrial toxicity (which can lead to liver steatosis), nevirapine (Viramune) can cause hypersensitivity reactions involving the liver, and some protease inhibitors can cause direct liver injury. Although atazanavir (Reyataz) and indinavir (Crixivan) can cause elevated bilirubin levels, this does not reflect liver damage.
Despite these concerns, the panel concluded that the benefits of antiretroviral therapy outweigh the risks, noting that many studies have shown lower rates of liver-related mortality in co-infected patients taking antiretroviral therapy (ART).
“Since severe immunosuppression accelerates HCV-related liver fibrosis progression, it may be advisable to start [HA]ART without unnecessary delays in co-infected patients and even consider earlier initiation of treatment,” they wrote. “Elevated plasma HIV RNA seems to be largely responsible for the accelerated course of hepatic fibrosis in co-infected patients, and accordingly time on successful [HA]ART has been shown to protect from rapid liver fibrosis progression.”
Assessment of fibrosis
Several non-invasive methods for assessing fibrosis have been proposed as alternatives to liver biopsy, including serum biomarkers and imaging techniques such as transient elastography. These newer methods perform well in diagnosing absent or mild fibrosis versus severe fibrosis or cirrhosis, which is the information needed to guide treatment decisions. The tests are less able to distinguish between histopathological stages, but the panel deemed this information unnecessary.
“[A] liver biopsy is not mandatory for considering the treatment of chronic HCV infection,” they concluded. “A combination of non-invasive methods to assess liver fibrosis accurately predicts hepatic fibrosis in most cases.”
Soriano V et al. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV-HIV International Panel. AIDS 21: 1073-1089, 2007.