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New International Guidelines for Management of HIV-HCV Coinfection

By Liz Highleyman

An international panel of experts issued updated guidelines for the management of HIV-HCV coinfected patients in the May 31, 2007 issue of AIDS. The new recommendations reflect an improved understanding of concurrent infection and its treatment since the previous guidelines were issued in 2004

 

As background, the authors noted that an estimated one-third of HIV positive individuals also have hepatitis C virus (HCV). Coinfected patients experience more rapid liver disease progression, though this may be less likely if they have well preserved immune function and high CD4 cell counts. In addition, coinfected patients typically do not respond as well as HCV monoinfected individuals to treatment with pegylated interferon plus ribavirin, but several recent studies have explored ways to optimize treatment in this population.

 

The panel issued recommendations in 11 areas:

Patients with persistently normal ALT: About 7%-9% of coinfected patients have persistently normal ALT, compared with about 25% of HCV monoinfected individuals. Research also suggests that 25%-40% of coinfected patients with normal ALT have significant liver fibrosis or cirrhosis, compared with 10%-30% of HCV monoinfected patients. Given that the prevalence of and progression to advanced fibrosis is higher among coinfected patients with normal ALT, the panel recommended that these individuals should be considered for hepatitis C treatment regardless of ALT level. 

Assessment of liver fibrosis: The panel reviewed non-invasive methods for assessing fibrosis using serum biomarkers and imaging techniques. While these methods perform well in diagnosing absent or mild fibrosis versus severe fibrosis or cirrhosis, they are less able to distinguish between intermediate stages. Given the improved rate of response to anti-HCV therapy, the faster rate of fibrosis progression in HIV positive patients, and the ability to assess early virological response, the panel stated that in most cases, “liver biopsy is not mandatory for considering the treatment of chronic HCV infection,” adding that a combination of non-invasive methods “accurately predicts hepatic fibrosis in most cases.” 

Predictors of response to anti-HCV therapy: Many factors that predict response to interferon-based therapy are the same in both coinfected and HCV monoinfected individuals (age, sex, race, HCV viral load, HCV genotype, body mass index, minimal liver fibrosis or steatosis), but there are some additional factors associated with poor response in coinfected patients, including lower CD4 cell count. Insulin resistance is also a concern, given its association with protease inhibitors. Rapid virological response (RVR) at week 4 predicts sustained virological response (SVR) in coinfected patients as it does in those with HCV monoinfection. Coinfected patients who do not achieve early virological response (EVR) by week 12, or who still have detectable HCV RNA at week 24, are unlikely to achieve SVR, and should be advised to stop treatment early. 

Optimal dosing of pegylated interferon and ribavirin: Adequate doses and duration of therapy are especially necessary for coinfected patients to obtain optimal treatment outcomes. Studies have shown that weight-based ribavirin (1000 mg/day if < 75 kg and 1200 mg/day if > 75 kg) is superior to an 800 mg fixed dose. While some studies have tested higher doses of pegylated interferon, the benefits have not been established in coinfected patients, and the panel recommended the standard dose: 180 mcg/week of pegylated interferon alfa-2a (Pegasys) or 1.5 mcg/kg/week of pegylated interferon alfa-2b (PegIntron).

Optimal duration of therapy: The panel recommended 48 weeks of pegylated interferon plus ribavirin for coinfected patients with all HCV genotypes. However, they said that 24 weeks may be adequate for those with genotypes 2 or 3, while slow-responding individuals with genotypes 1 or 4 (those who achieve EVR but not RVR) “might benefit from extended (60-72 weeks) courses of therapy.”

Treatment of coinfected non-responders and relapsers: A growing number of coinfected patients have already been treated with interferon-based therapy without achieving SVR. Based on available data, the panel stated that, coinfected non-responders and relapsers “are a heterogeneous population and therapeutic interventions in them should be individualized.” Those who previously received suboptimal therapy (e.g., conventional interferon, interferon monotherapy, low ribavirin doses) may be retreated with the best current standard therapy. While SVR is uncommon in true prior non-responders and relapsers to optimal treatment, even failed therapy or long-term interferon maintenance monotherapy may help slow liver disease progression. The panel suggested that investigational drugs¾including new types of interferon and HCV protease and polymerase inhibitors¾offer the prospect of improved outcomes, recommending that, “Trials exploring the efficacy and safety of these drugs in coinfected patients should be prioritized, without waiting for the final results of Phase III trials conducted in HCV-monoinfected.”

Patients with end-stage liver disease: The panel noted that management of coinfected persons with advanced liver cirrhosis is complex. Antiretroviral therapy “may significantly improve short- and mid-term outcomes in HIV positive patients with hepatic decompensation and, therefore, HAART should not be discouraged,” they wrote. The authors added that HIV infection should no longer be considered a contraindication to liver transplantation, but said that the procedure should be performed by a multidisciplinary team with experience in managing coinfected patients. 

Treatment of acute hepatitis C: The panel noted recent outbreaks of acute, apparently sexually transmitted HCV infection among mostly HIV positive men who have sex with men in Europe. Although 25%-30% of HIV negative individuals with acute HCV infection experience spontaneous viral clearance, HIV positive individuals are more likely to develop chronic hepatitis C. For this reason, the panel wrote, “early therapeutic intervention in acute HCV infection is particularly indicated in patients with HIV disease.” They recommended that HIV positive individuals with acute HCV should be treated for 24 weeks with pegylated interferon plus weight-based ribavirin, after waiting 12 weeks to allow for possible spontaneous clearance without treatment.

Patients with multiple hepatitis viruses: The prevalence of multiple hepatitis viruses (HBV/HCV, HBV/HDV, HBV/HCV/HDV) is low in developed countries, but more common in HIV-HCV coinfected patients than in HCV monoinfected individuals. People with more than one hepatitis virus may experience accelerated liver disease progression and are at higher risk for hepatocellular carcinoma. Whenever possible, the panel recommended, “treatment of all replicating viruses should be pursued.”

Interactions between anti-HCV and antiretroviral therapy: The major interaction concerns relate to concurrent use of ribavirin with ddI (Videx) or AZT (Retrovir). Both ddI and ribavirin can cause mitochondrial damage (which can lead to lactic acidosis, pancreatitis, and decompensated cirrhosis), and the panel said that this combination “should never be used.” Similarly, both AZT and ribavirin can cause anemia, and the authors recommended that AZT “should also be avoided when possible.”

Hepatotoxicity of antiretroviral drugs: The panel noted that various antiretroviral drugs affect the liver in different ways. Certain nucleoside reverse transcriptase inhibitors -- especially ddI and d4T (Zerit) -- can cause mitochondrial toxicity (which can lead to liver steatosis). Nevirapine (Viramune) can cause hypersensitivity reactions that damage the liver, and some protease inhibitors -- such as full-dose ritonavir (Norvir) -- can cause direct liver injury. Atazanavir (Reyataz) and indinavir (Crixivan) can cause elevated bilirubin, but this does not reflect liver damage. In addition, as HAART enables CD4 cell recovery, immune reconstitution can worsen liver inflammation (a concern for patients with HBV).

Despite the various complexities related to concurrent management of HIV and HCV infection, the panel concluded that the benefits of antiretroviral therapy outweigh the risks, noting that several studies have demonstrated lower rates of liver-related mortality in coinfected patients taking HAART.

“Since severe immunosuppression accelerates HCV-related liver fibrosis progression, it may be advisable to start HAART without unnecessary delays in coinfected patients and even consider earlier initiation of treatment,” the authors wrote.

Hospital Carlos III, Madrid, Spain; University Hospital, Brescia, Italy; Johns Hopkins Medical Institutions, Baltimore, MD; Ospedale Sacco, Milan, Italy; Hopital Pitie-Salpetriere, Paris, France; University of California, San Francisco, CA; Center for HIV and Hepatogastroenterology, Duesseldorf, Germany; Mount Sinai Medical School, New York, NY; Athens University Medical School, Athens, Greece; Necker-Cochin Hospital, Paris, France; University Hospital, Bonn, Germany.

06/01/07

References
V Soriano, M Puoti, M Sulkowski, and others. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV-HIV International Panel. AIDS 21(9): 1073-1089. May 31, 2007.