There has been a new focus of research attention on studying hepatitis C virus (HCV) in people with HIV-disease. HCV has always been of concern to people living with HIV-disease, the majority of people with hemophilia and HIV also received HCV through contaminated blood products. HCV has become even more a concern as many of the new anti-HIV drugs greatly stress the liver, making management of HIV and HCV difficult. There are approximately 4 million Americans infected with hepatitis C (HCV) and that number is increasing dramatically with about 150,000 newly infected people each year. A growing number of those people are co-infected with HCV and HIV. There are many similarities between HCV and HIV, one being that people with HCV experience high increases in liver enzymes (specifically ALTs or alanine aminotransferases) after initial infection with HCV. With the help of the immune system, the level of liver enzymes decreases, but gradually increases again over time. Antibodies against HCV take a while to develop, rendering HCV antibody testing during the acute phase unreliable. In most people with HCV, their HCV levels, without treatment, are in the 100,000 to 10,000,000 copies HCV RNA range. These numbers, however, should not be compared to the viral load numbers we are accustomed to seeing from HIV. Currently, there is little or no information about how specific viral load levels of HCV relate to clinical illness, and therefore, treatment decisions should not be made based on viral load levels alone. Unlike hepatitis B, in which only a small percentage of people develop chronic liver disease, a majority of people with hepatitis C develop chronic illness. Serious symptoms do not develop until someone reaches an advanced stage of disease but patients often suffer a series relapses characterized by sometimes severe fatigue and other gastrointestinal symptoms. For some people, the disease can be mild and symptoms do not develop.
The current recommendation for treating HCV is a 12 month course of interferon-alfa (Intron-A®, 3 million units three times a week) which results in a long-term response (no detectable HCV RNA levels) in about 20% of people treated. However, for the other 80% of people, HCV RNA levels and liver enzymes increase. The recommendation to use interferon-alfa for only 12 months is because the drug can cause flu-like side effects and has to be administered by injection under the skin (subcutaneous). It is believed that many people are unwilling to use this drug for a longer period. Recently, the combination of ribavirin and interferon-alfa (sold together as Rebetron®) has increased the long-term response rate to between 35-40%.
People who are co-infected with HIV and HCV tend to have higher HCV levels which usually leads to a more rapid progressive disease. The recommendation for treatment and reports of effectiveness do not include people co-infected with HCV and HIV. Results form a small study in Spain showed that co-infected people had similar responses to those only infected with HCV when treated with interferon-alfa. People with HCV levels below 10 million copies and a CD4+ cell count above 500 were most likely to respond.
There has been a lot of controversy in the past few years whether people co-infected with HIV and HCV can safely use protease inhibitors. A study conducted at Johns Hopkins University showed that people receiving the protease inhibitor ritonavir (Norvir®) were significantly more at risk for severe liver toxicity compared to people receiving other anti-HIV therapy regimens. This study involved 381 people, approximately two-thirds were receiving a protease inhibitor and one third were on a two-drug nucleoside analogue reverse transcriptase inhibitor (NARTI) regimen. People receiving ritonavir or ritonavir + saquinavir (Invirase® or Fortovase®) were about fives times more likely to develop severe liver toxicity than people receiving the other protease inhibitors or the NARTI regimen. Interestingly there were no differences in serious liver toxicity in people with or without chronic HCV and/or hepatitis B infection who received ritonavir. However, people with viral hepatitis who received saquinavir, nelfinavir (Viracept®) or indinavir (Crixivan®) were at greater risk for developing liver toxicity compared to people on a two-drug NARTI combination. The good news from this study is that about 90% of people with HCV were able to safely use a protease inhibitor-containing regimen without serious side effects. Results from this study suggest that people who are co-infected can safely use the protease inhibitors while monitoring their liver enzymes closely.
Most people with HIV have been or are still on a 3TC (lamivudine, Epivir®) containing regimen. 3TC also has potent activity against hepatitis B virus (HBV), although it is generally used at a lower dose than is recommended for HIV when used to treat HBV. However, HBV can become resistant to 3TC when a dose of 50-100mg/day is used. A study in France followed 19 people who were HBV and HIV co-infected who started 3TC (150mg twice a day for a total daily dose of 300mg) as part of their anti-HIV regimen. Study participants also received another NARTI and most also received a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor. About a third of the participants had failed interferon-alfa for treating their HBV infection. All of the participants were men with a mean CD4+ cell count of about 200 and HIV levels of 50,000 copies HIV RNA. Almost all of the participants had good anti-HIV and anti-HBV responses with 14 people having HBV levels below the limits of detection with the currently available HBV tests. However, four people developed 3TC resistant HBV even with the higher 3TC dose. People who developed 3TC resistant HBV generally had lower CD4+ cell counts (about 30) and have been on anti-HIV therapies longer. Interestingly, HBV levels were not predictive of HBV resistance to 3TC. There were cases of increases in HBV levels when 3TC was stopped in people whose HBV was still sensitive to 3TC. People who are co-infected with HIV and HBV may want to consider continuing on 3TC even if their HIV is resistant to the drug, as it may still be active against HBV.
People who are most likely to respond to interferon-alfa therapy are likely to be younger, do not have cirrhosis, have low HCV levels and have HCV types 2 or 3. In clinical studies, approximately 65% of people with HCV type 2 or 3 responded to interferon-alfa and ribavirin compared to about 30% in people with HCV type 1.
Hepatitis C deserves research attention as there are only a few therapeutic options, most of which have quite a few side effects. Additionally, we do not know how well these therapies work in people who are co-infected with HIV and HCV, if they will experience more side effects and how these therapies might affect the course of HIV disease. Furthermore, there is some potentially dangerous drug interactions between therapies for HCV and commonly used HIV therapies. For instance, people receiving ribavirin (Rebetol® or Rebetron®) should not take AZT (zidovudine, Retrovir®) as ribavirin significantly decreases the anti-HIV activity of AZT. More studies need to be conducted to determine which anti-HIV and anti-HCV drugs can be safely used together.
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