Chronic infection with the hepatitis C virus (HCV) has become a major concern for people living with HIV (PLWH). In the United States, over 200,000 people -- an estimated 25% of all PLWH -- also have hepatitis C. The majority of HIV/HCV co-infected persons acquired both viruses from injection drug use with contaminated equipment. While the course of hepatitis C infection varies widely, research indicates that HIV can accelerate the course of hepatitis C, leading to more rapid progression of liver disease and increasing HCV viral loads. Hepatitis C treatment does not work as well in HIV-positive people, and people with hepatitis C can have more trouble tolerating antiretrovirals for HIV, which can be hard on the liver (hepatotoxic). In recent years, end-stage liver disease from hepatitis C has become a leading cause of death for people living with HIV. This article will review recent research on hepatitis C and HIV coinfection, with a focus on new data on hepatitis C treatment for PLWH.
The hepatitis C virus infects the liver, the organ responsible for storing, filtering, and metabolizing chemicals that pass through the body, including nutrients from food, drugs, and medications. Most people who acquire HCV develop chronic infection, though about 30% can clear the virus spontaneously within a few months after being infected. Hepatitis C is thought to damage the liver by triggering immune responses that attempt to kill infected liver cells. As cells die, the liver responds by producing fibers to seal up the damaged areas, a process called fibrosis. This allows the liver to regenerate while preventing further damage.
The good news is that for people with hepatitis C, liver damage is typically a very slow process, occurring over decades. Some people never develop any significant liver damage, and the majority does not progress to cirrhosis. However, several studies have documented more rapid fibrosis progression in people co-infected with hepatitis C and HIV. It is unclear why co-infected people experience more rapid and severe liver disease, though people with low CD4 T-cell counts are at highest risk of cirrhosis and end-stage liver disease. HIV may impair the immune system's ability to respond effectively to hepatitis C, particularly in people with low CD4 T-cell counts. The result is the worst of both worlds -- higher hepatitis C viral loads and more liver damage. Some people hope that successful highly active antiretroviral therapy (HAART) might offset HIV's effect on fibrosis progression, while others worry that HIV medications may worsen liver disease due to hepatotoxicity. Available research has been inconclusive or shown little effect of HAART on fibrosis, positive or negative. Some HIV medications -- particularly Viramune (nevirapine) and full-dose Norvir (ritonavir) are more likely to be hepatotoxic, particularly in people co-infected with hepatitis C, and require careful monitoring.
Despite this grim outlook, two recent reports from Johns Hopkins University, presented at the 11th Conference on Retroviruses and Opportunistic Infections (CROI) in February, offer some good news for people co-infected with hepatitis C and HIV. Both studies used liver biopsies, the most accurate test for liver damage. The liver biopsy is a procedure that uses a long needle to take a small sample of liver tissue that can be examined for signs of fibrosis and inflammation. One study looked at a random selection of 115 co-infected patients in a clinical cohort. Only 17% had cirrhosis, and 43% showed no fibrosis. A second study looked at fibrosis progression in 116 injection drug users with chronic hepatitis C who had received two liver biopsies, averaging four years apart. Over half of the people in the study showed little or no fibrosis, and only 6% had cirrhosis. Fibrosis progression was fairly slow overall. Though 28% of the study group was co-infected with HIV, HIV status did not influence the rate of fibrosis progression. Together, these studies suggest that earlier assessments of fibrosis in co-infected people may have been overly pessimistic.
In the Johns Hopkins studies, elevated liver enzyme levels (ALTs, for alanine aminotransferase, or ASTs, for aspartate aminotransferase) were associated with greater risk of fibrosis progression and/or serious fibrosis. Another report from Italian researchers supports these results, finding that 75% of co-infected persons with persistently normal ALT levels had little or no fibrosis, while those with elevated ALTs tended to have more serious fibrosis. However, some people with normal liver enzyme levels do have cirrhosis, which can only be determined through liver biopsy. Because biopsies are invasive procedures that can be painful and carry a small risk of complications, several researchers are looking for ways to gauge fibrosis and cirrhosis through blood tests. So far, results from various types of blood tests have not been as accurate at fibrosis, though another Johns Hopkins poster at CROI described a combination of tests that could identify a substantial proportion of co-infected people with minimal liver damage, reducing the need for biopsy.
Liver biopsies provide crucial information for people considering hepatitis C treatment. People with minimal fibrosis may choose to defer treatment and get a follow-up biopsy in another 2-3 years. However, HCV treatment is recommended for people with moderate to severe fibrosis or compensated cirrhosis. Treatment is not indicated for people with decompensated cirrhosis, where damage to the liver has compromised its ability to function. Decompensated cirrhosis generally requires a liver transplant.
Treatment for hepatitis C consists of a combination of two drugs, pegylated interferon and ribavirin. Pegylated interferon is a synthetic form of interferon alpha, an antiviral molecule naturally produced by the body. Pegylated interferon is taken once a week by injection. The FDA has approved two forms of pegylated interferon: Pegasys, made by Roche, and Peg-Intron, marketed by Schering-Plough. Ribavirin is a nucleoside analogue (like AZT and Epivir) that comes in pill form, taken orally twice a day. Both drugs can have serious side effects, including flu-like symptoms, fatigue and anemia, and depression and insomnia. A substantial number of people have to reduce their doses of pegylated interferon and/or ribavirin at least temporarily due to side effects, and some people cannot tolerate a full course of therapy and discontinue treatment early. A small but worrisome number of suicides have been reported among people undergoing hepatitis C treatment. People with histories of drug use may have particular difficulty dealing with the side effects of treatment, putting them at risk of relapse to addiction.
The goal of hepatitis C treatment is total clearance of HCV, with an undetectable hepatitis C viral load. People maintaining an undetectable viral load six months after the end of treatment are called sustained virologic responders. Studies in people with hepatitis C alone show that the vast majority of people who experience a sustained virologic response (SVR) remain undetectable after several years of follow-up. Many people that clear hepatitis C during treatment relapse on or after therapy, with their viral load rebounding to detectable levels, and do not achieve an SVR. Even people who do not achieve an SVR may benefit from hepatitis C treatment; some people who do not clear HCV experience improvements in the condition of their liver, which may reduce long-term risk of end-stage liver disease.
The main determinant of treatment success is hepatitis C genotype, or strain of HCV. At least six HCV genotypes exist; genotype 1 is most common in the United States, followed by genotypes 2 and 3. Genotype 1 is the hardest to clear. In hepatitis C monoinfection (HIV-negative), those with genotype 1 are treated for a full year, and treatment results in an SVR in about half of people receiving therapy. In contrast, people with genotype 2 or 3 require a shorter duration of treatment, typically 6 months. In people with hepatitis C alone, those with genotype 2 or 3 respond very well to HCV treatment, and the majority -- over 80% -- achieve a sustained virologic response. Studies in people infected with hepatitis C alone (HCV monoinfection) show that for all genotypes, if their HCV viral load does not drop 100-fold or become undetectable by the end of 12 weeks of hepatitis C treatment, they will not achieve an SVR.
Until recently, most information about HCV treatment has come from studies of people with hepatitis C monoinfection. The FDA approved combination therapy with Pegasys or Peg-Intron and ribavirin without any substantive data on the safety and efficacy of these treatments in co-infected people. The tolerability of these drugs in people with HIV was a central concern. For instance, interferon reduces the CD4 T-cell count during treatment, though levels return to baseline after therapy. Ribavirin can induce anemia, a condition already common in people living with HIV, especially among those taking AZT-containing regimens (including Combivir and Trizivir). Moreover, rates of depression run high among PLWH, and the majority of co-infected persons have histories of drug use, indicating that management of mental health and substance abuse would be vital. Finally, preliminary studies suggested that co-infected people may be less likely to achieve an SVR on hepatitis C treatment, especially since their hepatitis C viral loads tend to be higher than people with HCV alone; studies in HCV monoinfection show that people with lower hepatitis C viral loads respond better to treatment. All of these issues raise thorny questions about the relative risks and benefits of HCV treatment for co-infected people, who have a higher risk of progressing to liver disease.
Three large clinical trials examining the efficacy and safety of hepatitis C treatment in co-infected people reported their final results at the 11th CROI, and this data will shape treatment decisions for the foreseeable future. All three studies compared pegylated interferon/ribavirin to the previous standard of care, combination therapy with standard interferon (requiring three injections per week, compared to once a week for the longer-acting pegylated versions) and ribavirin. One study also compared pegylated interferon/ribavirin to pegylated interferon alone. All showed that pegylated interferon/ribavirin was superior, though SVR rates were lower than those seen in HCV monoinfection studies.
APRICOT (AIDS Pegasys-Ribavirin International Coinfection Trial): An international trial of 860 co-infected persons (289 receiving 180 µg of Pegasys once a week and 800 mg of ribavirin daily). About 60% had HCV genotype 1. Median CD4 T-cell count was about 530, and 85% were receiving antiretroviral therapy, with 60% having undetectable HIV viral loads. About 60% had a history of injection drug use.
ACTG 5071: A U.S. study conducted by the Adult AIDS Clinical Trials Group of 133 co-infected persons (66 receiving 180 µg of Pegasys once a week with daily ribavirin). Ribavirin was initially dosed at 600 mg/day, with the ribavirin dose increasing every four weeks by 200 mg to a maximum 1000 mg/day as tolerated. About 77% had HCV genotype 1. Median CD4 T-cell counts ranged from 444-492, and about 86% were receiving antiretroviral therapy, with 60% having undetectable HIV viral loads.
RIBAVIC (ANRS HC02): A French study conducted by the Agence Nationale de Recherches sur le SIDA of 412 co-infected persons (205 receiving 1.5 µg/kg of Peg-Intron once a week and 800 mg of ribavirin daily). About 60% had HCV genotype 1. Median CD4 T-cell count ranged from 501-527, and about 83% were receiving antiretroviral therapy, with 66% having HIV viral loads below 400. About 79% had a history of injection drug use.
Results of these studies for participants in the pegylated interferon/ribavirin arms appear below, with discontinuation rates for adverse events (for side effects and lab abnormalities, see table below).
The highest SVR in co-infected people with genotype 1 was seen in APRICOT -- about twice as high as rates in the other studies. Both APRICOT and ACTG 5071 had fairly high SVR rates for people with genotype 2 or 3. RIBAVIC had the highest rate of premature treatment discontinuations for adverse events. While it can be difficult and misleading to compare results across studies, due to differences between protocols and patient populations, several reasons for the disparate results have been proposed:
Further analyses of these studies are on-going, in an attempt to clarify factors that influence treatment response. The next major question for coinfection research is whether extending the duration of treatment can improve sustained virologic response (SVR) rates. APRICOT treated people with genotypes 2 and 3 for 48 weeks, rather than the standard 24 weeks used in HCV monoinfection, and found that virtually no people relapsed. Some doctors have already begun extending treatment for people with genotype 1. Further research is also underway investigating whether long-term maintenance therapy with a half-dose of pegylated interferon can improve or stabilize the condition of the liver in people who do not achieve an SVR.
In the meantime, co-infected people now have more information for making hepatitis C treatment decisions. Beyond treatment, PLWH should make sure that they have been successfully vaccinated for the hepatitis A and hepatitis B viruses. Other strategies for liver health include reducing or eliminating alcohol, careful monitoring of liver enzyme levels when starting new medications, good nutrition, and reducing stress. These factors can help to protect your liver until better hepatitis C medications become available, hopefully in the next four or five years.
|Study (Regimen)||Genotype 1 SVR||Genotype 2/3 SVR||Discontinuations (Adverse Events)|
|ACTG 5071 (Pegasys/RBV)||14%||73%||12%|
|RBV = ribavirin|
Daniel Raymond is Hepatitis C Policy Analyst for the Harm Reduction Coalition, in New York City. Special thanks to Tracy Swan for her comments and suggestions.