Hepatitis C: The Changing Picture
As if having HIV weren't already enough of a challenge, about 25% of people with this virus also have the hepatitis C virus. Over time, this can lead to serious liver disease, and some studies show that this happens faster in people who also have HIV.
In addition, people with both HIV and hepatitis C virus (HCV) may not respond to HCV treatment as well as people who have HCV only. But many coinfected people have good treatment outcomes, and effective HIV treatment may slow liver disease progression. Promising new HCV treatments are now in the final stages of development, but these drugs also need to be tested in people with HIV.
Like HIV, HCV can be transmitted through direct blood-to-blood contact -- sharing needles, for example. Many people were infected through blood transfusions before screening of the blood supply began in 1992. Often, however, the transmission route is unknown.
The CDC estimates that about 3 million people in the U.S. have HCV. Fortunately, the rate of transmission has fallen dramatically since its peak, with new infections declining steadily after 1992 and leveling off in 2003. A CDC study of 5,000 injection drug users in four cities found that the number with HCV fell from 65% in 1994 to 35% ten years later. But many people who were infected decades ago are just now starting to reach the advanced stages of liver disease. And, because hepatitis C usually has no symptoms in its early stages, people often don't know they carry the virus.
Since HIV treatment has dramatically lowered the number of deaths from AIDS, liver disease related to hepatitis B or C has become a major cause of illness and death for people with HIV. But studies suggest that the number of coinfected people and their risk of dying from liver disease are both now starting to fall, thanks to fewer new infections and better HCV treatment. Spanish researchers, for example, recently reported that while 71% of people with HIV entering their study in 1997 had HCV, only 16% did in 2006, largely due to fewer injection drug users becoming infected.
It used to be thought that HCV was rarely transmitted through sex, based on studies of long-term, monogamous heterosexual couples. Since the early 2000s, however, doctors in Europe have reported outbreaks of HCV that appear to be sexually transmitted. These mostly involve HIV-positive gay and bisexual men, though there have been a small number of cases in HIV-positive women and HIV-negative men. Similar outbreaks have been reported in Australia and the U.S.
A study done at a British sexual health clinic found that men with HIV were 13 times more likely than HIV-negative men to have HCV. A similar study at a clinic in Amsterdam found that 18% of gay men with HIV also had HCV, compared with less than 1% of HIV-negative gay men. While the risk factors vary from study to study, these outbreaks have been linked to unprotected anal sex, fisting, sex toys, multiple sexual partners, sex in group settings like bathhouses, using recreational drugs during sex, and having other STDs. While some HCV may be present in semen, experts suspect most transmission during sex is probably the result of contact with small amounts of blood.
A recent analysis of more than 200 men in the U.K., Netherlands, Germany, France, and Australia who were diagnosed with acute hepatitis C between 2000 and 2006 found evidence of HCV transmission within sexual networks. Genetic analysis showed that most of the men had closely related virus, and about a quarter of them had HCV genotype 4, which is uncommon in Europe -- further evidence of a sexual network of transmission.
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Over years or decades, HCV can lead to advanced liver disease, including cirrhosis and liver cancer. Many studies have found that people with HIV tend to experience faster disease progression than their negative counterparts. Coinfected people are more likely to have liver fibrosis (scarring) than people with HCV alone, and the degree of damage can be worse. But recent reports suggest that people whose HIV is well controlled by meds and who have higher CD4 counts may not have worse liver disease outcomes than people who do not have HIV.
Some of the most worrisome findings come from Daniel Fierer, MD, at Mt. Sinai in New York City. He first reported at the 2007 Retrovirus conference that a small group of HIV-positive gay men recently infected with HCV seemed to be experiencing unusually rapid liver disease progression. As reported in the Journal of Infectious Diseases, liver biopsies of 24 men found that one had serious stage 3 fibrosis (on a scale of 0 to 4), 18 had moderate stage 2 fibrosis, three had mild stage 1 liver damage, and two showed no evidence of fibrosis (stage 0). A related analysis found that even the few men who were able to clear HCV without treatment still had moderate fibrosis.
These results were quite surprising, since the men had shown signs of HCV infection for only about four months. Dr. Fierer's work suggests that having HIV at the time of HCV infection may promote rapid liver damage. This was the case even though his patients had well-preserved immune function, with a median CD4 cell count of 535, and more than 90% had an undetectable HIV viral load. Researchers studying the acute HCV outbreaks in Europe have not reported similar findings, but they mostly use the less accurate FibroScan method instead of liver biopsies to estimate fibrosis.
The reasons for faster fibrosis progression in people with HIV are not well understood. Once recent laboratory study showed that HIV can enter specialized cells in the liver and trigger them to produce scar tissue. In addition, the risk of liver toxicity from HIV drugs can be higher in people who also have HCV. On the other hand, two of the drugs most commonly associated with liver damage -- Videx and Zerit -- are no longer widely used.
Other research suggests that the immune system activation and inflammation caused by ongoing HIV replication contributes to liver disease progression. In the SMART study, people who stopped HIV meds when their CD4 count fell below 350 were more likely to develop serious liver disease than those who stayed on continuous therapy. Further, recent research shows that HIV treatment slows fibrosis progression and may even help reverse liver damage. Jose Pascual-Pareja from Spain reported in AIDS that in coinfected people with CD4 counts above 350, HIV treatment was associated with reduced liver inflammation and cell death, which in turn was strongly associated with less fibrosis.
Other evidence indicates that HIV treatment may not completely reverse the effects of HCV. A University of Toronto analysis of 17 studies (3,567 people) found that coinfected people not taking HIV meds were about 2.5 times more likely to develop cirrhosis than people with HCV alone. But the risk remained 1.7 times higher even for those taking HIV meds. Similarly, a recent French study showed that advanced liver fibrosis or cirrhosis was twice as common in coinfected people, compared with people with HCV only (39% vs. 18%), even though most of the former were taking HIV meds and their average CD4 count was nearly 500.
Finally, an analysis of repeated liver biopsies from 47 coinfected people in Virginia (mostly on HIV meds with an average CD4 count of about 600) found that 33% saw their fibrosis worsen, 44% saw no change, and 21% saw their fibrosis improve. There was no link between progression and baseline liver damage, CD4 count, use of HIV meds, or response to HCV treatment. Because no obvious factors predicted worsening fibrosis, the researchers recommended that all coinfected people should be offered HCV treatment since it is not possible to tell who will progress.
Current treatment for HCV is pegylated alfa interferon injections (Pegasys or PegIntron) once a week plus twice-daily ribavirin pills. Most people in the U.S. have HCV genotype 1, which is harder to treat than genotypes 2 or 3. African-Americans do not respond as well as whites, but we don't know why. Latinos may respond slightly less well than non-Hispanic whites, while Asians seem to do better.
Interferon can cause difficult side effects, including depression, fatigue, and low white blood cell count, and ribavirin can cause anemia. Many people are reluctant to start treatment for this reason, but not everyone has these side effects and they can often be managed. Recent studies, for example, have demonstrated the benefits of drugs that stimulate blood cell production and of starting antidepressants before the interferon.
About 20% of people with HCV will clear the virus without treatment, though this occurs less often in people with HIV. If treated soon after infection, cure rates are very high for both coinfected people and those with HCV alone. Among the men with new HCV infections in the Mt. Sinai study, for example, 80% who were treated for six months had a sustained virological response (SVR -- an undetectable HCV viral load six months after finishing treatment), which most likely means they were cured.
The standard length of treatment is 48 weeks for genotypes 1 or 4 and 24 weeks for genotypes 2 or 3. Current guidelines recommend that coinfected people be treated for 48 weeks regardless of genotype, but recent research shows that 24 weeks appears adequate for those with 2 or 3.
As a group, coinfected people do not respond as well to treatment as those with HCV alone. This may be because interferon works by stimulating the immune system, which is weaker in people with HIV. On the other hand, some recent studies show that coinfected people with well-controlled HIV and high CD4 cell counts can achieve results almost as good as those for HIV-negative people.
In the APRICOT trial, about 40% of coinfected people with HCV genotype 1 and about 60% of those with genotypes 2 or 3 achieved an SVR using peg-interferon plus ribavirin. This compares with about 50% and 75% in studies of HIV-negative people. Similarly, in the Spanish PRESCO trial, 36% of coinfected patients with genotype 1 and 70% with genotypes 2 or 3 achieved sustained response.
The impact of coinfection on treatment response seems to vary based on HCV genotype. In a recent Swiss study, coinfected people and those with HCV alone had similar SVR rates if they had genotype 2 or 3. But among people with genotypes 1, 4, or 5, many more people with only HCV achieved an SVR (58%) compared to coinfected people (13%).
In an effort to improve response rates and reduce side effects, researchers have studied different doses and durations of treatment. It is difficult to summarize this research, since the data are mixed and sometimes contradictory. While higher doses generally offer little extra benefit, extending treatment to 72 weeks may improve response in some coinfected people. People who do not have a substantial drop in HCV viral load within 4 to 12 weeks are unlikely to achieve an SVR and are usually advised to stop treatment.
While it is clear that people who achieve an SVR lower their risk for cirrhosis and liver cancer, the best course for nonresponders is less clear. The HALT-C trial of people with HCV alone showed that long-term maintenance therapy with low-dose peg-interferon reduced HCV viral load and liver enzymes, but that did not translate to lower rates of cirrhosis, liver cancer, or death. At the 2008 Retrovirus conference, the SLAM-C trial likewise reported that maintenance therapy did not prevent fibrosis progression in coinfected people.
The only treatment for end-stage liver disease or advanced liver cancer is a liver transplant. Several studies have shown that HIV-positive liver or kidney transplant recipients with well-controlled HIV and higher CD4 counts do nearly as well as HIV-negative patients. But in coinfected people, HCV almost always reinfects the new liver, leading to complications and shorter survival.
Because of the limited response rates and difficult side effects of interferon, researchers are studying new types of drugs that directly target different stages of the HCV lifecycle. Furthest along are the HCV protease inhibitors telaprevir and boceprevir.
The PROVE 1 and 2 studies included nearly 600 people with HCV only, who had genotype 1 and had not taken treatment before. They took telaprevir and peg-interferon, with or without ribavirin. People who took all three drugs had the best chance of an SVR -- around 65%, compared with about 45% for standard treatment. In PROVE 1, the benefit of telaprevir was especially large for African-Americans. A 24-week regimen worked nearly as well as one that lasted 48 weeks, but 12 weeks was too short, and omitting ribavirin increased the relapse rate. People taking telaprevir were more likely to drop out due to side effects, including skin rash and anemia. The PROVE 3 trial enrolled relapsers and nonresponders, and about half of those taking the best telaprevir regimens achieved an SVR, compared with just 14% of those taking standard treatment. In this study, the shorter regimens had higher relapse rates, leading the researchers to conclude that treatment-experienced patients might need longer treatment.
In the SPRINT-1 trial, about 600 people with genotype 1 who had not taken treatment before took boceprevir, peg-interferon, and ribavirin. People who took peg-interferon and ribavirin for a 4-week "lead-in" period before adding boceprevir for 44 more weeks had an SVR rate of 75%, compared with 38% for those taking standard treatment. Those who took a lower dose of ribavirin were more likely to relapse.
Several other new drugs are also being studied, including HCV polymerase inhibitors and entry inhibitors. For the near future, treatment with the new drugs will still include peg-interferon and probably ribavirin, although the length of treatment may be shortened. But in the longer term, HCV treatment may start to look more like HIV treatment.
The INFORM-1 study was the first to combine two new HCV drugs without peg-interferon or ribavirin -- the protease inhibitor R7227 and the polymerase inhibitor R7128. At the end of this 14-day study, 25% of those taking the highest doses had an undetectable HCV viral load. As with HIV, combination therapy should reduce the risk of drug resistance.
So far, these new drugs have not been studied in people with HIV. This is an important research need, since coinfected people may have faster disease progression and a more urgent need for treatment. It is also important to see if there are any interactions with HIV meds, good or bad. Some early studies suggest there may be drugs that work against both HCV and HIV (for example, the cyclophilin inhibitor Debio 025), so future HIV regimens might include drugs that fight both viruses.
While new drugs are eagerly awaited, many people who could benefit from current treatment are not getting it. A recent survey of patients receiving care from the Veterans Administration found that while most needed treatment, only 14% of coinfected people and 22% with HCV alone actually received it.
Many doctors are reluctant to treat HCV in current or former drug users. Several recent studies shave shown that people on methadone maintenance and even active users can achieve good treatment outcomes if they have the support they need to stay adherent. Even as we learn how to improve HCV therapy with better strategies and new drugs, it is crucial to offer the best treatment available now to those who need it.
Liz Highleyman is a freelance medical writer and journalist based in San Francisco.
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