HIV & Hepatitis C Virus (HCV) Coinfection: 7th Retrovirus Conference Update
by Michael Marco

Hepatitis C (HCV) is the insidious bad boy of the hepatitis-causing viruses. Unlike its liver-loving cousins hepatitis A (HAV) and B (HBV), a slow-acting, virtually symptom-free chronic HCV infection can eventually cause life-threatening liver complications in 20% and death in about 5% of those infected. Documented cases of HCV have been traced back to the mid-1950s, yet until its isolation in 1989, HCV infection was termed non-A non-B hepatitis by default. With a diagnostic test for HCV came evidence that HIV and HCV coinfection was actually quite common, yet only in the last four years have AIDS researchers and clinicians started to pay serious attention to the implications of dual infection. Since it can take twenty to forty years for HCV to cause clinically significant liver damage, most clinicians initially presumed that individuals with both HIV and HCV would die of AIDS before liver disease became a concern. Now that people with HIV are living longer due to better therapies, the long-term management and treatment of people with HIV/HCV coinfection has emerged as a crucially underresearched issue.

At this year's Retrovirus Conference, a three-hour symposium and many data presentations were devoted to HCV research. Two big-name presenters at the symposium were David Thomas and Mark Sulkowski from Johns Hopkins University. Thomas and Sulkowski have contributed greatly to our fledgling knowledge of the epidemiology, natural history, and response to treatment of hepatitis in those with HIV/HCV coinfection. Their lectures were eagerly awaited by numerous HIV clinicians in the audience not yet familiar with all aspects of disease progression and clinical management of individuals with HCV.

Thomas noted that a recent CDC study estimated four million persons nationwide are HCV antibody positive and about three million of those are chronically infected with HCV (meaning they have a detectable HCV viral load). This could mean that about 1.8% of the U.S. population is HCV-positive. Although we do not know the total number of those coinfected with HIV and HCV, it is clear that HCV prevalence is very high among injecting drug users (IDUs). The problem for inner-city methadone and HIV/AIDS clinics is staggering -often more than half the clients have HIV and HCV. One Baltimore methadone clinic reported a HIV/HCV coinfection rate of 97%.

Unlike hepatitis A and B, only 20-30% of people who have HCV will experience any symptoms (namely, jaundice, nausea, and fatigue). Doctors rarely test for HCV and thus do not recognize the presence of infection. During the follow-up period in their natural history study, Thomas and his colleagues at Johns Hopkins documented many HCV-positive IDU patients who were previously untested. Most had been regularly seeing a doctor who failed to recognize any of the signs and symptoms of HCV.

People who have any history of injection drug use should be tested for HCV because they are likely to have been exposed. An excellent epidemiological study (again from Johns Hopkins) estimated that the risk of acquiring HCV infection was as high a 65% for new injectors within six to twelve months of beginning injection drug use; by two years it was almost 90%. The risk of acquiring HCV from injecting drug use is much higher than that of other viral infection such as HIV. The same study documented the rate of HIV infection in IDUs during this short window as only 14%.

Thomas also stated that having HIV gives a poor prognosis for one's HCV infection and that those with coinfection are at increased risk for liver disease progression. I differ with Thomas on this conclusion. The out-of-date data he presented were from cohorts of HIV-infected patients (mostly hemophiliacs) obtained before the widespread use of highly active antiretroviral therapy (HAART). HIV-infected patients who had worse liver disease than their HIV-negative counterparts in the late 1980s and early 1990s had high HIV loads and CD4 cell counts below 200. Today, effective anti-HIV drugs allow much better control of HIV, which can result in increased CD4 cell counts (and improved immune function). This may mean that individuals with suppressed HIV who have HCV can fare just as well as those without HIV.

This was documented in a brilliant French study published last year. Yves Benhamou and colleagues from Paris reported on liver fibrosis progression (the liver deterioration process) in a well-characterized HIV/HCV coinfected cohort. Low CD4 counts (<200 cells/mm³) and more than five glasses of alcohol (50 grams) a day were shown to be associated with a higher liver fibrosis progression rate leading to cirrhosis (end-stage liver disease). When they analyzed all patients by CD4 count above or below 200 cells and by alcohol consumption, there was little difference in the time from HCV infection to cirrhosis between the HCV+/HIV+ patients and the matched HCV+/HIV- groups. For example, for someone with a CD4 cell count below 200 who drank more than five glasses of alcohol a day, progression to cirrhosis would be expected in an average of fifteen years. But for someone who drinks less and has over 200 CD4 cells, the estimated time to cirrhosis is thirty-six years. This is very close to the estimated time to cirrhosis of forty years for an HIV-negative person who is not a heavy drinker. Below is a chart that documents progression to cirrhosis.

The same researchers also presented some good news at this year's Retrovirus Conference about coinfected individuals on protease inhibitor therapy. Originally, the study was done because researchers thought they would show that protease inhibitors would do damage to the HCV-positive patients' livers. In fact, the opposite was shown. Those on protease inhibitors for approximately one year who had CD4 counts above 200 had a slower progression to liver disease than those not on protease inhibitors. (Note: they did not look at NNRTIs such as efavirenz or nevirapine).

What these data tell us:

1. It is safe for HCV-infected patients with HIV to take protease inhibitors.
2. HCV-related liver disease complications are reduced when coinfected individuals keep their CD4 counts above 200.
3. Heavy alcohol consumption is bad for one's liver. We still don't know how much alcohol is too much. One beer or glass of wine may not hurt one's liver, but five glasses a day (as is often the practice for the French, who love their wine) could be disastrous.

What about sexual transmission of HCV?
Many gay men want to know if HCV is sexually transmissible-especially those who decide not to use condoms if both are HIV-infected. It's a controversial subject on which no two hepatitis researchers agree. For monogamous heterosexual couples who only have vaginal intercourse, the risk appears slim to none. However, there are some convincing reports that gay men with numerous sexual partners who engage in high-risk behavior are at increased risk for becoming HCV-positive. Likewise, those with sexually transmissible disease (STDs) and people with HIV and hepatitis B may be more likely to transmit HCV to their partners. While it appears there must be blood-to-blood contact, the risk of HCV transmission among high-risk individuals may be as high as 15%. The table below summarizes several international epidemiology studies that documented numerous risk factors for developing HCV disease.

An excellent Canadian study presented at the conference reported that gay men with HIV had a higher incidence of HCV than their gay, HIV-negative counterparts. Importantly, the act of "fisting" was found to be the only sexual practice associated with an increased risk for HCV infection. Below is a table of the results:

RISK FACTORS FOR HCV IN HOMOSEXUAL MEN

• 232 men selected out of a cohort of 1,000 sexually active homosexual men in British Columbia, Canada
• 112 (48%) were HIV- & 120 (52%) were HIV+; 20 (8.6%) were HCV+
• HCV prevalence was higher in HIV+ men vs. HIV- men: 14.2% vs. 2.7% (p = 0.002)

Treatment of HIV and HCV Coinfection
For many years the recommended treatment for HCV was alpha interferon (IFN). The current standard of care is a combination of IFN with ribavirin (RBV). The combination of IFN and RBV has been shown in clinical studies as far superior to IFN alone. Unfortunately, all people with HIV were excluded from the original studies of this combination for HCV. Douglas Dieterich and colleagues from New York conducted a trial to determine if IFN/RBV combination therapy was safe and effective in HIV-positive individuals with HCV. Although the trial results appear promising for those in the combination group, we can not be certain that combination therapy was more effective than IFN alone because patients were unevenly randomized (assigned by chance) into the two treatment arms. Importantly, though, the IFN/RBV combination appeared safe for people who were also on HAART. Side effects, such as depression, flu-like symptoms, and anemia (low red blood cell count) were no more prominent in the combination group than in the IFN group.

A few concerns about the safety of ribavirin in HIV-positive people linger. There is a possibility for increased toxicity, including hemolytic anemia (destruction of red blood cells), and a potential adverse interaction between ribavirin and certain anti-HIV drugs, particularly AZT, 3TC, and d4T. Ribavirin potentially decreases the intracellular activation of these three nucleoside analogues -- although some early data suggest that this interaction is not clinically significant. However, more studies are needed to address these concerns.

A new formulation of IFN (called pegylated interferon) is now in clinical trials. Two companies, Roche and Schering-Plough, are testing different pegylated IFNs. Both appear to be more effective than regular IFN and need only be given once a week, rather than the three- to five-times-a-week IFN dosing schedule. Although easier to take, the pegylated IFNs are no gentler, and the side effects are similar to those for IFN.

Slowly we are learning how to manage and treat individuals with HIV and HCV coinfection. Yet much remains to be done. More research money and a strong commitment from the National Institutes of Heath (NIH) and the pharmaceutical industry are badly needed to continue this progress.

Related Articles
• Hepatitis C abstracts on HIV Insite
• HIV and Hepatitis website
• Community Forum: Hepatitis C Coninfection
• Simple Facts Sheet on Hepatitis C