Progress Is Being Made But Much Remains to Be Done in the Treatment of Hepatitis C Infection
Sexual Transmission Controversy
Michael Marco, TAG's Infections and Oncology Project Director, had his plate full in San Francisco this past February where he doubled up his conference coverage. Along with his dependable insights into the research and treatment of the opportunistic pathogens associated with HIV infection, Michael has also become somewhat of a hepatitis C guru. What follows is his springtime update on the treatment and research issues of this increasingly menacing viral infection of the liver.
Hepatitis C is the insidious bad-boy of the hepatitis-causing viruses. Unlike its liver-loving cousins hepatitis A and B, a slow-acting, virtually symptom-free chronic hepatitis C infection can eventually cause life-threatening liver complications in 20% and death in about 5% of those infected. Documented cases of hepatitis C have been traced back half a century, yet until its isolation in 1989 hepatitis C infection was termed "non-A non-B" hepatitis by default. With a diagnostic test for hepatitis C came evidence that HIV and hepatitis C 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 hepatitis C to cause clinically significant liver damage, most clinicians initially presumed that individuals with both HIV and hepatitis C 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 under-researched issue.
At this year's Retrovirus Conference, a three-hour symposium and many data presentations were devoted to hepatitis C research. Two big-name presenters at the symposium were David Thomas and Mark Sulkowski from Johns Hopkins University. Brilliant young Turks of hepatitis research, 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 the numerous HIV clinicians in the audience not yet familiar with all aspects of disease progression and clinical management of HIV-infected individuals with hepatitis C.
Thomas noted that a recent CDC study estimated 4 million persons nationwide are hepatitis C antibody positive and about three million of those are chronically infected with hepatitis C (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 hepatitis C, it is clear that hepatitis C prevalence is very high among injecting drug users. The problem for inner-city methadone and HIV/AIDS clinics is staggering -- often more than half the clients have HIV and hepatitis C. One Baltimore methadone clinic reported a HIV/HCV coinfection rate of 97%.
Unlike hepatitis A and B, only 20-30% of people who have hepatitis C will experience any symptoms (namely, jaundice, nausea, and fatigue). Doctors rarely test for hepatitis C and thus do not recognize the presence of infection. Thomas and his colleagues at Hopkins documented many previously untested injection drug using patients who tested HCV-positive upon entering their study during follow-up in their natural history study, even though most were regularly seeing a doctor who failed to recognize any of the signs and symptoms of hepatitis C.
People who have any history of injection drug use should be tested for hepatitis C because they are likely to have been exposed. An epidemiology study (again, from Johns Hopkins) estimated that the risk of acquiring hepatitis C infection was as high as 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 hepatitis C from injecting drug use is much higher than from other viral infections such as HIV. The same study documented the rate of HIV infection in injection drug users during this short window was only 14%.
Thomas also stated that having HIV gives a poor prognosis for one's hepatitis C 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 hepatitis C can fare just as well as those without HIV.
This was shown in a 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 hepatitis C infection to cirrhosis between the HCV+/HIV+ co-infected individuals and the matched HCV+/HIV- control 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 36 years. This is very close to the 40-year estimate for an HIV-negative person who is not a heavy drinker.
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 worried 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 the non-nuke class of drugs such as efavirenz or nevirapine).
What do the findings from this study tell us?
- It is safe for HCV-infected patients with HIV to take protease inhibitors.
- HCV-related liver disease complications are reduced when co-infected individuals keep their CD4 counts above 200.
- 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 your liver, but more than five glasses a day might not be a good idea.
What About Sexual Transmission of Hepatitis C?
Many gay men want to know if hepatitis C is sexually transmissible, especially those who decide not to use condoms. It's a controversial subject where no two hepatitis researchers agree. For monogamous couples who only have vaginal intercourse, the risk appears slim to none. However, there are some convincing reports that men who have sex with 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 and people with HIV and hepatitis B may be more likely to transmit hepatitis C to their partners. While it appears there must be blood-to-blood contact, the risk of hepatitis C transmission among high-risk individuals may be as high as 15%. The accompanying table summarizes fourteen epidemiology studies from around the world which have documented man-man sexual contact, sexually transmitted diseases, and other risk factors for transmitting hepatitis C.
|Studies Which Found Sexual Transmission or an Infectious Disease As Risk Factors for HCV Transmission|
|Risk Group||Country||N||N (%) HCV+||Risk Factors||Study|
|MSM||US||926||15 (1.6%)||HAV||Donahue 1991|
|STD Clinic (MSM & HET)||UK||MSM = 275|
HET = 771
|HIV+, HBV+, and lifetime number of STDs (MSM only)||Tedder 1991|
|Female (F) sex partners of male (M) hemophiliacs||US||F = 234|
M = 231
|5 (2.6%)||Sex with an HCV+/HIV+ M: 3% HCV+ for sex with HIV+/HCV+ M vs. 0% with HIV-/HCV+ M||Eyster 1991*|
|MSM||US||735||34 (4.6%)||>50 sex partners/year >25 oral receptive partners per year||Osmond 1993|
|MSM, prostitutes, & HET partners of an HCV+ person||Spain||168 MSM|
|Sex with HCV+/HIV+ (9.2% vs. 4.1% for HET sex with HCV+/HIV+ vs. HCV+ only)||Lissen 1993*|
|Prostitutes||Taiwan||622||74 (12%)||History of paid sex >6 months||Wu 1993|
|STD Clinic (MSM & HET)||US||1,257||122 (9.7%)||M = >29 years & lack of condom use|
F = >29 years & >1 sex partner prior month
|STD Clinic (MSM & HET)||US||1,039:|
M = 555
F = 484
|37 (7%) M|
19 (4%) F
|Age >28; >24 lifetime sex partners; HIV+; Trichomonas infection; cigarette smoking. Omitting HIV+ showed MSM significant risk (p = 0.012)||Thomas 1995|
|MSM||Australia||1,038||79 (7.6%)||HIV+||Bodsworth 1996|
|Women with or at risk for HIV||US||296||123 (42%)||HIV+, sex with male IDU, history of gonorrhea, >35 years, not graduating high school||Hershow 1996|
|Volunteer blood donors||US (REDS)||862,398||3,126 (0.36%)||HTLV I or II, HBV or HIV (OR, 10.4)||Murphy 1996|
|HCV+ blood donors & HCV-controls||Canada||267 HCV+|
|N/A||Sex with an IDU (OR, 6.9)||Delage 1999|
|HCV+ blood donors & HCV- controls||US (REDS)||2,316 HCV+|
|N/A||Sex with an IDU (OR, 6.3)||Murphy 2000|
|For the HIV+ men: Insertive fisting (OR, 4.06)|
|* = subset analysis; BT = blood transfusion; HAV = hepatitis A; HBV = hepatitis B; MSM = men who have sex with men; HET = heterosexual; STD = sexual transmitted disease; IDU = injection drug user; OR = odds ratio|
A Canadian study presented at the conference reported that gay men with HIV had a higher incidence of hepatitis C 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 hepatitis C infection.
Treatment of HIV and HCV Coinfection
For some years in the 1990s the recommended treatment for hepatitis C was alpha interferon. The current standard of care is a combination of interferon with ribavirin. The combination of interferon and ribavirin has been shown in clinical studies to be superior to interferon alone. Unfortunately, all people with HIV were excluded from the original studies of this dual combination for hepatitis C. Douglas Dieterich and colleagues from New York conducted a trial to determine if interferon/ribavirin combination therapy was safe and effective in HIV-positive individuals with hepatitis C. Although the trial results appear promising for those in the combination group, we cannot be certain that combination therapy was more effective than interferon alone because patients were unevenly randomized into the two treatment arms. Importantly though, the interferon/ribavirin 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 interferon 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 may not be clinically significant. More studies are needed to address these concerns.
A longer lasting pegylated formulation of interferon is currently in clinical trials. The two companies, Hoffmann-La Roche and Schering Plough, have different pegylated interferons. Both appear to be more effective than regular interferon and need only be given once a week, rather than the 3-5 times a week current dosing schedule. Although the less frequent dosing makes them easier to take, the pegylated interferons are no gentler than -- and the side effects are similar to -- regular interferon.
Slowly we are learning how to manage and treat individuals with HIV and HCV coinfection, but much remains to be done. More research money and a strong commitment from the National Institutes of Health (NIH) and the pharmaceutical industry is badly needed to continue this progress.