When HIV and HCV Cohabitate
Infection with hepatitis C virus (HCV) in those already infected with HIV poses some particular concerns resulting from the specific interaction of these two viruses and from the difficulties that arise from attempts to control their replication. In testing for HCV it is recommended that those who are coinfected with both viruses utilize a PCR test to determine the presence of HCV viral RNA. A single negative result on an HCV antibody assay is not sufficient as the loss of HCV antibodies has been demonstrated to occur three times as frequently in individuals coinfected with HIV as in those who are not. Therefore, it is possible that sole reliance on an antibody assay may mistakenly rule out HCV infection.(1)
Coinfection with HCV is conservatively estimated to occur in about 14% of persons with HIV, whereas only 1.4% of the general population carries HCV. Among those who acquired HIV through the use of intravenous recreational drugs or blood clotting factor, coinfection with HCV is estimated at between 50% and 90%. The rate of HCV among persons with HIV is 26% in Asia while it ranges widely, from 28% to 46%, in various European countries. The HCV coinfection rate is 40% in New York City and 56% in Boston.(2, 3)
HCV is frequently spread through infected blood products (prior to the development of HIV and HCV screening tests) as well as through contaminated intravenous, piercing, or tattooing needles. HCV has been shown to be approximately 10 times more infectious than HIV through these routes, and it appears to be only rarely transmitted through sexual exposure. Concurrent HIV infection probably does not increase this risk of sexual transmission of HCV.(4)
HIV Lends HCV a Helping HandA New York City study confirmed findings from earlier studies in Madrid that end-stage liver disease was diagnosed in 8.5% of hospitalized HIV patients. Approximately 90% of these cases were a result of infection with HCV. In the Madrid study, liver disease represented the fifth most frequent cause of death in coinfected individuals. Excluding death due to severe immune suppression (AIDS), liver failure represented the number one cause of death among the patients in the New York study. Still, at least one study found that among those coinfected individuals who have already progressed to AIDS, HCV does not adversely affect survival time from the date of AIDS diagnosis.(5)
Conversely, two Spanish studies involving patients with and without HIV observed that coinfection may reduce the time between contracting HCV and the development of fibrosis and/or cirrhosis. In a New York study, cirrhosis occurred in 33% of coinfected individuals, compared to 11% in those with HCV alone. Another study confirmed these results and indicated that HCV coinfection with HIV resulted in liver-related mortality ten years before individuals infected with HCV alone. Coinfection with HCV appears to lead to an estimated 20% lifetime overall risk for developing cirrhosis, and cirrhosis correlates with a 1% to 4% yearly incidence of liver cancer (hepatocellular carcinoma).(6)
It should be made very clear that there is currently no significant evidence for the acceleration of HIV disease in those individuals with HCV. Disease promotion appears to be a one-way street.(7) However, in those with severely compromised immune systems due to AIDS, cholestasis (obstruction of bile within the bile duct) appears to be a predominant clinical symptom of hepatitis.(8)
As of yet, there is no conclusive correlation between the level of HCV virus in the blood (viremia) and the severity of liver disease.(9) Nor have blood levels of ALT and AST (liver enzymes whose blood levels commonly serve as a marker of liver damage) proved to be an accurate predictor of liver disease in coinfected individuals. Although HCV PCR and liver enzymes (ALT and AST) may be used to monitor the progress of HCV infection, one's CD4 count and duration of infection with HCV are the strongest prognosticators of liver disease.
Similarities and Differences
HIV and HCV viruses reproduce in huge numbers. To maintain a steady viral load, HIV produces about 10 billion new particles each day and HCV produces 10 trillion each day. HCV and HIV operate quite differently in their method of infection, though. In HIV, the RNA-based viral genes are translated into DNA and integrated into the host cell's gene set. This makes infection of that cell irreversible. HCV, on the other hand, does not integrate into a liver cell's genome. Replication instead takes place within the cell's cytoplasm. This, in turn, may make HCV elimination a more likely possibility.(10) Both HIV and HCV have significant variance in their viral genes, producing a variety of genotypes called quasispecies. This genetic variability is a result of replication errors due to their lack of any correction, or "proofreading," capability. The rate of mutation is much faster in HIV than HCV and so is the evolution of quasispecies. The bad news is that as a result, among those infected with hepatitis C, the most frequent subtype in the United States (80%) is type 1a and 1b. In recent studies, type 1 has been associated with a more rapid progression to AIDS and death -- 2.8 times higher -- than other genotypes.(11) Type 1 has also been demonstrated to be less responsive to treatment with alpha interferon. These results were independent of other markers such as the individual's age and the stability of CD4 counts.(12, 13)
Immune ResponseAside from HCV-specific antibodies and natural virus inhibitors such as alpha interferon, HCV infection is under attack by the cytotoxic lymphocytes (CTLs, or killer CD8 cells), which eliminate infected liver cells. Individuals with prolonged HIV infection have reduced CTL responses to infection, probably due to the HIV-induced loss of the CD4 cells controlling these responses. The result is reduced destruction of virus-infected cells.(14, 15)
Although a lower CD4 cell count correlates with higher HCV viral load, no significant association seems to exist between HCV RNA and CD8 cell counts.(16) HCV-specific CTL responses don't exert much control over chronic HCV infection. In HIV on the other hand, persons with preserved, stable CTL activity are often long-term non-progressors. Patients with higher CD4 cell counts and lower HIV levels are more likely to obtain the greatest benefits from treatment with interferon against HCV. Response to treatment for HCV in those individuals coinfected with HIV was similar to those with HCV alone as long as they were not severely immunosuppresed or suffering advanced fibrosis or cirrhosis.(17)
Mastering HIV During CoinfectionThe viral protease enzymes are necessary for cutting large proteins into pieces for viral assembly. They have no close analogue in human cells, which makes them good candidate targets for drugs attempting to control viral replication. Protease inhibitors for HIV have not been shown to have a significant effect on the replication of HCV, regardless of HCV genotype. On the contrary, treatment with HIV protease inhibitors in immunosuppressed individuals can temporarily increase HCV blood levels,(18) though this has not always been observed.(19) This is likely the result of an increase in the number of available CD8 cytotoxic lymphocytes (CTLs), which kill the HCV-infected liver cells. The damage to liver tissue is reflected in an increase in the liver enzyme ALT and a release of HCV into the bloodstream. The transient increase in HCV viral load may also stem from an overall decrease in the level of protective alpha interferon due to the suppression of HIV replication. However, it is important to note that the improvement in the reduction of HIV achieved by protease inhibitors will likely result in a long-term improvement in the coinfected individual and should not deter their use.(20)
The use of protease inhibitors for HIV may also produce other unwanted results. Of concern for those with HIV, with or without coinfection with HCV, is the risk of possible liver toxicity that may result from treatment with antiretroviral drugs. Nonetheless, this seems to be of particular concern in those who are coinfected. In a study done in France last year it was found over the course of a year that the protease inhibitor indinavir (Crixivan) was associated with an increased incidence of hepatoxicity in the form of hyperbilirubinemia (jaundice) among those who were coinfected.(21) Contrary to earlier indications, there does not appear to be a higher risk for hepatoxicity in antiviral regimens that include AZT (zidovudine/retrovir).(22)
Treating HCV in the Presence of HIVResults from early studies indicate that using interferon to treat HCV in HIV-infected individuals resulted in a response rate similar to that in persons who are HIV-negative. At last year's World AIDS Conference, though, German investigators reported that the use of alpha interferon (Intron 2a) in coinfected individuals may be less effective and cause more nerve damage.(23) It is possible that their findings were due to the low CD4 counts in their coinfected patients as well as possible reactions to treatment with other (HIV) antivirals.
A new form of interferon, pegylated alpha interferon, will become available in the next two years. Polyethylene glycol (PEG) surrounds the alpha interferon molecules, shielding it from the body's metabolic processes and creating a sustained release form of alpha interferon. Alpha interferon's half-life in the body can be extended up to ten times, and its dosage schedule reduced to once per week. Following clinical trials, pegylated interferon is likely to be combined with ribavirin. The effect of ribavirin, an antiviral nucleoside analog, is uncertain in hepatitis C. It has no apparent influence on HCV viral loads by itself, but it greatly enhances the effectiveness of alpha interferon in both HIV negative and positive individuals with HVC.(24)
In May, Roche Pharmaceuticals released the initial results from its phase 2 study of Pegasys, its version of pegylated alpha interferon. Volunteers in the Pegasys cohorts received 45, 90, 180 or 270 micrograms of Pegasys. A 33-peson control group received 3 million international units of standard alpha interferon, injected three times per week. After 48 weeks of therapy and 24 weeks of post-treatment follow-up, 36% of the 45 persons in the 180-microgram cohort had HCV viral loads below the level of detection, compared to only 3% in the control group. Disappointingly, the side effects with Pegasys occurred at about the same rate as with standard alpha interferon. (Side effects included fatigue, headache, muscle and joint pain, flu-like symptoms, nausea and vomiting, injection site irritation, fever, chills, diarrhea, hair loss, abdominal pain, depression, irritability, insomnia, dizziness and anorexia.) Reduced white blood cell counts were even more common with Pegasys than with standard interferon. The participants in this study were all HIV-negative and free of cirrhosis.
This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.