HIV and Hepatitis Coinfection

Coinfection with HIV and the hepatitis C virus (HCV) or hepatitis B virus (HBV, see table below) is a growing public health concern. Because the diseases are spread in similar ways -- notably through shared use of needles to inject drugs and sexual activity -- many people are coinfected with HIV and HCV, HIV and HBV, or even all three viruses.

Hepatitis C and hepatitis B are viral infections of the liver; over time they can lead to serious consequences including liver cirrhosis and liver cancer. Most studies show that HIV infection leads to more aggressive hepatitis C or hepatitis B and a higher risk of liver damage. Studies of how HCV and HBV affect HIV disease are less clear. Most research shows that HCV does not accelerate HIV disease progression, but HIV/HCV coinfection may impair immune system recovery after starting antiretroviral therapy.

Coinfection can complicate treatment. People with liver damage due to chronic hepatitis are more likely to experience hepatotoxicity (liver toxicity) related to anti-HIV drugs. In addition, drugs used to treat HIV and hepatitis can interact and side effects may be exacerbated. Most experts recommend that HIV should be controlled first before a person begins HCV treatment. With careful management, most people with HIV/HCV or HIV/HBV coinfection can be successfully treated for both diseases. In fact, several recent studies suggest that HIV/HCV-coinfected people with well-controlled HIV disease and relatively high CD4 cell counts may do as well as those with HCV alone.

HIV/HCV: A Growing Public Health Problem

Coinfection refers to infection with two or more different disease-causing organisms. Hepatitis C is a common coinfection in people with HIV. An estimated 200,000-300,000 people in the U.S. have both HIV and HCV. Experts believe that about 25% of Americans with HIV also have HCV; conversely some 10% of people with HCV are thought to also have HIV. In an analysis published in the March 15, 2002 issue of Clinical Infectious Diseases, Kenneth Sherman, M.D., of the University of Cincinnati, Ohio, and colleagues found an overall HCV prevalence rate of 16% in a cohort of people with HIV; in different subpopulations coinfection rates ranged from 3% to 73%.

HIV/HCV coinfection is increasingly recognized as a growing public health problem. Early in the HIV/AIDS epidemic most people with HIV were expected to die from AIDS, and less attention was devoted to other long-term conditions. Because chronic hepatitis C progresses so slowly, many HIV positive people who were infected with HCV in the 1970s or 1980s are only now beginning to develop advanced liver disease. At several recent conferences a number of presentations were devoted to HIV/HCV coinfection. David Thomas, M.D., from Johns Hopkins University in Baltimore, Maryland, reviewed the current state of knowledge about HIV/HCV coinfection at a June 2002 meeting convened by the National Institutes of Health (NIH) to generate a new consensus statement about HCV treatment, care, prevention, and future research.

As improved HIV treatment has reduced mortality due to opportunistic illnesses (OIs), liver failure -- often related to chronic viral hepatitis -- has become a major cause of hospitalization and death in people with HIV/AIDS. In some recent studies liver failure due to HCV was the leading cause of death.

Several studies at the 9th Conference on Retroviruses and Opportunistic Infections (CROI) held in February 2002 looked at illness and death in HIV/HCV-coinfected people. Ronald Reisler, M.D., M.P.H., of the NIH and colleagues reported that the rates of severe (grade 4) adverse events and death were higher in HIV positive people coinfected with HCV or HBV than in those with HIV alone. David Rimland, M.D., of the Atlanta Veterans' Administration Medical Center and colleagues showed that coinfected people had shorter survival times after an HIV or AIDS diagnosis than those with HIV alone. Kelly Gebo, M.D., of Johns Hopkins and colleagues found that HIV/HCV coinfection substantially increased the likelihood of hospitalization compared with those who had only HIV. On the other hand, Ellen Tedaldi, M.D., of Temple University in Philadelphia and colleagues reported that after controlling for CD4 cell count, survival rates were comparable in HIV/HCV-coinfected people and those with HIV alone, suggesting that effective HIV treatment can minimize the detrimental effects of HCV coinfection.

Because the presence of HIV accelerates the progression of hepatitis C, HCV is thought of as an OI in people with HIV; however, it is not considered an AIDS-defining illness.

The "Twin Epidemics"

HCV and HIV share many characteristics. Both are blood-born RNA viruses that replicate rapidly. The two viruses also share similar transmission routes. Direct blood-to-blood transmission -- for example through needle sharing -- is the most efficient means of transmitting both viruses. Among some populations of injection drug users, the HIV/HCV coinfection rate may be as high as 90%. Coinfection is also common among hemophiliacs and others who received repeated blood product transfusions before such products were heat-treated to inactivate pathogens. Some people contracted HCV through blood transfusions before the early 1990s. A reliable HCV blood test became widely available in 1992. The rate of HIV/HCV coinfection is also high among prisoners.

Along with these similarities, there are also several differences between the two viruses. HCV, unlike HIV, does not integrate into human cells and is thus easier to eradicate. HCV is less likely than HIV to be transmitted sexually or from mother to child during pregnancy, birth, or breast-feeding. According to the Centers for Disease Control and Prevention (CDC), people who contracted HIV through sexual activity have HCV infection rates similar to those of the adult population as a whole (estimated at under 3% for people in monogamous heterosexual relationships, but somewhat higher among gay men and people with multiple sex partners).

However, studies show that the risk of sexual or perinatal transmission of HCV is greater if a person also has HIV -- possibly due to the fact that HIV/HCV-coinfected people tend to have higher HCV viral loads. Recent data reported by researchers from Chelsea and Westminster Hospital in London suggest that sexual transmission is responsible for an increasing proportion of HCV infections among people with HIV. And while 5% or less of HCV-infected mothers without HIV transmit HCV to their infants, among HIV/HCV-coinfected mothers the transmission rate may be three times as high.

Because many people are coinfected with HCV and HIV, the U.S. Public Health Service and the Infectious Disease Society of America recommend that all people with HIV should be screened for HCV. Detecting HCV in people whose immune systems are severely compromised can be difficult because they may not produce enough antibodies to show up on a test. In HIV positive people with a CD4 cell count over 200 cells/mm³, a standard HCV antibody test is usually sufficient; if the CD4 cell count is below 200 cells/mm³, an HCV RNA viral load test may be necessary to diagnose hepatitis C.

Hepatitis C Basics

Hepatitis C is a slowly progressing disease of the liver. Because this organ carries out some 500 bodily functions, damage to the liver can lead to a variety of symptoms and associated conditions. HCV was identified only in 1989; before that it was known as non-A/non-B hepatitis. In some people infected with HCV the immune system can completely eradicate the virus, but in an estimated 80% of infected people hepatitis C becomes chronic (lasting more than six months). HCV is most often spread through contaminated needles used to inject drugs. Tattoo needles and shared personal items such as razors and toothbrushes may also spread the virus. As discussed above, HCV transmission through sexual contact or from mother to infant are uncommon, but do occur.

Most people with acute or chronic HCV have no symptoms. Those that do may experience fatigue, nausea, loss of appetite, abdominal pain, and a flu-like feeling. An estimated 10-25% of people with chronic HCV develop severe liver disease -- usually after 10-40 years -- which may include liver inflammation, fibrosis (the development of tough, stringy tissue in the liver), cirrhosis (scarring), hepatocellular carcinoma (liver cancer), and liver failure. A minority may develop jaundice (yellowing of the skin and whites of the eyes). When people develop decompensated cirrhosis, scar tissue blocks the flow of blood through the liver and the organ is no longer able to function properly. This can lead to serious conditions such as bleeding veins (varices) in the esophagus or stomach, abdominal swelling (ascites), and brain dysfunction (hepatic encephalopathy). Liver failure due to HCV is the leading reason for liver transplants in the U.S.

Antibody tests (ELISA and RIBA) are used to detect whether a person has been infected with HCV. Genotype tests are used to determine what strain of HCV a person has. There are six known HCV genotypes; 1a and 1b, which are most common in the U.S., are more difficult to treat. Liver enzymes, in particular alanine transaminase (ALT) and aspartate transaminase (AST), are measured as an indication of liver inflammation. Many -- but not all -- people with chronic hepatitis have elevated liver enzyme levels. Viral load tests (PCR, bDNA, and TMA) measure the amount of HCV genetic material (RNA) in the blood, and can help indicate whether treatment is working. In contrast with HIV, HCV viral load is not correlated with disease severity.

Liver biopsy, in which a small sample of tissue is withdrawn using a needle and examined under a microscope, is considered the "gold standard" for gauging the extent of liver damage. Biopsies are used to help make decisions about whether treatment is needed. Liver tissue damage is graded on a scale of 0-4. Although several tests are under study, there currently is no reliable noninvasive means of detecting liver fibrosis.

Not everyone with HCV needs to be treated. Many different factors -- such as a person's age, how long he or she has been infected, HCV genotype, and extent of existing liver damage -- should be taken into account when deciding whether to treat. The usual treatment for HCV is a combination of interferon-alpha (Intron-A or Roferon-A) plus ribavirin (Rebetol, Copegus). Pegylated interferon (Peg-Intron or Pegasys) is a new, chemically altered form of interferon that lasts longer in the body and appears to work better than standard interferon.

Recent studies show that combination therapy with pegylated interferon plus ribavirin can clear HCV in about 50% of HIV negative people with genotype 1 and about 80% of those with genotypes 2 or 3. As discussed below, treatment response rates tend to be lower in people coinfected with HIV. Traditionally, HCV therapy is administered for a specified period of time (usually 6-24 months) and discontinued if HCV viral load does not decrease. However, experts increasingly believe that treatment may reduce liver damage even if HCV viral load does not become undetectable. A trial called HALT-C is now underway to study the possible benefits of long-term HCV maintenance therapy.

Side effects of interferon are common, and may include fever, fatigue, headaches, flu-like symptoms, muscle aches, low blood cell counts, and irritability or depression. Ribavirin may cause hemolytic anemia (destruction of red blood cells) and birth defects.

How HIV and HCV Interact

The Impact of HIV on HCV

HIV/HCV coinfection is still poorly understood, but recent research has shed light on how the two viruses interact. In the February 2002 issue of Current Gastroenterology Reports, Andrew Ta lal, M.D., M.P.H., from Cornell University's Weill College of Medicine in New York City and colleagues reviewed the pathophysiology of HIV/HCV coinfection. According to the authors, a strong cell-mediated immune response involving both CD4 and CD8 cells is required to keep HCV under control. A strong immune response also appears necessary to enable successful HCV treatment with interferon. In people with HIV, the immune response may be compromised, making it less likely that an infected person will clear HCV and allowing HCV to replicate more rapidly.

Much of the liver damage related to hepatitis C is caused not by the virus itself, but rather by the immune system's response to HCV. Thus, it might be expected that people with compromised immune systems would mount a weaker immune response that causes less liver tissue damage. However, research indicates that the opposite seems to be the case.

Most studies show that HCV disease progression is more rapid in HIV/HCV-coinfected people and is more likely to lead to severe liver damage. Many studies show higher rates of cirrhosis in coinfected individuals. For example, at the November 2001 meeting of the American Association for the Study of Liver Disease, Vincent di Martino, M.D., and colleagues with the French MULTIVIRC study team reported that coinfected people died earlier than those with only HCV because they progressed to cirrhosis sooner. At the XIV International AIDS Conference held in Barcelona this past July, A.H. Mohsen from St. Thomas School of Medicine in London and colleagues estimated that the average time between HCV infection and the development of cirrhosis is 22 years in coinfected people compared with 33 years in those with HCV alone -- a 1.5-fold increase in the rate of liver disease progression.

At the June NIH consensus meeting Dr. Thomas cited a meta-analysis showing that HIV/HCV-coinfected people had a two-fold greater risk of progression to cirrhosis and a six-fold greater chance of developing end-stage liver disease. Javier Garcia-Samaniego from Madrid, Spain, and colleagues reported in the January 2001 issue of the American Journal of Gastroenterology that HIV/HCV-coinfected individuals had a higher rate of hepatocellular carcinoma than people with HCV alone. In addition, most research indicates that HIV/HCV-coinfected people typically have higher HCV viral loads than those with only HCV.

Importantly, the longer-term studies of HIV/HCV coinfection were initiated prior to the widespread use of highly active antiretroviral therapy (HAART), and many of the participants had low CD4 cell counts. More recent research suggests that the differences in HCV disease progression between coinfected people and those with HCV alone may not hold for people who have well-controlled HIV and whose immune systems remain relatively intact with high CD4 cell counts. For example, Yves Benhamou, M.D., and colleagues, also with the MULTI-VIRC team, reported in the October 1999 issue of Hepatology that HIV/HCV coinfection, having a CD4 cell count below 200 cells/mm³, and heavy alcohol consumption were all associated with a greater likelihood of HCV disease progression. But HIV/HCV-coinfected participants with over 200 cells/mm³ had hepatitis C progression rates similar to those of people with HCV alone.

Massimo Puoti, M.D., and colleagues with the HIV-HCV Coinfection Study Group reported in the January 1, 2001 issue of the Journal of Infectious Diseases that the presence of fibrosis was associated with CD4 cell counts below 500 cells/mm³, whether or not a person had HIV. And at the Barcelona AIDS conference C. Arizcorreta and colleagues from Cadiz, Spain, presented research showing that both lower CD4 cell counts and higher HIV viral loads were associated with worse liver damage in coinfected individuals.

In a study published in the August 2001 issue of Hepatology, Dr. Benhamou's team reported that people receiving antiretroviral regimens that included a protease inhibitor (PI) had lower fibrosis scores and lower rates of progression to cirrhosis than those who had not taken PIs (2% vs. 5% progression rate at five years, 5% vs. 18% at 15 years, and 9% vs. 27% at 25 years). This and other research suggests that by keeping their HIV under control, HIV/HCV-coinfected people may do nearly as well as people with HCV alone.

The Impact of HCV on HIV

The impact of HCV on HIV disease is less clear, and study results are conflicting. However, a majority of research indicates that HCV does not increase HIV viral load or directly accelerate HIV disease progression. For example, Mark Sulkowski, M.D., of Johns Hopkins and colleagues reported at the Barcelona AIDS conference and in the July 10, 2002 issue of the Journal of the American Medical Association (JAMA) that among their cohort of nearly 900 HIV/HCV-coinfected people, those with both viruses were not more likely to experience accelerated HIV disease progression, develop an AIDS-defining illness, or die from AIDS. HCV coinfection did not appear to reduce the effectiveness of HAART, and the researchers concluded that HCV should not be seen as a barrier to HIV treatment. Notably, in this cohort coinfected people were less likely than those with HIV alone to be taking HAART, and most deaths occurred in the untreated subjects.

Similarly, Dr. Rimland's team reported in the July 1999 issue of Clinical Infectious Diseases that HIV/HCV coinfection appeared to have no effect on the progression of HIV disease or survival in 100 coinfected people treated between January 1992 and May 1997. Dr. Rimland concluded that there was "absolutely no difference" in HIV disease progression and survival -- as assessed by time from HIV diagnosis to AIDS diagnosis, from HIV diagnosis to death, or from AIDS diagnosis to death -- in HIV/HCV-coinfected people compared with those who had HIV alone.

However, not all research confirms that HCV has no effect on HIV progression. Some studies suggest that infection with certain HCV genotypes may be associated with more rapid progression to AIDS or death. Dr. Sherman's team found that HCV genotype 1 is more common in people with HIV/HCV coinfection (about 83%) than in people with HCV alone (about 70%), which may contribute to more aggressive hepatitis C. In the October 14, 2002 issue of the Archives of Internal Medicine, Andrea de Luca, M.D., and colleagues with the Italian Cohort Naive Antiretrovirals Study Group reported that coinfection with HCV (but not HBV) was associated with increased risk of progression to AIDS-defining illness and death. In addition, coinfected people in this study experienced "consistently reduced recovery" of CD4 cells when treated with HAART compared with those who had HIV alone.

Several other studies confirm that immune recovery after starting HAART may be impaired in HIV/HCV-coinfected people. For example, in the November 25, 2000 issue of The Lancet Gilbert Greub, M.D., and colleagues with the Swiss HIV Cohort Study reported on response to HIV treatment in 3,111 HIV positive participants, 1,157 of whom also had HCV. Both the coinfected participants and those with HIV alone were equally likely to achieve HIV viral loads below 400 copies/mL after starting HIV treatment. But the coinfected people were less likely than those with HIV alone to experience a CD4 cell count increase of at least 50 cells/mm³ (75% vs. 84%). By the end of follow-up, about 8% of the coinfected participants had developed an OI compared with about 5% of those with HIV alone, and the death rate due to all causes was more than twice as high among the coinfected participants.

More recent studies offer similar results related to immune recovery. At the 8th Retrovirus conference in February 2001, J. Martin and colleagues from Madrid reported that among 902 study participants with HIV -- 72% of whom were coinfected with HCV -- responses to HAART differed dramatically. Participants with HIV alone experienced an average HIV viral load decrease of over 5,700 copies/mL and an average CD4 cell count increase of 111 cells/mm³. In contrast, the HIV/HCV-coinfected participants experienced an HIV viral load decrease of only 606 copies/mL and a CD4 cell count increase of just 53 cells/mm³. At the Barcelona AIDS conference Juan Antonio Pineda and colleagues from Seville, Spain, presented evidence showing that CD4 cell recovery after starting HAART is slower in HIV/HCV-coinfected people compared with those who have HIV alone. Likewise, Maria Dorrucci, M.D., and colleagues from Rome also reported at the same conference that coinfected people had a poorer response to HAART.

The question of how HCV affects HIV disease remains unsettled. As HIV/HCV-coinfected people live longer, more data will become available that should shed light on how HCV infection influences the long-term natural history of HIV disease.

Summary

• Hepatitis C progresses more rapidly and is more likely to lead to serious liver damage in people coinfected with HIV.
• The effect of HCV on HIV disease is less clear, but most studies show that HCV does not increase HIV viral load or directly accelerate HIV disease progression.
• Coinfection with HCV does appear to impair immune recovery after starting HAART.

HCV Treatment in People With HIV

Treatment Considerations

Treatment of HIV/HCV-coinfected people is not well understood, largely because most of the studies that led to the approval of HCV treatments excluded difficult-to-treat populations such as people with HIV. With the improvements in health and longevity brought about by HAART, however, views about hepatitis C treatment for people with HIV/HCV coinfection have changed. At the June NIH consensus conference Dr. Thomas reported that HIV/HCV-coinfected people can achieve good responses to HCV treatment and that the rate of side effects appears similar in people with and without HIV. The final NIH consensus guidelines released i