Special Retrovirus Update
March 28, 2002
HIV/HCV Co-InfectionHepatitis C (HCV) affects 40 to 175 million people worldwide and 3 million people in the U.S. alone. Hepatitis C directly infects the liver cells and it is unknown whether liver damage is due to the direct effects of the virus, the person's immune-mediated response, or more likely, both. Unlike hepatitis B, HCV has no virological latency (the virus does not incorporate into the host cell's DNA) and therefore it is one of the few chronic viral infections that are potentially a curable disease. There are six major HCV genotypes (species) worldwide. In the U.S., more than 75 percent of the people with HCV have genotype 1, which, unfortunately, is the most difficult genotype to treat, because it does not respond as well to the current therapies available.
In patients with HIV, higher HCV viral loads are associated with an increased risk of HCV transmission and accelerated liver disease (Abstract 657). Co-infection with HIV and HCV is frequent given the shared routes of infection (e.g., IV drug use, sexual contact, blood contact). Increased survival in HIV+ people, since the era of HAART, has made morbidity and mortality from HCV of increased importance. Potential benefits of treatment for HCV in HIV+ people not only includes delaying progression of liver disease, but may also include improvement in the tolerability and possibly the effectiveness of HAART. HAART causes flares in the liver enzymes (ALT and AST) in people with HCV and people with HCV have a two- to four-fold risk of liver toxicity due to HAART (e.g., Viramune) (Abstract 662). There was also some concern that HCV accelerates HIV progression, but this has not been shown to be true. Of note, it is important for all people with HIV/HCV co-infection to get vaccinated for hepatitis A and to limit their alcohol intake.
The combination of interferon (IFN) with ribavirin has a decreased sustained viral response rate in HIV+ compared to HIV- people. Studies using IFN daily rather than three times per week have had better success rates, but the discontinuation rates were higher (up to 23 percent) (Abstract 651). Theories for why response rates are less in HIV/HCV co-infected people include the higher discontinuation rates, a poorer immune response to HCV, increased HCV levels, more inaccessible reservoirs of HIV (compartmentalization) and altered cytokines. However, in all studies, HIV control was maintained throughout HCV therapy.
Pegylated-IFN (Peg-IFN) has a longer half-life than regular IFN, which results in better overall sustained virologic response rates in both HIV- and HIV+ individuals. Peg-IFN with Ribavirin has become the standard of care for chronic HCV. HCV clearance is slower in HIV/HCV patients, so HIV+ patients may need to be treated longer to ensure sustained response rates similar to HCV mono-infection.
ACTG trial 5071 was a prospective multicenter trial of IFN with ribavirin compared to peg-IFN with ribavirin for 134 HCV/HIV co-infected patients (Abstract LB15). If there was virological response by week 24, treatment was continued through 48 weeks. The preliminary 24-week HCV viral suppression rate for IFN with ribavirin was 15 percent compared to 44 percent for peg-IFN with ribavirin (comparable to the sustained response rates in HIV- people). The response rates were, as predicted, worse with genotype 1 virus (7 percent vs. 33 percent) and better with non-genotype1 virus (40 percent vs. 80 percent). These results are very preliminary, and need to be followed to see what the sustained viral suppression rate is after the interferon is stopped.
Another study of peg-IFN with ribavirin in 65 HIV+ subjects with chronic HCV revealed that the regimen is relatively well tolerated in people on HAART, with only a 14 percent discontinuation rate (Abstract 652). There was a response in 50 percent of patients, but in only 33 percent was the response sustained over time. A reduction in the ribavirin dose was necessary in 3 percent of the patients due to toxicities. One patient on Videx developed pancreatitis, and 3 percent of patients had a significant decrease in their CD4 count during the study, which may or may not have been related to the HCV treatment.
A last resort treatment for HCV and end-stage liver disease is liver transplant. A study of 23 HIV+ patients, from four major transplant centers, showed comparable survival to HIV- people undergoing liver transplantation. HCV infection was the most common reason for the transplant. Deaths following liver transplantation in HIV+ recipients were found to be strongly associated with the inability to tolerate HAART after transplantation (Abstract 125). Additional experience with liver transplants in HIV+ people is needed before definitive recommendations can be made about its indications. However, the blanket exclusion of HIV+ people from most liver transplant centers can no longer be scientifically justified.
HIV/HBV Co-InfectionA total of 300 million people worldwide are infected with hepatitis B virus (HBV). Of people with HIV, 70 to 90 percent have a history of HBV exposure and 10 to 15 percent have chronic HBV infection. It has been found that people with HIV have higher HBV DNA levels (evidence of more virus present) secondary to an inadequate immune response, about a 10-fold increased mortality secondary to liver disease compared to people with HBV alone (Abstracts 656, 657), and an increased risk of liver inflammation (hepatotoxicity) associated with antiretrovirals (e.g. Viramune) (Abstract 662). Thus, recognition of HIV/HBV co-infection and focusing on treatment of both viruses simultaneously is of growing importance.
Liver disease associated with HBV is not due to direct effects of the virus on the liver cells, but is instead due to damage from the host's immune response to the HBV. Therefore, in people with HIV/HBV co-infection who are very immunosuppressed and who do not have an active immune response, there is little to no liver damage but high HBV DNA levels. On the other hand, when the HIV is controlled with HAART and the immune system is restored, there is subsequent liver damage with an increase of the liver enzymes as a result of immune reconstitution. This demonstrates the importance of not treating HIV alone but instituting treatment of HBV at the same time as HIV, since HAART may induce reactivation hepatitis as the HIV is suppressed. It is also important not to treat HBV alone either, since it can result in resistance of the HIV virus to the drugs used to treat HBV (e.g., Epivir, Viread, adefovir).
Dr. Marion Peters in her lecture on HBV stressed that the best treatment for HBV is prevention with the vaccine. Unfortunately, only 12 percent of HIV+ people are currently being vaccinated for hepatitis A and HBV. It is also important to remember that although immunity against HBV after receiving the vaccine lasts about 10 to 15 years in HIV- people, it is unclear how long it is effective in HIV+ people. It is recommended that people with HIV have their HBV immunity levels checked yearly and get re-vaccinated if their HBV antibody level is below 10u/ml.
Very exciting data was presented at the Ninth Retrovirus Conference on new drugs to treat HBV in co-infected individuals. Dr. David Thomas reviewed the use of IFN and Epivir and then preliminary data using adefovir and Viread was discussed. Success of treatment is measured by decreased levels of HBV DNA viral load, decreased liver enzymes, and histologic improvement on biopsy.
IFN alpha 2a or 2b is given as 5 million units subcutaneously (under the skin) every day, or 10 million units three times a week. In one study, HBV DNA became undetectable in about 35 percent treated with IFN, compared to approximately 15 percent of the controls. There is now very early data showing that the use of the newer formulation of IFN, pegylated IFN, may have better results. However, IFN has not been well studied in HIV+ people.
Epivir, an NRTI, is also used for the treatment of HBV, especially in people with decompensated cirrhosis (severe liver scarring), when IFN is contraindicated. It has a very high rate of success that is similar in HIV+ and HIV- subjects. Greater than 90 percent of people treated with Epivir suppress their HBV DNA, but unfortunately, resistance develops at a rate of 20 percent of people per year (Abstract 673). After 4 years, about 90 percent of HIV/HBV co-infected people are Epivir resistant (Abstract 123). Also, Epivir only decreases HBV DNA levels in the blood, it does not completely eliminate the virus, so when treatment stops, the virus often returns eventually. There have been some studies looking at using IFN and Epivir together, but only about 29 percent of study participants cleared the virus. This is why new treatments are needed to treat HBV in both the HIV- and HIV+ individuals.
Two promising options in the treatment of HBV are adefovir and Viread, both of which are effective not only against wild-type virus (virus without any mutations) but also virus that is already resistant to Epivir. Both drugs decreased the HBV DNA by similar amounts at 24 weeks, but additional data is necessary to determine long-term outcomes.
Adefovir 10 mg once daily was started in 35 HIV/HBV co-infected people (34 male, 1 female) who were already on Epivir as part of their HAART regimen (Abstract 123). All the people had developed Epivir resistance mutations with detectable HBV DNA in their blood. The drug was well tolerated and no people had HBV DNA rebound during the 72 weeks of treatment. There was no kidney damage seen, as had been observed in studies using higher doses of adefovir (60 to 120 mg) in HIV trials. In HIV/HBV co-infected people, adefovir resulted in a continued decline of the serum HBV DNA at 72 weeks and histologic improvement. (In the biopsies done, there was a decrease in the amount of inflammation and fibrosis.) However, there was no significant change in the CD4 cell count with the addition of low dose adefovir to the HAART regimen.
Viread, 300 mg once daily, was also added to a stable regimen of HAART in HIV/HBV co-infected people in a double blinded, placebo controlled study of 14 people (12 Viread, 2 placebo) (Abstract 124). Viread was well tolerated. Preliminary analysis at 24 weeks reveals a significant decrease in the HBV DNA of both wild-type and Epivir-resistant virus in HIV/HBV co-infected people. There was a slight decrease in the HIV RNA in people treated with Viread, as well.
Other treatments for HBV are currently being evaluated, including entecavir, ribozymes, immunotherapy, L-dT, and liver transplant. Hopefully, with continued research there will be better treatments for co-infected individuals soon.
This article was provided by Seattle Treatment Education Project. It is a part of the publication STEP Ezine.