HIV and the hepatitis viruses B (HBV) and C (HCV) share routes of transmission that explain the high rate of hepatitis co-infection in HIV-infected individuals. Indeed, 10% of patients with HIV-infection reveal markers of chronic hepatitis B (HBV) infection (1). Around 30% of all HIV-infected individuals in Western industrialized countries have a concomitant HCV infection (2). Especially high rates of HIV/HCV co-infection can be observed in intravenous (i.v.) drug users and hemophiliacs, in whom rates of co-infection reach 90%. HIV accelerates HBV and/or HCV liver disease, especially when HIV-associated immunodeficiency progresses. Morbidity and mortality due to the sequelae of HBV and HCV infections now play a leading role in HIV-infected individuals in place of the usual HIV-associated opportunistic infections. The aim of this review is to outline management strategies in the HBV/HIV or HCV/HIV co-infected individual.
EPIDEMIOLOGY OF HBV AND HIV CO-INFECTION
More than a third of the world population has been infected with HBV (3). It is estimated that there are 350 million chronic carriers of HBV worldwide. Many are lifelong carriers, although not all are infectious and some clear the virus after varying intervals. One million people are estimated to be infected with HBV in the WHO's European region each year (4). Of these approximately 90,000 will become chronically infected and approximately 22,000 will eventually die from cirrhosis or liver cancer (5). The sexual route is the most common means of spread of the virus in Europe and North America. This explains the high rate of HBV infections in homosexual men which, in some studies, approaches 90% (6). Patients with HIV infection are approximately 3-6× more likely to become chronic carriers of HBV than those who are HIV-negative (7,8). Accordingly, 10% of patients with HIV infection are also carriers of HBV surface antigen. Transmission rates for perinatal and sexual exposure, as well as after needle-stick injury, for HBV are summarized in Table 1.
However, it should be emphasized that no exact calculation of transmission risk is possible on an individual basis as risk is also influenced by a high number of other, often uncertain, variables such as gender, type of sexual practice, other concomitant sexual diseases, skin lesions, circumcision, possible damage to the mucosa, stage of HIV infection as well as viremia of the index person and amount of inoculated virus.
NATURAL HISTORY OF HEPATITIS B IN HIV CO-INFECTED INDIVIDUALS
The natural history of HBV virus infection is modified by co-infection with HIV. After initial HBV infection, both development and persistence of chronic HBV infection are greater among people with prior HIV-1 infection than those who are HIV-negative. Most studies on the course of HBV in HIV-positive persons have indicated that HIV infection is associated with an increased frequency of markers of replicative HBV infection (HBe-Ag, HBV-DNA positivity), consistent with loss of immune control of viral replication (17-19). Conversely, HIV-infected patients with chronic HBV exhibit lower alanine aminotransferase (ALT) activity. Indeed, cytotoxic T-lymphocytes play an important pathogenetic role in the clearance of HBV and are responsible for inflammatory disease activity (20). In patients with evidence of ongoing HBV replication, co-infection with HIV apparently results in a much lower rate of spontaneous reduction in viral replication (21).
Studies investigating the histological activity of chronic HBV in HIV co-infected patients have generated controversial results. Initial studies assessing liver disease activity found the histology activity index to be somewhat diminished in HIV-positive patients compared with HIV-negative patients (22,23). Recently, studies assessing the influence of HIV infection on chronic HBV infection, including liver biopsy, found that HIV infection is associated with a higher level of HBV replication and a higher risk for cirrhosis without increased liver necrotic-inflammatory process in homosexual men with chronic HBV infection (24). Moreover, reduced survival in HIV/HBV co-infected patients, especially when they have developed AIDS-defining events, has been reported (25).
EFFECTS OF HEPATITIS B ON HIV INFECTION
Early studies looking at the influence of HBV infection on the course of HIV did not detect any difference in HIV disease progression in HBs-Ag positive homosexual men versus HBs-Ag negative patients (26). Within one study, 511 HIV-infected patients were retrospectively analyzed for evidence of HBV. The overall prevalence of HBV markers was greater in patients with AIDS (89%) compared with those without AIDS (80%). These findings suggest that patients with more advanced immunosuppression may be less likely to clear HBV infection after exposure or more likely to reactivate late in HIV infection or both.
THERAPY OF HEPATITIS B IN HIV CO-INFECTED PATIENTS
Treatment of HIV-positive patients who have chronic HBV has been difficult given the patients' decreased immune mediated response towards HBV. Indeed, initial studies looking at treatment response rates with interferon alone or interferon in combination with azidothymidine (AZT) identified response rates as low as 0% (27,28). However, therapeutic trials of interferon for the treatment of HBV in HIV co-infected patients were conducted in an era where highly active antiretroviral therapy (HAART) was not available. Accordingly, the role of interferon for treatment of HBV in HIV co-infection has to be newly defined, taking into account HAART-induced immune reconstitution and the newly introduced pegylated interferons. Preliminary data from trials of pegylated interferon for the treatment of HBV in HIV-negative patients indicate a more favorable biological response rate (29). Trials of pegylated interferon for the treatment of HBV in HIV co-infected patients are currently underway and will define the therapeutic role of these drugs in this patient group.
Among the antiretroviral (ARV) agents available for HIV treatment, lamivudine (3TC), in doses typically used to treat HIV infection, has excellent activity against HBV, both in resolution of markers of viral replications as well as in improvement of histological activity (30-32). In a recent study, 40 consecutive patients infected with both HIV and HBV received 3TC, 600 mg/day or 600 mg per day followed by 300 mg/day, as therapy for HIV disease (33). After 12 months of treatment, 26 of 27 patients (96.3%; 95% confidence interval (CI), 81-99%) who had had high HBV replication at baseline had serum HBV concentrations <5 pg/mL. However, PCR could still detect HBV DNA in serum from 11.5% (CI, 2-30%) of these patients. Among patients who had had low HBV replication at baseline, the PCR results for serum HBV-DNA became negative in the six patients who had had a positive PCR result at baseline. No serious adverse events occurred during treatment.
Similar effects were observed in the HBV substudy of the CAESAR study (34). Despite the effects of 3TC on the replication of HBV in HIV-infected persons, long-term treatment with 3TC is limited by the development of resistant HBV in a significant proportion of patients. Indeed, emergence of resistance can occur concomitantly with a flare of HBV. Patients taking 3TC treatment, with controlled HBV replication, may also develop an acute HBV flare if medication is withdrawn for any reason (35). Studies of the long-term incidence of HBV resistance to 3TC in HIV-positive patients have found that 3TC resistant HBV emerges in 20% of patients per year (36). The observed resistance rate was similar to the 14-27% rate observed after one year of 100 mg 3TC/day in non-HIV-infected patients with HBV (37). More recently, trials have investigated the safety and efficacy of adefovir dipivoxil or tenofovir in patients co-infected with HIV-1 and 3TC-resistant HBV (38,39). In the first trial, 35 HIV/HBV co-infected patients received 3TC therapy (150 mg twice daily) as part of their current HIV-1 ARV regimen (38). Lamivudine resistance had developed, resulting in rebound in serum HBV DNA and elevated ALT levels. Patients were treated for 48 weeks with a 10 mg daily dose of adefovir dipivoxil. Overall, four patients withdrew from the study (two because of adverse events); hence, 31 patients received adefovir dipivoxil for a median of 48 weeks. Median decreases in serum HBV-DNA concentrations from baseline (8.64 log10 copies/mL) were −3.40 log10 copies/mL at week 24 (n = 31) and −4.01 log10 copies/mL at week 48 (n = 29; p < .0001). Two patients underwent HBe-Ag seroconversion: one at week 32 and one at week 36. Adefovir dipivoxil was generally well tolerated but was associated with a transient increase in serum ALT levels in 15 patients. There were no significant changes in HIV-1 RNA levels or CD4 cell counts. In a smaller, recently presented study, 10 HIV/HBV co-infected patients, receiving 3TC (150 mg twice a day) as part of their current ARV therapy, were enrolled in a prospective non-comparative open-label study (39). Tenofovir (300 mg once daily) was added to the regimen. All patients had detectable serum HBV-DNA, despite ongoing 3TC therapy (median 3TC experience 54.2 ± 13.5 months). The median decrease in serum HBV-DNA level from baseline (8.1 ± 1.41 log10 copies/mL) was −3.34 ± 1.31 log10 copies/mL at week 12 (p < .01). There were no significant changes in mean serum ALT from baseline and no ALT flares during treatment. These preliminary results indicate that 12 weeks' dosing of tenofovir 300 mg once daily has significant activity against 3TC-resistant HBV in HIV/HBV co-infected patients.
In summary, treatment of HBV with 3TC remains the best treatment option at this time. The use of pegylated interferons should be investigated in trials before they are recommended for general use. Initial results with adefovir (low dose) and tenofovir demonstrate good antiviral efficacy, even in the presence of 3TC-resistant HBV, and represent alternative therapies for patients failing 3TC therapy.
Hepatitis B vaccination is clearly recommended for all HIV patients with negative HBV serology to prevent infection with HBV. However, the HBV vaccine is less effective in immunocompromised patients. In non-responsive cases, re-vaccination with a double dosage and four vaccination steps (month 0, 1, 6, and 12) can be performed.
EPIDEMIOLOGY OF HCV AND HIV CO-INFECTION
Hepatitis C is transmitted mainly by percutaneous exposure to blood. Until recently, transfusion of contaminated blood was the major source of HCV transmission. With the introduction of routine screening of blood donations for antibodies to HCV, post-transfusion HCV infections have decreased dramatically. Currently, injection drug use is the leading route of HCV transmission in the western world. Worldwide, the number of HCV-infected individuals is estimated to be 170 million. In the U.S.A., it is estimated that one third of the 800,000 living HIV-infected patients are co-infected with HCV. Even higher transmission rates have been reported for southern European countries, mainly due to the high number of drug addicts within HIV-infected cohorts. Hepatitis C is detected in up to 20% of infants born to HIV/HCV-infected mothers (9,10,40). Indeed, higher levels of HCV viremia in the HIV co-infected mother increases the risk of perinatal HCV transmission. Table 1 summarizes the average estimated transmission risks for different transmission routes.
NATURAL COURSE OF HEPATITIS C IN HIV INFECTION
Hepatitis C in patients with HIV infection is characterized by a much more rapid progression of HCV-related liver disease. In the American Multicenter Hemophilia Cohort study, liver failure occurred after a latency period of 10-20 years in 9% of multi-transfused HCV/HIV co-infected adult hemophiliacs without an AIDS-defining opportunistic infection or malignancy (41). No cases of liver failure were observed during the same observation period in HCV-positive, HIV-negative hemophiliacs. Furthermore, studies in HIV/HCV co-infected hemophiliacs clearly demonstrated that progression of HCV occurred particularly in patients with progressive immunodeficiency and CD4 cell counts <100/μl (42). Moreover, two Spanish studies of relatively large series of HCV-infected drug users (116 and 32 HIV/HCV co-infected patients, respectively) indicated that the time between HCV acquisition and development of cirrhosis was significantly shorter in the co-infected subjects (43,44). Indeed, within 10-15 years of initial HCV infection, 15-25% of HIV co-infected patients develop cirrhosis compared with 2-6% of HIV-negative patients. Moreover, hepatocellular carcinoma appears to occur at a younger age and after shorter duration of HCV infection in HCV co-infected individuals (45). The accelerated natural course of HCV and its rapid progression to cirrhosis in patients with HIV co-infection is best documented by the epidemiological survey of Darby et al. (46) who reported a significant increase in liver-related mortality which occurred 10 years earlier in HIV/HCV co-infected hemophiliacs than in HCV mono-infected patients.
The unfavorable course of HCV infection in HIV co-infected patients has resulted in a recent and significant increase in liver disease-associated mortality in this patient group, despite the overall reduction in HIV-associated morbidity and mortality associated with the use of HAART (47-50). In the U.S.A., end-stage liver disease was the leading cause of death in HIV-infected patients by 1998, causing 50% of in-hospital deaths (48).
EFFECTS OF HEPATITIS C ON HIV INFECTION
The observation that HIV accelerates HCV liver disease is widely accepted. However, the question of whether HCV induces clinical progression of HIV disease has caused controversy. The Swiss cohort study demonstrated that HCV was independently associated with an increased risk of progression to AIDS and death (51). These findings were partially explained by the observation that HCV-positive individuals were less likely to achieve a CD4 cell increase of ≥50 cells/mm3 at one year following the start of HAART compared with HCV-negative individuals. In the Johns Hopkins Cohort Study, however, after correction for use of HAART, no survival difference with regard to HIV could be demonstrated for patients with HIV/HCV co-infection versus HIV mono-infection (52).
THERAPY OF HEPATITIS C IN HIV CO-INFECTED PATIENTS
Within the last two years, combination treatment with interferon-α and ribavirin has been established as the standard therapy for HCV. Results from studies of this combination on HCV infection in HIV co-infected patients are summarized in Table 2.
In comparison to HCV mono-infected patients, HIV/HCV co-infected patients receiving interferon-α and ribavirin combination therapy experienced overall lower sustained response rates as well as increased drop-out rates due to adverse events. These data highlight the limitations of these therapies in co-infected populations. The introduction of pegylated interferon enables once weekly interferon administration. Results from pegylated interferon plus ribavirin combination trials in HCV mono-infected patients have demonstrated superior virological efficacy of this combination versus standard therapy (non-modified interferon-α plus ribavirin). Hence, the efficacy of this regimen in the co-infected population is being studied in an attempt to obtain improved sustained response rates. The limited data available from ongoing trials are summarized in Table 3.
Initial data from pilot studies of the virological efficacy of pegylated interferon and ribavirin combination therapy in HIV/HCV co-infected patients are superior to the published data for non-modified interferon-α plus ribavirin combination. However, as no sustained response data are currently available, these initial data should be interpreted with caution.
Prior to the use of ribavirin in combination therapy of HCV in HIV/HCV co-infected patients, considerable concern was expressed with regard to drug-drug interactions and dose-dependent anemia. Indeed, ribavirin, which is a guanosine nucleoside analog, inhibits intracellular phosphorylation of AZT (ZDV), d4T and ddC in vitro (60,61). Moreover, ribavirin enhances the phosphorylation of ddI which may be the underlying mechanism for the increased risk of pancreatitis and mitochondrial toxicity in subjects receiving ribavirin and ddI (62,63). Therefore, if possible AZT (ZDV) and ddI should be avoided by HIV-infected subjects beginning anti-HCV combination treatment. Serum lactate and amylase levels in all HCV/HIV co-infected patients exposed concomitantly to ARV drugs and ribavirin therapy should be monitored routinely.
The development of more potent HCV-specific treatment options for HIV co-infected patients underlines the necessity for developing treatment guidelines (Table 4).
The possibility of treating HCV in HIV co-infected patients needs to be discussed with each patient. The patient's lifestyle, working situation and psychological and psychiatric background needs to be evaluated in order to determine the best treatment starting point or whether therapy should be delayed. Side-effects of combination therapy are common and may affect quality of life. If patients do not respond (negative HCV-PCR at month 6), treatment can be terminated as no further response is expected. Patients with low HCV viremia (<2,000,000 copies/mL) and more favorable genotypes (2 or 3) may also be treated for 6 months. All other patients should be treated for 48 weeks. The primary goal of HCV treatment is to achieve a sustained virological response which permits fibrosis regression, disappearance of extrahepatic manifestations, and a reduction in transmission risk. If HCV is eradicated, this will help to reduce concomitant hepatotoxicity observed during administration of various HAART regimens.
The increasing mortality due to liver disease and liver cancer in HCV/HIV or HBV/HIV co-infected patients clearly underlines the importance of treatment options for this patient group. Treatment guidelines may facilitate management of hepatitis co-infection in HIV-infected patients. With the availability of ARV agents that are equally effective against HIV and HBV, treatment options, such as 3TC and tenofovir, exist for HBV/HIV co-infected patients. The role of pegylated interferon for the treatment of HBV in HIV co-infected individuals still needs to be evaluated. In HIV/HCV co-infected patients, pegylated interferon and ribavirin offers improved virological sustained response rates. This option should be discussed with each patient. However, data from ongoing trials are urgently needed to clarify the remaining questions in the management of HIV/HCV co-infection: who and when to treat for optimal results.
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This publication has been made possible by an educational grant from Boehringer Ingelheim.