Chapter 32 Hepatitis virus infections
Introduction
Viral hepatitis has become one of the major causes of morbidity and mortality in HIV-infected individuals worldwide [1]. For those on antiretroviral therapy (ART), co-infection with either hepatitis B (HBV) or hepatitis C (HCV) leads to accelerated progression to chronic hepatitis, cirrhosis, and hepatocellular carcinoma [2]. For those initiating ART, co-infection is associated with higher rates of hepatotoxicity and immune recovery may be associated with reactivation of viral hepatitis, especially with HBV [3]. For these reasons, understanding the basic epidemiology, natural history, and therapy of viral hepatitis is essential in HIV-infected individuals. Since the introduction of ART, immune restoration has prolonged the lives of HIV-infected patients. As a result, morbidity and mortality associated with chronic liver disease have emerged as a significant problem facing HIV and viral hepatitis co-infected patients and their caregivers. Hepatotoxicity associated with ART complicates the treatment of HBV/HCV-HIV-co-infected patients, and anti-HCV treatment is complicated by lower response rates and toxic drug interactions.
Epidemiology
Hepatitis A virus (HAV) is an RNA virus that occurs worldwide in sporadic or epidemic forms. It is transmitted almost exclusively by the fecal–oral route, but can also be transmitted from person to person as a sexually transmitted disease, described primarily among homosexual men [4]. Risk factors for HAV infection in homosexual men include high numbers of sexual partners and sexual practices that involve oro–anal contact [5].
Hepatitis B is a partially double-stranded DNA virus and a member of the Hepadnaviridae family. Worldwide, over 400 million individuals are infected with HBV, approximately two-thirds of cases in Asia and 25% in Africa [6]. The majority of individuals in these areas acquire HBV infection vertically at birth or in infancy, but infections can also be acquired by parenteral or sexual routes in adults. After exposure, the risk of development of chronic disease varies with age and immune status. While over 95% of neonates, compared to 5% of adults exposed to HBV, develop chronic hepatitis, approximately 20% of HIV-infected individuals who are exposed as adults develop chronic HBV [7]. The eight known genotypes vary in distribution geographically: predominantly genotypes B and C in Asia; genotype A in Northern Europe; genotype D in the Mediterranean and Middle East; genotype F in South America; and genotypes A and E in Africa [6]. Because of the diversity of the population in the United States, genotypes A through D are commonly found. Co-infection with HBV in seen in two distinct settings: in regions of high endemicity (Asia and Africa), HIV may affect populations with a high background incidence of HBV; or both HIV and HBV infection may be acquired in adulthood through similar modes of transmission (USA, Europe). Thus, co-infection with HBV and HIV varies geographically, with high rates in sub-Saharan Africa (up to 25.9% of HIV positive Nigerians in Nigeria are HBsAg positive) compared to 6–10% of HIV positive individuals in the United States [8].
Hepatitis C virus is an RNA flavivirus that infects approximately 4.1 million persons in the United States and an estimated 170 million persons worldwide. HCV is mainly transmitted parenterally, with the highest prevalence of HCV infection found among injection drug users, hemophiliacs who received pooled clotting factor concentrates, and recipients of multiple blood transfusions prior to testing. The recent epidemic of acute HCV in men who have sex with men (MSM) is associated with traumatic sex and sexually transmitted diseases and likely predominantly transmitted via blood contact [9]. Due to the shared modes of transmission, co-infection with HCV and HIV is common; there are an estimated 150,000 to 300,000 HIV–HCV co-infected individuals in the United States. Twenty-five to 30% of HIV-infected persons in the United States and Europe are infected with HCV, while 5 to 10% of HCV-infected persons are also infected with HIV [10]. The prevalence of HCV-HIV-co-infection differs by the population studied. Approximately 50–90% of HIV-infected injection drug users, the majority of HIV-infected hemophiliacs, but only 4–8% of HIV-infected homosexual men are infected with HCV, which is similar to the prevalence found in HIV-uninfected homosexuals [11]. Sexual and vertical transmission of HCV is, at best, inefficient (see earlier comment about MSM epidemic) but co-infection with HIV and HCV increases the risk of perinatal transmission of either virus. Percutaneous exposure to infected blood carries a 30% risk of HBV transmission and a 3% risk of HCV transmission, compared to < 0.3% risk of HIV transmission. HCV HIV-co-infection is associated with higher HCV RNA levels and an accelerated rate of progression to cirrhosis [10]. In the United States, HIV individuals are usually infected with genotype 1, but in Europe, genotypes 2 and 3 are also found in HIV co-infection, and genotype 4 is frequent in some injection drug user populations [10].
Hepatitis D (HDV) infection occurs in the setting of HBV. HDV is a defective RNA virus that requires HBV for replication and utilizes the hepatitis B surface antigen (HBsAg) as its envelope protein. It occurs most commonly in HIV-infected drug users [12].
Hepatitis E (HEV) is a zoonotic, single-stranded RNA virus with an incidence of approximately 7/100,000 in the US [13]. HEV is most commonly transmitted through fecally contaminated water and consumption of undercooked or raw meats, and is less readily transmitted between humans. The most common animals reservoirs of HEV include fish, swine, deer, chicken, wild rats, and shellfish. There are four HEV genotypes: genotypes 1 and 2 infect humans almost exclusively while genotypes 3 and 4 infect animals and humans. The incubation period ranges from 15 to 60 days and the clinical presentation ranges from asymptomatic disease to subacute and acute liver failure. Chronic HEV has been reported in HIV-infected patients and after organ transplantation.
Natural History
Hepatitis A
Hepatitis A virus is an RNA virus that occurs worldwide in sporadic or epidemic forms and does not cause chronic disease. Risk factors for HAV infection in MSM include high numbers of sexual partners and sexual practices that involve oro-anal contact [5]. A case-control study MSM found that during a prolonged outbreak of acute HAV, the HAV viral load was higher and the duration of viremia was longer in HIV-infected patients as compared to those without HIV during a single, prolonged outbreak of acute HAV. It also found that, at the onset of symptoms, HAV viral load was higher and the duration of HAV viremia was longer in HIV-infected subjects compared to HIV-uninfected subjects [4]. In this study, the alanine transaminose (ALT) level in the HIV-infected subjects was also lower than in HIV-uninfected subjects, corresponding to a less severe illness in HIV-infected individuals. Since hepatic injury in HAV is the result of host immune response, immunosuppression in HIV may result in a less severe and more prolonged HAV infection. Though this study was conducted after the introduction of ART, no information on ART use was provided and no correlation between duration or severity of HAV infection and CD4 counts were noted.
Hepatitis B
Co-infection with hepatitis B and HIV leads to increased chronicity [14], accelerated progression of liver disease to end-stage liver disease, and higher mortality [15]. In addition, HIV infection can lead to reactivation of HBV and higher HBV DNA levels, likely due to immunosuppression as is seen after organ transplantation and chemotherapy. Serum aminotranferases are usually lower in HIV co-infected individuals and are less useful in determining the need for therapy. The majority of patients with HBV worldwide have immune-controlled and inactive disease with HBsAg positivity but normal liver enzymes and low HBV DNA titers. Reactivation of HBV can occur at any time and is manifest by the presence of HBeAg, elevated serum aminotransferases and elevated serum HBV DNA ( 2,000 IU/mL). Mutations in the core gene may lead to inability to produce HBeAg in the presence of active viral replication (elevated HBV DNA and serum aminotransferases with no HBeAg in serum), so-called “precore mutant” HBV infection. This type of infection is increasing worldwide, particularly in those infected since birth with genotypes B and C (Asia) and D (Mediterranean). In immune suppressed patients, serum HBV DNA is higher and reactivation of HBV (with flares in serum aminotransferases) may occur with recovery of immune control, usually 8–12 weeks after starting ART therapy. In addition, seroconversion to anti-HBe and anti-HBs are less commonly achieved with HIV co-infection, therefore long-term therapy is the rule.
Hepatitis C
Co-infection with HIV is associated with increased levels of HCV RNA and accelerated progression of HCV-related liver disease [16]. HIV seropositivity, alcohol consumption, older age at the time of HCV infection, and CD4 count < 200 cells/mm3 are associated with a higher rate of fibrosis progression [17]. Prior to the widespread use of ART, HIV-HCV co-infection was associated with more rapid progression to cirrhosis by 1–2 decades [17, 18]. Overall progression to cirrhosis is three-fold higher in HIV-infected patients, and more than a third progress to cirrhosis in less than 20 years [19]. ART has improved liver-related outcomes in patients with HIV and HCV but they are still increased over those with HCV alone [19, 20]. The risk of hepatocellular carcinoma is also increased in patients with HIV–HCV co-infection and occurs at a younger age [21]. Liver-related deaths are now the most common cause of non-AIDS-related mortality among HIV-infected patients, an observation that is mainly due to concurrent HCV infection [1].
The effect of HCV infection on the natural history of HIV is controversial. The Swiss HIV Cohort Study [22], a prospective cohort study of 3,111 HIV-infected subjects receiving ART, demonstrated an increased risk of progression to AIDS and death, as well as decreased CD4 cell recovery, in co-infected individuals compared with HCV-uninfected individuals. Even among those with well-controlled HIV– HCV-infected people had over three times the risk of developing AIDS-defining opportunistic illnesses and death compared with those without HCV infection. Though the study initially reported delayed CD4 cell recovery one year after the start of ART among HCV-infected compared with HCV-uninfected people, further data showed no difference in recovery of CD4 cells after four years of follow-up [23]. A prospective cohort study of 1,955 patients in an urban HIV clinic in Baltimore, Maryland, found no difference in progression to AIDS, death, or decline in CD4 count below 200 cells/mm3 when comparing HCV-infected with HCV-uninfected patients, even after controlling for ART use and well-controlled HIV replication [24]. A 20-year prospective study of IV drug using HIV-infected and HIV-uninfected individuals also found that despite ART, liver-related deaths were significantly higher among these HIV-infected individuals [25]. These and other data suggest that HCV may affect the natural history of HIV disease and supports early introduction of HCV therapy in HIV-infected patients.
Hepatitis D
HDV is the most aggressive viral hepatitis. Its poor prognosis is accentuated in HIV patients [26]. The prevalence of HDV antibodies in HIV and HBV patients ranges from 15 to 50%, depending on geographical region and risk group category. In Western countries, HDV is more frequent in intravenous drug users than persons sexually infected with HIV. HDV viremia is common in HIV positive patients with detectable antibodies to HDV.
Hepatitis E
HEV is most commonly manifest as an acute, self-limited icteric hepatitis, though fulminant hepatic failure occurs at disproportionally high rates among pregnant women, particularly those in the third trimester. Severe presentations are also more common in individuals with underlying liver disease. Although chronic HEV is less common than an acute self-limited hepatitis, this chronic carrier state does afflict immunocompromised patients. HEV seroprevalence is actually higher among HIV-infected than HIV negative patients, and chronic HEV has been reported in HIV-infected individuals [27].
Patient Evaluation
Patients with viral hepatitis and HIV co-infection should be evaluated for the presence of chronic liver disease (Table 32.1). This includes history and physical examination for signs of chronic liver disease, as well as measurement of serum albumin, aminotransferases (AST and ALT), bilirubin, prothrombin time, and platelet count. Histologic evaluation by liver biopsy is at present the most reliable method to determine disease activity and fibrosis stage. However, discordance of at least one stage of fibrosis has been noted in up to 30% of paired liver biopsies [28]. Sampling error, heterogeneity of liver fibrosis and associated procedural risks have encouraged investigation of non-invasive measures of fibrosis. These measures include ultrasound-based images such a transient elastometry (FibroScan) [29] and serological measures of fibrosis markers. FibroScan is not currently available in the USA. Serum markers of fibrosis that are available include APRI [30], FIB-4 [31], and fibrotest [32]. These tools are generally accurate in identifying patients with no fibrosis or existing advanced fibrosis/cirrhosis but do not distinguish between moderate stages of fibrosis. Screening for hepatocellular carcinoma with abdominal imaging, with or without alpha feta protein, is recommended for all cirrhotic patients. In addition, for those with HBV, HCC screening should start in Asian males at age 40 years, asian females at age 50 years, sub-Saharan African males over age 20 years, and those with a family history of HCC [33]. It is not clear how frequently to image HIV/HCV or HIV/HBV patients who acquire infection as adults and do not have cirrhosis.
Table 32.1 Monitoring clinical status of patients with liver disease
| Synthetic function | Prothrombin time, serum albumin |
|---|---|
| Inflammation | AST, ALT, liver biopsy |
| Fibrosis | Liver biopsy, serum markers, transient elastography |
| Hepatocellular carcinoma | Alpha-fetoprotein, imaging studies |
| Check HAV (HAV IgG) and HBV status (HBsAg, anti-HBc, anti-HBs) | Vaccinate to HAV and HBV if not immune |
| Check HCV Ab |
Patients should also be vaccinated against hepatitis A and hepatitis B if they are susceptible [34]. Vaccination against HAV is safe and well-tolerated and confers protective immunity in virtually all healthy recipients. However, lower responses are noted in older subjects, patients with liver disease, and immune suppressed individuals [34]. Prior to the introduction of ART, vaccination with two double doses of HAV vaccine, given either 1 or 6 months apart, resulted in a protective serologic response in 88% of HIV-infected MSM compared with 100% response in HIV-uninfected MSM [5]. A CD4 count > 200 cells/mm3 correlated with an increased chance of seroconversion and a higher titer of anti-HAV antibody, but those initiating ART after a nadir CD4 count of > 50 cells/mm3 demonstrated even lower response rates to HAV vaccination, with only 46% seroconverting after two vaccinations. For HBV vaccination, the responses are low (47%): even using double dose (40 μg), in those with CD4 counts ≥ 350 cells/mm3, only 64% of individuals responded [35]. This suggests that, even with ART-induced restoration of immune function, HIV-infected patients may have an inadequate response to HAV and HBV vaccinations. Two large randomized clinical trials of HEV vaccines are promising, with efficacy rates of 95–100% [36, 37]. These vaccines have not been studied in HIV-infected individuals and are not commercially available.
Diagnosis
Given the high prevalence of co-infection in certain populations, all HIV-infected persons should be screened for HCV and HBV infection. For diagnosis of acute HBV infection, hepatitis B surface antigen (HBsAg) and IgM antibody to hepatitis B core antigen (anti-HBc) are used. For chronic HBV infection, both HBsAg and total anti-HBc should be tested. If either is positive, then serum HBV DNA should be tested as atypical serologies occur with HBV and HIV co-infection. Some studies have shown HBV viremia in subjects whose only marker for HBV in the serum was total anti-HBc for over 2 years [38]. The prevalence of serum HBV DNA in HIV individuals whose sole marker for HBV is total anti-HBc varies from 2 to 45% depending on the study, but viremia is rare in HBV mono-infected individuals [39, 40].
For chronic HCV infection, serum HCV antibody should be tested using an enzyme immunoassay (EIA). Positive EIA results should be confirmed by quantitative testing for HCV RNA. There is a 4 to 6% false-negative rate with EIA in HIV infection, especially in those with low CD4 counts [10]. HIV-infected patients with undetectable HCV antibody should undergo HCV RNA testing if there is unexplained liver disease, such as elevated liver enzymes.
Treatment
HBV therapy
Current recommendations are to start ART regardless of HBV DNA level in co-infected individuals who have HBV [41]. Two anti-HBV drugs must be included as part of the ART regimen. Currently licensed therapies for the treatment of HBV infection are interferon-alpha (IFN-α) an immunomodulatory agent, and nucleos(t)ide analogs lamivudine (3TC), adefovir dipivoxil, entecavir, and tenofovir. In addition, emtricitabine (FTC) is licensed for HIV but has activity against HBV. Tenofovir, entecavir, lamivudine, emtricitabine, and telbivudine should not be used in HIV-infected patients in the absence of ART because of the development of resistance to HIV [3, 42].
Recombinant IFN-α’s were the first drugs approved for the treatment of hepatitis B infection. However, their use in HIV co-infection is limited, as response rates have generally been poor. Studies of newer pegylated interferons in HBV are limited to those without HIV infection and show benefit of pegylated forms over standard conventional IFN in both HBV HBeAg positive and negative disease, with control of HBV DNA in 41–73% of cases [43]. Predictors of response are female gender, low serum HBV DNA levels, and high serum ALT. The latter two are uncommonly found in HBV-HIV co-infection, limiting its use. In addition to the goals of therapy noted above, goals specific for the management of HBV infection are seroconversion from HBeAg to anti-HBe and ultimately loss of HBsAg with seroconversion to anti-HBs [6].
Nucleos(t)ides are competitive inhibitors of HBV DNA polymerase (reverse transcriptase), causing premature termination of DNA chain elongation, resulting in inhibition of viral replication. However, the inhibition of polymerases is not entirely specific, and can also bind to human DNA polymerase. Thus, there is a potential to induce mitochondrial toxicity and multi-organ failure, and mitochondrial toxicity has been implicated in the etiology of some of the dose-limiting adverse effects such as peripheral neuropathy, lactic acidosis, and steatosis associated with nucleoside analogs. Entecavir and tenofovir are potent antivirals with a high barrier of resistance. Tenofovir is active against both wild-type HBV and HBV with lamivudine (3TC)/emtricitabine resistance mutations (YMDD and other compensatory mutations). Resistance to lamivudine increases with time on therapy and is more rapid in patients co-infected with HIV, with 90% of subjects who have HIV and HBV developing HBV resistance to lamivudine by 4 years [44]. Adefovir has been used successfully in co-infected individuals for up to 4 years with no reports as yet of resistance [44]. However, resistance up to 18% after 4 years has been reported in mono-infected HBV individuals who have HBeAg-negative disease [3].
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