Management of Hepatic Complications in HIV-Infected Persons
- Reprints or correspondence: Dr. Mark S. Sulkowski, Johns Hopkins University School of Medicine, 600 N. Wolfe St., 1830 Bldg., Rm. 445, Baltimore, MD 21287 (msulkowski{at}jhmi.edu).
Abstract
In the era of effective antiretroviral therapy (ART), liver disease is the second most common cause of death among persons with human immunodeficiency virus (HIV) infection. Liver disease-related deaths mostly result from chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV). In addition, recent reports suggest that HCV infection may be transmitted sexually between HIV-infected men who have sex with men. Management of these conditions in HIV-infected persons requires careful consideration, balancing the potential benefits of therapy with the potential for significant treatment-related adverse effects (HCV infection) and viral resistance and/or hepatitis flares (HBV infection). Furthermore, several antiretroviral agents are active against HBV infection, including lamivudine, emtricitabine, tenofovir, and, more recently, entecavir. Despite the complexity and potential for antiretroviral-associated hepatotoxicity, ART usually is safe for patients with viral hepatitis coinfection, and, in some cases, treatment for HIV infection may be beneficial for the liver.
In the era of effective antiretroviral therapy (ART), the management of liver disease has become an increasingly important part of HIV care. Liver-related disease is the most common non-AIDS-related cause of death among persons with HIV infection, according to a large prospective observational study ( N = 23,441 ; median follow-up time, 3.5 years; table 1) [1]. For HIV-infected persons, liver disease-related death stems mostly from coinfection with hepatitis C virus (HCV; adjusted relative risk [RR], 6.7 [95% confidence interval {CI}]4.0–11.2]) or active hepatitis B virus (HBV; adjusted RR, 3.7 [95% CI]2.4–5.9]) [1]. Furthermore, CD4 cell depletion is associated with an increased risk of death due to liver disease, with the greatest risk observed at CD4 cell counts of <50 cells/µL. Other potential causes of liver disease in HIV-infected persons included hepatic injury associated with antiretroviral agents (ARVs), alcohol abuse, and non-alcoholism-related fatty liver disease. In view of the growing importance of liver disease in HIV-infected persons and the interaction of liver disease with HIV infection and its treatment, clinicians who treat HIV infection must consider the treatment of multiple viral infections (HIV, HBV, and/or HCV) when considering the most safe and effective management strategies. This review will focus on the management of coinfection with HBV or HCV, as well as of ART-associated liver injury, in persons with HIV infection.
Figure 1.
Incidence of hepatotoxicity, by antiretroviral therapy regimen. Of the 98 HIV-infected subjects, 54% were coinfected with hepatitis B virus (HBV) or hepatitis C virus (HCV). Adapted from [67], with permission from the American Medical Association.
Figure 2.
Kaplan-Meier survival curves for the probability of developing cirrhosis in 4 study groups. Group 1, patients with hepatitis C virus (HCV) monoinfection; group 2, patients with HIV/HCV coinfection who did not receive therapy or who received nonnucleoside reverse-transcriptase inhibitors (NRTIs) only; group 3, patients with HIV/HCV coinfection who received highly active antiretroviral therapy (HAART); group 4, patients with HIV/HCV coinfection who initially received NRTIs, followed by HAART. P < .001 for group 1 vs. groups 2 and 4; P = .02 for group 1 vs. group 3. Adapted from [106].
Table 1.
Most common causes of death among HIV-infected persons.
Hbv Coinfection
Epidemiology
Because of similar modes of transmission, HBV infection is common among persons with HIV infection. In many settings, as many as 90% of HIV-infected persons have evidence of previous (inactive) HBV infection, whereas the prevalence of chronic HBV infection, defined as hepatitis B surface antigen (HBsAg) positivity for >6 months [2], is 6%–14%, depending on the HIV risk group [3]. Recent estimates suggest that ∼7%–10% of HIV-infected persons in the United States have chronic HBV infection [4].
Although guidelines for HBV testing and vaccination have been in place since early during the HIV epidemic, the management of chronic HBV infection has been inconsistent and marked by the failure to recognize and appropriately treat persons with active HBV infection-related liver disease [5]. This is particularly important before the initiation of ART, since the presence of active HBV infection must be considered in the selection of an ART regimen.
Diagnosis
Recently, a consensus among experts has emerged on many facets of the management of HIV/HBV coinfection in patients [6, 7]. All HIV-infected persons should be screened for active HBV infection by testing for the presence of HBsAg. Persons found to be HBsAg nonreactive should be tested for evidence of protective immunity to HBV infection (presence of hepatitis B surface antibody); if nonreactive, HBV vaccine should be provided. Some controversy exists about the need for vaccination of persons with isolated IgG antibody to hepatitis B core antigen (HBcAg) in the absence of other markers of HBV infection. Recently, Gandhi et al. [8] suggested that many persons found to have isolated anti-HBc may benefit from vaccination. Thus, testing for antibodies to precore or core antigen may be unnecessary before vaccination.
If a patient is found to be HBsAg positive, further evaluation of HBV replication status is critical; such persons should be tested for both hepatitis B e antigen (HBeAg) and HBV DNA. Individuals with evidence of HBV DNA in the blood have active HBV infection, independent of HBeAg status [9]. Active HBV replication in the absence of HBeAg continues in many persons because of mutation in the core and precore promoter regions of the HBV genome. HBsAg-positive persons with no or low levels of detectable HBV DNA should be followed closely, since reactivation has been reported in some persons. In addition, serum alanine aminotransferase (ALT) levels should be assessed, since elevated levels are indicative of active liver disease. Patients with chronic HBsAg positivity should be screened periodically for hepatocellular carcinoma, by means of liver imaging (e.g., ultrasound) and assessment of serum a-fetoprotein levels.
HIV-infected patients with chronic HBV infection have a significantly higher risk of liver disease-related mortality than do patients infected with only HIV or HBV [10]. Among men followed in the Multicenter AIDS Cohort Study, Thio et al. [10] observed an increased risk of liver disease-related death among HIV/HBV-coinfected patients with significant CD4 cell depletion, which may permit more-aggressive HBV disease and higher levels of HBV replication. In other studies, HIV/HBV coinfection often has been characterized by higher levels of serum HBV DNA, compared with levels in HBV-monoinfected patients [9]. Recent data suggest that higher levels of HBV replication or decreased HBV immune clearance may be correlated with the long-term risk of HBV disease-related outcomes. In a prospective evaluation of HBV DNA levels in a large cohort of HIV-seronegative persons with HBV infection, HBV viral load (VL) at study entry exhibited a dose-response relationship with the subsequent development of hepatocellular cancer [11] and cirrhosis [12]. Thus, the higher levels of HBV DNA observed in persons with HIV/HBV coinfection may explain, in part, the increased risk of liver disease-related mortality in this population, compared with that among persons with HBV infection alone.
Treatment
Acute HBV infection. Acute HBV infection usually resolves spontaneously [9] but is more likely to become chronic in persons with HIV infection [13]. Among HIV-seronegative persons, the treatment of acute HBV infection for 3 months with lamivudine was not associated with improved biochemical and clinical response, compared with treatment with placebo [14]. Thus, treatment is not routinely recommended for persons with acute HBV infection; however, ART may be appropriate when symptomatic disease or severe liver dysfunction (e.g., coagulopathy) is present.
Chronic HBV infection. Unfortunately, there is no clear consensus on when to initiate anti-HBV therapy in HIV-infected persons. Although some experts recommend anti-HBV therapy for all persons with active HBV infection, others recommend consideration of treatment on the basis of several disease parameters, including HBV DNA level, HBeAg status, serum ALT level, and liver histology. For example, the European Consensus Conference guidelines recommend that anti-HBV therapy should be initiated when HBV DNA level is >20,000 IU/mL in an HBeAg-positive patient or when HBV DNA level is >2000 IU/mL in an HBeAg-negative patient [9]. Once initiated, the duration of therapy for HIV/HBV-coinfected patients also is poorly defined. For HBeAg-positive patients, treatment until anti-HBe seroconversion is recommended, followed by ∼6 months of “consolidation” therapy. For HBeAg-negative patients, many experts recommend indefinite anti-HBV therapy.
Several medications have been approved by the US Food and Drug Administration (FDA) for the treatment of chronic HBV infection: interferon-α, peginterferon-α2a, adefovir, lamivudine, telbivudine, and entecavir. In addition, tenofovir and emtricitabine have been approved for the treatment of HIV infection and are dually active against HBV infection (table 2).
Table 2.
Medications with anti-hepatitis B virus (HBV) activity, approved by the US Food and Drug Administration.
Standard or pegylated interferon-α. Few studies have addressed the efficacy of interferon-α treatment in patients with HIV/HBV coinfection. Peginterferon-α appears to be more effective than standard interferon-α for the treatment of chronic HBV infection in HIV-uninfected persons, but there are no published data on the efficacy of peginterferon-α in HIV/HBVcoinfected patients. However, limited data suggest that interferon-α therapy will be relatively ineffective for the treatment of HBV infection in HIV-infected patients [15].
Lamivudine. Lamivudine is a nucleoside analogue that, in its active triphosphate form, inhibits HBV DNA polymerase and HIV reverse transcriptase. Although HBV DNA levels decrease by an average of 2.7 log10 copies/mL in HIV/HBV-coinfected patients taking lamivudine for 1 year, the incidence of lamivudine-resistant HBV infection is ∼20%/year among those infected with HIV [16, 17]. When lamivudine-resistant HBV variants emerge, HBV DNA levels increase, liver-enzyme levels may increase, and the resulting HBV infection can be fatal in a minority of patients. Thus, the clinical effectiveness of lamivudine monotherapy is limited by the frequent emergence of resistant HBV variants.
Entecavir. A nucleoside analogue, entecavir is licensed for the treatment of chronic HBV infection in both HIV-infected and -uninfected persons. Entecavir inhibits all 3 functions of HBV polymerase, including base priming, reverse transcription of the negative strand of HBV DNA, and synthesis of the positive strand of HBV DNA. The presence of lamivudine-resistant HBV variants causes decreased susceptibility to entecavir; thus, the recommended doses are 1 mg for lamivudine-experienced patients and 0.5 mg for lamivudine-naive patients [18]. In a randomized controlled trial with 68 HIV/HBV-coinfected persons with lamivudine-resistant HBV, 24 weeks of treatment with entecavir resulted in a reduction in HBV DNA levels of 3.66 log10 copies/mL, which is similar to reductions observed in HBV monoinfection [19]. However, after 48 weeks of entecavir treatment, suppression of HBV replication to <300 copies/mL was achieved in only 9% of patients. To date, resistance to entecavir has not been reported in patients with wild-type HBV infection. However, resistance to entecavir occurred in 7% of HBV-monoinfected patients with lamivudine-resistant HBV who received entecavir for 48 weeks. Although initial reports indicated that entecavir was not active against HIV, clinical observations of significant reductions in HIV RNA levels in 3 HIV/HBV-coinfected patients receiving entecavir for the treatment of HBV infection in the absence of treatment for HIV infection led to in vitro experiments that confirmed the anti-HIV activity of entecavir and the potential for the selection of drug-resistant HIV variants [20]. Accordingly, entecavir should be used only for the management of HBV infection in HIV-infected persons receiving effective ART.
Adefovir. Adefovir dipivoxil is a nucleotide analogue that, in its active diphosphate form, inhibits HBV DNA polymerase and reduces HBV DNA levels by an average of 3.5 log10 copies/ mL by 48 weeks of treatment [21, 22]. Adefovir is licensed for the treatment of chronic HBV infection in patients with HBV monoinfection and is active against lamivudine-resistant HBV. In one study, a total of 35 HIV/HBV-coinfected persons were treated with adefovir for 192 weeks, and substantial reductions in HBV DNA levels were achieved [23]. It is clear from the results of this study and from data for HBV-monoinfected patients that the incidence of clinically evident HBV resistance to adefovir is substantially lower than that to lamivudine. However, in theory, the use of adefovir in HIV/HBV-coinfected patients may involve a risk of selection for HIV cross-resistance to tenofovir, because adefovir is active against HIV at higher doses than those used for the management of HBV infection. Nonetheless, to date, HIV resistance after adefovir treatment has not been reported [10].
Tenofovir. Tenofovir, a nucleotide analogue approved by the FDA for the treatment of HIV infection, is structurally related to adefovir, which differs by 1 methyl group. In vitro, the activity of tenofovir against HBV is at least equivalent to that of adefovir, with a similar IC50. In a prospective nonrandomized study involving 53 patients with lamivudine-resistant HBV and high HBV VL, all 35 patients receiving tenofovir had HBV DNA levels of <105 copies/mL at week 48, compared with 44% of the 18 patients receiving adefovir ( P = .001 ) [24]. In the setting of HIV/HBV coinfection, in which lamivudine-resistant HBV is common, the anti-HBV activity of tenofovir has been demonstrated to be noninferior to that of adefovir. AIDS Clinical Trials Group A5127 was a randomized placebo-controlled trial in which 52 HIV/HBV-coinfected patients, most (74%–80%) of whom had previously taken lamivudine, received either tenofovir or adefovir [25]. The time-weighted mean change in HBV DNA level did not differ significantly between treatment arms at week 48, by any analysis method used, and treatment with tenofovir reached the protocol-defined criteria for noninferiority to treatment with adefovir (table 3) [25].
Table 3.
Decrease in serum hepatitis B virus (HBV) DNA level during therapy with adefovir or tenofovir, in study subjects from AIDS Clinical Trials Group A5127.
Emtricitabine. Emtricitabine is a nucleoside analogue that, after intracellular phosphorylation, exerts potent inhibition of both HIV and HBV replication. FTCB-301 was an international randomized study in which 248 HBV-infected patients who were naive to HBV nucleoside/nucleotide-analogue therapy received either emtricitabine or placebo [26]. At week 48, 54% of patients in the emtricitabine group had HBV DNA levels of <400 copies/mL, compared with 2% of patients in the placebo group ( P < .001 ). Resistance mutations emerged in 13% of those receiving treatment with emtricitabine. HBV variants resistant to emtricitabine also display decreased sensitivity to lamivudine and entecavir.
Telbivudine. Approved for use in patients with chronic HBV infection, telbivudine is a thymidine nucleoside analogue that has no activity against HIV. After 52 weeks of therapy in HBeAg-positive and -negative patients, 600 mg/day of telbivudine was associated with a decrease in HBV DNA levels of 6.45 log10 copies/mL in HBeAg-positive patients and 4.45 log10 copies/mL in HBeAg-negative patients. Viral suppression to undetectable levels was achieved in 60% of HBeAg-positive patients randomized to receive telbivudine, compared with only 40% of those receiving lamivudine. Resistant HBV variants emerged in 8.1% of HBeAg-negative and 21% of HBeAg-positive patients taking telbivudine for 52 weeks. HBV variants resistant to telbivudine also are resistant to emtricitabine and lamivudine. Among HIV-infected persons, telbivudine may play a unique role because it can be used safely in persons not taking fully suppressive ARVs, since telbivudine has no anti-HIV activity.
Combination therapy versus monotherapy. Data that support the use of combination anti-HBV therapy, rather than single agents, in HIV/HBV-coinfected patients are limited. The GS 903 study was a randomized trial designed to compare the efficacy of 2 first-line ART regimens in HIV-infected patients [16]. All participants received efavirenz and lamivudine, plus either tenofovir or stavudine. The inclusion of a small number of individuals with HBV coinfection enabled the investigators to compare the efficacy of lamivudine monotherapy versus lamivudine plus tenofovir dual therapy in the treatment of HBV infection. At week 48, the mean reduction in HBV DNA level among 6 patients receiving lamivudine alone was 3.0 log10 copies/mL, compared with 4.7 log10 copies/mL among 5 patients receiving dual therapy ( P = .055 ).
Nelson et al. [27], from the United Kingdom, reported the results of an open-label, randomized trial comparing lamivudine versus tenofovir versus lamivudine plus tenofovir for the treatment of HBV infection in HIV/HBV-coinfected individuals. Treatment was administered as part of a highly active ART (HAART) regimen. Among 27 patients who were naive for lamivudine at study entry, the median reduction in HBV DNA level at week 24 was significantly greater with use of the combination regimen (5.03 log10 copies/mL, vs. 3.31 log10 copies/ mL with lamivudine monotherapy and 4.66 log10 copies/mL with tenofovir monotherapy; P = .045 for dual therapy vs. lamivudine monotherapy). In 32 lamivudine-experienced patients, switching to or adding tenofovir resulted in superior antiviral activity at week 24, compared with continuing to receive lamivudine alone ( P < .001 ).
Resistance. Resistance to lamivudine may develop in ∼20% of HIV/HBV-coinfected patients/year [17]. It is assumed that any HBV-infected patient who has received lamivudine for a prolonged period will have HBV variants that are resistant to the drug. Variants resistant to lamivudine also exhibit high-level resistance to emtricitabine and lamivudine and partial resistance to entecavir [28]. Resistance to lamivudine also raises the risk of resistance to entecavir. Resistance to entecavir is rare in nucleoside-naive patients with chronic HBV infection [29]. HBV virologic rebound due to resistance to entecavir appears to require 2 preexisting lamivudine-resistance mutations plus additional changes, at least in HBV-monoinfected patients [18, 30]. Entecavir, therefore, should be used with caution in HIV-infected persons with lamivudine-resistant HBV.
Tenofovir and adefovir are active against HBV variants resistant to lamivudine, emtricitabine, telbivudine, and entecavir. Resistance to adefovir has been reported after long-term therapy, particularly in the absence of complete viral suppression. However, few data are available regarding the incidence and characteristics of HBV variants resistant to tenofovir. Currently, guidelines for the management of HBV infection in HIV-infected persons emphasize the need for combination antiviral therapy. However, there are few data to guide the treatment of HIV-infected persons coinfected with lamivudine-resistant HBV. The European Consensus Conference guidelines recommend the use of tenofovir alone in patients infected with lamivudine-resistant HBV [9]. Although HBV variants resistant to tenofovir appear to emerge slowly, other expert guidelines suggest the use of tenofovir plus entecavir in this situation, since both drugs demonstrate potent suppression of HBV DNA when resistance to lamivudine is present and since both select nonoverlapping resistance mutations. Furthermore, in vitro studies have not demonstrated a drug-drug interaction between tenofovir and entecavir [31].
Treatment Guidelines
Both the US Department of Health and Human Services (DHHS) [32] and the European Consensus Conference [9] have issued guidelines for the treatment of HIV/HBV coinfection. Given the dearth of data from well-designed clinical trials, these recommendations are based primarily on expert opinion.
Anti-HBV management in patients who require both anti-HIV and anti-HBV therapy. For patients with no prior exposure to lamivudine or emtricitabine, the use of 2 agents active against HBV is recommended in the setting of fully suppressive ART. The first choice of a nucleoside reverse-transcriptase inhibitor (NRTI) backbone of an ART regimen is tenofovir plus either emtricitabine or lamivudine [33]. Other options include the use of entecavir plus tenofovir (without emtricitabine or lamivudine). If the patient has had prior exposure to lamivudine and/or emtricitabine or confirmed resistance to either agent, tenofovir should be included in an ART regimen with lamivudine or emtricitabine. Some experts recommend the addition of entecavir to tenofovir because of its documented activity against lamivudine-resistant HBV variants.
Dually active agents (i.e., lamivudine, emtricitabine, and tenofovir) carry a black-box warning regarding the danger of severe acute exacerbations of hepatitis if therapy is stopped [33–36]. This danger is sometimes forgotten when ART is changed for reasons unrelated to anti-HBV therapy—for example, stopping an ART regimen because of efavirenz-associated central nervous system adverse effects may lead to an HBV flare. Such exacerbations can be life threatening for patients with cirrhosis or decompensated liver disease. If a dually active agent must be discontinued, then the patient should be monitored with frequent liver-function tests, and the prescription of telbivudine or adefovir should be considered, to prevent HBV flares. This is especially important for patients with a marginal hepatic reserve [33].
Anti-HBV management in patients who require anti-HBV but not anti-HIV therapy. To prevent the emergence of HIV resistance, the primary recommendation is to avoid the use of drugs active against HIV and HBV (including lamivudine, emtricitabine, and tenofovir) without the use of a fully suppressive ART regimen [33]. Entecavir now must be included in this category, because therapy with this agent was found to lead to the development of resistance in HIV isolates from an HIV/ HBV-coinfected patient treated with entecavir alone [20].
Given the need to consider dual anti-HIV and -HBV activity, 3 options may be considered. First, peginterferon-α therapy could be used for persons with high CD4 cell counts (>350 cells/µL), elevated serum ALT levels, and infection with HBV genotype A. Second, telbivudine and a low dose of adefovir (10 mg/day) do not exert anti-HIV activity. These agents could be considered for use as combination therapy, since they select for nonoverlapping HBV resistance mutations. However, there are limited in vitro data and no in vivo data to support this approach. Finally, some experts recommend that all patients with HIV/HBV-coinfection receive a fully suppressive ART regimen, because of the negative effect of immunosuppression on the natural course of HBV infection and the availability of tenofovir as a potent dually active agent. Treatment based on a CD4 cell count threshold may be recommended in the future, because the relative rate of liver disease-related death increases with the level of immunodeficiency. A CD4 cell count ≤500 cells/µL has strongly and independently predicted the risk of liver disease-related death among HIV-infected patients [1]. Thus, some experts treat HIV infection with ART in all HBV-infected persons with a CD4 cell count <500 cells/µL.
Hepatitis B during pregnancy in HIV-infected women. HBV can be readily transmitted from mother to infant. Accordingly, testing for HBV infection is indicated during pregnancy; if active HBV infection is detected, standard protocols for the delivery of HBV vaccine and hepatitis B immunoglobulin to the newborn infant should be strictly followed [37]. Data on the use of antiviral drugs for the treatment of HBV infection during pregnancy are limited; however, data suggest that HBV suppression with lamivudine may effectively decrease vertical transmission, particularly in women with high serum HBV DNA levels [38, 39]. Despite the paucity of data regarding women coinfected with HBV and HIV, the delivery of ARVs targeting both HIV and HBV infection (e.g., tenofovir, emtricitabine, and lamivudine) should be strongly considered. Current DHHS guidelines recommend the use of 2 drugs active against HBV infection (tenofovir plus lamivudine or emtricitabine), to prevent the emergence of resistant HBV variants [32]. Further research is needed to define the best approach for the treatment of HBV and HIV infection during pregnancy [37–39].
Hcv Coinfection
In the United States and Europe, HCV coinfection is more common than chronic HBV coinfection among HIV-infected persons (25%–30% vs. 6%–14%, respectively) [3, 4]. The transmission of HCV infection is driven mostly by injection drug use, whereas HIV infection may be transmitted effectively by injection drug use or by high-risk sexual behavior; therefore, the proportion of HIV-infected persons who are coinfected with HCV varies widely by mode of HIV acquisition, with the highest rates of coinfection observed among injection drug users (72%–95%, compared with 1%–12% of men who have sex with men [MSM] and 9%–27% of heterosexual persons) [3].
Acute HCV infection. Increasingly, clinicians are recognizing the transmission of acute HCV infection among HIV-infected MSM. Although the reason for the apparent emergence of HCV infection in this group is unclear, acute HCV infection has been associated with high-risk sexual practices (e.g., anal fisting), which may facilitate blood exposure [40, 41]. For many asymptomatic patients, acute HCV infection is diagnosed after the detection of elevated ALT levels during routine monitoring [40].
The early detection of acute HCV infection is critical and should prompt the consideration of anti-HCV therapy, to prevent chronic HCV infection. Although ∼25% of HIV-seronegative persons who acquire acute HCV infection may clear viremia, several studies have suggested that HIV-infected patients are more likely to develop chronic HCV infection. In one study, Thomas et al. [42] found that ∼8% of HIV-infected persons cleared HCV; in another study [43], HCV clearance was rare among HIV-infected persons with acute HCV infection (1 in 25 patients). There are not many data to guide the treatment of acute HCV infection. Expert guidelines recommend treatment with peginterferon-α (2a or 2b) alone or in combination with ribavirin for 24–28 weeks. In one series, 10 of 14 HIV-infected patients treated with peginterferon-a plus ribavirin for 6 months showed no evidence of chronic HCV infection, which demonstrated sustained viral response (SVR) [43]. On the other hand, some studies have suggested that treatment with peginterferon-a alone may be sufficient [44].
Chronic HCV infection. All HIV-infected persons should be screened for HCV infection, by use of antibody testing; if a seropositive result is obtained, active HCV infection should be confirmed by testing for HCV RNA, by use of commercially available assays. For all patients with active HCV infection, the potential benefits and risks of anti-HCV therapy should be weighed carefully. Multiple factors should be considered, including HIV-disease status, comorbid medical and psychiatric diseases, HCV genotype, and stage of hepatic fibrosis. For example, some experts recommend consideration of anti-HCV treatment for patients with high CD4 cell counts for whom ART is not needed [9]. For most patients with HIV/HCV coinfection, the anti-HCV treatment regimen is 180 µg of peginterferon-α2a or 1.5 µg/kg peginterferon-α2b, via subcutaneous injection weekly, plus ribavirin. For persons infected with HCV genotype 2 or 3, the ribavirin dose is 800 mg/day, whereas weight-based dosing is recommended for persons infected with HCV genotype 1 (1000 mg/day for persons <75 kg; 1200 mg/ day for persons ≥75 kg).
Genotype and fibrosis stage. In the absence of a contra-indication for peginterferon-a and/or ribavirin, some experts recommend that all patients with HCV genotype 2 or 3 infection, as well as those with HCV genotype 1 infection and low baseline HCV VL ( ≤800,000 IU/mL), should receive anti-HCV therapy, because of the relatively high likelihood of SVR (∼60%). Furthermore, liver biopsy is not recommended for these patients if treatment is initiated. However, if anti-HCV therapy is deferred, liver biopsy must be strongly considered, to provide information regarding liver-disease stage and the need for anti-HCV treatment [45].
In contrast, compared with those with favorable response characteristics, HIV-infected patients with HCV genotype 1 infection and high HCV VL (>800,000 IU/mL) are less likely to achieve SVR (rate, ∼18%). Furthermore, in most studies, African American patients have been found to be less responsive to interferon-based therapy (50% lower SVR than that in white patients) [46, 47]. The management of HIV infection in patients with such unfavorable response characteristics must be individualized. Some experts recommend liver biopsy in this setting, with deferral of anti-HCV treatment for those with minimal liver disease (i.e., stage 0 or 1 fibrosis). Conversely, other experts recommend that such patients be treated with peginterferon-a plus ribavirin, with monitoring of treatment response after 4 and 12 weeks of therapy and discontinuation of therapy if the HCV RNA response is insufficient. Patients who do not achieve an undetectable HCV RNA level or a 2-log10 reduction after 12 weeks of therapy are unlikely to achieve SVR (<1%). In one study, the failure to suppress HCV RNA level to <460,000 IU/mL after 4 weeks of therapy was associated with subsequent failure to achieve SVR in all patients (negative predictive value for SVR, 100%) [48]. On the basis of these prediction guidelines, clinicians can discontinue therapy early, to avoid unnecessary adverse effects, while providing patients with an adequate therapeutic trial.
In addition, guidelines that rely on liver biopsy are problematic, since the procedure is expensive, invasive, and subject to sampling error. Furthermore, in some settings, liver biopsy is not readily available, limiting access to anti-HCV treatment. Accordingly, there is considerable interest in the development and validation of noninvasive tests such as those based on biochemical markers and/or transient elastography (FibroScan; table 4) [49–54].
Table 4.
Selected noninvasive measures for testing for liver fibrosis.
HIV-disease stage. In general, HIV disease should be stable with or without ART. For patients with CD4 cell counts <200 cells/µL, anti-HIV treatment is typically the priority, and anti-HCV treatment is deferred. In addition, several studies using treatment with standard interferon plus ribavirin have suggested that patients with CD4 cell counts <200 cells/µL achieve a lower SVR than do other patients, but there is insufficient evidence to establish a CD4 cell count threshold for anti-HCV therapy [9]. In addition, patients with higher CD4 cell counts may better tolerate anti-HCV therapy. However, CD4 cell count thresholds are not rigid but, rather, are one factor to consider. Indeed, some patients with low CD4 cell counts may experience recurrent ART-related hepatotoxicity; anti-HCV treatment may be considered as a means to improve HCV infection-related liver disease and ART tolerability.
Management of adverse effects related to anti-HCV treatment. The major toxicities associated with interferon-a (pegylated or standard) include influenza-like symptoms (e.g., fever, myalgia, headache, and fatigue), neuropsychiatric abnormalities (e.g., depression, irritability, and cognitive dysfunction), cytopenias (e.g., thrombocytopenia and neutropenia, including a reversible reduction in CD4 cell count), retinopathy, neuropathy, and exacerbation of autoimmune disease. Depression might be severe enough to trigger suicide. Depending on the severity of these toxicities and individual patient tolerance, adverse effects may be dose limiting or may interfere with the ability to complete a course of treatment.
The major toxicities associated with ribavirin include dose-dependent hemolytic anemia, cough, and dyspepsia. Ribavirin potentiates the intracellular activity of didanosine through inhibition of inosine monophosphate dehydrogenase. Multiple reports have indicated that the interaction between ribavirin and didanosine may lead to clinically significant inhibition of mtDNA polymerase γ, resulting in severe pancreatitis, lactic acidosis, and, in some patients, death. The combination of ribavirin and didanosine is strictly contraindicated [55]. Zidovudine can potentiate ribavirin-related anemia, and, if other ARVs are available, modification of the ART regimen to remove zidovudine is recommended before anti-HCV treatment [56].
Patients for whom the discontinuation of zidovudine is not feasible should be monitored closely (every 2 weeks) for the development of severe anemia during the first 8 weeks of treatment. Studies support the use of erythropoietin for the management of clinically significant anemia during anti-HCV treatment. The use of epoetin-α may permit maximization of the ribavirin dose, which in turn may preserve SVR rates and has been associated with improved quality of life [57].
Mental health should be evaluated before initiation of anti-HCV therapy and should be monitored at regular intervals during treatment. Some experts recommend the use of a standardized depression-screening tool, such as the Center for Epidemiologic Studies Depression Scale. The adverse effects associated with peginterferon-α and ribavirin might be modified by the use of adjunctive agents, such as antidepressants (neuropsychiatric) and hematopoietic growth factors (e.g., filgrastim for neutropenia and erythropoietin for anemia).
New anti-HCV treatments. Current therapies are relatively ineffective for the management of HCV infection in HIV-infected persons. Many coinfected patients, particularly those who use injection drugs, often are not referred for anti-HCV treatment [58] or do not enter treatment even when it is available at no cost [59]. Active drug or alcohol use is not a treatment contraindication [60]. Still, interventions to reduce or stop substance abuse (e.g., methadone maintenance therapy) likely will enhance the effectiveness of anti-HCV therapy.
Major advances in the understanding of HCV biology have led to the development of novel antiviral drugs [59, 61]. In 2007, drugs targeting the NS3 serine protease, a major catalyst in posttranslational polyprotein processing, and the NS5B RNA-dependent RNA polymerase, a major catalyst in HCV replication, were in phase 2 clinical trials [62, 63]. Early studies of these agents as monotherapy led to the rapid selection of drug-resistant HCV variants; these agents are being studied in conjunction with peginterferon-α/ribavirin [64]. Telaprevir, an oral HCV protease inhibitor (PI), is an example of a novel agent in phase 2 clinical trials. Early studies suggest the potential for significant anti-HCV activity for this drug in combination with peginterferon-a/ribavirin [65]. After 12 weeks of therapy, HCV RNA level was <10 IU/mL in 85% of patients with HCV genotype 1 infection who were receiving telaprevir (oral dose every 8 h) plus peginterferon-α/ribavirin, compared with only 43% of those receiving peginterferon-α/ribavirin plus placebo (P < .001 ) [66]. However, telaprevir also was associated with more adverse effects, such as anemia, gastrointestinal symptoms, and skin rash; more patients taking telaprevir stopped therapy because of adverse effects. Viral breakthrough consistent with resistance to telaprevir was observed in a minority of patients.
Art And The Liver
Drug-Related Hepatotoxicity: Incidence and Risk Factors
In randomized controlled trials, the incidence of significant, grade 3 (>5× the upper limit of normal [ULN]) and grade 4 (>10× the ULN) elevations in serum ALT or aspartate aminotransferase levels that were associated with the use of combination ART (cART) has varied between ∼1% and ∼14%. In such studies, the incidence of hepatotoxicity typically reflects not only the toxicity associated with the ARV of interest but also that of concurrently administered ARVs. In addition, the population studied may have profound effects on the incidence of severe hepatotoxicity (e.g., treatment-experienced vs. treatment-naive populations). Given the substantial heterogeneity in patient populations and drug regimens, comparison of hepatotoxicity incidence rates for individual ARVs across clinical trials is difficult (figure 1) [67]. Nonetheless, in such studies, the highest incidence rates of grade 3 or 4 elevations in liver-enzyme levels have been observed during therapy with cART regimens that include nevirapine or full-dose ritonavir (600 mg twice daily) or tipranavir (boosted by low-dose ritonavir) [68–71]. Interestingly, other PIs that are pharmacologically boosted with low-dose ritonavir, such as lopinavir, have not been associated with higher rates of hepatotoxicity, compared with other regimens, suggesting that the observed hepatotoxicity with low-dose ritonavir boosting is largely a function of the primary PI [72]. Patients taking the PIs indinavir or atazanavir may experience a >2.5-fold increase in total bilirubin level, which represents unconjugated or indirect hyperbilirubinemia. However, indinavir-or atazanavir-induced hyperbilirubinemia does not reflect drug-induced liver injury but, rather, a drug-mediated impairment of bilirubin uridine diphosphate-glucuronosyltransferase activity that leads to inhibition of bilirubin conjugation and the development of reversible, asymptomatic, indirect hyperbilirubinemia, which clinically resembles Gilbert syndrome [73, 74]. Overall, in these large registration studies, elevations in liver-enzyme levels were infrequently symptomatic or dose limiting, and permanent liver injury was a distinctly rare event.
Since registration studies may not reflect real-world patient populations, hepatotoxicity also has been evaluated in large patient cohorts, to determine the incidence of significant elevations liver-enzyme levels in HIV-infected adults after the administration of HAART [67, 75–85]. For example, Wit et al. [82] conducted a retrospective cohort analysis ( N = 560) that identified several risk factors associated with grade 4 hepatotoxicity in patients receiving HAART. Table 5 lists the findings of this study [82]. Chronic HBV or HCV infection and certain ARVs are among the risk factors noted.
Table 5.
Risk factors for grade 4 elevations in liver-enzyme levels in HIV-infected persons receiving highly active antiretroviral therapy.
Mechanisms of Hepatotoxicity
The pathogenesis of ART-induced liver injury is not known but is likely to be heterogeneous, varying with respect to the drug and the patient population in which it is used [86]. Nonetheless, potential mechanisms of liver injury include mitochondrial toxicity, immune reconstitution, direct toxicity and/ or drug metabolism, and hypersensitivity reactions.
Mitochondrial toxicity. Liver injury—namely, the accumulation of microvesicular steatosis in liver cells and mitochondrial depletion—is part of a spectrum of delayed toxicities associated with NRTI exposure in which the inhibition of human mtDNA polymerase is the primary inciting cellular event. The greatest inhibition of mtDNA synthesis in vitro has been observed with the NRTIs zalcitabine, didanosine, and stavudine [87]. More-recent studies have assessed the relationship between liver fibrosis and steatosis and the use of ARVs, particularly stavudine, in persons with chronic HCV infection. Sulkowski et al. [88] observed steatosis in 40% of 112 HIV/ HCV-coinfected patients who underwent liver biopsy; the presence of steatosis was associated with white race, weight 186 kg, hyperglycemia, and stavudine use. In addition, patients with steatosis also were more likely to have greater hepatic fibrosis and necroinflammatory activity. Similarly, McGovern et al. [89] found steatosis in 69% of 183 HIV/HCV-coinfected patients who underwent liver biopsy. In this study, factors associated with steatosis included use of the dideoxynucleoside analogues didanosine and stavudine. Lipodystrophy related to ART also has been linked to the finding of hepatic steatosis in HIV/HCVcoinfected patients [90]. Although data regarding the prevalence of steatosis are more limited for patients without chronic HCV infection, several case series have reported cryptogenic cirrhosis or nodular regenerative hyperplasia in the setting of chronic dideoxynucleoside-analogue therapy [91]. Considered together, these preliminary data suggest that ART may contribute to the development of chronic hepatic steatosis; however, the long-term significance of this observation is unknown.
Immune reconstitution. Some evidence supports the association between immune restoration (e.g., increasing CD4 cell count) as a result of HAART and the development of acute liver injury related to viral hepatitis [92–95]. The evidence that immune recognition of a viral pathogen is responsible for increases in liver-enzyme levels is strongest for HBV infection, for which seroconversion has been reported in the setting of HAART [77]. Overall, the evidence is less convincing for the occurrence of immune-related flares related to chronic HCV infection. However, a recent study reported that HAART-associated hepatotoxicity was associated with increases in serum HCV-specific IgG and soluble CD26 dipeptidyl peptidase IV enzyme activity in 11 HIV/HCV-coinfected patients [95]. Thus, although enhanced immune response to HBV or HCV infection may account for some episodes of elevated liver-enzyme levels after HAART, this proposed mechanism cannot explain the occurrence of drug-induced liver injury in HIV-infected patients who do not have concurrent HBV or HCV infection.
Direct toxicity/alteration of metabolism. The third potential mechanism of ART-associated liver injury is an alteration in metabolism, since many drugs are metabolized in the liver by various isoforms of the cytochrome P-450 system [96]. Accordingly, some experts have speculated that liver injury may be due to supertherapeutic serum levels of PIs in patients with HCV or HBV coinfection or with preexisting liver disease [86]. Recently, González de Requena et al. [97] reported that elevated levels of the nonnucleoside reverse-transcriptase inhibitor (NNRTI) nevirapine were associated with the development of HAART-associated hepatotoxicity. Although there is strong evidence that decompensated liver disease is associated with substantial decreases in the metabolism of some PIs, there are no published data that link elevated serum PI levels to the development of hepatotoxicity [98]. Prospective studies are currently under way to determine the association between serum PI concentration and the development of drug-induced liver injury, but there currently is insufficient evidence to recommend the routine use of the therapeutic drug monitoring of PIs as a means to decrease the risk of HAART-associated hepatotoxicity.
Hypersensitivity reactions. Finally, idiosyncratic hypersensitivity reactions have been observed with ARVs—namely, with abacavir and nevirapine. Such reactions usually become apparent within the first 12 weeks of treatment. Among patients taking nevirapine, the incidence of symptomatic events involving the liver has been reported to be 4.9%. The risk of a severe hypersensitivity reaction after nevirapine use appears to be increased in women with CD4 cell counts >250 cells/µL, compared with that in men and those with lower CD4 cell counts [68]. Interestingly, patients with an MDR1 variant (MDR1 3435C→T) appear to have a significantly decreased risk of nevirapine-associated hepatotoxicity, suggesting that genetic determinants may be useful in the prediction of the risk of adverse events [99]. However, until such strategies are confirmed, the routine use of nevirapine for women with high CD4 cell counts is not recommended.
HIV-Associated Hepatopathy
As early as 2001, rare, unexplained, serious cases of liver disease have been reported in HIV-infected patients who do not have hepatitis coinfection [100–103]. Reported rates have ranged from 1% (32 of 3200) of HIV-infected patients at 3 clinics to 8% (8 of 97) of HIV-infected patients presenting to a liver-disease center in Paris. Findings have included abnormal results of liver-function tests, portal hypertension, and nodular regenerative hyperplasia. Although no single etiology or characteristic histologic finding has been identified, researchers have suggested that chronic exposure to nucleoside analogues with significant mitochondrial toxicity (e.g., didanosine and stavudine) may play a role in the etiopathogenesis of liver disease. For example, in one study, all but 3 of 32 HIV-infected patients with cryptogenic liver disease in one series had been exposed to didanosine. Didanosine treatment was withdrawn from most of these patients (27 of 29), and nearly half (13 of 27) showed clinical signs of improvement 1 year later [100]. Mean ALT levels fell significantly (from 75 to 49 IU/mL; P = .001 ). Further research is needed to better define this condition and to elucidate the role, if any, of ARVs.
Beneficial Effects Of Art on the Liver
Despite their potential liver toxicity, ARVs usually are safe for coinfected patients. In one series, 84% of 568 HIV-infected patients with HBV or HCV coinfection did not develop severe hepatotoxicity [85]. Another evaluation found no evidence that ART caused severe histologic liver disease in HIV/HCV-coinfected patients ( N = 210 ) [104]. In fact, in this series, suppression of HIV VL to undetectable levels was associated with less liver necrosis and inflammation ( P < .01 ) [104].
Furthermore, in many studies, advanced immunosuppression (e.g., CD4 cell count <200 cells/µL) has been independently associated with an increased risk of advanced histologic and/or clinical liver disease in persons with HIV/HCV coinfection. This inverse relationship between CD4 cell count and liver disease supports the hypothesis that reversal or prevention of immunosuppression by means of HAART will decrease the rate of HCV-related fibrosis progression and the risk of cirrhosis and its clinical consequences (end-stage liver disease, hepatocellular carcinoma, and death) in HIV-infected patients. For example, Benhamou et al. [93] reported that HIV/HCV-coinfected patients who received PI-based HAART had a significantly decreased rate of fibrosis progression, compared with those who did not receive treatment or who received less-effective ART regimens. Similarly, Macías et al. [105] reported that HCV-infected patients exposed to PI-based HAART had less fibrosis than those who did not receive treatment or who received other ARVs.
More recently, Verma et al. [106] reported that the liver histology findings for HIV/HCV-coinfected patients receiving HAART as their only therapy ( n = 22) were comparable to those for HCV-monoinfected patients ( n = 296). The mean fibrosis stage for coinfected patients who did not receive therapy or who received NRTIs only ( n = 25) or who received HAART after NRTIs ( n = 38) was significantly more advanced than that for HCV-monoinfected patients (figure 2). The rate of fibrosis progression in those receiving only HAART was similar to that in HCV-monoinfected patients but was significantly faster than that in other HIV/HCV-coinfected patients. In another study, HAART that led to an undetectable HIV VL (<400 copies/mL) in HIV/HCV-coinfected patients was found to be associated with rates of fibrosis progression similar to those in HCV-monoinfected patients. In addition, coinfected patients with undetectable HIV VL had rates of fibrosis progression that were slower than those in patients with any detectable HIV RNA level [107].
Finally, Qurishi et al. [108] reported decreased liver disease- related mortality among HIV-infected persons who had received HAART. ART reduced long-term liver disease-related mortality, compared with no therapy or NRTIs alone, among HIV/HCV-coinfected patients ( N = 285). Subjects were followed from 1990 to 2002. Liver disease-related mortality rates were 0.45, 0.69, and 1.70/100 person-years for the groups receiving HAART, ART, or no therapy, respectively ( P = .018 for the benefits of ART). Independent predictors of liver disease- related survival included HAART, ART, and CD4 cell count. Nearly 14% (13 of 93) of those who received HAART developed severe drug-related hepatotoxicity, but none died. The benefit of HAART clearly outweighed its toxicity in this analysis, although the study results were flawed by survivor bias.
Conclusions
Because of increasing morbidity and mortality, the management of HBV and HCV infection is increasingly part of HIV care. Proper screening for both infections is important for early diagnosis and appropriate treatment. In particular, the diagnosis of chronic HBV infection must be considered before HAART is started, since several anti-HIV and -HBV medications are active against both viruses. Anti-HBV monotherapy should be avoided, to reduce the risk of resistance. Despite the high prevalence of hepatitis C, anti-HCV therapy is underutilized in the HIV-coinfected population. Supportive therapy can help patients complete anti-HCV therapy despite the neuropsychiatric and hematologic adverse effects of the treatment regimen. Finally, the effect of ART on liver disease remains controversial. Although drug-induced liver injury occurs in a minority of HIV-infected persons receiving ART, current data support the recommendation that physicians treating HIV infection should not withhold HAART from HCV-infected patients because of concerns about acute or chronic, medication-related hepatic injury. Furthermore, some studies have reported decreased progression of liver disease in patients with viral hepatitis in whom treatment with ART was successful.
Acknowledgments
Eileen A. McCaffrey (Clarus Health) provided medical writing support.
Supplement sponsorship. This article was published as part of a supplement entitled “Significant Challenges Facing HIV Practitioners,” sponsored by Bristol-Myers Squibb.
Footnotes
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Potential conflicts of interest: M.S.S. receives research support from Humane Genome Sciences, Roche, Schering Corporation, Valeant Pharmaceuticals, and Vertex Pharmaceuticals and is a consultant to Bristol-Myers Squibb, Merck, Roche, and Vertex Pharmaceuticals.
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Financial support: National Institutes of Health (grant R01DA16065) and an independent educational grant from Bristol-Myers Squibb. Supplement sponsorship is detailed in the Acknowledgments.
- © 2008 by the Infectious Diseases Society of America
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