Infectious Diseases in Clinical Practice:
Liver-Related Complications in HIV-Infected Individuals
Chun, Helen M. MD*; Landrum, Michael L. MD†; on behalf of the Tri-Service AIDS Clinical Consortium
*Department of Infectious Diseases, Naval Medical Center, San Diego, CA and †Wilford Hall Medical Center, Lackland AFB, TX.
Support for this work was provided by the Tri-Service AIDS Clinical Consortium (TACC), managed by the Uniformed Services University of the Health Sciences (USUHS) Infectious Diseases Clinical Research Program (IDCRP). The IDCRP is a DoD tri-service program executed through USUHS and the Henry M. Jackson Foundation for the Advancement of Military Medicine (HJF), in direct partnership with HHS/NIH/NIAID/DCR.
The views expressed here are the private opinions of the authors and are not to be considered as official or reflecting the views of the US Air Force, the US Navy, the US Army, the US Department of Defense, or the US Department of Health and Human Services.
Address correspondence and reprint requests to Helen M. Chun, MD, Division of Infectious Diseases, Naval Medical Center San Diego, 34800 Bob Wilson Drive, San Diego, CA 92134. E-mail: email@example.com.
Liver-related complications in human immunodeficiency virus (HIV)-infected patients are increasingly common clinical occurrences as patients have longer life expectancies in the highly active antiretroviral therapy era. The differential diagnosis of abnormal liver function tests in this population is extensive, with many of the etiologies having a significant impact on short-term and long-term morbidity and mortality. Chronic coinfection with hepatitis B virus (HBV) and hepatitis C virus (HCV) occurs in approximately 10% and 30%, respectively, of all HIV-1-infected patients. Although the impact of these viruses on HIV disease remains debated, HIV infection significantly worsens the course of HBV and HCV infection. In addition, treatment of both HBV and HCV is less effective and more toxic in HIV-infected patients than in patients without HIV infection. The presence of HBV and HCV also complicates antiretroviral therapy by increasing rates of drug toxicity and possibly reducing immune reconstitution. With decreasing rates of death due to opportunistic infections and increasing morbidity and mortality due to liver-related complications, it is essential for clinicians caring for patients with HIV to remain abreast of the latest developments in this area.
Since the advent of potent antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection, there has been a dramatic decline in opportunistic complications previously seen with severe immunodeficiency.1 Concomitant with increasing survival, there has been an increasing number of liver-related complications in HIV-infected patients. End-stage liver disease was found to be the leading cause of death in one hospitalized HIV-seropositive population.2 Understanding the pathogenesis and how to manage this comorbidity is becoming increasingly important for clinicians who care for HIV-infected patients. The purpose of this review is to update clinicians on recent developments and outline current management for HIV-infected individuals with hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection, antiretroviral (ARV) hepatotoxicity, or nonalcoholic fatty liver disease (NAFLD).
HEPATITIS B AND HIV COINFECTION
Due to shared routes of transmission, exposure to HBV is common in HIV-infected individuals. Serologic markers of prior exposure to HBV are found in more than 80% of HIV-infected individuals.3,4 Isolated anti-hepatitis B core antigen is often seen in this population, particularly among patients with HCV coinfection.5,6 The presence of detectable HBV DNA in the liver and/or serum in hepatitis B surface antigen (HBsAg)-negative patients, referred to as "occult" HBV infection, is of unclear significance. Approximately 10% of individuals infected with HIV are chronically infected with HBV compared with less than 5% of HIV-uninfected individuals.3,7-10 HIV coinfection increases the risk of HBV-associated end-stage liver disease, with liver failure and hepatocellular carcinoma occurring in up to 30% of individuals.3,4,11-14 HIV infection decreases the rates of spontaneous resolution after acute infection, anti-hepatitis B e antigen (anti-HBe), and anti-HBs seroconversion and increases the levels of HBV DNA replication.11 There is also a high rate of seroreversion in those with spontaneous or interferon-induced anti-HBe seroconversion in individuals with low CD4+ cell counts.15 Liver enzyme elevations in coinfected individuals, however, are often milder than in patients with chronic HBV monoinfection, especially in HBeAg seropositive individuals.9,16 There is evidence that HIV may modify the natural history of HBV infection, with coinfected patients demonstrating a more rapid progression of liver fibrosis and hepatic decompensation, leading to an increased risk of HBV-related liver complications and death.3,9,11 Data from the Multicenter AIDS Cohort Study (MACS) demonstrated that patients with coinfection are at greater risk for hepatic decompensation, death after ART initiation, death with low CD4 nadir levels, and hepatotoxicity.4 Conversely, studies examining the effect of HBV on HIV disease progression have been conflicting, with the majority demonstrating no independent association between HBV infection and worse HIV outcomes; however, further studies are needed.3,17-19
Hepatitis B virus, a partially double-stranded hepatotropic DNA virus, mediates liver damage through mainly immune-mediated mechanisms.20 Persistent HBV infection is established through a reservoir of genetic material in the form of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes.9 Our understanding of the natural history of chronic hepatitis B infection today recognizes the dynamic relationship between the host immune system and HBV replication, with ongoing aminotransferase and HBV DNA fluctuations, even after HBeAg seroconversion. The natural history of hepatitis B consists of 4 phases.21 The first phase of immune tolerance is characterized by HBeAg positivity, high levels of HBV DNA, normal serum aminotransferases, and minimal or no inflammation on liver biopsy. The second phase of immune clearance is characterized by chronic HBeAg-positivity with high/fluctuating HBV DNA levels, flares in serum aminotransferases, and active inflammation on liver biopsy. Seroconversion to anti-HBe is an important part of this second phase.21 The third phase, inactive carrier, is characterized by anti-HBe positivity, normal aminotransferases, low/undetectable HBV DNA, and minimal fibrosis on liver biopsy.21 The fourth phase, reactivation, is characterized by HBeAg negativity, anti-HBe positivity, detectable HBV DNA, aminotransferase elevation, and ongoing liver inflammation.22 The latter represents the selection of HBeAg-defective viral variants, as a result of mutations in the precore region or the core promoter region, which abolish the expression of HBeAg.9 HBeAg-negative chronic hepatitis B is associated with active liver disease at lower levels of HBV DNA, poor sustained response, and poor long-term prognosis in most patients.7,20 In individuals with precore or core promoter mutations, HBeAg (core-mutant) seroconversion is not considered an end point, and long-term therapy is the rule.7 Triple infection with HIV, HBV, and HDV seems to be associated with an increased risk for the development of cirrhosis and higher rates of hepatic flares. Hepatic decompensation and mortality have been observed, without negative effects on HIV virologic and immunologic responses to highly active antiretroviral therapy (HAART), in patients with HDV superinfection of chronic HBV and HIV coinfection.23
Recommendations for the treatment of chronic HBV in HIV-infected patients are complex.24 The goals of treatment of chronic HBV infection are to delay and halt liver disease progression, ultimately preventing liver cirrhosis and hepatocellular carcinoma.24,25 Goals of treatment include a significant reduction or clearance of serum HBV DNA, loss of HBeAg, and seroconversion to anti-HBe. Treatment-induced reduction in HBV DNA level can be used for assessing the efficacy of treatment regimens, especially in HBeAg-positive patients, and correlates with an improvement in histological activity index and HBeAg seroconversion.26 Clearance of serum HBsAg is considered another goal; however, this is difficult to achieve.27 A decrease in cirrhosis with anti-HBV therapy has been reported in monoinfected patients. The decision to start HBV therapy is currently made considering the markers of alanine aminotransferase (ALT), HBeAg, HBV DNA, and the need for HAART. The use of ALT as a surrogate treatment marker is of limited value, especially in coinfected individuals, given the frequent fluctuations that can be seen with ARVs, other hepatitis coinfection such as HCV, alcohol use, and immune reconstitution.13 Individuals with any evidence of liver disease (eg, elevated transaminases, high levels of HBV DNA, liver biopsy demonstrating necroinflammation, and fibrosis) should be considered for anti-HBV therapy. Individuals not treated for HBV should be reassessed for the need for anti-HBV treatment using biochemical and virologic markers every 3 to 6 months.28 Treatment guidelines in HIV-negative individuals recommend consideration for therapy with HBV DNA levels greater than 105 copies/mL, with lower thresholds around 103 to 104 copies/mL in HBeAg-negative patients. However, no definitive recommendations for treatment have been made in coinfected patients.9
Currently, there are 6 FDA-approved drugs for the treatment of chronic HBV (Table 1): interferon alfa-2b (IFN-α), peginterferon alfa-2a, lamivudine, adefovir, and entecavir (ETV). In addition, the ARVs tenofovir and emtricitabine have dual antiviral activity against HIV and HBV, broadening the armamentarium in the coinfected population. Lamivudine, a nucleoside analogue, demonstrates significant HBV suppression with improvement in liver enzymes and histologic findings, with HBV DNA reduction between 40% and 87% and anti-HBe seroconversion between 22% and 29% in coinfected patients.29-31 Nevertheless, monotherapy with lamivudine selects for HBV resistance (YMDD mutant) at a rate of 20% per year3 and up to 90% after 4 years in coinfected patients.31 Emtricitabine, a nucleoside analogue with dual HIV and HBV activity and an excellent safety profile similar to lamivudine, has been shown to lead to a rapid reduction in HBV DNA.32 Emtricitabine is considered interchangeable with lamivudine and is also not recommended for use as monotherapy in coinfected patients. Emtricitabine is associated with a relatively high incidence of resistance, with rates of 18% after 2 years of treatment.33 Adefovir and tenofovir have the advantage of a higher genetic barrier for resistance26 and are active against lamivudine-resistant HBV strains.24,34-36 In vitro data have demonstrated additive effects of adefovir when combined with other HBV active agents including lamivudine, emtricitabine (FTC), or telbivudine (Tyzeka), and moderately synergistic effects when combined with ETV or tenofovir.37 Mutations at codon rt236 and A181V have been associated with adefovir resistance38,39 occurring at 0% at 1 year, 2% to 6% at 2 years, and 14% at 4 years.40 Adefovir resistant HBV, however, remains sensitive to lamivudine, emtricitabine, and ETV.39 Tenofovir has been shown to be as efficacious as adefovir in decreasing HBV DNA levels in coinfected individuals, with similar activity in patients with wild-type and lamivudine resistant HBV, with an approximate 5-log reduction in HBV DNA after 48 weeks of therapy.41,42 Combination therapy using tenofovir and lamivudine has been shown to have greater antiviral efficacy and delays the selection of drug-resistant strains.41,43 The use of combination therapy is under investigation.
Entecavir, a deoxyguanosine analogue specific for HBV, has increased potency compared with lamivudine, adefovir, and interferon, demonstrating virologic activity in patients with lamivudine resistance, and is well tolerated.32,40 Resistance to ETV has been infrequently reported, emerging during prolonged therapy in patients with prior lamivudine use. The selection of additional reverse transcriptase substitutions within a lamivudine-resistant HBV background leads to reduced ETV susceptibility and treatment failure.44 Dosing in drug-naive patients is 0.5 mg/d, whereas dosing for patients with lamivudine resistance is 1.0 mg/d.
For coinfected patients not requiring HAART who are HBeAg-positive, IFN-α may be the best option, with consideration also for adefovir, ETV, or telbivudine, and in the future, clevudine.24,45 IFN-α has been associated with favorable response rates, especially with high ALT levels, low HBV DNA titers, and higher CD4 counts.15 The reported response rates in HIV coinfected patients, however, are conflicting, with some studies showing a lower response in coinfected patients compared with HBV monoinfected patients.24,46 The benefits of interferon, however, are its lack of resistance, short duration of therapy, long-term improvement in necroinflammation, possible loss of surface antigen, and conversion to anti-HBs.7 The results for HBV monoinfected individuals show improved responses using pegylated IFN-α. Extrapolating from the treatment in HBV monoinfected patients, pegylated IFN-α is given once a week for 6 to 12 months.9 In patients with decompensated liver disease, IFN-α is contraindicated, and it should be used with caution in patients with cirrhosis as the flare of necroinflammation accompanying HBeAg clearance may lead to hepatic decompensation.9
The efficacy and safety of new and more potent drugs such as telbivudine and clevudine need to be confirmed, but telbivudine has been shown to be more efficacious at 2 years in mean reduction in HBV DNA levels, normalization of ALT when compared with lamivudine monotherapy, with proportionally greater HBeAg seroconversion and less viral breakthrough.47 Lamivudine and telbivudine share cross-resistance.9 In preliminary studies, clevudine, a pyrimidine analogue, with activity against HBV but not HIV, has been shown to produce potent viral suppression even after termination of therapy and has an excellent safety profile.32 The future of chronic hepatitis B therapy is drug combinations with different sites of action on HBV DNA replication, a potent antiviral effect sustained off-therapy response rates, excellent safety profiles, and decreased resistance.20,26,32,48 Whether combination therapy can reduce HBV cccDNA, responsible for persistent infection, is unclear.26
In summary, for the individual in need of HAART, a regimen containing agents with dual HIV and HBV activity is advised with recommendations for combination therapy using a nucleoside analogue (eg, lamivudine or emtricitabine) with tenofovir. Interferon, adefovir, ETV, telbivudine, or clevudine should be considered in HBeAg-positive individuals not requiring HAART.24
Highly active antiretroviral therapy may influence the natural history of chronic hepatitis B by restoring adaptive HBV-specific immune responses and innate nonspecific immune responses and may slow the progression of chronic hepatitis B in coinfected patients.11 If HAART is not needed, the use of anti-HBV agents without anti-HIV activity, such as IFN-α, low-dose adefovir, or ETV, may be preferred. It is generally agreed that agents with activity against HIV and HBV should not be used as monotherapy, given the high risk of selecting for HIV-resistant variants.9
In addition to increased rates of hepatotoxicity from ART, flares in transaminases and reactivation of HBV have been seen upon discontinuation of lamivudine, emtricitabine, or tenofovir, and with the development of lamivudine or emtricitabine resistance.49-52 Cases of reactivation of HBV replication postinitiation of HAART and in individuals undergoing immunosuppressive therapy, such as cancer chemotherapy, have been reported.11,53-55 The presence of anti-HBs and anti-HBc without other markers for HBV may be considered "latent" infection, with the potential for reactivation with immunosuppression.7
Preventing hepatitis B by vaccination is essential in HIV-infected patients. The seroresponse to standard doses of HBV vaccine in HIV-infected patients is lower than in HIV-uninfected patients, with lower rates of anti-HBs response seen in individuals with detectable HIV RNA and positive anti-HCV.56-60 Lower CD4 counts have not consistently predicted lower response rates.56,59,61-63 Regarding clinical outcomes, receipt of at least 1 dose of vaccine has been shown to reduce the incidence of acute hepatitis B by 40%.8 Lack of HAART at the time of vaccination and anti-HCV positivity have been shown to be associated with hepatitis B infection after vaccination.64 Standard dosing schedules are recommended.65,66 All patients should have anti-HBs testing after completion of the vaccine series, and for patients who do not respond to the standard 3 doses, a repeated course of vaccine administration is recommended.67 Given the seroresponse rate to vaccination may be as low as 17.5% to standard vaccine dosing schedules,56,61-63,68,69 some authors have recommended using other dosing schedules with either higher doses or greater frequency, in an attempt to increase response rates.9 Data, however, are very limited regarding the efficacy of these various approaches. Yearly monitoring of anti-HBs in coinfected patients, given the risk for acute infection with waning protective anti-HBs, has been advocated.57 The efficacy of prescribing booster doses of vaccine to those with waning anti-HBs levels less than 10 IU/L is unknown. A study of breakthrough infections in vaccinated individuals with waning antibody titers in HIV-infected subjects is ongoing (Landrum, in the TACC). Lastly, given the risk for fulminant hepatitis A in HBV-infected individuals, hepatitis A virus vaccination should be administered to all patients infected with HIV and all patients with chronic hepatitis B.13
Current guidelines advise screening patients for HCC at 6-month intervals using ultrasonography and measurement of alpha-fetoprotein levels. Patients with end-stage HBV-related liver disease should be considered for liver transplantation if their CD4 cell counts are greater than 100 to 200 cells/μL, no prior opportunistic infections, and undetectable HIV RNA levels on HAART.9
Future research needs in the field of HIV/HBV coinfection include the impact of HIV-induced changes in immunologic response with and without HAART on the pathogenesis and natural history of chronic hepatitis B, the impact of HAART with dually active drugs on chronic HBV and cirrhosis, the role of occult HBV infection on liver injury, if any, and the role of nonalcoholic liver diseases on the course of chronic hepatitis B.11
HEPATITIS C AND HIV COINFECTION
Like hepatitis B, infection with HCV among HIV-infected individuals is common due to shared modes of transmission. In the United States and Europe, an estimated 15% to 30% of all individuals infected with HIV are also infected with HCV.9,70-73 Risk of coinfection varies markedly based on HIV exposure category, with 70% to 88% prevalence among patients with a history of injection drug use compared with 2% to 14% among individuals who acquired HIV through sexual contact.70,72,73 Because of the high prevalence of coinfection, screening for HCV infection is recommended for those infected with HIV.74 Third-generation assays, which have sensitivities of 99%, are preferred over previous generation tests, which are less sensitive.73,75-77 Hepatitis C virus RNA testing is recommended following a positive anti-HCV enzyme immunoassay (EIA) to document chronic infection, or in individuals with a high suspicion of HCV infection with negative anti-HCV, especially those with possible acute HCV infection during the seroconversion window, or those with advanced acquired immunodeficiency syndrome (AIDS).73
The impact of HIV on the natural history of HCV has been well documented. Studies have found a more rapid rate of progression to cirrhosis, increased rates of hepatic decompensation, and hepatocellular carcinoma occurring at a younger age with a more aggressive course in coinfected versus HCV-monoinfected patients.78-86 In contrast, the effect of HCV on HIV disease progression remains controversial.72,87-92 In a European cohort of more than 3000 subjects, of whom 37% were HCV seropositive, the adjusted hazard ratio for an AIDS-defining event or death was 1.70 (95% confidence interval [CI], 1.26-2.30).72 On the other hand, in an urban US cohort of 1955 patients, of whom 45% were coinfected, no association between HCV serostatus and HIV disease progression or immunologic response to HAART was found.92 More recently, one study found that HCV serostatus did not alter HIV disease progression in the pre-HAART era but did increase the risk of progression to AIDS in the HAART era (hazard ratio (HR) 1.77; 95% CI, 1.15-2.73).90 The reasons for the different findings are not entirely clear, but potential factors contributing to the varied results include reduced exposure to HAART in coinfected subjects,90 different study populations,87,92 and confounding by unaccounted for variables, such as an unrecognized parenterally transmitted infection in injection drug use,72 geographic variation in HCV genotype,93 and variation in host immune response genes.94
The treatment of HCV in HIV-infected individuals, including doses of medications and duration of therapy, has been addressed by recent guidelines.73,95 Three recent randomized clinical trials have evaluated combination therapy with pegylated interferon and ribavirin in coinfected patients (Table 2).96-98 Combination therapy resulted in sustained virologic response rates (SVRs) of 27% to 40%, noticeably lower than response rates in HCV monoinfected patients.99
Consistent predictors for failure to achieve an SVR were lack of an early virologic response, HCV-genotype 1, and a pretreatment HCV viral load >800,000 IU/mL for those with genotype 1 infection.96-98 One trial included patients with CD4+ counts above 100 cells/μL and did not find CD4+ cell count to be a risk factor for treatment failure.98 Possible explanations for lower SVRs in HIV/HCV coinfected patients include HIV-induced immune suppression and dose reductions of anti-HCV medications due to increased rates of toxicity. In addition, in 2 of the trials, the daily dose of ribavirin was 800 mg;96,97 however, recent guidelines recommend higher doses of ribavirin for HIV/HCV genotype 1-coinfected patients, postulating that higher doses may be more effective.73 Treatment-related adverse events are common, and risk factors for hepatic decompensation in coinfected patients include concurrent didanosine use, cirrhosis, and increased bilirubin.100,101 Lastly, for coinfected patients who fail to respond or are not candidates for HCV therapy, screening for hepatocellular carcinoma is recommended at 6-month intervals with ultrasound and alpha-fetoprotein, similar to patients coinfected with HIV and hepatitis B.102
Less is known regarding the optimal approach to ART in HIV/HCV coinfected patients. The central issues complicating the administration of HAART to coinfected individuals are the potential reduced efficacy of HAART, increased rate of hepatotoxicity, and concern that HAART may actually worsen HCV-related hepatic damage. These topics have been addressed by a recent comprehensive review.103
The response to HAART in HIV/HCV coinfected patients has been evaluated by several studies. Most have found no impact on the HIV virologic response to HAART,72,87,91 but results have varied regarding the immunologic response.72,87,91,92,104,105 One study found that the mean increase in absolute CD4+ cell count was significantly lower in coinfected compared with HCV uninfected subjects after 48 weeks, 20 versus 75 cells/μL, respectively.104 However, another study found no difference in the immunologic response to HAART defined as either a ≥50% increase or a ≥50 CD4+ cells/μL increase, nor in the time to achieve a response.87 The explanation for the discordant results is not clear, but the nonstandardized end points and the different patient populations make direct comparisons between many of these studies difficult.
Hepatotoxicity associated with ARVs in HIV/HCV coinfected individuals has been evaluated by several studies, and most have found that coinfected subjects have higher rates of hepatotoxicity.106-110 Many investigations have evaluated the risk of hepatotoxicity with nonboosted protease inhibitors (PIs), but one recent study found that the relative risk of severe hepatotoxicity associated with lopinavir/ritonavir was not increased in coinfected patients, with an overall rate of 13%.109 Data regarding hepatotoxicity in coinfected patients taking atazanavir (ATV)- or amprenavir-containing HAART regimens have not yet been reported. Of the nonnucleoside reverse transcriptase inhibitors, risk of severe hepatotoxicity in coinfected individuals seems greater in those taking nevirapine (NVP) (15.6%) compared with efavirenz (EFV) (8.0%), and even greater with concurrent use of a PI (approximately 20% for either NVP or EFV).107 Similarly, in one report, stavudine use was associated with 5-fold higher risk of hepatic steatosis in coinfected patients.111 Lastly, recent evidence suggests an increased risk of fulminant hepatic failure in coinfected patients compared with HIV-positive/anti-HCV-negative patients in the HAART era, 3.28/1000 person-years versus 0.58/1000 person-years, respectively (adjusted hazard ratio (AHR) 5.62; 95% CI, 2.36-14.50).112
Mitigating the risk of HAART-associated hepatotoxicity is the impact of HAART on the rate of liver fibrosis and mortality. Risk factors for fibrosis progression in coinfected patients include heavy alcohol consumption, low CD4+ cell count, age 20 years or older at HCV infection, and absence of PI-based therapy.79 A longer interval between HCV infection and HAART initiation has been shown to be associated with fibrosis progression, arguing for earlier initiation of HAART in coinfected individuals.80 The protective effect of PI-based HAART has also been confirmed.113 Surprisingly, an accelerated fibrosis progression in HIV/HCV coinfected patients taking NVP has also been seen (adjusted odds ratio (AOR) 3.82; 95% CI, 1.9-7.6).113 Lastly, and most importantly, in a cohort of HIV/HCV-coinfected patients, HAART use was independently associated with reduced all-cause mortality and reduced liver-related mortality.114 Considering the information available, all HIV/HCV-coinfected patients should be considered for treatment with HAART. The specific regimen and timing of initiation, however, remain unclear.
Each of the 3 major ARV classes has been associated with hepatotoxicity, and more extensive reviews of this topic are available.115-119 Approximately 5% to 15% of patients receiving ART will experience elevations of liver enzymes, and consistent risk factors for more severe hepatotoxicity include coinfection with HBV or HCV and elevated baseline levels of ALT.106-111,120-122 With the exceptions of NVP122 and full-dose ritonavir,110,120,122 no consistent findings regarding specific drugs or drug classes and risk of hepatotoxicity have been described by large cohort investigations.121
The best-described mechanism associated with hepatotoxicity due to nucleoside reverse transcriptase inhibitors (NRTIs) is steatohepatitis and lactic acidosis due to inhibition of mitochondrial DNA polymerase γ.123 Of the NRTIs, stavudine and didanosine seem to have the highest risk.111,115,123,124 Additional risk factors include Caucasian ethnicity, obesity, and hyperglycemia.111 Clinical manifestations vary from asymptomatic hyperlactatemia, which may be seen in 10% or more of patients on NRTIs, to acute hepatitis with an anion gap metabolic acidosis with a high mortality rate.124,125 Because of the reduced specificity of serum lactate levels in predicting those at risk for severe steatohepatitis, some have advocated using a ratio of mitochondrial DNA to nuclear DNA, but this is currently not widely available.123 Treatment for those with asymptomatic, low-level hyperlactatemia remains unclear, whereas aggressive supportive care in conjunction with immediate discontinuation of the offending agent is needed for patients with severe steatohepatitis with lactic acidosis.
Two different mechanisms of toxicity are hypothesized to cause hepatic injury due to nonnucleoside reverse transcriptase inhibitors, drug hypersensitivity, and direct toxicity. Although the overall rate of hepatotoxicity associated with EFV or NVP is roughly equivalent to that of other ARVs,107,118 NVP-associated liver injury has been studied more extensively due to its unique association with fulminant hepatitis and death in both HIV-infected and uninfected patients, typically occurring during the first 12 weeks of therapy.126,127 Patient-risk groups for early, severe, symptomatic hepatotoxicity from NVP include women with CD4+ cell counts ≥250 cells/μL, men with CD4+ cell counts ≥400 cells/μL, body mass index <18.5 kg/m2, serum albumin level <3.5 g/dL, mean corpuscular volume >85 fL, and HIV-RNA load <20,000 copies/mL.127,128 Symptoms in those with early severe hepatotoxicity include rash, nausea, and fever.128 These features, along with eosinophilia, and an increased incidence in those with higher CD4+ counts support an immune-mediated hypersensitivity mechanism.128 As with severe NRTI-associated hepatotoxicity, treatment includes supportive care in conjunction with discontinuation of NVP.128 The safety of substituting EFV for NVP after the development of hepatotoxicity is not known.
There are 2 patterns of elevated hepatic enzymes associated with PI use: unconjugated hyperbilirubinemia seen with indinavir and ATV, and elevated liver enzymes from other PIs due to hepatotoxicity.119 Unconjugated hyperbilirubinemia due to indinavir or ATV results from inhibition of UDP-glucuronosyltransferase, is not associated with signs or symptoms of hepatocellular injury, and occurs in up to 40% of patients treated with either agent.119 Conversely, the mechanism of PI-associated hepatocellular injury is not known. As stated above, the best-described risk factors for PI-associated liver injury include coinfection with either HBV or HCV. Other reported risk factors include use of HAART in ARV-naive patients,122 injection drug use, and alcohol abuse.110 Although discontinuation of therapy is warranted for those with signs and/or symptoms of liver dysfunction, studies have shown that most asymptomatic liver enzyme elevations less than 10 times the upper limit of normal tend to improve despite continuing therapy.106,122
NONALCOHOLIC FATTY LIVER DISEASE AND HIV
Concomitant with increasing survival in HIV-infected patients are an increasing number of metabolic complications, including dyslipidemia, impaired glucose tolerance and insulin resistance, and body fat redistribution.128 Individuals with chronic HIV infection may be at increasing risk of NAFLD, given the rising incidence of concomitant metabolic disorders of obesity, diabetes, hyperlipidemia, coinfection with viral hepatitides, and possibly mitochondrial toxicity associated with some ARVs.129-131 Nonalcoholic fatty liver disease, which includes both simple steatosis and nonalcoholic steatohepatitis, is characterized by an alcoholic-like histology pattern on biopsy in nonalcoholic patients. Risk factors associated with NAFLD include obesity, insulin resistance, diabetes mellitus, hyperlipidemia, total parenteral nutrition, rapid weight loss, protein calorie malnutrition, drugs such as nucleoside analogues, calcium channel blockers, and glucocorticoids, among others and toxins such as organic solvents, viral hepatitis (HCV > HBV), and possibly HIV infection.130,132
Pre-HAART, fatty liver was found in more than 30% of liver histopathologic specimens of HIV-infected patients on autopsy.133 Many of these patients had NRTI exposure before death, but many also had other risk factors for NAFLD, including rapid unintentional weight loss and other metabolic abnormalities.130
Currently, in the era of HAART, whether HIV-positive individuals have a higher prevalence of NAFLD compared with the general population is still unknown. Many HIV-infected patients on HAART have risk factors associated with NAFLD, including lipodystrophy (LD), hypertriglyceridemia, insulin resistance, and obesity. Higher liver fat content, insulin resistance, and leptin concentrations have been found in HIV-positive individuals with LD as compared with HIV-positive individuals without LD and HIV-negative individuals.134 Antiretrovirals contribute to the metabolic syndrome with insulin resistance, hypertriglyceridemia, and central adiposity, and plausibly have common pathophysiologic mechanisms underlying NAFLD and ARV-associated fatty liver.135 Nucleoside reverse transcriptase inhibitor therapy may worsen insulin resistance by decreasing adiponectin levels.130,136 Adiponectin has been found to be inversely correlated with abdominal visceral fat mass, serum triglycerides, and insulin resistance in a sample of HIV-infected patients treated with HAART.136 In addition, derangements in lactate homeostasis lead to fatty acid accumulation in hepatocytes.137 The NRTIs, specifically stavudine, didanosine, and zidovudine, are the most often cited offending agents leading to hyperlactatemia.137 Protease inhibitor therapy has also been associated with glucose intolerance, dyslipidemia, and increased hepatic fat.130 Lastly, as mentioned above, steatosis was noted in 40% of HIV/HCV-coinfected patients with extensive ART exposure and was associated with more severe HCV-related liver disease.111 It is thought that steatosis may accelerate HCV disease progression, which may in turn accelerate hepatic fatty infiltration through increased drug-related hepatotoxicity.138 Hepatitis C virus infection has also been noted to increase the risk for the development of diabetes mellitus type 2. These complex interactions have led to the need for evaluating the efficacy of combined antiviral and "metabolic" approaches versus standard antiviral regimens in patients with steatosis and HCV chronic infection.138
Similar to many other forms of chronic liver disease, patients with NAFLD are often asymptomatic and are usually incidentally found on routine laboratory evaluation demonstrating elevated ALT levels.139,140 After exclusion of alcohol-related and viral hepatitis, NAFLD accounts for most cases of aminotransferase elevation.141 Individuals may present with nonspecific symptoms of fatigue, malaise, and right upper quadrant pain.142 Liver ultrasound, in most cases, often shows a hyperechogenic parenychma.140 Histologically, findings range from macrovesicular steatosis to more advanced forms of NAFLD involving necroinflammation, classified as nonalcoholic steatohepatitis, where steatosis is combined with inflammation, ballooning degeneration of hepatocytes, perisinusoidal fibrosis, and Mallory hyaline deposition.143
The management of fatty liver disease in HIV-infected patients depends on the individual clinical circumstances in which it occurs and the degree of inflammation and fibrosis seen on liver biopsy.130 Predictors of fibrosis include older age, obesity, and diabetes, and not liver enzyme elevation.144 Although absolute guidelines do not exist, general indications for liver biopsy include confirming or excluding the diagnosis of NAFLD and/or assessing the degree of necroinflammation, fibrosis, and extent of architectural alterations.144,145
In individuals with NAFLD and hyperlactatemia, discontinuation of all NRTIs may reverse the hyperlactatemia and transaminase elevations. Antiretroviral therapy that is NRTI-sparing or containing NRTIs such as lamivudine, abacavir, and tenofovir, thought to carry a lower risk for lactic acidosis, may be used in the future.136,146
General treatment guidelines for NAFLD, which are not evidence based, may be reasonably applied to HIV-infected individuals and include gradual weight loss in addition to improving underlying conditions such as diabetes and hyperlipidemia.130 Individuals with sustained viral suppression who are on PIs and have dyslipidemia, LD, or glucose intolerance may benefit from switch therapy to a non-PI-containing regimen147 or to ATV, a PI not associated with lipid elevations traditionally seen with other PIs.148 Switching patients from stavudine to tenofovir has also been demonstrated to improve lipid profiles.149 Small studies in HIV-negative subjects using insulin sensitizing agents or antihyperlipidemic medications point to possible improvements in liver histology or aminotransferases, but data in HIV-infected patients are lacking.144,150 Numerous pharmacologic agents, such as ursodeoxycholic acid, vitamin E, betaine, and N-acetylcysteine, have been studied in HIV-negative individuals but have not been studied in controlled trials in HIV-infected patients.130,140
Efforts to refine the complex interactions of multiple comorbidities, such as hepatotoxic drugs, viral hepatitis coinfection, alcohol use, and immunologic and genetic influences, are greatly needed to lead to a better understanding of NAFLD in HIV-infected patients. The research agenda for the future include establishing the role of insulin resistance and abnormal lipoprotein metabolism in NAFLD, determining the pathogenesis of cellular injury, defining predisposing genetic abnormalities, identifying noninvasive predictors of disease, and identifying effective therapy.144
Hepatitis in HIV-infected patients is a common occurrence which will only become more prevalent as patients continue to live longer on HAART. Although the common etiologies of this condition are discussed above, clinicians should also be aware of the many other potential causes, including many of the opportunistic infections and other drugs commonly used in caring for HIV-infected patients. Future research in this area should address questions now confronting clinicians, including the impact of HBV and HCV coinfection on HIV-related disease; the optimal approach to ART in coinfected patients to improve the response to ART, minimize side effects, and improve liver-related outcomes; and the improvement in prevention of HBV and HCV infection.
The authors thank Ms Waine MacAllister, EdM, for her editorial review of this manuscript.
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