Hepatotoxicity from first line antiretroviral therapy: an experience from a resource limited setting

Background

Highly active antiretroviral therapy (HAART) has been associated with liver toxicity. The role of monitoring for liver toxicity has not been well studied in resource-limited settings (RLS).

Objectives

To determine the background prevalence and incidence of liver injury and describe the associated signs and symptoms of acute hepatitis after initiating HAART; and to determine the role of liver enzyme tests in monitoring hepatotoxicity.

Methods

In this prospective study, in Mulago Hospital AIDS Clinics, we consecutively enrolled adult patients initiated on one of three first line HAART regimens [Stavudine (d4T)-Lamivudine (3TC) and nevirapine (NVP); Zidovudine (AZT)-3TC and Efavirenz (EFV) or d4T-3TC-EFV]. We monitored ALT (alanine aminotransferase) and clinical evidence of acute hepatitis at baseline, 2^nd, 6^th, 10^th and 14^th week of therapy.

Results

Two hundred and forty HIV-positive HAART- naïve patients were enrolled in the study. The baseline prevalence of transaminitis was 1.7% with an incidence of 4.2% at 14 weeks. Grade 3–4 hepatotoxicity was documented in 1.3%. Jaundice was seen in grade 2–4 ALT elevations. Being on concurrent HAART and antituberculous drugs was associated with grade 2–4 toxicity compared to those who were only on HAART [OR; 16.0 (95% CI; 2.4–104.2)].

Conclusions

Incidence of severe hepatotoxicity within three months of first-line antiretroviral therapy was low, suggesting that routine measurement of transaminases may not be necessary in all patients initiating HAART in RLS. Routine measurement may be important in following patients on HAART and concurrent TB treatment as well as those with jaundice to avoid missing hepatotoxicity.     

Hepatotoxicity development during antiretroviral therapy containing protease inhibitors in patients with HIV: the role of hepatitis B and C virus infection.

To evaluate the occurrence of hepatotoxicity in patients during antiretroviral therapy (ART) that contains protease inhibitors and the role of hepatitis viruses in its development, we performed a retrospective study including 1325 HIV-infected patients treated with ART for at least 6 months. Presence or absence of hepatitis viruses, alanine aminotransferase (ALT), total bilirubin, CD4 cell count, and plasma HIV RNA levels were evaluated. Hepatotoxicity developed in a few study subjects without coinfection, whereas it was significantly higher in coinfected patients. Univariate logistic regression analysis showed that viral hepatitis coinfections are independent risk factors for hepatotoxicity. After 6 months of treatment, ritonavir was associated with higher rates of severe hepatotoxicity in the coinfected group; in fact, ritonavir seems to be the most strongly hepatotoxic agent among coinfected patients. After 12 months of therapy, hepatotoxicity occurred more frequently in patients with hepatitis C virus who did not respond to antiretroviral therapy (ART), whereas patients who did respond to ART showed decreased ALT levels. Hepatotoxicity is not exclusively an effect of drug toxicity, and the presence of hepatitis coinfection is an independent risk factor. Moreover, chronic hepatotoxicity mainly occurs in patients who did not respond to therapy. Conversely, patients who did respond to ART seemed to show improvement of chronic liver infection.     

Autoimmune hepatitis in a patient infected by HIV-1 and under highly active antiretroviral treatment:Case report and literature review

Liver disease has recently been described as an important cause of morbidity and mortality in patients infected with human immunodeficiency virus(HIV). Liver test changes are useful surrogates of the burden of liver disease. Previous studies have shown that transaminase elevations are frequent among these patients. The cause of those changes is harder to establish in HIV-patients. We present a 61-year-old caucasian male,diagnosed with HIV type 1 infection since 1998,under highly active antiretroviral treatment(HAART),with virological suppression and immunological recovery. He presented in a follow-up laboratory workup high values of transaminases,arthralgia at the hip joints and hepatomegaly. Liver function tests were normal. The antibodies to hepatitis viruses were negative. However,autoimmune study and liver biopsy were compatible with autoimmune hepatitis(AIH). The AIH is a rare di-agnosis in HIV-infected patients perhaps because the elevation of transaminases and changes in liver function tests are often associated to HAART or to other possible liver diseases,namely viral hepatitis and non-alcoholic steatohepatitis. The diagnosis may be underestimated. There are no specific recommendations available for the treatment of HIV-associated AIH although the immunosupression with slower tapering seems the most reasonable approach.     

Pretreatment of chronic active hepatitis C in patients coinfected with HIV and hepatitis C virus reduces the hepatotoxicity associated with subsequent antiretroviral therapy

Chronic hepatitis C virus (HCV) is an independent risk factor for antiretroviral-related hepatotoxicity, but little is known about the frequency of severe liver toxicity in patients with HIV-HCV coinfection first treated for HCV (pretreated). The aim of this prospective study of 105 patients was to compare the incidence of progression to severe antiretroviral-related liver toxicity in 66 patients pretreated (36 with interferon-alpha [IFNalpha], 30 with IFNalpha plus ribavirin), and 39 patients not pretreated. The subjects could choose whether to receive anti-HCV therapy. Severe liver toxicity was defined as alanine aminotransferase (ALT) level > or =5-times the upper limit of normal in patients with normal baseline levels and > or =3.5-times in those with increased baseline levels. The authors also estimated the hepatotoxicity-related risk of discontinuing antiretroviral therapy. During antiretroviral therapy, 10 subjects (9.5%) experienced severe hepatotoxicity: 4 of 66 pretreated patients and 6 of 39 untreated patients (24-month survival: 94% +/- 2.9% vs. 85% +/- 5.8%). After adjusting for baseline CD4 cell counts, ALT levels, histologic scores, HCV and HIV viremia, HCV genotype (genotype 1 in 29% of pretreated patients and 20% of patients not pretreated), and previous anti-HCV therapy, the risk of discontinuing anti-HIV treatment was significantly higher in the anti-HCV untreated patients (RR = 10.4; 95% CI: 1.6-66; p =.0127) and in those with increased baseline ALT levels (RR = 1.014; 95% CI: 1.006-1.021; p =.0005). The authors' data suggest that previous treatment of chronic active HCV is an independent factor associated with a decrease of severe liver toxicity as the result of a subsequent antiretroviral regimen. The authors also confirm that the baseline level of ALT is an important prognostic factor for increased liver damage during antiretroviral therapy.     

Toxicité des antirétroviraux chez les patients co-infectés par les virus VIH et VHC

The introduction of HAART (Highly Active Antiretroviral Therapy) has deeply modified the epidemiologic data on HIV infection. Consequently, chronic hepatotoxicities, particularly those related to HCV, became a leading cause of morbidity and mortality amongst co-infected HIV-HCV patients. They became a major factor to be considered before starting and conducting a HAART regimen. Due to the epidemiology of these two infections and referring to several huge randomised prospective clinical trials recently reported, understanding the antiretroviral toxicity is a true challenge in the follow-up of co-infected patients. It includes: i) understanding the intrinsec toxicities of each antiretroviral class, particularly drugs-related hepatotoxicities; then ii) the incidences of those treatments in co-infected patients, with or without anti-HCV bitherapy; and iii) the pathogenic reciprocal interactions between HIV and HCV and between anti-HIV and anti-HCV treatments. Four mechanisms of drug-related liver toxicity have been recognized: i) direct drug toxicity; ii) immune reconstitution; iii) hypersensitivity reactions with liver involvement; and iv) mitochondrial toxicity. The benefit-risk ratio notion must be strongly evaluated and the therapeutic strategy must include, for each patient, a strict monitoring of biochemichal (liver parameters, hemogram, amylasemia, lipasemia, evaluation of liver fibrosis index) and clinical (weight, lipodystrophy) parameters. A better pharmacological knowledge, a global view and the development of new drugs with less hepatotoxicity, like fusion inhibitors, would increase the quality of life of co-infected patients. Liver transplantation could be a hope for patients with severe hepatic failure.     

Management of chronic viral hepatitis in HIV-infected patients: Spanish Consensus Conference. October 2000

Co-infection by human immunodeficiency virus and hepatitis B and C viruses is quite common because they share similar routes of transmission. The introduction of highly active antiretroviral therapy has significantly improved the life expectancy of HIV-infected patients in the last few years. However, chronic viral hepatitis represents an emerging cause of morbidity and mortality in this population, either as a result of end-stage liver disease or as a consequence of hepatotoxicity induced by antiretroviral drugs. The main goal of the Consensus Conference was to establish specific recommendations for the management of chronic viral hepatitis B and C in HIV-infected patients. The role of orthotopic liver transplantation for co-infected individuals with end-stage liver disease was also assessed.     

Clinical experiences with interferon as monotherapy or in combination with ribavirin in patients co-infected with HIV and HCV

Human immunodeficiency virus (HIV) co-infection accelerates progression of hepatitis C virus (HCV) toward cirrhosis. Thus, with the increase of life expectancy observed after introduction of combination antiretroviral treatment, liver disease is becoming an increasing cause of morbidity and mortality in HIV-infected patients. In addition, HCV co-infection blunts CD4 restoration induced by HAART and increases HAART hepatotoxicity. For all these reasons, anti-HCV treatment is mandatory in HIV seropositives. The perfect treatment of hepatitis C should not only be safe and effective, but it should not have any adverse impact on HIV diseases and concurrent anti-HIV therapy. Two drugs are currently licensed for treatment of HCV: interferon alfa (IFNalpha) and ribavirin. Three hundred and thirty-eight patients have been included in pilot studies on the efficacy and tolerability of IFNalpha monotherapy: 16% showed sustained response and 10% dropped out. No significant adverse impact of IFNalpha monotherapy on HIV diseases or antiretroviral treatment has been observed. IFNalpha and ribavirin in combination have been introduced more recently: only 88 patients were included in pilot studies published as full papers with a 25% sustained response and an 11% rate of drop outs. Anemia and cumulative toxicity with didanosine were the most important side effects of combination treatment, but it did not affect HIV disease progression. Higher rates of sustained response (33%) without increase of side effects have been observed in preliminary experiences with the new long-acting pegylated interferons in combination with ribavirin. The search for the perfect treatment continues.     

Long-term survival and interruption of HAART in HIV-related pulmonary hypertension

Reported here is a case of a patient with pulmonary arterial hypertension related to HIV (PAHRH) in which lipodystrophy necessitated interruption of highly active antiretroviral therapy (HAART) and long-term survival was the outcome. Although previous studies have suggested antiretroviral therapy may benefit patients with this rare complication of HIV infection, no worsening of PAHRH was observed when HAART was interrupted. Clinical and echocardiographic parameters remained stable during 7 months of follow up. In cases in which HAART is associated with relevant toxicity, interruption of HAART in patients with PAHRH can be considered, but should be used only if no alternatives are available. Close follow-up is warranted.     

Antiretroviral-associated toxicity among HIV-1-seropositive pregnant women in Mozambique receiving nevirapine-based regimens

OBJECTIVE: To assess toxicities associated with highly active antiretroviral therapy (HAART) among HIV-1-infected pregnant women treated with nevirapine-based regimens according to Mozambican national guidelines. STUDY DESIGN: Prospective cohort study. METHODS: HIV-1-infected antiretroviral-naive pregnant women with CD4 counts < or =350 cells/microL were initiated on nevirapine, lamivudine, and stavudine or zidovudine and followed monthly. Severe hepatotoxicity was defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels > or =5-fold the upper limit of normal. Analyses were stratified by baseline CD4 count (<250 vs. 250-350 cells/microL). RESULTS: Among 146 pregnant women, 75 (52%) began nevirapine, lamivudine, and zidovudine and 71 (48%) began nevirapine, lamivudine, and stavudine. Overall, 79 (54%) women had CD4 counts <250 cells/microL, 7 (5%) had grade II hepatotoxicity, and 4 (3%) had severe (grade III or IV) hepatotoxicity. All 4 women with severe hepatotoxicity had baseline CD4 counts > or =250 cells/microL (P = 0.02). Rates of skin toxicity, anemia, and peripheral neuropathy did not differ by CD4 cell count group. Overall, 12 (8%) women changed or discontinued HAART as a result of drug toxicity. CONCLUSIONS: Severe hepatotoxicity from nevirapine-containing HAART in this cohort of pregnant women was more common at higher CD4 counts (6% vs. 0% among women with CD4 counts > or =250 cells/microL and CD4 counts <250 cells/microL, respectively), suggesting that laboratory monitoring is necessary when administering nevirapine-containing regimens to pregnant women with CD4 counts > or =250 cells/microL.     

HIV and hepatobiliary disease

Liver disease is an increasingly important cause of morbidity and mortality in patients with HIV/AIDS. With the availability of highly active anti-retroviral therapy (HAART), there has been a change in the pattern of liver disease seen. Although opportunistic infections and neoplasms are still seen, co-infection with hepatitis viruses, especially HCV, is now emerging as the most significant cause of liver disease in this group of patients. In addition, drug-induced liver damage is becoming more prevalent due to the increased complexity and toxicity of the HAART regimens used.     

Clinical Experiences with Interferon As Monotherapy or in Combination with Ribavirin in Patients Co-Infected with HIV and HCV

Abstract

Human immunodeficiency virus (HIV) co-infection accelerates progression of hepatitis C virus (HCV) toward cirrhosis. Thus, with the increase of life expectancy observed after introduction of combination antiretroviral treatment, liver disease is becoming an increasing cause of morbidity and mortality in HIV-infected patients. In addition, HCV co-infection blunts CD4 restoration induced by HAART and increases HAART hepatotoxicity. For all these reasons, anti-HCV treatment is mandatory in HIV seropositives. The perfect treatment of hepatitis C should not only be safe and effective, but it should not have any adverse impact on HIV diseases and concurrent anti-HIV therapy. Two drugs are currently licensed for treatment of HCV: interferon alfa (IFNα) and ribavirin. Three hundred and thirty-eight patients have been included in pilot studies on the efficacy and tolerability of IFNα monotherapy: 16% showed sustained response and 10% dropped out. No significant adverse impact of IFNα monotherapy on HIV diseases or antiretroviral treatment has been observed. IFNα and ribavirin in combination have been introduced more recently: only 88 patients were included in pilot studies published as full papers with a 25% sustained response and an 11% rate of drop outs. Anemia and cumulative toxicity with didanosine were the most important side effects of combination treatment, but it did not affect HIV disease progression. Higher rates of sustained response (33%) without increase of side effects have been observed in preliminary experiences with the new long-acting pegylated interferons in combination with ribavirin. The search for the perfect treatment continues.     

Hepatitis C in HIV-infected patients—therapeutic approach

The use of highly active antiretroviral therapy (HAART) has extended the lifespan of patients infected with human immunodeficiency virus (HIV). As the prognosis of HIV infection has improved, liver disease associated with hepatitis C virus (HCV) has become clinically significant in patients with HIV, liver failure being a frequent cause of death in this population. HIV infection may accelerate the course of liver disease in patients co-infected with HCV, so infection with HCV should be treated like any other opportunistic disease in these patients. Nowadays, combination therapy with interferon-alpha and ribavirin is the standard treatment for chronic hepatitis C in HIV-negative patients. Preliminary results of combination therapy in HIV/HCV co-infected patients have been promising, showing a sustained response rate in 40% of these patients. Patients with higher CD4 counts and lower HCV/HIV viral load and those infected with HCV genotype 3a have a better response to therapy. Potential drug interactions between HAART therapy and interferon and ribavirin treatment emphasize the importance of initiating treatment of HCV infection in HIV-positive individuals as soon as possible and ideally before the need for anti-HIV therapy. Recent case reports have suggested that liver transplantation might be an appropriate procedure in HIV patients with undetectable HIV viral load, high CD4 counts and HCV advanced liver disease. However, the limited amount of available information and the complexities of drug interactions between HAART therapy and immunosuppressive drugs oblige us to be prudent within considering such a procedure.     

Timing of antiretroviral therapy initiation in tuberculosis patients with AIDS: a decision analysis

In HIV-infected tuberculosis patients with <200 CD4 lymphocytes/mm, highly active antiretroviral therapy (HAART) improves survival but can be complicated by immune reconstitution inflammatory syndrome (IRIS) and drug toxicity. We conducted a decision analysis in hypothetical cohorts of 1000 patients in which HAART was initiated during the first 2 months of tuberculosis therapy (early) or during months 2 through 6 of tuberculosis therapy (deferred) or was withheld until after tuberculosis therapy (no HAART). Outcomes assessed were 1-year mortality and the combined outcome of 1-year mortality, new AIDS-defining illness, severe IRIS, and severe drug toxicity. There were 33, 48, and 147 deaths and 497, 501, and 501 combined outcome events in the early HAART, deferred HAART, and no-HAART groups, respectively; most events were drug toxicity in the early and deferred groups and HIV-related mortality or AIDS-defining illness in the no-HAART group. In a 2-way sensitivity analysis of mortality, early HAART was favored, even with the highest reported rates of IRIS (70%) and severe drug toxicity (56%). Deferred HAART was favored over early HAART only if the IRIS-related mortality rate in the early group exceeded 4.6%. These results support early initiation of HAART in patients with AIDS, except when IRIS-related mortality rates are high.     

Role of hepatitis C virus genotype in the development of severe transaminase elevation after the introduction of antiretroviral therapy

OBJECTIVE: To assess the role of different hepatitis C virus (HCV) genotypes in the development of transaminase elevation after treatment with highly active antiretroviral therapy (HAART). DESIGN: Retrospective cohort study at one referral HIV outpatient clinic. METHODS: HCV genotype was determined in plasma samples from all consecutive HCV-HIV coinfected patients initiating HAART between March 1998 and January 2000. Clinical and laboratory data were recorded during the following 9 months. Severe transaminase elevation was defined as > or = fivefold increase over upper normal limits (AIDS Clinical Trials Group grades 3 or 4) when baseline alanine transaminase (ALT) and aspartate transaminase (AST) values were normal, and as > or = 3.5-fold increase above baseline ALT and AST values if they were abnormal. RESULTS: Twelve of 70 subjects (17%) developed severe transaminase elevation. Their HCV genotypes were distributed as follows: type 1, 5/39 (13%); type 2, 0/3 (0%); type 3, 7/21 (33%); and type 4, 0/7 (0%). The incidence of severe transaminase elevation was significantly higher among subjects with HCV genotype 3 (HCV-3) compared with those with non-type 3 (OR, 4.4 [95%CI, 1.2-16.1]; P =.02). In the multivariate analysis, HCV-3 remained associated with severe transaminase elevation when adjusted for baseline HCV viral load and degree of immune recovery seen during follow-up evaluation. CONCLUSIONS: HCV-3 is an independent risk factor for developing severe transaminase elevation after HAART. HCV genotyping before initiating antiretroviral therapy may be useful for assessing the risk of hepatotoxicity and for choosing the most appropriate drugs to prescribe for HIV-HCV coinfected patients. Given that the best response to interferon plus ribavirin occurs in patients with HCV-3, treatment should be specially encouraged in coinfected persons carrying HCV-3.     

Challenges in the treatment of HIV and HCV coinfection

HIV and hepatitis C virus (HCV) infections are pandemic illnesses that represent serious global public health problems. It is estimated that there are currently 38 million people infected with HIV and 60–180 million people infected with HCV worldwide. Owing to similar transmission pathways, HIV/HCV coinfection occurs frequently and, indeed, affects approximately a third of all European and North American HIV patients. With the successful introduction of highly active antiretroviral therapy (HAART) for the treatment of HIV in 1996, the morbidity and mortality owing to HIV declined drastically. As the prognosis of HIV infection has improved, liver disease caused by chronic infection with HCV has become increasingly important for mortality and morbidity among HIV/HCV-coinfected patients. Coinfection leads to accelerated progression of liver fibrosis and development of cirrhosis, as well as earlier emergence of hepatocellular carcinomas. Pegylated interferon and ribavirin combination therapy of HCV in coinfected patients showed reasonable sustained virological responses in randomized clinical trials, ranging from 27 to 44%, which, however, is substantially lower than in HCV monoinfected patients. Furthermore, cohort analyses have shown that HAART-induced immune reconstitution can improve the natural course of hepatitis C significantly and delay fibrosis progression. As pharmacokinetic drug–drug interactions and higher rates of hepatotoxicity following HAART initiation must be considered in HIV/HCV coinfection, specific treatment and management guidelines have been developed to optimize care in this clinically challenging group of patients.     

Mortality due to Liver Failure and Impact on Survival of Hepatitis Virus Infections in HIV-Infected Patients Receiving Potent Antiretroviral Therapy

The aim of the present study was to examine the causes of death, the mortality attributable to liver failure, and the impact of hepatitis virus infections on the survival of a cohort of HIV-infected patients before and after the extensive use of highly active antiretroviral therapy (HAART). Liver disease associated with hepatitis C virus (HCV) seems to be accelerated in patients infected with the human immunodeficiency virus (HIV). On the other hand, the effect of HCV on HIV progression was controversial before the introduction of HAART. However, the last study to report changes in mortality due to liver failure was published in 1997, and the impact of HCV carriage on the survival of HIV-infected patients receiving HAART needs to be clarified. In this investigation, 492 patients who were prescribed antiretroviral drugs between April 1989 and September 2000 were included in the study cohort. The median duration of follow-up of the cohort was 1,392 days. HCV infection was present in 323 (68%). Mortality attributable to AIDS decreased from 4.5 to 1.8 per 100 persons per year. Mortality due to liver failure increased from 0.3 to 0.5 per 100 persons per year (P<0.01). The survival of patients with and without HCV infection was similar (P=0.8). Although liver failure is an increasing cause of death among HIV-infected patients receiving HAART, HCV infection has still no impact on the survival of HIV-infected patients. Electronic Publication