[NATAP] HAART/HCV & Liver Enzyme Elevations

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Liver enzymes elevation after HAART in HIV-HCV co-infection

Journal of Viral Hepatitis

July 2005

L. Servin-Abad1, E. Molina2, G. Baracco3, L. Arosemena2, A. Regev2, L. Jeffers2,4 and E. Schiff2

1Internal Medicine Department, Memorial Hospital, Miami, FL; 2The Center of Liver Diseases, University of Miami, Miami, FL; 3Infectious Diseases Department, Department of Veteran's Affairs, Miami, FL; and 4Hepatology Department, Department of Veterans Affairs, University of Miami, Miami, FL, USA

…..The primary outcome was the development of hepatotoxicity in this population…. it is important to know that the HIV-HCV co-infected patients more prone to develop important hepatotoxicity, are the ones with a higher baseline AST, higher INR (international normalized ratio) and lower albumin. This population requires a closer follow up of their liver enzymes after they start HAART; and if they develop grade 4 LEE (liver enzyme elevations), it is advisable to stop therapy. Probably of more clinical importance is the fact that patients with an AST level <98.4 U/L (or below 2.09 times the ULN of AST) had a negative predictive value of 92% of developing a grades 3 + 4 LEE….

……Hepatotoxicity was defined biochemically or clinically… We found an incidence of 10.6% of severe hepatotoxicity (grades 3 + 4) or 4.0% per person-years. Other studies reported very similar incidences from 2.7 to 10.8% of grades 3 + 4 LEE (liver enzyme elevations), and from 4.2 to 6.3% of grade 4 LEE. If we include all patients who had an elevation 2.5 times or greater the ULN (grades 2 + 3 + 4 LEE) the incidence was 34.1%, showing that LEE after the initiation of HAART is a very common event….. Baseline variables associated with increased toxicity included high AST, low albumin and high INR. Our patients with severe hepatotoxicity had slightly higher ALT level than those without, but this difference did not achieve statistical significance….. We did not identify any clinical manifestations associated with these biochemical abnormalities, or even an increased number of opportunistic infections or deaths in the group with hepatotoxicity. None of the patients stopped HAART because of hepatotoxicity…..There was no relationship between the development of severe hepatotoxicty and the use of any of the different groups of antiretroviral medications (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors or protease inhibitors) or any individual drug (even including three patients treated with nevirapine in the group with severe hepatotoxicity and 10 in the other group; other individual analysis for other drugs did not show any statistical difference)…. the number of patients included in the analysis for individual HIV antiretroviral drugs was very small…

Note from Jules Levin: I have included in this report just after the Summary links to several key recently reported studies examining HAART, hepatoxocity, elevations in liver enzyme tests, and liver disease.

INTRODUCTION

The widespread use of high active antiretroviral therapy (HAART) has prolonged the survival of patients with human immunodeficiency virus (HIV) infection. As a consequence, these patients are more likely to develop chronic illnesses, such as coronary artery disease and chronic liver disease [1,2].

Hepatitis C virus (HCV) infection is a common cause of chronic liver disease in HIV-positive patients, with a reported prevalence between 30 and 100% [3-6].

The HIV infection potentiates the progression of HCV disease. This results in higher degrees of fibrosis, higher incidence of cirrhosis, liver failure and hepatocellular carcinoma in a shorter period of time [7-9]. It is characterized by higher levels of alanine aminotransferase (ALT) and, higher HCV load. Alcohol intake, hepatitis B virus (HBV) co-infection, male sex and severe immunosupression (<200 CD4/mL) [7,10-13] have also been correlated with an accelerated course of HCV disease.

The use of HAART in HIV/HCV co-infected patients has been associated with variable outcomes. Most studies show an early increase in the HCV load and transaminases in the first 3-4 months of therapy, with return to their baseline after the first year of treatment [14-18]. Other studies show an improvement in the HCV infection with undetectable HCV-RNA in 20% of the patients after the initiation of HAART [19,20]. On the contrary, there are also some reports of acute exacerbation of HCV-related liver disease after the initiation of antiretroviral therapy [21,22]. The liver of patients co-infected with HIV and HCV, can also be adversely affected by toxicity of some of the antiretroviral drugs. Nevirapine [23-26], protease inhibitors [22,26,27], and nucleoside analogues [23,28] (particularly stavudine) have produced hepatotoxicity in a small but significant proportion of patients. The objective of this study was to evaluate the frequency of severe hepatotoxicity in patients co-infected with HIV and HCV after the introduction of HAART, and to determine if there were any factors that could predict its development. We also evaluated the clinical significance of this toxicity.

Summary.

Hepatitis C virus (HCV) co-infection is common among human immunodeficiency virus (HIV) patients. The incidence and risk factors associated with hepatotoxicity in this population after high active antiretroviral therapy (HAART) is initiated are still not well-understood. We argued to evaluate the incidence and risk factors associated with liver enzyme elevation (LEE) and their clinical significance. A retrospective chart review of patients who started HAART and had follow up at our centre for at least 1 year was undertaken. The frequency and severity of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation after treatment initiation were investigated and searched for clinical manifestations.

Between January 1996 and March 2002, 85 HIV-HCV co-infected patients began HAART and continued follow up for at least 1 year. The incidence of severe toxicity [grades 3 + 4 LEE: >5 and >10 times the upper limit of normal (ULN) of ALT or AST] was calculated at 4% per person-years. There were no clinical manifestations of liver toxicity, and patients continued their treatment with a trend towards a decrease of their enzymes. No statistical differences in opportunistic infections or mortality were evident. The variables associated with severe hepatotoxicity were a higher baseline AST, higher international normalized ratio (INR) and lower albumin. A baseline AST < 2.1 ULN had a negative predictive value of 92% of leading to severe hepatotoxicity.

In HIV-HCV co-infected patients therefore, the group at a higher risk of developing higher transaminase elevations is the one with a higher baseline AST, higher INR and lower albumin.

LINKS TO RELATED STUDIES:

The effect of antiretroviral therapy on liver disease among adults with HIV and hepatitis C coinfection

(Hepatology 1/2005)

We found no evidence for the alternate hypothesis that ART causes chronic histological liver disease. Rather, we found the long-term liver enzyme pattern to be a much stronger predictor of eventual liver fibrosis….persons with long-term patterns of elevated liver enzymes (having more than 1 in every 3 ALT or AST measurements > 100 U/L) had a more than five-fold greater risk of bridging fibrosis or cirrhosis compared with those persons with lower liver enzyme levels….our data indicate that the range of HCV-related liver disease among HIV-infected persons treated with ART is broad, supporting recent recommendations that the management of hepatitis C in HIV-infected patients must be individualized….It is important to identify the HIV/HCV-coinfected patients who have significant liver disease….physicians caring for coinfected patients should not underestimate the significance of persistent ALT and/or AST elevations (note from Jules Levin: normal liver enzymes do not necessarily rule out advanced liver disease)….. we did find that greater effectiveness and longer duration of ART exposure were independently associated with decreased necroinflammatory activity (those with undetectable HIV RNA at the time of biopsy had significantly lower activity scores); too little is known about how HIV infection influences the pathogenesis of HCV-related liver disease to speculate on the basis for this finding….

http://www.natap.org/2005/HCV/010305_05.htm

Hepatotoxicity and Protease Inhibitors:

nelfinavir, Kaletra, IDV/r ….

The study authors found that the rates of severe hepatoxicity occurred in patients receiving nelfinavir regimen at 11%, Kaletra (LPV/rtv) 9%, IDV/RTV (200-400mg/day) 12.8%, SQV/RTV (400mg/day) 17.2%. The risk was significantly greater among persons with chronic viral hepatitis (63% of cases); however, the majority of hepatitis C virus (HCV)-infected patients treated with nelfinavir (84%), saquinavir/RTV (74%), indinavir, 86%, indinavir/RTV (90%) or lopinavir/RTV (87%) did not develop hepatotoxicity

www.natap.org/2004/HIV/030804_06.htm

www.natap.org/2004/HIV/120804_03.htm

Study Finds that Severity of Liver Damage May Predict Risk for Hepatotoxicity on HAART

www.natap.org/2005/HIV/020205_03.htm

This study found that the stage of liver disease found by liver biopsy may be the best predictor of whether a patient will experience hepatotoxicity (elevated ALT) on HAART…...Our study shows that the risk of hepatotoxicity for HIV- and HCV-coinfected patients undergoing treatment depends on the stage of liver fibrosis. Patients with mild or moderate liver fibrosis had an incidence of toxicity of 15%, and we observed a 3-fold increase in the risk of liver toxicity among those with advanced chronic liver disease or cirrhosis. Moreover, as discussed below, the incidence of toxicity was similar for all of the antiretroviral regimens, including NNRTIs or protease inhibitors, used by coinfected patients with mild or moderate fibrosis….But, for patients with later stage HCV disease (F3/F4), there was a higher rate of liver toxicity undergoing NNRTI-based therapy, compared with patients with stage F3 or F4 fibrosis who were not exposed to NNRTIs, (note from Jules Levin: if you look at the table below you can see this analysis is based on a small number of patients. note from Jules Levin: these study findings suggest it may be important to evaluate the stage of liver disease with a liver biopsy before starting HAART, because this study suggests the risk for hepatoxicity is greater when the patient has later stage HCV disease. If later stage HCV disease is identified by a liver biopsy, you may decide to treat the HCV before treating HIV. If you do decide to treat HIV first after finding later stage disease by a liver biopsy these study findings suggest it is important to monitor ALT/AST closely after starting HAART & to take note of any development of clinical symptoms of hepatoxicity such as fatigue, nausea, or malaise, jaundice or vomiting).

RESULTS

Between January 1996 and March 2002, 591 HIV-positive patients were treated at the Miami VAMC. A total of 188 (31.8%) of them had co-infection with HCV. From this group, 85 patients began HAART and continued follow up at this centre for at least 1 year. The mean follow up of these patients was 1037 days.

Of these 85 patients, 36.0% developed grade 1 LEE, 23.5% grade 2, 8.1% grade 3 and 2.5% grade 4. None of the patients developed clinical liver toxicity. The incidence of severe toxicity (grades 3 + 4) was calculated at 4% per person-years; or 10.6% of the population. The mean time to the onset of severe hepatotoxicity was 146 days.

There were no differences between the groups regarding age, gender, race, transmission risk factor, alcohol use and prior exposure to HBV.

The baseline CD4+ lymphocyte count, HIV viral load and ALT were not different between both groups. The increase of the CD4+ lymphocytes after 6 and 12 months of HAART did not show any statistical difference.

The variables that showed statistical difference in the univariate analysis were: aspartate aminotransferase (AST), albumin and international normalized ratio (INR). The baseline AST was higher in the group that developed severe toxicity (98.4 U/L in the group with grades 3 + 4 LEE, and 57.5 U/L in the group without it; P =0.0274), the albumin was lower (3.4 g/dL in grades 3 + 4, compared with 3.8 g/dL, P = 0.0134) and the INR was higher (1.3-1.1, P = 0.0466). The analysis of the patients that began HAART with an AST < 98.4 U/L (or below 2.09 times the ULN of AST) showed that the values below this number had a negative predictive value of 92% of developing grades 3 + 4 LEE.

The trend of AST after the patients started HAART can be seen in Fig. 1. After they developed LEE, the transaminases decreased again (but still elevated compared with the ULN and to the grades 0 + 1 + 2) and continued at this level without stopping the antiretroviral treatment.

There was no relationship between the development of severe hepatotoxicty and the use of any of the different groups of antiretroviral medications (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors or protease inhibitors) or any individual drug (even including three patients treated with nevirapine in the group with severe hepatotoxicity and 10 in the other group; other individual analysis for other drugs did not show any statistical difference). There was no difference in the incidence of opportunistic infections and mortality between both groups.

AUTHOR DISCUSSION

This is the first study carried out on an urban population, most of them African-Americans, which included only HIV-HCV co-infected patients. HCV has been suggested as a risk factor of LEE in HIV patients after initiating HAART [22,25,26,30,31]. Our goal was to find variables that would predict the development of hepatotoxicity in this specific population.

We found an incidence of 10.6% of severe hepatotoxicity (grades 3 + 4) or 4.0% per person-years. Other studies reported very similar incidences from 2.7 to 10.8% of grades 3 + 4 LEE [22,27], and from 4.2 to 6.3% of grade 4 LEE [26,31]. If we include all patients who had an elevation 2.5 times or greater the ULN (grades 2 + 3 + 4 LEE) the incidence was 34.1%, showing that LEE after the initiation of HAART is a very common event. Once this elevation had occurred, the trend was towards a decrease to the baseline, still remaining elevated almost always over the ULN (see Fig. 1).

Baseline variables associated with increased toxicity included high AST, low albumin and high INR. Our patients with severe hepatotoxicity had slightly higher ALT level than those without, but this difference did not achieve statistical significance. Other groups have reported high initial transaminases (mainly ALT) as predictive of LEE [22,26,31,32], but only the study by Puoti et al. [31] described a prolonged prothrombin time (PT) as a risk factor for severe hepatotoxicity (grade 4 LEE). Monga et al. [33] described increased mortality and liver-related morbidity in their group of patients co-infected with HIV-HCV compared with those only infected with HIV. High baseline ALT and low albumin predicted an adverse outcome in his series.

We did not identify any clinical manifestations associated with these biochemical abnormalities, or even an increased number of opportunistic infections or deaths in the group with hepatotoxicity. None of the patients stopped HAART because of hepatotoxicity. Bonfanti et al. [22] reported that 26.7% of all the patients with grades 3 + 4 LEE had to stop the treatment because of hepatotoxicity, but these studies included HCV-positive and -negative patients. However, in the study by Wit et al. [26] six of 35 patients with grade 4 LEE (17.1%) had symptoms compatible with acute hepatitis. Of these six patients, four had co-infection with HBV or HCV. The LEE resolved in all patients, regardless of whether they continued HAART or not. Recently, Puoti et al. [31] described 26 patients with grade 4 LEE, of which seven patients developed liver failure and died. The only variable that was significantly associated with a poor outcome in this study was a lower CD4. Liver biopsies were performed on most patients with grade 4 LEE. Chronic hepatitis was found, and there was no evidence of drug-induced hepatitis or opportunistic infections.

There are some details to take into consideration. First, the compliance of the patients with HAART. Both groups had a consistent increase in the CD4+ lymphocyte counts, but this was not accompanied by a decrease in HIV load. This can be explained by the fact that some subjects were not compliant with the treatment thus heading to an increase in the mean HIV load. Secondly, the effects of alcohol on the liver are well-known. The data in this study was obtained from the charts to yes/no questions and not in a quantitative manner. Thirdly, the number of patients included in the analysis for individual HIV antiretroviral drugs was very small. Future studies of this topic need to take these considerations into account and well-controlled in a prospective study.

In conclusion, it is important to know that the HIV-HCV co-infected patients more prone to develop important hepatotoxicity, are the ones with a higher baseline AST, higher INR and lower albumin. This population requires a closer follow up of their liver enzymes after they start HAART; and if they develop grade 4 LEE, it is advisable to stop therapy. Probably of more clinical importance is the fact that patients with an AST level <98.4 U/L (or below 2.09 times the ULN of AST) had a negative predictive value of 92% of developing a grades 3 + 4 LEE. We have to acknowledge the limitations of the retrospective nature of our study and the small number of cases involved. We believe that larger, prospective studies are warranted.

Study patients

We retrospectively reviewed the medical records of patients co-infected with HIV and HCV at the Veterans Affairs Medical Center (VAMC) in Miami, Florida, after Institutional Review Board (IRB) approval. We included patients who had started taking HAART between January 1996 and March 2002, and who were followed for at least 1 year whether they continued or stopped the antiretrovirals during this time. The patients had to be 18 years or older, HIV Western blot-positive, and HCV antibody or HCV-RNA-positive. HAART is defined as a 'high active antiretroviral therapy' that consists in the use of at least three drugs against the HIV. We excluded patients previously treated for HCV to avoid heterogeneity in the population studied. We do not know if the HCV treatment decreases the possibility of getting an adverse drug reaction. We also excluded from the analysis, deaths and opportunistic infections occurring within 2 months after the initiation of HAART because the immune recuperation after starting the antiretrovirals would take several weeks, and in this period the infections and deaths are probably not related to adverse reactions but most likely to the degree of immunodeficiency before starting the medications.

Characteristics of the study population

Age: 47

97% men

15-22% white; 55-68% black; 13-22% Hispanic

risk factor for transmission: 44-60% IDU; 'homosexual': 0-11%

alcohol: 75-100%

NNRTI use: 11-27%

PI use: 70-88%

CD4 before HAART: 23change in CD4 in first 6 months on HAART: +24 to +92

Change in CD4 in first 12 months on HAART: +13 to +116

HIV viral load before HAART: 55,000 to 10,000 copies/ml

ALR before HAART: 57-77 U/L

AST before HAART: 57-98 U/L

Albumin before HAART: 3.4 to 3.8 g/dL

INR before HAART: 1.1 to 1.3

Opportunistic infections; 8-11%

Mortality: 11-18%

Hepatitis B: 75-88% (hep B was defined as previous exposure to hep B virus being positive for hep B surface antigen, or hep B core antibody).

Outcome

The primary outcome was the development of hepatotoxicity in this population. Hepatotoxicity was defined biochemically or clinically. Biochemical hepatotoxicity was defined as per the AIDS Clinical Trial Group (ACTG) classification [29] of liver toxicity - grade 0 liver enzymes elevation (LEE): <1.25 times upper limit of normal (ULN), grade 1 LEE: 1.25-2.5 times ULN, grade 2 LEE: 2.6-5.0 times ULN, grade 3 LEE: 5.1-10.0 times ULN, grade 4 LEE: >10 times ULN. In addition, to avoid misclassification of patients in the different categories because of high baseline aminotransferase levels, for grade 4 there must have been at least an increase of >200 U/L and for grade 3 an increase of 100 U/L from baseline.

Clinical hepatotoxicity was defined by the development of decompensated liver disease, in the form of ascites, gastrointestinal bleeding from varices, encephalopathy and hepatorenal syndrome; or hepatocellular carcinoma. We defined severe hepatotoxicity as grades 3 + 4 LEE and/or the occurrence of clinical events.

Secondary outcomes measured were a response to HAART (change of CD4 and viral suppression), occurrence of opportunistic infections and death.

Study design and statistical analysis

The study was designed as a retrospective case-controlled study. A case was defined as a patient who developed severe hepatotoxicity, as defined above. We analysed the different variables with chi-square and Student's t-test to check if there was a statistically significant association between these variables and the development of hepatotoxicity. A P-value of <0.05 was considered to indicate statistical significance. All the studies were conducted using statistica Software (version 5.0) and excel 9.0.2812.

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