New risk factors for severe liver toxicity identified in largest ever clinical trial-based analysis

The largest ever clinical trial-based analysis of predictors of serious liver toxicity in HIV-positive individuals starting antiretroviral therapy (ART) has identified some newly defined risk factors, including the hepatotoxic (liver damaging) potential of concomitantly administered medications; renal (kidney) insufficiency; and thrombocytopoenia (low platelet count).

The study, published in the November 1^st issue of the Journal of Acquired Immune Deficiency Syndromes also found an 8.7% incidence rate after one year on ART; confirmed that both ddI and nevirapine may carry higher risks for serious liver toxicity; and highlighted the importance of baseline screening for, and routine follow-up of, individuals with pre-existing risk factors.

As the numbers of individuals receiving ART increases worldwide, providing major health benefits for those who are able to access it, the importance of monitoring ART's associated risks should not be overlooked. One of the most important and prevalent complications of ART is drug-induced hepatotoxicity.

Past studies have found an overall incidence rates of ART-related severe hepatotoxicity that ranges between 8.5% to 23%, and a clinical trial-based analysis of almost 3000 individuals published in JAIDS in 2003, found that serious life-threatening liver events among patients on ART occur at a rate of 2.6 per 100 person-years.

In order to better understand predictors of severe hepatotoxicity, United States investigators from Massachusetts General Hospital and Harvard Medical School in Boston, and the University of Maryland School of Medicine in Baltimore, undertook a retrospective analysis of 16 AIDS Clinical Trials Group (ACTG) studies, comprising 8851 individuals – the largest HIV cohort studied to date.

The 8,851 individuals in the ACTG database enrolled in one of 16 clinical trials between October 1989 and June 1999. These studies included investigations into mono- or dual therapy comprising a one of two nucleoside reverse transcriptase inhibitors (NRTIs) - including AZT (zidovudine, Retrovir), ddI (didanosine, Videx), ddC (zalcitabine, Hivid), d4T (stavudine, Zerit), and 3TC (lamivudine, Epivir). Other studies comprised triple ART, based on two NRTI(s) and a non-nucleoside reverse transcriptase inhibitor (NNRTI), either nevirapine or delavirdine; or two NRTIs and a single, unboosted, protease inhibitor, indinavir (Crixivan).

Because this analysis included single and dual NRTI regimens, this, notes the investigators “allowed for the evaluation of antiretrovirals when they are used singly and in pairs to [their] isolate hepatotoxic effects”.

The cohort mainly comprised men – although 1260 (14.2%) were women – with a median age of just under 36 years. Two thirds of the cohort (65%) were Caucasian, one-in-five (19.7%) were African American, and just under one-in-eight (13%) were Hispanic.

Risk factors

Abnormal baseline laboratory values were defined as follows: creatinine greater than 1.5 times ULN; glucose greater than 55 mg/dL; AST and ALT greater than 2.5 times ULN; total bilirubin at any measurement above the ULN; and platelets below 75,000/_L. The investigators looked for the short-term (the first six months on ART) risk factors as well as the longer-term (the second six months on ART) risk factors associated with serious liver toxicity.

Among the 1958 individuals on NRTI monotherapy, abnormal baseline ALT was significantly associated with both short-term (OR 1.61; 95% CI: 1.1-2.3), and longer-term (OR 1.86, 95% CI: 1.2-2.8) risk.

Short-term risk factors included:

• abnormal baseline AST (Odds Ratio 2.64; 95% CI: 1.9-3.7)
• or total bilirubin (OR 2.55, 95% CI: 1.4-4.6).
• or ddI-containing single NRTI regimens (OR 1.62, 95% CI: 1.1-2.4).

A baseline WBC count <3900/mm³ (OR 0.65, 95% CI: 0.45-0.95) was associated with a reduced risk of serious liver toxicity within the first six months on ART.

Among the 2,464 individuals on multiple NRTI therapy, short-term risk factors included:

• abnormal baseline AST (OR 2.38; 95% CI: 1.8-3.1)
• or abnormal baseline creatinine (OR 3.81; 95% CI: 1.8-8.2)
• or low platelets at baseline(OR 2.43; 95% CI: 1.3-4.5).

Longer-term risk factors included:

• abnormal baseline ALT (OR 2.08; 95% CI: 1.5-2.9)
• or use of concomitant hepatotoxic medications (OR 1.44; 95% CI: 1.0-2.0)

A history of Mycobacterium avium intracellulare (MAI) infection (OR 0.21; 95% CI: 0.05-0.86) and the use of 3TC (OR 0.37; 95% CI: 0.20-0.68) was associated with a reduced risk of serious liver toxicity within the first six months on ART.

Among the 872 individuals on NNRTI-containing regimens, short-term risk factors included:

• abnormal baseline AST (OR 2.63; 95% CI: 1.7-4.1).

Longer-term risk factors included:

• nevirapine-containing regimens (OR 3.54; 95% CI: 1.2-11.0)
• or abnormal baseline ALT (OR 2.58; 95% CI: 1.4-4.9).

Among the 774 individuals on indinavir-containing regimens, short-term risk factors included:

• d4T-containing ART (OR 1.94; 95% CI: 1.1-3.3)
• or abnormal baseline AST (OR 2.64, 95% CI: 1.8-4.0)
• or abnormal baseline total bilirubin (OR 4.27, 95% CI: 2.4-7.6). Longer-term risk factors included:
• use of concomitant hepatotoxic medications (OR 4.20; 95% CI: 1.3-13.4)
• injecting drug use (OR 4.22; 95% CI: 1.5-11.9)
• or abnormal baseline total bilirubin (OR 4.1; 95% CI: 1.3-12.6).

Incidence

Just under ten percent of the cohort (824; 9.3%) developed serious hepatotoxicity during the twelve months of the study ART regimen: this developed in 613 (6.92%) during the first six months, and 211 (2.38%) during the following six months. The investigators defined serious hepatotoxicity as AST (aspartate aminotransferase) or ALT (alanine aminotransferase) greater than five times the upper limit of normal (ULN), or total bilirubin greater than 2.5 times the ULN.

After excluding the 56 individuals on invinavir-based regimens who developed hyperbilirubinaemia alone, the incidence of serious hepatotoxicity during the first twelve months or ART was 8.7%. In addition, out of total of 1,137 deaths (12.8% of the cohort), 79 (0.9%) were found to be liver-related.

Potential liver-damaging drugs

The investigators note that medications with potential hepatotoxicity included:

• antifungals (fluconazole)
• antibiotics (e.g., cotrimoxazole, erythromycin, co-amoxiclav, dapsone,)
• anti-TB drugs (e.g., ethambutol, isoniazid, pyrazinamide, rifampin, rifabutin, clofazimine)
• and anticonvulsants (e.g., phenytoin, carbamazepine).

“The association between [potential hepatotoxic drugs and severe liver toxicity] underscores the importance of a comprehensive survey of all medications to identify agents that may predispose patients to hepatotoxicity, especially among individuals with other risk factors [for severe liver toxicity],” they write.

Kidney function and low platelet counts

The investigators not that their analysis also revealed risk factors for severe hepatotoxicity that has not previously been reported in the literature: creatinine greater than 1.5 times ULN, and platelets <75,000 cells/mm³.

“Elevated baseline creatinine may be associated with decreased clearance of some hepatotoxic agents [and] decreased renal clearance may itself be a marker of chronic liver disease,” they note. “In addition, thrombocytopoenia may be a surrogate for chronic liver disease with portal hypertension.”

Conclusions

The investigators concede that their analysis “included combinations that are currently less commonly used in the developed world,” but note that due to the “availability of generics and combination antiretroviral formulations…they are commonly prescribed in resource-limited environments.”

They suggest that their study “confirms the importance of evaluating HIV-infected patients for their risk of developing [severe liver toxicity] during the first year of ART.”

The investigators recommend that “pre-ART screening should include baseline liver function testing and assessment of hepatitis coinfection status, particularly HCV.”

They note that since, ddI and nevirapine “may carry higher risks” for liver toxicity “alternative regimens should be considered in some cases.”

They add that the newly defined risk factors of potentially liver-toxic concomitantly administered medications, renal insufficiency, and low platelet count, should also be factored into treatment monitoring. “Although further study is necessary to confirm these findings,” they argue, “the presence of these risk factors in patients initiating ART should prompt more vigilant monitoring for ART-related hepatotoxicity.”

“A practical application of these findings,” they conclude, is that in resource-limited settings, individuals with all of the above pre-existing risk factors for severe hepatotoxicity should “undergo routine liver test monitoring.”

Hepatitis B and C

Baseline hepatitis B virus (HBV) and hepatitis C virus (HCV) status was not available for the cohort. However, the investigators undertook a case-control study to assess whether hepatitis status was associated with a risk of severe hepatotoxicity during the first year of ART.

Among the 132 case-control pairs analysed, 30% of cases versus 14% of controls had evidence of active HCV infection (OR 2.7; p<0.003). This suggests, write the investigators, “that HCV coinfection was associated with a statistically significant increased risk of [severe hepatotoxicity] among ACTG participants during the first year.”

However, just 11% of cases versus 8% of controls were found to be HBV surface antigen-positive (OR 1.44; p=0.40). The investigators note, however, that “the incidence of active HBV was low in this population; as a result, the case-control study was not adequately powered for HBV. Therefore, the existence of a smaller but nonetheless important association with HBV, as has been cited in other studies cannot be excluded.”