Boosted Atazanavir (Reyataz) and Etravirine (Intelence) Are Safe and Well-tolerated in Patients with Hepatitis B or C Coinfection

Antiretroviral therapy (ART) may cause liver toxicity, indicated by elevated liver enzymes, and studies have shown that this is more likely to occur in HIV positive individuals with hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection. Two studies presented at the recent 9th International Congress on Drug Therapy in HIV Infection in Glasgow, Scotland, looked at the safety of 2 newer antiretroviral drugs in patients with hepatitis B or C.


J. Absalon and colleagues analyzed data from the subgroup of hepatitis B and C patients in the CASTLE trial, which compared ritonavir-boosted atazanavir (Reyataz) versus lopinavir/ritonavir (Kaletra), both in combination with tenofovir/emtricitabine (the drugs in the Truvada coformulation pill) in treatment-naive patients.

As previously reported, among the 883 patients in the study population as a whole, similar proportions taking atazanavir/ritonavir and lopinavir/ritonavir achieved HIV viral load < 50 copies/mL at 48 weeks (78% vs 76%, respectively) and at 96 weeks (74% vs 68%, respectively), though atazanavir/ritonavir had a more favourable side effect profile overall. At 48 weeks, the mean CD4 count increases were 203 cells/mm3 in the atazanavir/ritonavir arm and 219 cells/mm3 in the lopinavir/ritonavir arm.

5% of CASTLE participants were coinfected with HBV and 8% were coinfected with HCV. 9% of women, 14% of men, 25% of Asians, 15% of blacks, 13% of whites, and 5% of other racial/ethnic groups had either hepatitis B or C. A total of 61 patients in the atazanavir/ritonavir arm and 51 in the lopinavir/ritonavir arm had HBV or HCV.

Within this coinfected group, 69% in the atazanavir/ritonavir arm and 73% in the lopinavir/ritonavir arm achieved HIV RNA < 50 copies/mL in a non-completer = failure analysis at week 48.

Mean CD4 cell increases were 196 cells/mm3 and 228 cells/mm3, respectively. This compared favorably to immunological responses in HIV monoinfected patients, failing to confirm previous research suggesting that HIV-HCV coinfected patients experience poorer CD4 recovery after starting ART.

Grade 2-4 hyperbilirubinemia (15% vs 0%) and jaundice (3% vs 0%) were more common in the atazanavir/ritonavir arm than in the lopinavir/ritonavir arm, while nausea (2% vs 8%) and diarrhea (0% vs 14%) were more common in the lopinavir/ritonavir arm.

Few serious adverse events were reported among hepatitis B or C patients in either treatment arm. Grade 3-4 elevations in alanine aminotransferase (ALT) occurred in 8% of patients in the atazanavir/ritonavir arm and 6% in the lopinavir/ritonavir. Serious aspartate aminotransferase (AST) elevations occurred in 8% and 0%, respectively, while serious total bilirubin elevations occurred in 38% and 0%, respectively.

Based on these findings, the researchers concluded, "Virologic and immunologic responses were comparable in patients chronically infected with HBV or HCV infection treated with atazanavir/ritonavir or lopinavir/ritonavir. Virologic and immunologic responses were also similar in hepatitis coinfected and hepatitis uninfected patients in both the atazanavir/ritonavir and lopinavir/ritonavir treatment arms."

"Atazanavir/ritonavir had a more favorable lipid profile and fewer [gastrointestinal] adverse events among hepatitis coinfected patients than lopinavir/ritonavir," they continued. "Lipid profiles were similar in hepatitis coinfected and hepatitis uninfected patients."

"Although the overall rates of elevated transaminases in hepatitis coinfected patients were low in this study compared with those observed in other clinical trials, a small number of patients receiving atazanavir/ritonavir and none receiving lopinavir/ritonavir had grade 3 to 4 AST elevations," they noted. "The cause of this higher proportion in the atazanavir/ritonavir treatment arm among this limited number of patients is unclear."

Finally, they advised, "With monitoring of liver function tests, atazanavir/ritonavir can be considered as part of HAART among ART-naive patients with chronic HBV or HCV infection."

Bristol-Myers Squibb Company, Wallingford, CT and Lawrenceville, NJ.


B. Clotet and colleagues reported 48-week safety and efficacy data for hepatitis B or C coinfected patients in the DUET-1 and DUET-2 trials, which compared the next-generation NNRTI etravirine (Intelence) versus placebo in combination with a background regimen that included ritonavir-boosted darunavir (Prezista) in 1203 treatment-experienced patients.

As previously reported, among the study population as a whole, 60%-61% of patients taking etravirine achieved HIV RNA < 50 copies/mL, compared with 39%-41% of those taking placebo.

At baseline, HBV and/or HCV status was known for 1129 study participants in the 2 DUET trials combined. A total of 139 patients (12.3%) were coinfected with either HBV or HCV, but the sample size was too small to analyze the HBV and HCV groups separately.

Among the coinfected patients, grade 3 or 4 adverse events, serious adverse events, and deaths were less frequent in the etravirine arm compared with the placebo arm. Grade 3 or 4 ALT or AST elevations were more common among coinfected patients receiving etravirine, but the differences between the etravirine and placebo groups was small. The incidence of grade 3 or 4 liver-related adverse events was similar in both treatment arms.

The incidence of rash, which was higher in the etravirine arm compared with the placebo arm overall, occurred with similar frequency in coinfected and HIV monoinfected patients in each arm. The incidence of nervous system and psychiatric adverse events was lower in patients receiving etravirine compared with placebo regardless of hepatitis coinfection status.

In general, the investigators concluded, "the incidence and severity of adverse events with etravirine was similar to placebo, irrespective of co-infection status."

"The incidence of hepatic adverse events and grade 3 or 4 AST/ALT elevations was higher in coinfected patients than in non-coinfected patients in both treatment groups, consistent with the underlying chronic hepatitis condition," they added. "Etravirine did not increase hepatic toxicity in patients with hepatitis co-infection and was generally well tolerated in all patients."

Hospital Universitari Germans Trias i Pujol and IrsiCaixa Foundation, Barcelona, Spain; Département des Maladies Infectieuses et Tropicales, Hôpital Pitié-Salpêtrière, Paris, France; San Raffaele University, Milan, Italy; Tibotec BVBA, Mechelen, Belgium; Tibotec Inc., Pennsylvania.



J Absalon, G Thal, A Thiry, and others. Atazanavir is safe and efficacious in HBV and HCV co-infected patients: results of AI424138 (CASTLE). 9th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland. November 9-13, 2008. Journal of the International AIDS Society 11(Suppl 1): P136. November 10, 2008.

B Clotet, C Katlama, A Lazzarin, and others. Safety and tolerability of etravirine (ETR; TMC125) in hepatitis B and/or C co-infected patients in DUET-1 and DUET-2: pooled 48-week results. 9th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland. November 9-13, 2008. Journal of the International AIDS Society 11(Suppl 1): P272. November 10, 2008.