Coinfection

ICAAC 2012: Raltegravir Shows Long-term Safety and Efficacy for HIV/HCV and HIV/HBV Coinfection

The HIV integrase inhibitor raltegravir (Isentress) was well-tolerated and demonstrated continued effectiveness for 5 years in treatment-naive and 3 years in treatment-experienced HIV patients coinfected with hepatitis B or C, according to a poster presentation at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) last week in San Francisco.

It is estimated that about one-third of people with HIV are coinfected with hepatitis C virus (HCV), and perhaps one-tenth have chronic hepatitis B virus (HBV) infection. While many of these people can be successfully treated for both diseases, coinfection raises additional concerns related to poorer treatment response, more adverse events, and potential drug-drug interactions.

Jürgen Rockstroh from the University of Bonn and colleagues from Merck evaluated the safety and efficacy of raltegravir-based antiretroviral therapy among coinfected participants in the pivotal Phase 3 STARTMRK (HIV treatment-naive) and BENCHMRK 1 and 2 (treatment-experienced) trials.

Raltegravir is among the most well-tolerated antiretroviral agents in HIV monoinfected people, and its mechanism of action -- blocking integration of retroviral genetic material into a host cell's chromosomes -- suggests it is unlikely to significantly impact HCV or its treatment.

As previously reported, at the XIX International AIDS Conference (AIDS 2012) this past July, Rockstroh and colleagues presented data showing that raltegravir continued to demonstrate overall good safety and efficacy in these trials for 5 and 3 years, respectively. The present analysis focused on the HIV/HBV and HIV/HCV coinfected participants in the studies.

STARTMRK compared 400 mg twice-daily raltegravir versus 600 mg once-daily efavirenz, both combined with tenofovir/emtricitabine (the drugs in Truvada), in treatment-naive adults. BENCHMRK 1 and 2 compared 400 mg twice-daily raltegravir versus placebo, both added to optimized background therapy, in heavily pre-treated patients with extensive resistance to antiretroviral drugs.

Most participants were men and the average ages were 37 year in STARTMRK and 45 years in BENCHMRK. People with chronic hepatitis B or C could enroll in the trials if they did not have severe active hepatitis, indicated by ALT and AST levels more than 5 times the upper limit of normal.

A total of 743 participants in this combined analysisreceived raltegravir, while 519 received the comparator regimen (either efavirenz/tenofovir/emtricitabine or placebo/OBT).

Results

• 34 treatment-naive participants, or 6%, in STARTMRK had hepatitis coinfection:

o   HIV/HBV: 4%;

o   HIV/HCV: 2%;

o   HIV/HBV/HCV: 0.2%.

• 114 treatment-experienced participants, or 16%, in BENCHMRK had hepatitis coinfection:

o   HIV/HBV: 6%;

o   HIV/HCV: 9%;

o   HIV/HBV/HCV: 1%.

• Raltegravir was generally well-tolerated and effective in both treatment-naive and treatment-experienced coinfected patients.
• In STARTMRK, 90.9% of coinfected people and 89.1% of HIV monoinfected people taking raltegravir had HIV RNA < 50 copies at 240 weeks, compared with 91.7% and 80.0%, respectively, taking efavirenz.
• In BENCHMRK 1 and 2, 62.3% of coinfected people and 57.9% of monoinfected people receiving raltegravir had undetectable HIV RNA at 156 weeks, compared with just 14.7% and 26.3%, respectively, taking placebo.
• Across treatment arms, moderate-to-severe liver enzyme elevations were more common among patients with HBV and/or HCV coinfection than among those with HIV alone.
• Most serious (grade 3-4) liver enzyme changes occurred within the first 48 weeks of treatment, with minimal further increases.
• In STARTMRK, 5.6% of HIV/HBV or HIV/HCV coinfected patients and 4.6% of HIV monoinfected participants taking raltegravir discontinued therapy due to adverse events, compared with 0% and 7.9% in the efavirenz arm; 0%, 0.8%, 0%, and 0.4%, respectively, did so due to liver-related events.
• In BENCHMRK, 3.8% of coinfected and 4.7% of monoinfected participants taking raltegravir discontinued due to adverse events, compared with 2.7% and 6.0% in the placebo arm; 0%, 0.5%, 0%, and 0.4%, respectively, did so due to liver-related events.

"Raltegravir was efficacious and generally well tolerated" in patients with HIV and HBV or HCV coinfection, the investigators concluded. "The majority of grade 3 and grade 4 liver enzyme elevations occurred during the first year of treatment and were more common among coinfected patients than among HIV monoinfected patients, irrespective of treatment group."

9/20/12

Reference

J Rockstroh, P Sklar, J Zhao, et al. Safety and efficacy of raltegravir (RAL) over 3 years in patients co-infected with HIV and hepatitis B and/or C virus (HBV/HCV). 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco. September 9-12, 2012. Abstract H-885.