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Friday, July 27, 2012

Ongoing research on licensed ARVs presented at AIDS 2012


Two major HIV treatment guidelines now recommended antiretroviral therapy (ART) for all HIV-infected individuals, regardless of CD4+ T-cell counts [1,2]. In light of this change, it is more important than ever that patients and health care providers have a variety of ART treatment options that are safe, well tolerated, durably effective and convenient to use over many years. Maintaining virologic suppression in certain circumstances also requires patients experiencing difficulty with their current ART regimen to transition safely to a new regimen. At the recently concluded XIX IAC, new data established the safety and durability of several licensed antiretroviral agents (ARVs) to help meet the needs of the expanding group of individuals receiving long-term treatment.

Four posters presented 5 year follow-up data from phase 3 clinical trials of licensed antiretrovirals. These studies all had primary end-points reported several years ago [3-6]. Two posters reported on the safety and efficacy of the HIV integrase inhibitor raltegravir (RAL), currently considered a preferred treatment option in HIV treatment guidelines [1,2]. The STARTMRK trial compared RAL to efavirenz (EFV), both given with tenofovir DF and emtricitabine. The study design was unique in that blinding was continued through 5 years. Virologic suppression with RAL was non-inferior to EFV at all time points, including the primary and secondary end-points at 48 and 96 weeks [7]. At weeks 192 and 240, exploratory analyses showed a small, statistically significant 9% advantage in the proportion of subject remaining virologically suppressed to <50 copies/mL, favoring RAL. This difference should not be overinterpreted as it emerged years after the primary end-point and the treatment arms were statistically equivalent over most of the life of the study. CD4+ T-cell counts were modestly greater in the RAL arm throughout the trial, a phenomenon that has been seen in studies of most ARVs when the comparator is EFV. Lower rates of neuropsychiatric adverse events, rashes, and lipid elevations were seen with RAL early on and were sustained out to 240 weeks. In BENCHMRK 1 & 2, triple-class resistant, treatment-experienced patients failing virologically on their current regimen were randomized 2:1 to RAL or placebo, both given with an optimized background regimen. After completion of 156 weeks, all patients were offered open-label RAL. Throughout the study, the proportion of patients achieving virologic suppression at either the 50 or 400 copy/mL level remained greater in the group originally randomized to RAL, although that proportion dropped similarly over time in both arms [8]. Improvement in CD4+ T-cell counts also was greater with RAL, was sustained throughout the study and the difference between arms increased over time. Rates of clinical and laboratory adverse events were lower in the RAL arm, but there was no detailed breakdown of specific types of adverse events that might allow detection of a pattern unique to RAL. These two presentations support the long-term safety and efficacy of RAL as a component of combination ART.

Maraviroc (MVC) is the first and to date the only licensed ARV to work by blocking CCR5, a cell surface molecule that is both a co-receptor for HIV entry and a receptor for beta-chemokines. Because CCR5 is plays a role in host immunity, unique long-term safety concerns were raised by this class of agents. Specifically, altered immune responses could theoretically alter risk of infection, cancer or myocardial infarction. Hepatotoxicity was also a concern because of experience with a previous drug candidate in this ARV class. Five year follow-up from the MOTIVATE 1 & 2 and MERIT trials were presented [9,10]. MOTIVATE 1 & 2 included treatment-experienced patients failing current ART who were randomized to MVC or placebo, each given with an optimized background regimen. After completion of 48 weeks of blinded therapy, participants were eligible for open-label treatment with MVC. MERIT compared MVC to EFV, both given with zidoudine/lamivudine in treatment-naive subjects. This trial entered an open-label phase after 96 weeks of blinded therapy were completed. Both trials pre-screened participants for the presence of R5 (CCR5 co-receptor utilizing) HIV. During 2639 patient-years of follow-up in the MOTIVATE trials, exposure-adjusted rates of events per 100 patient-years were 0.2 for hepatic failure, 1.0 for MI/cardiac ischemia, 2.4 for malignancy and 4.7 for infections reported as serious adverse events [9]. While these numbers are not easy to put into context, they did not stand out clearly above rates reported in other large ART-treated cohorts. Rates of MI were noted to be higher than reported in some other large cohorts that included all types of patients, but were similar to those seen in cohorts of similar treatment-experienced/treatment failure patients. Findings from MERIT included similar rates of virologic suppression and modestly better CD4+ T-cell rises when MVC and EFV-treated patients were compared [10]. There were slightly more than 1200 patient-years of follow-up in each treatment arm. Rates of hepatic failure, MI, malignancy, and serious infections were very similar between treatment arms. These two analyses serve to reassure that there are no striking long-tern safety concerns with maraviroc.

The co-formulation of tenofovir DF, emtricitabine and rilpivirine is a single tablet ART regimen taken once daily. The SPIRIT study compared outcomes in 476 patients virologically suppressed on a regimen of 2 NRTIs plus a boosted PI-based who were randomized 2:1 to switch to the rilpivirine-based single tablet regimen or stay on their current ART [11]. At entry, 20% were taking darunavir, 33% lopinavir, 37% atazanavir and 81% were already using tenofovir DF/emtricitabine at baseline. At study week 24, 94% and 90% had HIV RNA <50 copies/mL (difference 3.8; 95% CI -1.6, 9.0) demonstrating the non-inferiority of switching. Only a single subject in the switch arm experienced virologic failure. Patients with prior NNRTI use or documentation of prior resistance to study drugs were excluded, but none of 17 patients with transmitted K103N who randomized to the rilpivirine-containing arm experienced failure, supporting in vitro evidence that this common EFV resistance mutation does confer resistance to rilpivirine. Lipids declined significantly from baseline in the switch arm and were essentially unchanged in those continuing a boosted PI. This study supports the safety of switching from PI-based ART to the rilpivirine-based single-tablet regimen, especially when patients are already taking and tolerating tenfovir and emtricitabine. The availability of baseline pre-ART genotypic resistance testing should be considered in the decision to switch, but it appears that the presence of the commonly transmitted NNRTI resistance mutation K103N does not preclude making the switch.

References:
1. Thompson MA, Aberg JA, Hoy JF, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel. JAMA 2012;308:387-402.
2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. 1–239. Available at http://aidsinfo.nih.gov/contentfiles/Ivguidelines/adultandadolescentgl.pdf
3. Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 2009; 374: 796–806.
4. Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med 2008; 359: 339–54.
5. Gulick RM, Lalezari J, Goodrich J, et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med 2008;359:1429­41.
6. Cooper DA, Heera J, Goodrich J, et al. Maraviroc versus efavirenz, both in combination with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection. J Infect Dis 2010;201:803-813.
7. Rockstroh J, DeJesus E, Saag M et al, Long-term safety and efficacy of raltegravir (RAL)-based versus efavirenz (EFV)-based combination therapy in treatment-naïve HIV-1-infected patients: final 5-year double-blind results from STARTMRK. Abstract LBPE19, XIX IAC, Washington DC, July 22-27,2012; http://pag.aids2012.org/abstracts.aspx?aid=21410
8. Eron J, Cooper D, Steigbigel R, et al. Final 5-Year Results of the BENCHMRK Studies: Sustained Antiretroviral Effect of Raltegravir, and Exploratory Analysis of Late Outcomes Based on Early Virologic Response. Abstract TUPE025, XIX IAC, Washington DC, July 22-27,2012; http://pag.aids2012.org/abstracts.aspx?aid=12576
9. Gulick R, Fatkenheuer G, Burnside R, et al. Five-year safety evaluation of maraviroc in HIV-1-infected, treatment-experienced patients. Abstract TUPE029, XIX IAC, Washington DC, July 22-27,2012; http://pag.aids2012.org/abstracts.aspx?aid=19743
10. Cooper DA, Heera J Ive P et al. Five-year efficacy and safety of maraviroc versus efavirenz, each in combination with zidovudine/lamivudine, in treatment-naive HIV‑1‑infected patients: open-label extension of the randomized, double-blind merit study. Abstract TUPE026, XIX IAC, Washington DC, July 22-27,2012; http://pag.aids2012.org/abstracts.aspx?aid=15477
11. Palella, F, Tebas P, Gazzard B et al. SPIRIT study: switching to emtricitabine/rilpivirine/tenofovir df (FTC/RPV/TDF) single-tablet regimen (STR) from a ritonavir-boosted protease inhibitor and two nucleoside reverse transcriptase inhibitors (NRTIS) maintains HIV suppression and improves serum lipids. Abstract TUAB0104, XIX IAC, Washington DC, July 22-27,2012; http://pag.aids2012.org/abstracts.aspx?aid=643


Source: Reporting for the PRN News: David H. Shepp, MD