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Darunavir/Ritonavir plus Raltegravir May Not Adequately Suppress High Viral Load

People with high baseline HIV viral load who used a NRTI-sparing regimen of ritonavir-boosted darunavir (Prezista) plus raltegravir (Isentress) had a higher than expected rate of virological failure and emergence of drug resistance mutations, according to research reported in the August 19, 2011, advance online edition of AIDS.

Highly active antiretroviral therapy (HAART) consisting of 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) plus either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor is the mainstay of modern HIV treatment.

But NRTIs -- especially older drugs in this class -- can cause adverse side effects ranging from fat wasting and bone loss to liver, kidney, and possibly heart problems. Researchers have therefore explored NRTI-sparing regimens, a strategy that became more viable with the advent of new drug classes including integrase inhibitors.

Babafemi Taiwo, Joseph Eron, and fellow investigators with the ACTG A5262 study evaluated the safety and efficacy of darunavir/ritonavir plus raltegravir, with no NRTIs, for HIV patients starting treatment for the first time.

This non-randomized, single-arm, open-label Phase 2b study included 112 antiretroviral-naive patients at 22 U.S. centers. Most (88%) were men, the median age was 36 years, 44% were white, and the median CD4 cell count was 271 cells/mm³.

The median HIV viral load was about 75,000 copies/mL, but 44% were classified as having high viral load > 100,000 copies/mL; 5% in this group had HIV RNA levels > 750,000 copies/mL.

Patients with more than 1 darunavir resistance-associated mutation or known major integrase resistance mutations were excluded, but 19% had pre-treatment resistance to some antiretroviral drugs.

All participants received 800/100 mg darunavir/ritonavir once-daily plus 400 mg raltegravir twice-daily. The primary endpoint was virological failure by week 24, defined as confirmed viral load of at least 1000  copies/mL at week 12, at least a 0.5 log increase from week 4 to week 12, or > 50 copies/mL at or after week 24.

Results

• 87% of participants completed 52 weeks of follow-up, while 13% discontinued early, almost always for reasons not related to treatment safety or efficacy (e.g., inability to get to the clinic, withdrawal of consent).
• In an intent-to-treat analysis, 74% of treated participants had undetectable HIV RNA at week 24, falling to 61% by week 48.
• The virological failure rate was 16% by week 24, rising to 26% by week 48.
• About 60% of failing patients had viral loads between 50 and 200 copies/mL at the time of virological failure.
• Patients with virological failure had significantly higher baseline viral load, on average, than those who maintained undetectable viral load (median of about 160,000 vs about 50,000 copies/mL, respectively; P=0.002).
• 75% of patients who experienced virological failure had baseline viral load > 100,000 copies/mL, and this subset also had more rapid virological failure.
• After adjusting for sex and age, virological failure was significantly associated with baseline viral load > 100,000 copies/mL, with a hazard ratio (HR) of 3.76, or nearly 4-fold higher risk (P = 0.004).
• Lower CD4 cell count was also an independent predictor of virological failure (HR 0.77 per additional 100 cells/mm³; P = 0.037).
• Conversely, people with baseline viral load > 100,000 copies/mL had smaller CD4 cell gains, on average (180 vs 233 cells/mm³, respectively, at week 48; P=0.044).
• High viral load continued to be a predictor of virological failure after taking into account trough (lowest between doses) raltegravir blood concentrations, but having no measurable raltegravir was associated with increased risk of failure (HR  3.42; P = 0.006).
• About 20% of participants experienced severe (grade 3) clinical side effects or laboratory abnormalities, but only 1 discontinued early for this reason.
• 5 participants with virological failure (out of 25 successfully tested) developed integrase resistance mutations, all of whom had baseline viral load > 100,000 copies/mL; none developed protease resistance mutations.
• In some cases integrase resistance emerged even when on-treatment viral load was quite low (< 200 copies/mL).

Based on these findings, the study authors concluded that while darunavir/ritonavir plus raltegravir was "effective and well tolerated" in most patients, "virological failure and integrase resistance were common," particularly in people with baseline viral load > 100,000 copies/mL.

The NRTI-free regimen met the protocol definition of "acceptable virologic efficacy" at week 24, even though only 71% of patients had viral load < 50 copies/mL at week 48, they elaborated in their discussion.

"The mechanisms underlying the poorer virologic outcomes in some patients with high baseline viral load, as observed in this study, are uncertain," the authors continued. "One possibility is that high baseline viral load may be associated with more extensive reservoir of infected cells and prolonged viral decay time...Another possibility is that high baseline viral load may predispose to greater diversity of HIV-1 quasispecies and an increased opportunity to select drug resistant mutants."

"[T]he results of A5262 raise important issues that should be examined carefully in future clinical trials evaluating darunavir/ritonavir plus raltegravir and perhaps in all [N]RTI-sparing two-drug regimen trials," they recommended. "We urge caution in patients with baseline viral load > 100,000 copies/mL and emphasize a need to further elucidate the implications of low-level viremia in patients receiving the regimen."

Investigator affiliations: Division of Infectious Diseases, Northwestern University, Chicago, IL; Statistical Data Analysis Center, Harvard School of Public Health, Boston, MA; Section of Retroviral Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA; Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, CO; Division of Clinical Pharmacology, Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL; ACTG Operations Center, Social & Scientific Systems, Inc., Silver Spring, MD; Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; Division of Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC.

9/6/11

Reference

Taiwo, L Zheng, S Gallien, J Eron, et al (ACTG A5262 Team). Efficacyof a Nucleoside-sparing Regimen of Darunavir/Ritonavir Plus Raltegravir in Treatment-Naive HIV-1-infected Patients (ACTG A5262). AIDS (abstract). August 19, 2011 (Epub ahead of print).