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NRTI-sparing Atazanavir + Raltegravir: Conflicting Data for Naive and Experienced HIV Patients

A NRTI-sparing antiretroviral regimen of unboosted atazanavir (Reyataz) plus raltegravir (Isentress) suppresses HIV in treatment-naive patients as well as standard 3-drug combinations, but its twice-daily dosing, side effects, and low barrier to resistance limit its appeal. For treatment-experienced people already doing well on atazanavir triple therapy, however, the dual regimen may be an attractive simplification option.

According to the latest U.S. antiretroviral treatment guidelines, preferred first-line regimens consist of a NNRTI, a ritonavir-boosted protease inhibitor, or the integrase inhibitor raltegravir, all combined with 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). NRTIs and ritonavir can cause multiple drug toxicities, however, prompting researchers to explore alternative regimens.

SPARTAN

In the May-June 2012 issue of HIV Clinical Trials, Michael KozalfromYale University School of Medicine and colleagues presented findings from the SPARTAN trial, a multicenter pilot study testing a twice-daily dual regimen of unboosted atazanavir plus raltegravir, with no NRTIs.

A total of 94 previously untreated participants were randomly assigned (2:1) to receive 300 mg twice-daily atazanavir plus 400 mg twice-daily raltegravir, or else a standard reference regimen of 300/100 mg once-daily atazanavir/ritonavir plus 300/200 mg once-daily tenofovir/emtricitabine (Truvada).

Results

• After 24 weeks of treatment, 74.6% of patients in the atazanavir/raltegravir arm had confirmed virological response (HIV RNA < 50 copies/mL), compared with 63.3% in the reference arm (not powered for statistical comparison of efficacy).
• Participants in the atazanavir/raltegravir arm had a more rapid initial response, with the reference group catching up with longer treatment.
• Atazanavir concentrations in the twice-daily atazanavir/raltegravir arm were higher than historically observed levels in people taking boosted atazanavir with tenofovir/emtricitabine.
• Consistent with these higher levels, grade 4 hyperbilirubinemia (bilirubin elevation) was more common in the atazanavir/raltegravir arm than in the reference arm (20.6% vs 0%).
• 6 of 63 patients in the atazanavir/raltegravir arm met the criteria for resistance testing (virological failure with HIV RNA > 400 copies/mL) compared with just 1 in the reference arm.
• 4 patients who experienced virological failure on atazanavir/raltegravir developed raltegravir resistance mutations.

Based on these findings, the researchers concluded, "Atazanavir + raltegravir, an experimental NRTI- and ritonavir-sparing regimen, achieved virologic suppression rates comparable to current standards of care for treatment-naive patients."

However, they continued, "[t]he overall profile did not appear optimal for further clinical development given its development of resistance to raltegravir and higher rates of hyperbilirubinemia with twice-daily atazanavir compared with atazanavir/ritonavir."

Australian Study

In a related study described in the June 1, 2012, Journal of Acquired Immune Deficiency Syndromes, Dianne Carey from the University of New South Wales and colleagues looked at drug concentrations in treatment-experienced people receiving boosted or unboosted atazanavir and different doses of raltegravir.

This open-label crossover study included 25 HIV positive men who were taking atazanavir and had suppressed viral load (< 50 copies/mL) at study entry. Participants were white, the mean age was 45 years, and they had been on antiretroviral therapy for a median of 4 years. Most (84%) were receiving boosted atazanavir at baseline, and none had previously taken raltegravir.

Participants were randomly assigned to take either 300 mg twice-daily atazanavir plus 400 mg twice-daily raltegravir for 4 weeks, followed by 300/100 mg once-daily atazanavir/ritonavir plus 800 mg once-daily raltegravir for another 4 weeks, or else the same 2 combinations in the reverse order.

Researchers performed extensive pharmacokinetic assessments at the end of each 4-week period, measuring atazanavir and raltegravir plasma levels. A subset of patients also had drug concentrations measured in their cerebrospinal fluid and semen. Participants then had the option to continue a study regimen with follow-up visits at weeks 24 and 48 to assess long-term safety and efficacy.

Results

• Both atazanavir and raltegravir exhibited considerable pharmacokinetic variability.
• Atazanavir trough or minimum concentrations were lower with twice-daily dosing than with once-daily boosted dosing.
• Raltegravir trough concentrations, in contrast, were lower with once-daily dosing than with twice-daily dosing.
• The median raltegravir concentration in cerebrospinal fluid averaged 6% of plasma concentrations -- lower than expected, suggesting the drug does not easily cross the blood-brain barrier; atazanavir concentrations were "extremely low."
• Raltegravir semen concentrations were variable but high overall, about 3-fold higher than plasma concentrations; atazanavir had "extremely limited" semen penetration with concentrations about 1% of those in plasma.
• Among the 76% of participants who elected to continued follow-up, there were no serious adverse events or discontinuations due to adverse events over 48 weeks.
• HIV RNA levels remained undetectable and CD4 T-cell counts remained stable.

"In virologically suppressed adults, regimens comprising atazanavir plus raltegravir were efficacious and safe," the study authors concluded. "Atazanavir [every 12 hours] troughs were lower than ritonavir-boosted atazanavir [every 24 hours]; raltegravir [every 24 hours] troughs were lower than [every 12 hours]."

Unlike SPARTAN, rates of grade 4 hyperbilirubinemia "were low and not different between strategies," they noted in their discussion. "The absence of discontinuations and low incidence of adverse events contrasts with findings in treatment-naive individuals" and probably reflects the inclusion criteria of an unchanged atazanavir-containing regimen for at least 24 weeks, "a surrogate for proven safety and tolerability."

"Our findings suggest that raltegravir plus atazanavir regimens may have the potential for use in induction-maintenance therapy and in individuals with ART-related toxicities, especially dyslipidemia, or where nucleoside-sparing regimens are required," they wrote.

Taken together, these studies suggest that while once-daily raltegravir and once-daily unboosted ritonavir is not an optimal combination for people starting treatment for the first time, it may be an effective and well-tolerated simplification strategy for people who are already doing well on atazanavir.

6/19/12

References

MJ Kozal, S Lupo, E DeJesus, et al. A Nucleoside- and Ritonavir-Sparing Regimen Containing Atazanavir Plus Raltegravir in Antiretroviral Treatment-Naive HIV-Infected Patients: SPARTAN Study Results. HIV Clinical Trials 13(3):119-130. May-June 2012.

D Carey, SL Pett, M Bloch, et al. A Randomized Study of Pharmacokinetics, Efficacy, and Safety of 2 Raltegravir Plus Atazanavir Strategies in ART-Treated Adults. Journal of Acquired Immune Deficiency Syndromes 60(2):143-149. June 1, 2012.