HIV Meds Quarterly

Summer 2009

Research Briefs

	Regimen Simplification: Atazanavir vs Atazanavir/Ritonavir
	Atazanavir/Ritonavir in Pregnancy
	Investigational Integrase Inhibitor Shows Potent Activity in Early Studies

Reference Table

	Updates to the Database of ARV Drug Interactions

Fast Takes

Raltegravir approved for initial therapy In July, the U.S. Food and Drug Administration approved raltegravir for use as initial therapy in the treatment of HIV infection. The FDA had previously approved raltegravir for treatment of patients with ARV-resistant strains of HIV. The new indication is based on a randomized double-blind noninferiority study of raltegravir vs efavirenz, each given in combination with tenofovir + emtricitabine in treatment-naive adults. At 48 weeks, similar rates of virologic suppression to <50 copies/mL were seen in the two treatment groups: 86% in raltegravir recipients and 82% in efavirenz recipients. CD4 increases also were similar: 189 cells/µL and 163 cells/µL, respectively. The recommended dosage of raltegravir is 400 mg orally BID. Treatment guidelines of the U.S. Department of Health and Human Services (most recently updated in November 2008) do not recommend raltegravir for use in initial therapy. more on raltegravir References 1. Lennox J, 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 Jul 31. [Epub ahead of print]

Regimen Simplification: Atazanavir vs Atazanavir/Ritonavir

The ARIES study evaluated induction-maintenance strategy in which ARV-naive patients were treated with atazanavir/ritonavir (ATV/r) + abacavir/lamivudine for 36 weeks. Patients whose HIV RNA was <50 copies/mL (n = 419) at that time were randomized to discontinue ritonavir (with dosage adjustment of ATV to 400 mg once daily) or to continue the ritonavir booster. The two groups were well matched for baseline HIV RNA and CD4 levels.

At 48 weeks into the maintenance phase, HIV RNA remained <50 copies/mL in 86% of ATV recipients vs 81% of ATV/r recipients; this difference was not statistically significant . With patients whose baseline HIV RNA was >100,000 copies/mL, the findings were similar: HIV RNA remained suppressed in 87% of ATV recipients and 82% of ATV/r recipients. Mean CD4 count increases were 240 cells/µL and 259 cells/µL, respectively. Modest decreases in total cholesterol, LDL, and triglyceride levels were seen in the ATV treatment arm, whereas small increases in these values were seen in the ATV/r arm. Of the patients who experienced virologic failure (1 on the ATV arm and 7 on the ATV/r arm), none accrued primary protease mutations.

Clinical Bottom Line

In patients with virologic suppression on an initial regimen of ATV/r + abacavir/lamivudine, simplification to unboosted ATV + these NRTIs is likely to maintain regimen efficacy.

References

Squires K, Young B, DeJesus E, et al. Similar efficacy and tolerability of atazanavir (ATV) compared to ATV/ritonavir (RTV, r), each in combination with abacavir/lamivudine (ABC/3TC), after initial suppression with ABC/3TC + ATV/r in HIV-1 infected patients: 84 week results of the ARIES trial. In: Program and abstracts of the 5th IAS Conference on HIV Pathogenesis, Treatment, and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract WELBB103.

Atazanavir/Ritonavir in Pregnancy

Pharmacokinetic (PK) changes during pregnancy can reduce serum levels of many protease inhibitors, posing a risk of virologic failure. The optimal dosages of several protease inhibitors for pregnant women are not known. A recent study evaluated the PK parameters as well as the efficacy and safety of two dosages of ritonavir-boosted atazanavir (ATV/r) in pregnant women.

Women in the second and third trimesters of pregnancy were treated with ATV/r at the standard dosage of 300/100 mg once daily (n = 20) or at a higher dosage of 400/100 mg once daily (n = 21); all were also given zidovudine + lamivudine. PK data were compared with historical results from studies of nonpregnant adults (presumably mostly men). During the third trimester, the mean ATV AUC was 21% lower in women who received ATV/r 300/100 mg than in nonpregnant adults, and the mean C _max was 27% lower. However, the mean C _min was equivalent to that in nonpregnant adults. In women who received ATV/r 400/100 mg, the mean AUC and C _max and were virtually the same as those in nonpregnant adults, but the mean C _min was 39% higher. Bilirubin elevations were more common in women on the higher dosage of ATV, and in their infants (though the bilirubin levels in the infants appeared to decrease sharply in the first 2 weeks of life, as would be expected in neonatal jaundice). Women in both treatment groups maintained virologic suppression to <50 copies/mL (1 patient had a single blip to 59 copies/mL), and none of the infants was HIV infected.

Clinical Bottom Line

In this small study, ATV/r at 300/100 mg daily in the third trimester of pregnancy (given with zidovudine + lamivudine) appeared to maintain adequate C _min in most women, and it was effective in both suppressing maternal HIV viremia and preventing HIV transmission to infants. These data will help in determining the appropriate dosage of ATV/r for pregnant women. It should be noted that, in this study as in others, there appeared to be significant individual variation in PK parameters, and some women may require higher dosages than others.

ATV/r is designated by the U.S. Public Health Service Task Force perinatal guidelines as an alternative agent for use in HIV-infected pregnant women. Atazanavir is in FDA Pregnancy Category B.

References

1. Conradie F, Zorilla C, Josipovic D, et al; AI424182 Study Group. The safety, efficacy, and steady state pharmacokinetics of atazanavir/ritonavir (ATV/r) once daily given in combination with twice daily AZT/3TC during pregnancy: results of study AI424182. In: Program and abstracts of the 5th IAS Conference on HIV Pathogenesis, Treatment, and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract LBPEB06.

Investigational Integrase Inhibitor Shows Potent Activity in Early Studies

In a small Phase I dose-finding randomized double-blind monotherapy trial, 35 patients were randomized to placebo or to 1 of 3 dosages of S/GSK1349572, a second-generation integrase inhibitor. The patients were not on ART, had a median HIV RNA level of approximately 4.4 log ₁₀ copies/mL, and had no previous exposure to integrase inhibitors. After 10 days of treatment, HIV RNA had decreased by a mean of 1.51 to 2.46 log ₁₀ copies/mL in the 3 treatment groups (2.46 log ₁₀ copies/mL in the 50 mg once-daily group). No significant adverse effects attributable to the integrase inhibitor were noted, and no integrase resistance mutations were detected.(1)

In in vitro studies, S/GSK1349572 has shown activity against some HIV isolates with resistance to raltegravir and elvitegravir.(2)

Clinical Bottom Line

Based on these early data, S/GSK1349572 appears to be potent and tolerable, and may be effective against some viruses with resistance to first-generation integrase inhibitors. It is dosed once daily and requires no pharmacokinetic boosting. Enrollment will begin soon for Phase II investigations of this agent in both initial and salvage therapy.

References

1. Lalezari J, Sloan L, Dejesus E, et al. Potent antiviral activity of S/GSK1349572, a next generation integrase inhibitor (INI), in INI-naive HIV-1-infected patients. In: Program and abstracts of the 5th IAS Conference on HIV Pathogenesis, Treatment, and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract TUAB105.
2. Underwood M, Johns B, Sato A, et al. S/GSK1349572: a next generation integrase inhibitor with activity against integrase inhibitor resistant clinical isolates from patients experiencing virologic failure while on raltegravir therapy. In: Program and abstracts of the 5th IAS Conference on HIV Pathogenesis, Treatment, and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract WEPEA098.

Updates to the Database of ARV Drug Interactions

The following table summarizes recent additions to the HIV InSite Database of Antiretroviral Drug Interactions . For a full description of the updates, including references to the studies from which the data were derived, click on a specific drug name in the table below and search for the interacting agent.