HIV Meds Quarterly

Winter 2010

Interactions

	Efavirenz and Levonorgestrel
	Lopinavir/ritonavir and Buprenorphine

Research Brief

	Vicriviroc in Treatment-Experienced Patients

Fast Takes

	Ritonavir tablet formulation Ritonavir (Norvir) tablets (100 mg) were recently approved by the U.S. Food and Drug Administration (FDA). The tablets are heat stable and do not require refrigeration. The ritonavir tablets are not bioequivalent to the capsules. After a 100 mg ritonavir tablet, the ritonavir AUC was comparable to that of the capsule formulation, but the mean C max was 26% higher. Food decreases the bioavailability of the ritonavir tablets to a similar degree with both high-fat and moderate-fat meals. There are no pharmacokinetic comparisons of ritonavir tablets and capsules taken under fasting conditions. Ritonavir tablets must be taken with food, though the type of food does not affect bioavailability. Ritonavir tablets should be swallowed whole, and not chewed, cut in half, or crushed. The tablets are stable at room temperature until the printed expiry date on the bottle (ritonavir capsules are stable at room temperature only for up to 30 days). The ritonavir tablet formulation is now available in pharmacies; it is unclear how long the manufacturer intends to keep the capsule formulation on the market. more on ritonavir References Norvir [package insert] . North Chicago, IL: Abbott Labs; February 2010.
	Maraviroc approved for initial therapy In November 2009, the FDA approved maraviroc for use as initial therapy in the treatment of HIV infection, for persons infected with only CCR5-tropic virus. The FDA previously had approved maraviroc for treatment of patients with ARV-resistant strains of CCR5-tropic HIV. The new indication is based on a randomized double-blind noninferiority study of maraviroc vs efavirenz, each given in combination with zidovudine + lamivudine for treatment-naive adults. At 96 weeks, similar rates of virologic suppression to <50 copies/mL were seen in the two treatment groups: 59% in maraviroc recipients and 63% in efavirenz recipients (at 48 weeks, 69% MVC, 68% EFV). These data are based on reanalysis of baseline tropism status using the enhanced sensitivity tropism assay (Trofile), and exclusion of 15% of subjects whose HIV was incorrectly identified as exclusively CCR5-tropic. CD4 increases also were somewhat higher in the maraviroc treatment group: 184 cells/µL vs 155 cells/µL. The recommended dosage of maraviroc depends on coadministered drugs: see package label for specific information. Treatment guidelines of the U.S. Department of Health and Human Services (most recently updated in December 2009) do not recommend maraviroc for use in initial therapy. more on maraviroc
	Saquinavir/ritonavir and possible risk of abnormal heart rhythms The FDA has announced that preliminary data suggest ritonavir-boosted saquinavir is associated with dose-dependent QT and PR interval prolongation in healthy adults. These conduction abnormalities may increase risk of arrhythmias, including torsade de pointes (from QT prolongation) and heart block (from PR prolongation). Pending further investigation, the FDA recommends that saquinavir/ritonavir be avoided in patients: With a history of QT prolongation, cardiac conduction system disease, ischemic heart disease, cardiomyopathy Who take Class 1A (eg, quinidine) or Class III (eg, amiodarone) antiarrhythmics, which prolong the QT interval Who take other medications known to prolong the QT or PR interval (these are numerous, and include many antifungals, macrolides and fluoroquinolones, atazanavir, phenothiazines, and tricyclics); consult with a pharmacist before coadministering. References Invirase (saquinavir): Ongoing safety review of clinical trial data . U.S. Food and Drug Administration MedWatch; February 23, 2010.

Reference Table

	Updates to the Database of ARV Drug Interactions

Lopinavir/ritonavir and Buprenorphine

This pharmacokinetic study investigated the interaction between lopinavir/ritonavir (800/200 mg given once daily) and buprenorphine/naloxone in 12 HIV-seronegative subjects who were on stable buprenorphine therapy.

After administration of lopinavir/ritonavir for at least 10 days, the buprenorphine AUC and C _max were not significantly different from baseline values. For norbuprenorphine, the primary metabolite of buprenorphine, the C _max was lower during coadministration with lopinavir/ritonavir (73.7 vs 52.7 ng•hr/mL, p < .05) whereas the AUC was not significantly lower (5.29 vs 3.11 ng/mL). Concentrations of naloxone were unchanged, and the lopinavir AUC and C _min were not significantly different from those of two historical comparators.

Clinical Bottom Line

Based on these data, no dosage modification of either buprenorphine/naloxone or lopinavir/ritonavir is needed when these drugs are coadministered.

References

1. Bruce D, Altice F, Moody D, et al. Pharmacokinetic Interactions Between Buprenorphine/Naloxone and Once-Daily Lopinavir/Ritonavir. In: Program and abstracts of the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco. Abstract 620.

Efavirenz and Levonorgestrel

A single-arm pharmacokinetic study investigated the interaction of efavirenz and levonorgestrel. HIV-seronegative women were given a single dose (0.75 mg) of levonorgestrel both before and after they had received efavirenz 600 mg daily for 14 days. Coadministration of efavirenz with levonorgestrel resulted in a 58% decrease in the levonorgestrel AUC and a 69% decrease in C _min . Efavirenz levels were not different than those in a historical comparator.

Clinical Bottom Line

Efavirenz significantly decreases levonorgestrel levels. Pending the results of clinical studies, an additional or alternative form of birth control (or emergency contraception [Plan B]) should be used for women who take efavirenz.

For more information on interactions between ARVs and hormonal contraceptives, see HIV InSite's Database of Antiretroviral Drug Interactions .

References

1. Carten M, Kiser J, Kwara A, et al. Pharmacokinetic interactions between the hormonal emergency contraception, levonorgestrel, and efavirenz. In: Program and abstracts of the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco. Abstract 934.

Vicriviroc in Treatment-Experienced Patients

Vicriviroc is an investigational CCR5 antagonist that has been undergoing clinical study in both treatment-experienced and treatment-naive individuals. At the 17th Conference on Retroviruses and Opportunistic Infections (CROI) this year, investigators presented results from two parallel randomized, double blind, placebo-controlled Phase 3 studies in treatment-experienced patients.

Study participants were required to have CCR5 tropic virus, as well as resistance to at least 2 of the NRTI, NNRTI, or PI drug classes, or ART experience for at least 6 months. Tropism was determined by the assay available at time of enrollment and confirmed by the enhanced sensitivity assay at the end of the study; data analysis was confined to patients with CCR5 by the more sensitive tropism assay (n = 721).

Study patients were randomized 2:1 to vicriviroc (30 mg once daily) or to placebo, each in combination with an optimized background regimen. At baseline, the mean CD4 count was 250 cells/µL, the HIV RNA was 4.5 log ₁₀ copies/mL, and the two groups were well matched for other baseline characteristics. About two thirds of study participants had ≥3 active agents in their background regimen.

In pooled analysis, by intention-to-treat analysis, the rates of HIV RNA suppression to <50 copies/mL at 48 weeks were statistically equivalent in the 2 groups: 64% in the vicriviroc group and 62% in the control group. Among the minority of patients with ≤2 active drugs in the background regimen, however, the vicriviroc group showed significantly higher rates of virologic suppression (HIV RNA <50 copies/mL in 70% in the vicriviroc group vs 55% in the placebo group, p = .02). The mean CD4 increase was 138 cells/µL in vicriviroc recipients and 129 cells/µL in controls.

In each treatment group, 15 % of participants experienced protocol-defined virologic failure. Of vicriviroc recipients with virologic failure, 13% had dual/mixed or X4 virus at time of failure, 4% had vicriviroc resistance. Rates of adverse events, including malignancies, infections, and cardiovascular events, were similar between treatment groups.

Clinical Bottom Line
This study showed that the addition of vicriviroc to an already-strong background regimen did not confer additional benefit. However, inclusion of this agent in regimens containing ≤2 active agents did improve regimen efficacy. In other words, vicriviroc is likely to be effective (and safe) as a component of salvage therapy for appropriate patients.

The study raises important questions about how to design studies to test efficacy of new ARV medications in treatment-experienced patients, now that several active agents are often available for patients with a history of virologic failure. It will be important to develop new study approaches that serve the dual goals of treating patients to the standard of care (with the aim of maximizing the likelihood of virologic suppression) while evaluating the efficacy of a new agent.

As a result of this study, the manufacturer of vicriviroc, Merck & Co, announced that it will no longer seek FDA approval for the use of vicriviroc with treatment-experienced patients, but will continue to study it in treatment-naive individuals.

References

Gathe J, Diaz R, Fatkenheuer G, et al. Phase 3 trials of vicriviroc in treatment-experienced subjects demonstrate safety but not significantly superior efficacy over potent background regimens alone. In: Program and abstracts of the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco. Abstract 54LB.

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, go to the database, click on a specific drug name, and search for the interacting agent.