High rate of rash in HIV negative volunteers combining raltegravir and darunavir

Rash flared in 8 of 18 HIV negative healthy adults (44%) combining raltegravir and darunavir/ritonavir in a pharmacokinetic (PK) study, and in one case the rash was serious. Only 6 volunteers completed the 18-day study. [1]

Potential interactions between darunavir/ritonavir and the integrase inhibitor raltegravir merit attention because many people already combine these drugs in rescue regimens. Clinical experience so far has not turned up a noticeably high rash rate in HIV-infected people taking these drugs together, according to Merck and Tibotec investigators.

However, raltegravir prescribing information lists rash and potentially fatal Stevens-Johnson syndrome as side effects reported from the clinic. In placebo-controlled trials of darunavir/ritonavir, rash did not affect more than 10% of people taking these protease inhibitors. But prescribing information for darunavir lists skin rashes ranging from mild to severe, including Stevens-Johnson syndrome as potential side effects of the drug. People in whom rash develops after starting darunavir are advised to contact their physician immediately, and physicians are told to stop darunavir/ritonavir in people with severe rash.

In the first 4 days of the PK study, volunteers took 400 mg of raltegravir every 12 hours with food. On days 5 through 18 they continued raltegravir and added 600/100 mg of darunavir/ritonavir every 12 hours with food.

Seven people had mild to moderate rash after combining the two drugs and 1 had a serious maculopapular rash. All rashes arose between days 8 and 12 of the combined treatment period and lasted for 11 to 33 days. The investigators rated the rashes “nonserious.” Six people dropped out of the study because of rash.

Because of the surprising rash rate, the researchers looked back at phase 3 trials of raltegravir, focusing on 200 people who took raltegravir plus darunavir/ritonavir as part of the background regimen and 101 who took placebo with darunavir/ritonavir in the background regimen. Rash affected 15.0% in the raltegravir/darunavir group and 4.0% in the placebo/darunavir group.

But rates of rash considered to be drug related were low and similar in the two groups – 3.5% with raltegravir/darunavir and 2.0% with placebo/darunavir.

The Merck-Tibotec team offered no advice to clinicians or patients about how they should interpret the rash findings in this study.

Because only 6 of 18 people (33%) completed the 18-day study, the investigators did not have a full data set on which to base drug interaction conclusions. The limited data suggested that doses of the coadministered antiretrovirals do not have to be altered, the researchers said. Geometric mean ratios of raltegravir with darunavir versus raltegravir alone were 0.71 (90% confidence interval [CI] 0.38 to 1.33) for 12-hour area under the curve, 0.67 (90% CI 0.33 to 1.37) for maximum concentration, and 1.38 (90% CI 0.16 to 12.12) for trough concentration. In other words, the critical trough concentration of raltegravir tended to be higher with darunavir/ritonavir than without darunavir/ritonavir, while the area under the curve and the maximum concentration tended to be lower.

The Merck-Tibotec team reported that darunavir concentrations with raltegravir aligned with concentrations reported in healthy volunteers taking darunavir/ritonavir without raltegravir in earlier PK studies.