Once-daily raltegravir effective as maintenance therapy

Almost all HIV-positive people with undetectable viral load who switched to once-daily raltegravir (Isentress) maintained viral suppression, French researchers reported at the 14th European AIDS Conference this month in Brussels. In an effort to facilitate once-daily dosing, Merck is working on a new tablet that appears less affected by food than the current formulation.

Raltegravir is a highly effective component of combination antiretroviral therapy (ART) and is one of the best-tolerated HIV medications, but its standard twice-daily dosing schedule makes it less convenient than once-daily options.

Fabienne Caby of Hôpital Pitié-Salpêtrière and colleagues evaluated whether once-daily raltegravir is able to maintain virological control when people switch from a fully suppressive combination regimen. 

Although pharmacokinetic data suggest that once-daily raltegravir may provide adequate drug levels, the randomised Phase 3 QDMRK trial showed that 800mg once-daily raltegravir failed to meet the criteria for non-inferiority to 400mg twice-daily raltegravir for people starting ART for the first time, with 83 vs 89% achieving undetectable viral load. This was largely driven by poorer efficacy among people with high baseline viral levels (74 vs 84%, respectively). But raltegravir may be able to keep HIV under control if viral load is already suppressed.

This observational study enrolled 71 people at 2 centres in Paris who had undetectable viral load (<50 copies/ml) for at least six months. A majority (66%) were men, the mean age was 46 years and the median CD4 cell count was 588 cells/mm³. At the time they switched, participants had been on ART for 14 years on average and had used five antiretroviral 'lines'.

Participants received treatment optimisation that included introduction of 800mg once-daily raltegravir. Nearly one quarter switched from 400mg twice-daily raltegravir (taken for an average of eight months), whilst the rest switched from other drugs and were integrase inhibitor-naive. This was not a randomised trial and patients were not assigned to a regimen.

In addition to once-daily raltegravir, 56% used tenofovir/emtricitabine (the drugs in Truvada) and 18% used abacavir/lamivudine (the drugs in Kivexa). Others were on non-standard regimens including 10% taking etravirine (Intelence), 10% taking boosted or unboosted atazanavir (Reyataz), three people taking nevirapine (Viramune) and one taking efavirenz (Sustiva). 

The most common reason for switching was abnormal blood lipid levels (20%), followed by liver toxicity or elevated bilirubin (15%), lipodystrophy (13%), neuropsychiatric symptoms (10%), prevention of drug interactions (8%), gastrointestinal symptoms (7%) and treatment simplification (6%).

At 24 weeks after switching, 99% of participants still had undetectable viral load, falling to 96% at 48 weeks. The median CD4 count remained stable at 24 weeks (589 cells/mm³) and rose to 631 cells/mm³ at 48 weeks.

One person experienced virological failure at week 24 (defined as any HIV RNA measurement >400 copies/ml or two measurements >50 copies/ml), joined by two more participants at week 48. In two of these cases, virological failure was associated with emergence of raltegravir resistance mutations. All three of these people received raltegravir with two NRTIs and had a prior history of virological failure on NRTI-containing regimens; two had pre-existing NRTI resistance mutations. 

Among participants with pharmacokinetic data, 17% (including two of the patients with virological failure) had raltegravir minimum concentrations below 50 ng/ml, considered the cut-off for adequate potency. 

"In this study, switching to raltegravir [once-daily] maintains virological suppression over 48 weeks as long as raltegravir is associated with a fully active backbone," the researchers concluded, emphasising that this requires clinicians to determine a patient's entire antiretroviral history and previous genotypic resistance test results.

New raltegravir formulation

Rajesh Krishna and colleagues from Merck conducted a study looking at the pharmacokinetics and effect of food on a new 600mg tablet formulation of raltegravir, part of an assessment of the feasibility of once-daily dosing using a higher dose.

This open-label, single-dose study enrolled 36 healthy HIV-negative volunteers. Participants were randomly assigned to take either three of the marketed 400mg raltegravir oral compressed tablets or two of the reformulated 600mg tablets, in either case receiving a total dose of 1200mg. 

The new formulation was found to be generally safe and well tolerated, with no clinical or laboratory serious adverse events reported and no discontinuations for this reason.

Taken while fasting, 1200mg doses of the new tablet and the old tablet led to similar drug exposure levels. The researchers noted that a recently concluded multiple-dose study found that steady-state 24-hour concentrations were virtually the same, 82 nM using the old tablet and 83 nM using the new version. 

The reformulated tablet was less affected by food, however. A low-fat meal reduced the 'area under the curve' (AUC) or overall drug exposure by 71% using the old tablet versus 40% using the new tablet. Administration with a high-fat meal, in contrast, increased AUC by 26% using the old tablet but by only 3% using the new formulation.

The clinical significance of changes in drug exposure with meals is being further investigated, they said.

In a press release issued to coincide with the conference, Merck indicated that it plans to initiate a phase 3 clinical trial of once-daily raltegravir in early 2014.

"The data we are presenting at the European AIDS Clinical Society conference, as well as other currently available data, provide a strong scientific basis to continue our investigational work toward a once-daily dosing regimen," said Merck Research Laboratories' Vice-President, Jeff Chodakewitz.