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CROI 2014: Novel 2-Drug Maintenance Combo Works Well, Stage Set for Long-lasting Injectables

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An oral combination of 2 antiretroviral drugs -- the non-nucleoside reverse transcriptase inhibitor rilpivirine (Edurant, also in Complera or Eviplera) and the new integrase inhibitor GSK1265744 -- was at least as effective as a standard NRTIs-plus-efavirenz triple combination in keeping viral load undetectable, according to a report presented at the 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014) last week in Boston.

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The dual combination was used as a maintenance therapy. This means patients did not start on it as their first treatment combination, but rather switched to it after 6 months on a NRTI-plus-GSK1265744 combination, as long as they had a viral load under 50 copies/mL. The reason for this is that there has been an increased risk of early treatment failure for rilpivirine-based combinations in people with high viral loads (over 100,000 copes/mL) in some drug trials, so the idea was not to start the 2-drug combination until study participants had already achieved virological suppression.

The point of doing this study is explained in its title -- the Long-Acting antiretroviral Treatment Enabling study, or LATTE for short. Rilpivirine and GSK1265744 (GSK744 for short) remain so long in the body that the potential exists for them to be used as injectable formulations that could be administered once a month instead of taking pills. Now that we know they are safe to use together as an oral maintenance therapy, there will be a new trial using them as an injected maintenance therapy.

The Retrovirus Conference also heard last week how an injectable formulation of GSK744 is being developed for pre-exposure prophylaxis (PrEP).

The Study

In the LATTE study, participants were divided into 4 groups, and for the first 6 months all the groups took triple combination therapy. All groups took 2 NRTIs: either tenofovir/emtricitabine (the drugs coformulated as Truvada) or abacavir/lamivudine (the drugs coformulated as Epzicom or Kivexa). The third drug was either the NNRTI efavirenz (Sustiva) or one of 3 different doses of GSK744 (10, 30, or 60 mg).

If, after 6 months, participants on this starting therapy had viral loads under 50 copies/mL, then those on GSK744 exchanged their NRTIs for rilpivirine (25 mg). Those taking efavirenz continued taking the 2 NRTIs. Although both GSK744 and rilpivirine are being developed as long-acting drugs, in this study both were taken as daily pills.

The Results

The results presented by David Margolis of GlaxoSmithKline are for the first 48 weeks of the study, i.e., 24 weeks each on the starting and maintenance combinations. The full 96-week results will be presented next year.

There were 243 participants in the study, all but 10 of them (96%) men. The media age was about 35 years, two-thirds were white, and 16% had an initial viral load over 100,000 copies/mL. Baseline CD4 count averaged 410 copies/mm3. The choice of NRTIs was up to doctor and patient: 69% were taking Truvada and 31% were taking  Epzicom.

At 24 weeks, 87% of study participants taking GSK744 plus 2 NRTIs had a viral load under 50 copies/mL -- with virtually identical viral suppression rates between the 3 doses -- compared to 74% of people taking efavirenz.

The 87% taking GSK744 (160 out of 181 starting therapy) switched their NRTIs to rilpivirine. Adding in 47 participants taking efavirenz, this meant there were 207 participants in the maintenance phase of the study.

At 48 weeks, 82% of all participants who started taking GSK744 (including 24-week dropouts) had a viral load under 50 copies/mL vs 71% of participants taking efavirenz. This 11% difference was not statistically significant due to relatively small numbers of participants.

The difference was driven entirely by the lower efavirenz viral suppression results during the first 24 weeks. The proportion of participants who had undetectable viral load at 48 weeks who continued into the maintenance phase was 94% for efavirenz and 93% for GSK744.

The lower rate of success for efavirenz during the first 24 weeks was largely driven by discontinuations due to toxicity, particularly this drug's well-known neuropsychiatric side effects. 13% dropped out of the efavirenz arm during the first 24 weeks due to toxicity compared with 3% in the GSK744 arms, and combined with drop-outs due to virological failure, 21% on efavirenz discontinued compared to 8% on GSK744. The only side effect that was significantly more common with GSK744 was headache, which was mainly mild (22% of people taking GSK744 had headaches compared with 11% taking efavirenz; no participants withdrew from the study for this reason).

These results support a trial of the injectable formulations of rilpivirine and GSK744 as maintenance therapy. As in LATTE, participants in that study will start on 6 months of oral therapy before switching to the maintenance regimen.

See also: CROI 2014: Long-Acting HIV Drugs for Maintenance Therapy [VIDEO]

3/10/14

Reference

D Margolis, C Brinson, J Eron, et al. 744 and Rilpivirine as Two-Drug Oral Maintenance Therapy: LAI116482 (LATTE) Week 48 Results. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6. Abstract 91LB.