February 24, 2017
This week, we're looking at four studies from CROI 2017. The first study finds that a two-drug regimen of cabotegravir (CAB) and rilpivirine (Edurant) works as maintenance therapy, according to 144-week results. The second study finds tenofovir alafenamide (TAF), as part of a single-tablet regimen, is superior to tenofovir disproxil fumarate (TDF), for more than two years.
Our third study finds that an investigational drug known as EFdA is highly effective against HIV-2. And finally, NMCAB, a nanoformulated prodrug of cabotegravir, works better than cabotegravir in animal models. To beat HIV, you have to follow the science!
For our complete conference coverage, visit our CROI 2017 home page.
The oral two-drug combination of cabotegravir and rilpivirine continues to suppress HIV viral load below detectable levels in the long term, week-144 data from the LATTE trial shows.
The medication is well tolerated, with only 4% of study participants reporting grade 2 or higher adverse events. The study started people who had never taken antiretroviral medications on an initial regimen that included another antiretroviral, or did not include CAB at all. Participants who achieved viral suppression on the CAB-based therapy were switched to a cabotegravir/rilpivirine-only maintenance regimen at week 24.
The current results therefore show only 120 weeks on the two-drug treatment. The drug combination is under development as an oral lead-in/bridge to a long-acting injectable form. Studies have been modest in size so far, with 160 participants starting the maintenance regimen and 138 continuing past week 96. Based on the current data, study authors recommend proceeding to a larger phase III trial for the two-drug treatment.
Tenofovir alafenamide is more effective in suppressing viral loads to undetectable levels in the long term than is tenofovir disproxil fumarate, week-144 data showed.
TAF is a modified version of TDF that had fewer kidney- and bone-related side effects than TDF in clinical trials. This improved profile was also evident in the long-term results presented, with no renal adverse events and no bone loss reported for the new version of tenofovir, compared to 12 renal events and 6 participants with reduced bone mineral density in the TDF arm.
Cholesterol levels, however, rose higher in those in the TAF arm than the TDF group, although approximately the same number of people were started on lipid-modifying agents, such as statins, in both groups. Participants in both arms also took elvitegravir, cobicistat and emtricitabine (E/C/F). Week 144 results "support the use of E/C/F/TAF as a safe, well-tolerated and durable regimen" for treating HIV-1, study authors concluded.
A new antiretroviral drug in early clinical trials appears to be highly effective against HIV-2, the strain of the virus common in West Africa, researchers reported.
The nucleoside reverse transcriptase translocation inhibitor (NRTTI) EFdA, also known as MK-8591, was tested in the laboratory against both HIV-1 and HIV-2 virus that had been isolated from people living with HIV who had never taken antiretroviral medications. HIV-2 was five times more susceptible to the new drug than was HIV-1.
This higher effectiveness is due to differences in the structure of a section of the virus, the 4'-ethynyl group, between the two strains of HIV. EFdA stands for 4'-ethynyl-2-fluoro-2'-deoxyadenosine. The drug also inhibited replication of virus that is resistant to other nucleoside reverse transcriptase inhibitors.
EFdA's antiviral activity had previously been documented in a small proof-of-concept trial, and its safety and efficacy have been shown in animal studies. The compound is also being investigated as pre-exposure prophylaxis for the prevention of HIV.
A modified version of cabotegravir , NMCAB, shows better antiretroviral activity and is released more slowly than the original drug, study authors reported.
Cabotegravir is currently in clinical trials as both an oral medication and a long-acting parenteral (LAP) antiretroviral. NMCAB, a nanoformulated prodrug of cabotegravir, was created for the injectable LAP version. Antiviral activity and pharmacodynamics of this modified version were compared to those of the original drug in mouse models and in vitro. Six to eight weeks after injection, NMCAB drug levels were up to 300 times higher than those of cabotegravir, with NMCAB antiretroviral activity persisting after the drug was removed from human monocyte-derived macrophages. By contrast, cabotegravir ceased to inhibit HIV replication within a day of removal.
Study authors are using a similar process to improve the characteristics of dolutegravir (Tivicay) as an LAP. Such "refinements in drug delivery platforms will enable LAPs to be more easily administered," they believe.
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