The combined pill with doravirin (another type three in one) looks good for the initial treatment of HIV
100 mg of doravirin, 300 mg of lamivudine (3TC) and 300 mg of tenofovir disoproxil fumarate (TDF) are the three antiretroviral agents
Kathleen Squires on IAS 2017. Photo by Liz Highleyman, hivandhepatitis.com
A single tablet regimen containing the latest generation NNRTI doravirin reduced HIV viral load as well as efavirenz-based co-formulation, but showed a more favorable side effect profile, according to the results of the DRIVE-AHEAD study this week at9A International AIDS Conference Society on HIV Science (IAS 2017), in Paris.
Current top-line antiretroviral therapy regimens are safe and highly effective. Integrase inhibitors have largely replaced non-nucleotide reverse transcriptase inhibitors (NNRTIs) for the first treatment in recent years, but having multiple potent and well-tolerated drugs from different classes of antiretrovirals offers more options for individualized therapy.
Kathleen Squires of Thomas Jefferson University in Philadelphia presented the results of the 3 DRIVE-AHEAD trial, which is evaluating a fixed dose co-formulation of 100 mg doravirin, 300 mg lamivudine (3TC) and 300 mg tenofovir disoproxil fumarate (TDF ).
Doravirin, a NNRTI from the research developed by Merck, has a unique resistance profile and is active against HIV with common mutations of NNRTI resistance including K103N.
It can be taken with or without food and has low potential for drug interactions.
Previous studies have shown that doravirine keeps the viral load suppressed as much as efavirenz(Sustiva orStocrin®),But with fewer neuropsychiatric side effects,In an 2 phase study. Doravirine plus two NRTIs of the investigator's choice - either TDF / emtricitabine(Truvada)Or abacavir / lamivudine(Kivexa® orEpzicom)- worked as well as darunavir boosted with ritonavir(Prezista®),But with a better lipid profile,In the 3 -FORWARD phase study.
DRIVE-AHEAD enrolled 728 people initiating HIV treatment for the first time. About 85% were men, half were white and the average age was 31 years. The mean CD4 count was approximately 420 cells /Mm3,About 22% had a high viral load above 100.000 copies / ml and 14% had a clinical history of AIDS.
Participants in this double-blind study were randomly assigned to receive the doravirine combination tablet or a co-formulation of efavirenz, emtricitabine and TDF(Atripla®).
To "blind" the study, because drug dosing regimens were not the same, participants were given Cohesive placebos that they were not taking. Doravirin allows a more flexible schedule: participants were invited to take the Doravirin Co-formulation or placebo whenever they chose - but at the same time every day - with or without food. They were told to take the efavirenz pill or placebo on an empty stomach at bedtime, as this was intended to decrease the neurological side effects.
Treatment was planned for 96 weeks, the primary outcome being the proportion of people with HIV RNA below 50 copies / ml at week 48.
After 48 weeks of treatment, 84% of the people in the arm of doravirin and 81% in the efavirenz arm had undetectable viral load, showing that the new Coformulation was not inferior. Those who started with a higher viral load had higher response rates, but these did not differ according to the regimen. In a modified analysis, about 90% of people with low baseline viral load and about 80% of those with high baseline viral load reached an undetectable level in both treatment arms.
People who took doravirin were more likely to suffer from protocol-defined virologic failure than those taking efavirenz, but this was uncommon in both arms (6% vs 4%). Among participants with virologic failure who underwent successful genotypic testing, 1,6% in the arm of doravirin and 3,3% in the efavirenz arm showed evidence of NNRTI resistance mutations.
Both treatment regimens were generally safe and well tolerated, but there were some notable differences in side effects.
Half of many people in the doravirin arm experienced drug-related adverse events in general (31% vs 63%, respectively), but severe events were rare in both arms (1% or less). Less than half of the arm of doravirin stopped treatment early due to adverse events (3% vs 7%). The most common adverse events in the doravirin arm were headache (13%), diarrhea (11%) and nasopharyngitis (11%), which occurred at similar rates in the efavirenz arm. The rash was less common with doravirin (5% vs 12%).
However, doravirin caused significantly fewer side effects of the central nervous system. For example, 9% of people taking doravirin reported dizziness compared to 37% of those taking efavirenz. Looking at a set of pre-defined neuropsychiatric events, half of the doravirin receptors reported disturbances or sleep disorders (12% vs 26%) and altered cognition (4% vs 8%). Depression and suicide or self-harm were also less frequent with doravirin (4% vs 7%).
Lipid profiles also favored doravirin. LDL cholesterol, total cholesterol, and triglyceride levels decreased slightly after initiation of treatment on the doravirin arm, substantially increasing the efavirenz arm.
"Doravirin is a novel, once-daily NNRTI for first-line treatment with consistent efficacy regardless of initial viral load and favorable tolerability and safety profile in clinical trials of 2 3 phases," the study's researchers concluded.
The DRIVE-AHEAD study had some limitations, including the fact that it compared doravirin against efavirenz, which is no longer recommended for first-line therapy in many treatment guidelines because of its adverse events. However, its low cost and wide availability mean that it is still commonly used in countries with limited resources.
In addition, session moderator Monica Gandhi of the University of California at San Francisco School noted that doravirin co-formulation contains TDF instead of the new formulation of tenofovir alaphaenamide (TAF), which causes less toxicity in the kidneys and In the bones. This was done because a generic version of the TDF is expected to be available soon, while the TAF will remain on the patent for another five years or more.
Liz Highleyman original in Doravirine combination pill looks good for initial HIV treatment
Publication: 27 of July, 2017