The next-generation NNRTI Merck Doravirine (formerly known as MK-1439) was as effective as efavirenz at suppressing HIV replication, and although half of the many study participants with Doravirine have experienced adverse events related to medication - in particular side effects on the central nervous system (CNS) - they were less likely to stop prematurely treatment, according to the study results, reported in this week 8º Conference of the International AIDS Society (IAS) on HIV pathogenesis, treatment and prevention of this week in Vancouver.
NNRTIs are generally effective, easy to use and well suited for antiretroviral therapy (ART) for the first line. But the widely used drugs in this class, nevirapine (Viramune) are likely to generate resistance to HIV drugs, rilpivirine (Edurant) is less effective in people with high viral load, and efavirenz (Sustiva) may cause neuropsychiatric side effects such as dizziness and dreams abnormal. As such, these drugs are not recommended for first-line ART in US treatment guidelines
The adoption of a powerful, well tolerated new NNRTI that offers more flexibility, especially for people with extensive drug resistance and limited treatment options.
Jose Gatell from Barcelona University reported the latest results of the ongoing study 007, which is comparing Doravirine against efavirenz, both taken once a day, for people not previously treated with HIV.
This 2b phase of the study included 2 parts. The 1 part of this study evaluated doses of 25 mg, 50 mg, 100 mg and 200 mg of Doravirine in combination with tenofovir / emtricitabine (Truvada drugs, medicine used in PrEP). As reported in Conference on retroviruses and opportunistic infections 2014 the 100Mg dose was selected because it offers the best balance of safety and efficacy based on an analysis 24 weeks.
At that time all participants of 1 phase remained or were associated with treatment with a dose of 100 mg Doravirine and monitoring was continued. More 132 people registered in the 2 the study and were randomly assigned to receive doses of 100 mg Doravirine or 600 mg efavirenz, both tenofovir / emtricitabine during 48 weeks.
At the HIV Medicinal Treatment Conference in Glasgow last November, Gatell reported that Doravirine was as effective as efavirenz in a study of 48 weeks of the 1 phase. He also presented data from a preliminary study of 8 weeks of safety and tolerability from a pool of all 108 participants who started on the dose of XAVUMX of Doravirine and the 100 who took efavirenz in both phases of the study.
This week at the IAS meeting, Gatell presented findings from the 24 study weeks on efficacy and safety for this combined population of 216 participants. More than 90% were male and 80% were white, and the mean age was approximately 35 years. The median cell count of CD4 was approximately 415 cells / mm3. Study participants were stratified by baseline viral load, with slightly more than one-third having HIV RNA counts greater than 100.000 copies / ml.
- The overall response rates were similar in both treatment groups, with only 73,1% of people who took Doravirine and 72,2% of participants who took efavirenz getting results as a viral load below 40 copies / ml (undetectable) in 24 weeks.
- 88,9 87,0% and%, respectively, had viral load below 200 copies / ml.
- Gains in CD4 cell counts were also similar, 154 and 146 cells / mm3 respectively.
- Looking response rates on viral function level pre-procedure, more than 90% of people who took the drug had reached HIV RNA counts down 200 copies / ml regardless of whether the treatment started with a low viral load or High.
- People who started with low viral load found it easier to suppress their HIV viral load to an undetectable level (below 40 copies / ml) (83,3% with Doravirine and 85,7% with efavirenz) than those who started with a higher level of viral load (60,5% vs 65,5%).
- Participants in the treated arm Doravirine showed a potential of noncompliance around 50% of those who received treatment with efavirenz for any reason (4,6 11,9% vs.%, respectively).
- The difference was driven by a higher dropout rate due to adverse events Doravirine and Efavirenz (0,9 5,6% vs.%, respectively).
- While most people in both treatment arms had at least 1 serious adverse events, other events were less common in Doravirine (0,9 4,6% vs%). Moreover, people having had Doravirine half of side effects that many drugs in general (27,8 55,6% vs.%).
- The primary safety comparison revealed that a significantly lower number of Doravirine recipients reported one or more CNS-related events per week, with dizziness (9,3% vs 27,8), abnormal dreams (6,5% vs. 17,6%) being the most common, and the nightmares (6,5% vs 8,3%).
- Depression was common in half of Doravirine users, for the users of Efavirenz, but the numbers were very small.
- Finally, the cholesterol levels "bad" LDL was found to be higher in efavirenz users.
Gatell noted that viral load was still falling in the week 24, and suggested that people with higher baseline levels probably still would not have enough time treatment to lower viral load to undetectable limit (40 copies of Viral RNA per cubic milliliter of blood ).
In summary, a daily dose of 100 mg Doravirine in combination with tenofovir / emtricitabine "shows antiretroviral activity and immunological effects similar to those of efavirenz" in 24a week, and "has much less adverse events related to the CNS linked to treatments and less severe events "than efavirenz, the researchers concluded.
Gatell said that a Phase 3 with a higher volume of Phase 3 Doravirine study is now underway.
Written by Liz Highleyman
CNS Side Effects by Ion 2015: New NNRTI Doravirine Suppresses HIV as Well as Efavirenz But with Fewer CNS Side Effects by Claudio Souza.
J Gatell, F Raffi, A Plettenberg, et al. Efficacy and safety of doravirine 100 mg QD vs efavirenz 600 mg QD with TDF / FTC in ART-naive HIV-infected patients: week 24 results. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Vancouver, July 19-22, 2015. Abstract TUAB0104.
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