At this year’s Conference on Retroviruses and Opportunistic Infections (CROI) in Atlanta there were several presentations about new treatments or new treatment strategies that could benefit both those new to treatment as well as treatment veterans. Merck presented data on a new non-nucleoside reverse transcriptase (NNRTI) inhibitor; Tobira offered new information about their entry inhibitor cenicriviroc; and researchers also suggested that nucleoside reverse transcriptase inhibitors (NRTIs) might not be needed for salvage therapy. Here’s how it all stacked up.
MK-1439
The drug company Merck, which makes the first FDA-approved integrase inhibitor raltegravir (Isentress), now has a new second-generation NNRTI in the works called MK-1439. They presented phase Ib data at CROI. MK-1439 may have less neurological side effects than the top-selling first-line therapy drug efavirenz (Sustiva) and also be effective against virus that has become resistant to either Sustiva or nevirapine (Viramune).
The new study compared multiple doses of MK-1439 for seven days compared with a placebo in HIV-positive study volunteers. Doses ranged from 25 millligrams (mg) to 200mg once daily.
“Non-serious” side effects included headache and loss of appetite. It should be noted that these kinds of side effects are commonly found with nearly any drug tested in humans. In terms of viral suppression, HIV levels were reduced almost equally by just over 1.25 logs in those taking the 25mg and the 200mg doses compared with no suppression in those taking the placebo. Further studies will be started by Merck in the near future. In a couple of years this drug may prove to become a potent first-line therapy, especially in those infected with HIV that is resistant to efavirenz or nevirapine or those who are treatment experienced.
Cenicriviroc
Cenicriviroc is an entry inhibitor that works against two immune co-receptors on CD4 cells, one of which HIV uses to enter cells, called CCR5, and a second called CCR2 that is not involved in cell infection. HIV uses CCR5 to infect many CD4 cells. CCR2 is implicated in many inflammatory diseases including rheumatoid arthritis.
This 48-week phase IIb study compared cenicriviroc to efavirenz (found in Sustiva and Atripla). A total of 143 people who were new to treatment were randomized into one of three groups: 100mg cenicriviroc + Truvada; 200mg cenicriviroc + Truvada; or efavirenz + Truvada (Atripla). The dosing schedule was called “double-dummy” since the people who took cenicriviroc also took a dummy efavirenz dose and those on efavirenz also took a dummy cenicriviroc dose.
Overall, the three arms of the study were quite similar. After 24 weeks, 76% of those who took 100mg cenicriviroc, 73% of those on 200mg cenicrivoric and 71% taking efavirenz had a viral load under 50 copies (undetectable).
There was a slight difference in efficacy based on how high a person’s starting viral load was, but the overall numbers in the high viral load group are too small to make strong conclusions. For those with a viral load under 100,000, cenivcriviroc was about 80% effective regardless of dose compared with 71% effective with efavirenz. For those with viral loads over 100,000, efavirenz had higher numbers with 75% reaching undetectable viral loads compared with 60% with 100mg of cenicriviroc and 50% with 200mg of cenicriviroc.
Protocol defined treatment failures were 12% with 100mg cenicriviroc and 16% with 200mg cenicriviroc and 11% with efavirenz. While people who stopped the study due to side effects was 0% with 100mg cenicriviroc and 2% in the 200mg cenicriviroc arm, it climbed to 18% in the efavirenz arm.
In terms of the CCR2 activity, which deals with HIV-related activation, there was a greater reduction in soluble CD14, an indication of HIV-related inflammation and relocation of gut bacteria into the bloodstream, in those taking cenivriviroc than those taking efavirenz.
ACTG OPTIONS Study
In the AIDS Clinical Trials Group (ACTG) OPTIONS study, the aim was to determine if the standard practice of keeping people with multiclass drug resistance on a backbone of NRTI therapy, even if their virus was largely resistant to those drugs, was even necessary.
A total of 360 people enrolled in the study from 2009 to 2011. Three-quarters were male and most were black or Hispanic. Everyone had multiclass drug resistance.
All of the participants had genotypic resistance tests and were guided to a regimen that seemed optimal against their strains of virus. The new regimens had to include darunavir (Prezista), enfuvirtide (Fuzeon), etravirine (Intelence), maraviroc (Selzentry), raltegravir (Isentress) or boosted tipranavir (Aptivus). People were then randomized to whether they would include NRTIs in their new regimen or not.
Overall success rates were fairly high and statistically similar in both arms. Only 26% of those without an NRTI in their regimen had treatment failure, while 30% in those with NRTIs in their regimen failed treatment.
Of note, there was a statistically significant difference in the number of deaths while on therapy. Among those who included an NRTI in their regimen, six people died, while none in the NRTI-free regimen died. In a couple of cases where people were taking NRTIs the researchers judged that the NRTIs could have contributed to the deaths.
In all, this study could substantially change the way we look at treatment of multi-class resistant HIV.