August 5, 2008
In a presentation perhaps most notable for what wasn't said, data on Tibotec's experimental first line NNRTI, rilpivirine, were presented today at the International AIDS Conference in Mexico City. The results showed that was equally potent and well tolerated as Sustiva (efavirenz) when taken as part of first line therapy. While the results presented were promising, the lack of forthrightness regarding questions on resistance and adverse events left many, including Project Inform, shaking their heads.
Developing rilpivirine as a first line NNRTI is welcomed by most in the scientific, activist and prescribing communities, since Sustiva has long been the only first line NNRTI option for many people. Sustiva's well known problems with sleep disturbances, depression and other neurologic and psychological adverse effects make it problematic, particularly those with pre-existing psychiatric issues -- which accounts for a large segment of people living with HIV.
The data presented were from a head-to-head, phase IIb study of 3 doses of rilpivirine vs. Sustiva, both taken along with 2 NRTIs [either Combivir (zidovudine/AZT + lamivudine/3TC) or Truvada (tenofovir + emtricitabine/FTC)]. In total there were 368 volunteers in the study: 279 in the 3 rilpivirine groups and 89 in the Sustiva group.
Interestingly all 3 doses of rilpivirine proved as good as Sustiva at reducing HIV levels. After 96 weeks, 71-76% of people on rilpivirine had HIV levels below 50 copies/mL, compared to 71% taking Sustiva. All groups experienced similar increases in their CD4 counts: 146-172 for people taking rilpivirine vs. 160 for those on Sustiva.
Overall there were similar rates of adverse events reported: 12.2% for rilpivirine vs. 14.6% for Sustiva. However, this is where things got interesting. Despite overall similar rates of adverse events, only data on ones like rash, neurologic disturbances and increases in cholesterol and triglycerides that were more common for Sustiva were detailed. Moreover, when an audience member asked the presenter, Dr. Santoscoy, what adverse events were more common for people taking rilpivirine, no clear answer was given.
The story was similarly vexing in terms of the emergence of resistance. Comparable numbers of people experienced failure taking rilpivirine or Sustiva -- around 6-7%. While the mutations, like K103N and Y181C, associated with failure on Sustiva are well known, little has been reported on which mutations confer resistance to rilpivirine. When asked by an audience member which mutations were seen on failure to rilpivirine, Dr. Santoscoy would only say that this study was too small to provide definitive answers to this question.
While it is true that this study is too small to provide definitive information on either resistance or adverse events, there's nothing preventing Tibotec from sharing what has been learned to date. It is fair to say that most in the audience were unhappy with the lack of direct answers provided by Dr. Santoscoy.
Until such time as Tibotec chooses to share detailed information on both adverse events and resistance, all we can say is that we don't know. Project Inform hopes that Tibotec doesn't wait long to provide the activist and scientific communities all the information we need to better understand rilpivirine.
While all 3 doses of rilpivirine reduced HIV levels equally, the higher doses were more likely to cause a change in heart rhythm called Q-T prolongation. The lower 25mg dose was chosen to move forward into larger studies. Martin Delaney, founder of Project Inform, wonders if 25mg worked as well as it did, and should an even lower dose be just as effective?
In the evening following this presentation, a member of Tibotec's research and development team responded to Project Inform's request for clarification on the outstanding issues regarding resistance and adverse events. Here is what we learned:
The most common NNRTI associated mutation that emerged in people experiencing virologic failure on rilpivirine was 138K. Earlier laboratory work had found that this mutation had only a small affect on rilpivirine's potency. One person in this study had this mutation at the beginning of the study and remained undetectable at 48 weeks.
More work will need to be done to see if 138K -- which was recently added to the IAS list of NNRTI associated mutations -- is indeed responsible for the virologic failures seen in this study.
The one adverse event that was seen significantly more often in people taking rilpivirine was anemia. All the cases of anemia were seen in people taking AZT, and improved when they switched from AZT to tenofovir. It's interesting to note that people taking AZT with Sustiva had lower rates of anemia than either people on rilpivirine in this study or people taking AZT + Sustiva in other studies. It might be that there's a synergistic relationship between rilpivirine and AZT, leading to higher rates of anemia, or it could be from chance. Earlier research on shorter term use of rilpivirine, both in HIV-positive and -negative people did not show anemia.
It should be noted that this information came from a phone conversation between Project Inform and a representative from Tibotec. Project Inform has not yet seen actual data on either resistance or adverse events. When such data are made available, we will promptly report them.