A new pill, for now called MK-8527, has the potential to prevent HIV infection for up to a month in its current formulation.(Photo: Freepik) 
There are several antiretroviral formulations proven to prevent HIV infection: a daily pill, two different jabs that offer protection for two and six months, respectively, and a vaginal ring for women that has to be replaced monthly. In a few years, a long-acting pill may join the ranks, if it works.
The pill, for now called MK-8527, has the potential to prevent HIV infection for up to a month in its current formulation. It is a nucleoside reverse transcriptase translocation inhibitor, which means it disrupts a specific step in the cycle by which the virus makes copies of itself.
The pill is now moving on to pivotal phase-three trials after promising results from a smaller phase-two study presented at the International Aids Society (IAS) conference held in Kigali, Rwanda.
The phase-two study, conducted in trial sites in South Africa, the US and Israel, showed that MK-8527 was well tolerated and had a safety profile similar to a placebo. It also showed the levels of the antiretroviral were at the required levels in participants’ bodies, although the study was not designed to determine whether it is effective.
Whether MK-8527 actually prevents HIV infection will now be tested in two large phase-three studies in multiple countries, including South Africa. In these studies, the efficacy of the monthly pill will be compared with that of a daily HIV prevention pill already widely available in South Africa’s public sector. The daily pill contains the antiretroviral drugs tenofovir disoproxil fumarate and emtricitabine.
Latest findings
The phase-two study looked at three different doses of the monthly pill – 3mg, 6mg and 12mg – as well as a placebo. The 350 participants, about one third of whom were from South Africa, were given one pill (either an active pill or placebo) every month for six months. They were monitored for at least two months afterwards. None of the participants acquired HIV during the study.
The researchers enrolled adults who were at a low risk of being exposed to HIV and excluded pregnant and breast-feeding women, and people who had previously used MK-8527 or a similar antiretroviral drug called islatravir, said Dr Kenneth Mayer, a professor of medicine at Harvard Medical School, who presented the findings in Kigali last week.
The levels of the antiretroviral in the blood of all the participants were measured on day one and two, on the last day of taking the pill, and again at the first follow-up visit after stopping the pill. Based on these results, Mayer said there doesn’t appear to be a build-up of drug in the body that might prove toxic over time.
This supports evaluating the use of a monthly pill over a longer time period (than the six months in the study), he said, “without concern that increasing drug levels will cause toxicity after a longer period of monthly administration”.
About 20 participants across the three active pill arms were monitored more closely to measure the levels of MK-8527 triphosphate in their blood at each study visit. Results showed that the 6mg and 12mg doses kept levels at “above the threshold of protection” for just more than 28 days.
Apart from staying in the body for a long time, it also seems that the drug works very quickly. Mayer told delegates that modelling, informed by measurements of how the drug is taken up in the body, suggests that the pill could offer protection against HIV infection potentially as soon as an hour after taking it.
How safe is it?
Since HIV-prevention medicines are offered to healthy people, or at least people who are not living with HIV, the safety of these drugs is particularly closely watched. This is because the risk-benefit trade-off is different than it is for people who are living with HIV and might be willing to accept more side effects if it means the medicines are keeping them alive and healthy.
The most common side effects reported in the phase-two study were headache, nausea and fatigue. The rates of these side effects were similar between participants who got the antiretroviral pills and those who got the placebo.
One concerning event in the 3mg arm was a spontaneous abortion at six weeks into a pregnancy. According to Mayer, this was seen as a serious adverse event related to the study drug. He explained that although he didn’t have all the details from the safety records, he understood that the participant had previously experienced pregnancy losses, but most if not all were induced.
“She did not have any other medical conditions that were associated with adverse pregnancy outcomes, so we had to consider the event related to the study medication, out of an abundance of caution, since this was a safety trial,” Mayer told Spotlight.
Participants had tests done to check their CD4 levels (an indicator of immune system health) and lymphocyte (a type of white blood cell) counts at each study visit. A significant drop in either or both of these indicators would lead to the drug being stopped. Mayer explained that CD4 and lymphocyte counts were specifically monitored because the monthly pill has the same mechanism of action as another drug called islatravir, which in high doses resulted in a decrease in both these counts.
“MK-8527 is chemically different [to islatravir], but since they both inhibit these steps in the virus life cycle, it was important to monitor these parameters during the safety trial,” Mayer said. “Fortunately, we did not see a significant trend affecting these clinical lab values.”
Only two participants dropped out of the study because of side effects in the two higher dose groups. One person from the 12mg arm dropped out because of hypaesthesia, which is a loss of sensation or numbness. Another person in the 6mg arm left because their CD4 and/or lymphocyte count dropped to levels that met the study’s rules for stopping the pill.
In the next few years, the larger phase-three studies should provide much more extensive and detailed data on the safety and side effect profile of MK-8527.
Is there a place for a monthly pill?
At last year’s Aids conference, delegates celebrated the success of the PURPOSE 1 and 2 trials that showed remarkable protection offered by lenacapavir, a long-acting HIV-prevention jab. It reliably offers protection against HIV infection for six months at a time. In June, it was approved for use by the US Food and Drug Administration for HIV prevention. It was previously approved only as treatment for hard-to-treat HIV.
In July, the World Health Organization released guidelines recommending its use for HIV prevention. Lenacapavir has not yet been registered by the South African Health Products Regulatory Authority.
Although most of the focus in HIV circles is still on lenacapavir, experts told Spotlight that even though MK-8527 may potentially only protect against HIV for about a month at a time, it could still be a useful option for HIV prevention.
“There is a real place for a long-acting, non-injectable PrEP [pre-exposure prophylaxis)]. And we believe there really is a role for a monthly pill – they are small [and] easy to take,” said Professor Linda-Gail Bekker, CEO of the Desmond Tutu Health Foundation and director of the Desmond Tutu HIV Centre. “There is potential for giving all 12 pills in one go or three pills in one go, or any variation,” she added.
This potential future option, provided it works, comes at a time when there is plenty of financial upheaval with the sudden termination of research funding and aid by the US. For Bekker, the hope is that a pill for prevention may prove to be an affordable and accessible option.
Mitchell Warren, executive director of the Aids Vaccine Advocacy Coalition, told Spotlight that a monthly pill for prevention will not replace but add to the existing basket of HIV prevention options.
“It may help people who have a hard time adhering to daily pill-taking. It will help people who don’t want to get an injection,” he said. “It [MK-8527] is just 12 pills a year – that’s a remarkable advance.”
Next steps — the phase-three trials
Merck, the pharmaceutical company that’s developing the pill, announced that, later this year, MK-8527 will be evaluated at clinical trials sites across the globe in two large phase-three studies called EXPrESSIVE-10 and EXPrESSIVE-11.
The studies will determine the safety and tolerability of the monthly pill, and whether it works as well as or better than the standard of care at preventing HIV.
“If MK-8527 is found to be comparable or superior to daily oral PrEP, it could be a game-changer for the HIV prevention field, offering people a simple way to protect themselves which would not require daily medication or injections,” said Mayer.
Warren said that, like the PURPOSE studies, if a woman becomes pregnant during the study, she will have the option to give consent again and continue. This allows researchers to collect data on pregnant and breast-feeding women too.
Although results from the phase-three studies are at least two years away, Merck appears set to try to roll out the product as soon as possible if it is successful.
“We are pursuing very optimistic and aggressive timelines,” said Dr Rebeca Plank, a scientist in clinical research at Merck, during an IAS press conference. DM
This article first appeared in Spotlight.
This story appeared in our weekly Daily Maverick 168 newspaper, which is available countrywide for R35.
