AIDS 2024, the 25th International AIDS Conference

With PrEP effort lagging, positive results for twice-yearly lenacapavir may give a lift

Because of the lack of a vaccine, pre-exposure prophylaxis (PrEP) with antiretroviral medication is currently seen by most HIV/AIDS experts as the best way to prevent new infections. But PrEP programs, in the U.S. and internationally, are lagging far behind their goals. The dependence on PrEP and shortfalls in current programs made the positive results for lenacapavir reported at the International AIDS Societyconference even more noteworthy.

Lenacapavir is administered as a subcutaneous injection in the abdomen twice a year. Currently, most PrEP regimens involve taking pills daily. Experts and others are hoping that a relatively long-acting injectable will be far more acceptable.

Results from the PURPOSE 1 trial, which were published simultaneously in the New England Journal of Medicine (NEJM), showed that none of the 2,134 cisgender women randomly assigned to lenacapavir PrEP were infected with HIV and that serious side effects were rare, affecting 4% of those in the lenacapavir arm.

Gilead, the maker of lenacapavir and sponsor of the trial, said in a news release announcing the positive results that it expects to see results from PURPOSE 2, a trial of lenacapavir among cisgender men, transgender men, transgender women and gender nonbinary individuals, later this year or early in 2025.

The company said in the news release that it plans to include results from both trials in its filings for approval from the FDA and drug regulators “to ensure lenacapavir for PrEP can be approved for multiple populations and communities most in need of additional HIV prevention options.” Presuming that lenacapavir is approved, questions about how Gilead will price the preventive product and possible technology transfer to generic companies are looming on the horizon, as most of the new 1.3 million HIV infections that occur annually are in low and middle-income countries.

“These data confirm that twice-yearly lenacapavir for HIV prevention is a breakthrough advance with huge public health potential. If approved and delivered — rapidly, affordably and equitably — to those who need or want it, this long-acting tool could help accelerate global progress in HIV prevention,” Sharon Lewin, president of IAS, said in a prepared statement.

Lenacapavir is approved as a treatment and marketed under the name Sunlenca for that purpose.

Moupali Das, M.D., M.P.H.

Experts have been urging drug developers to include pregnant women and adolescents in HIV/AIDS treatment trials. Corresponding investigator Moupali Das, M.D., M.P.H., executive director, HIV clinical research, at Gilead, and her colleagues reported that there were 510 pregnancies among the study participants, including 193 in the lenacapavir group. None of those who were pregnant acquired HIV. The trial included 124 women ages 16 or 17.

The PURPOSE 1 results were heralded at the meeting but did not catch anybody off guard. The trial was halted last month, and the positive results were announced in a Gilead news release in June. The IAS presentation and the publication in NEJM filled in details, but the outline of the positive results was known.

Das and her co-authors noted that other PrEP options, which include a vaginal ring that delivers dapivirine and Apretude (cabotegravir), which is also injected but on a more frequent every-other-month schedule, as well as the daily pills. “Nevertheless,” they wrote in the discussion section of the NEJM paper, “PrEP use remains suboptimal among women, particularly in populations with disproportionate HIV incidence, including young women, women in Africa, women of color in the United States and migrant women in multiple countries. Twice-yearly lenacapavir offers a highly effective and discreet choice to potentially improve PrEP use among women.”

The Purpose 1 trial enrolled cisgender women at 25 sites in South Africa and three in Uganda. They were randomly assigned to lenacapavir, once-daily Descovy (200 milligrams [mg] of emtricitabine and 25 mg of tenofovir alafenamide), or once-daily Truvada (200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate). The trial did not include a placebo group because having an untreated group was deemed unethical. Instead, the main comparison was the background incidence of those screened for the trial, which was calculated at 2.41 infections per 100 person-years.

With no cases, the incidence of infections in the lenacapavir group was zero per 100 person-years. There were 39 infections among the 2,136 participants randomly assigned to Descovy, which worked out to 2.02 infections per 100 person-years, and 16 among the 1,068 assigned to Truvada, which worked out to 1.69 infections per 100 person-years. In the Descovy and Truvada groups, most of those who became infected with HIV had levels of antiretroviral medicine in their blood that suggested that they were not taking the pill on a daily basis.

The results reported in NEJM didn’t set off any strong safety signals about lenacapavir as PrEP. The most common side effect was injection-site reactions; 69% (1,470 of 2,138) had those, but all but four were categorized as mild (grade 1 or 2). Aside from injection-site reactions, the most common side effects in the lenacapavir group were urinary tract infection (14.4%), headache (13.3%) and genitourinary chlamydia infection (14%). Those proportions were similar to those seen among the participants who were assigned to the Descovy and Truvada arms of the trial.

Another patient has been cured of HIV, but this case is different

Another patient appears to have been cured of HIV following a stem cell transplant, making this the seventh person who has achieved remission from HIV and has been able to stop taking antiretroviral medications, according to a case presented by Christian Gaebler, M.D., professor for translational immunology of viral infections at Charité — Universitätsmedizin Berlin. The presentation was made at a press conference several days before the start of the International AIDS Society conference.

Even more important is that this is the first case of remission in which the stem cell donor had a single, rather than double, CCR5-delta32 mutation. In previous cases of remission following stem cell transplants, the stem cell donors had two copies of the CCR5-delta32 mutation, which hampers HIV’s ability to infect cells.

“We believe that this remarkable case and the results of our studies really suggest that it is possible to cure HIV, even when the functional receptor for the virus is present. And it shows us that polygenic immunity plays a fundamental role in HIV eradication beyond this rare Delta 32 CCR5 mutation,” Gaebler said at the news conference.

The patient in this case, who has chosen to remain anonymous, was diagnosed with HIV in 2009 and then required chemotherapy and stem cell transplantation to treat acute myeloid leukemia in 2015. Gaebler and his team were unable to find a donor with two copies of the CCR5-delta32 mutation, but a donor with one copy was found.

“The allogeneic stem cell transplantation went well,” Gaebler said. “It was well tolerated and successfully treated the blood cancer. However, to our great surprise, it also became clear that the stem cell transplantation had effectively depleted the HIV reservoir after the patient discontinued his recommended antiviral treatment on his own in 2018.”

Gaebler said that since then, the patient has been in remission and has shown no detectable HIV in his blood. “We’ve performed comprehensive HIV reservoir testing, including in blood but also various tissues from tissue reservoirs, and we have found no signs of HIV,” he said. “In addition, HIV-specific antibody levels decreased since the transplantation and HIV-specific T-cell responses were undetectable.”

He suggested in a question and answer session that immunity from the allogeneic stem cell transplantation is what led to the depletion of the HIV reservoirs, and the addition of the CCR5-delta32 mutation added protection with a resistant immune system.

Researchers suggest the stem cell donor pool could be expanded to those with one copy of the CCR5-delta32 mutation. This also opens the doors to more cures for HIV, possibly based on gene therapy. Gaebler said a possible gene therapy could target the CCR5 receptor. “These human cases really show us that maybe it would be possible to achieve a level of reservoir depletion reduction that could lead to long-term HIV cure cases.”

Should HIV vaccine development still be a priority?

Leading AIDS experts addressed frequently asked questions at the International AIDS Society conference about whether developing an HIV vaccine should remain a priority. HIV vaccine development has recently faced significant setbacks, with trials such as PrEPVacc, Mosaico and Imbokodo ending early due to a lack of preventive efficacy. Meanwhile, hopes are riding high for HIV pre-exposure prophylaxis (PrEP), partly because of the positive phase 3 results for lenacapavir reported at the conference.

Jeanne Marrazzo, M.D., M.P.H.

Jeanne Marrazzo, M.D., M.P.H., director of the National Institute of Allergy and Infectious Diseases (NIAID), highlighted during her co-presentation that these discussions should be celebrated due to the “rich options” of therapies that are available today.

“We at NIAID, and I think in general, the scientific field, are 100% committed to continuing to work full speed and very deeply on the development of an HIV vaccine,” Marrazzo said. “The process has been an incredible path to basic discovery science that has led to a better understanding of the immunology required to generate protection. This has taken us in directions we couldn’t have envisioned 10, let alone 20, years ago.”

Marrazzo emphasized that achieving a cure and eliminating HIV must involve an HIV vaccine.

“These are incredible tools that we’re beginning to bring forward, but I don’t think that we’re going to get there with antiviral therapy as prevention alone,” she said.

“I think we cannot, and I’ve said this before, take our foot off the gas to advance vaccine science,” she added. “With the incredibly exciting publications and results that have come out just in the last six months, the path forward is much clearer than it ever has been. Now is not the time to quit.”

Also during the session, Maureen Luba, M.M.Sc., who works with several organizations, including the AIDS Vaccine Advocacy Coalition, highlighted significant financial barriers to accessing HIV vaccines.

Luba shared that while the need for an HIV vaccine remains critical, financial constraints impede progress, especially in low- and middle-income countries.

“We are in a time where the HIV landscape is facing a very difficult time in terms of funding,” Luba stated, noting that HIV funding is at a standstill. Governments in these regions are continually urged to domestically finance their HIV responses.

Although there are available HIV prevention tools, structural barriers still limit access, with only about 6 million people having initiated PrEP since its introduction.

She stressed the need for sustained funding for HIV vaccine research and development, collaboration between researchers and the industry, and the importance of local manufacturing capacity in Africa.

Luba added that an HIV vaccine could potentially address cost concerns and improve access, particularly for those less likely to engage with traditional healthcare settings.

In a panel session at the end of the presentation, Mark Feinberg, M.D., Ph.D, president and CEO of the International AIDS Vaccine Initiative, agreed, adding that those in the pharmaceutical industry need to move forward with the HIV vaccine effort.

“I’m happy to say that we, I think, have a clear path forward. Whether it will be successful or not, I don’t know, but it’s really important that we maintain the commitment to that goal,” he said.

Chronic viral infections common in those with HIV

Chronic viral infections from diseases such as herpes simplex virus (HSV), human papillomavirus (HPV) and cytomegalovirus (CMV) can have a serious impact on those with immune systems already compromised by HIV, according to research presented at the International AIDS Society meeting.

Léna Royston, M.D., Ph.D., a researcher in the chronic viral illness service at McGill University Health Centre in Montreal, Canada, discussed CMV, which is in the herpes family and is extremely common. It is not considered a sexually transmitted infection. Most people will contract CMV in their lives but will be symptomatic only if they a have compromised immune system from another infection such as HIV. In advanced stages of HIV infection, CMV can lead to nausea, headaches, fever, confusion and even blindness. According to Royston, people living with HIV have the highest prevalence in the global CMV population. “We think,” she said, “that there might be some kind of synergy between the two viruses on immune activation and immunosenescence.” Immunosenescence refers to age-related changes in the immune system. As people get older, their immune systems usually weaken. The main way CMV is treated is through antiviral drugs, which have a high rate of toxicity, leading to
further complications.

Nelly Mugo, associate research professor of global health at the University of Washington and the Center for Clinical Research, Kenya Medical Research Institute, discussed HPV. She estimated that 5% of all cancers are caused by HPV. About 85% of those cancers are cervical cancer, Mugo said.

“In the HPV world, especially related [to] cervical cancer, we know a lot, but we implement really poorly,” Mugo said. “We have very high recurrence among women living with HIV.”

“The road looks clear because we know what the pathogen is and what to do about it, [but] we’re unable to deliver so the outcome is still a distance away from us,” she said.

Anna Wald, M.D., a professor of epidemiology, medicine, and laboratory medicine and pathology at the University of Washington and co-director of the virology research clinic, discussed HSV, a disease characterized by painful blisters and ulcers that are often spread by sexual contact. People with HIV are two to three times more likely to contract HSV because the open sores provide a pathway for the virus to travel from partner to partner during sex. There are currently no biomedical interventions for HSV prevention that are effective. It is not curable, but it can be managed with daily antiviral medication.

“I think there’s a huge need for an accurate test,” Wald said. “People both with HIV and without HIV want to know their HSV status. We can’t really control a disease unless we have reliable diagnostics.”

Thumbs-up results for injectable Cabenuva in the real world

One-year results from a real-world study of Cabenuva (cabotegravir/rilpivirine) presented at the International AIDS Society conference showed that switching to injectable HIV medication improved patients’ outlook and kept viral loads low.

Cabenuva, approved by the FDA in 2021, is delivered as a pair of intramuscular shots — one of cabotegravir and one of rilpivirine — usually every two months. A healthcare professional delivers the shots. Long-acting injectable formulations are coming on strong as an alternative to daily pills for HIV treatment for several reasons. The shots are more convenient; increase adherence; and are just as, if not more, effective than daily pills, partly due to better adherence.

The BEYOND trial, which is sponsored by ViiV Healthcare, the maker of Cabenuva, is a two-year study of the utilization, outcomes and experience of people living with HIV after they started treatment with Cabenuva. It is being conducted at 30 sites in the U.S. A total of 308 people living with HIV were enrolled in the study. At the six-month mark, 36 had dropped out. A year out, 245 remained on treatment.

Cindy Garris

Cindy Garris, M.S., senior director of U.S. health outcomes at ViiV Healthcare, presented findings from the BEYOND trial that showed that 181 (97%) of the 187 people who started the study with a viral load at less than 50 copies per milliliter (c/mL) were still at that level after a year of treatment. All 13 of the people who started the trial at 50 c/mL or higher and who were still receiving treatment had viral loads of less than 50 c/mL. There was one case of confirmed virological failure, defined as two consecutive viral load measurements of 200 c/mL or more or one such measurement followed by discontinuation of Cabenuva.

The results from the real-world trial were similar to those seen in the phase 3 trials of Cabenuva, according to Garris and her colleagues.

William Valenti, M.D., co-founder and staff physician at Trillium Health and a professor of clinical medicine at the University of Rochester in New York, presented the findings from BEYOND about people’s experiences and outlook. At the start of the study, just under half (49%) of participants reported sometimes, often, or always hiding their oral medication out of fear of showing their HIV status. After a year of treatment with Cabenuva, that percentage had fallen to 15%, and two-thirds of the BEYOND trial respondents indicated that they never were concerned about their HIV status becoming known. The vast majority (97%) of the study participants indicated that they preferred Cabenuva, and less than 1% preferred daily pills.

The responses to the surveys showed that an additional benefit of seeing a healthcare professional to get the shots was a greater opportunity to discuss HIV treatment and other issues with a healthcare provider on a regular basis.

Pediatric AIDS: Progress but then a plateau

Despite substantial progress in reducing vertical transmission from mothers to children, efforts to curtail HIV/AIDS among children and adolescents are plateauing in some respects and falling short of the goals set by the Joint United Nations Programme on HIV/AIDS (UNAIDS), according to a leading investigator of HIV/AIDS treatment of children.

Speaking for 40 minutes at the opening plenary session at the International AIDS Society conference, Anna Turkova, M.D., spoke optimistically about the potential for long-acting injectable antiretrovirals to alter the course of pediatric AIDS worldwide while also emphasizing the importance of nonpharmaceutical interventions that provide social support.

“Antiretrovirals alone can’t treat HIV. To keep children and adolescents alive and enable them to reach their life potential, families and young people need support in many areas,” said Turkova, including food, nutrition, education and dealing with stigma. Turkova singled out SEARCH Youth, a youth-focused program tested in Kenya and Uganda, as a “beautiful example” of an intervention that didn’t depend on antiretrovirals and was effective in increasing virologic suppression.

Turkova, a research clinician at the Comprehensive Clinical Trials Unit at University College London, England, is the lead investigator on several large global trials assessing new treatments for HIV and AIDS. She led the ODYSSEY trial, conducted in South Africa, Uganda and Zimbabwe, which established that dolutegravir-based antiretroviral therapy was superior to other regimens in children and infants.

Setting the tone for the conference, Turkova balanced praise for achievements in the global effort to combat pediatric AIDS with data and observations chronicling recent shortcomings and flagging efforts.

In 2023, there were 1.4 million children in the world living with HIV and an additional 1 million older adolescents, ages 15-19, infected with the virus. Most live in the global south, Turkova said, and 60% in eastern Southern Africa. Turkova noted the striking similarity between a map showing where children living with HIV reside and one showing impoverished populations.

That’s the statistical and geographic backdrop to what Turkova said was the “remarkable progress” made in stopping vertical transmission of HIV from infected mothers to children, which is accomplished by having both mothers and children take antiretroviral medication. The number of new infections has been halved over the past decade and the number of AIDS-related deaths among children has dropped by more than that, according to Turkova.

Programs to stop vertical transmission of syphilis and hepatitis B are also meeting with some success. “We are now firmly on the path of triple elimination of vertical transmission of HIV, syphilis and hepatitis B,” Turkova told the IAS conference attendees. “Prevention of three infections allows us to leverage cross-cutting opportunities for investments across many areas and make a substantial impact on health outcomes in children.”

Turkova said that Cuba, in 2015, was the first country to eliminate HIV vertical transmission, and now 18 have validated that they have done so. She credited the validation process with requiring the government to commit to policies and prioritize women’s health.

But Turkova did not take a victory lap. Progress in halting vertical transmission has slowed; in 2023, the vertical transmission rate was 10% worldwide, she said. Some regions (Eastern Europe, Central Asia) have made strides, but others haven’t. Turkova noted that in North Africa and the Middle East, where the use of antiretroviral medication is not common, the vertical transmission rate is 1 in 3 among infants exposed infants.

Globally, just under half of all new infections of infants are due to infected mothers not being treated with antiretroviral therapy when they are pregnant or breastfeeding, and a quarter occur in women who have been newly infected, Turkova said. Approximately 43% of new infections in infants occur during breastfeeding.

“These data call for better programs — for mothers to be tested, [be] diagnosed, and receive ART [antiretroviral therapy] during pregnancy and throughout breastfeeding,” Turkova said. Children and adolescents are lagging behind adults when it comes to two of the three of UNAIDS’ 95-95-95 goals, testing and virological suppression, according to data
cited by Turkova.

Among adults living with HIV, 87% have been tested and identified as being infected with the virus. The UNAIDS goal is 95% (thus the 95-95-95 label for the goals). Among children, that percentage is just 66%, according to Turkova. There is also a gap between treated adults achieving virological suppression (94%) and children who have done so (84%).

Early infant diagnosis (EID) programs identify children who haven’t been tested for HIV. Health officials in Eastern Europe, Central Asia and eastern Southern Africa have embraced the approach, Turkova said, and coverage in those regions is 80%.

She discussed some of those programs’ limitations. For example, they are not likely to identify infants living with HIV if their mothers are not engaged with the healthcare system. Turkova said programs that deal with HIV at the community level would help improve testing. She also said that stigma and ignorance about HIV are factors in testing and other shortfalls in HIV prevention and treatment. “If we want to find undiagnosed children, we all need to take action to improve knowledge of HIV in the general population,” she said.

Turkova discussed various oral regimens for treating HIV in children, noting that resistance to an important antiviral, dolutegravir, is beginning to occur. Groups are collaborating to make generic alternatives to dolutegravir available in low- and middle-income countries. Generic versions of the TAF/XTC regimen — which consists of tenofovir alafenamide and either emtricitabine or lamivudine — are not available. Turkova said the absence of a generic version poses equity issues that call for urgent action to address them.

She emphasized that choice is important in treatment and that access to long-acting injectable antivirals as an alternative to oral drugs is essential. Turkova said the long-acting injectable could revolutionize the prevention of vertical transmission of HIV if it were to be used broadly as pre-exposure prophylaxis for women during pregnancy and breastfeeding and as postnatal prophylaxis for infants. The long-acting injectables include cabotegravir, which is marketed under the name Apretude, and lenacapavir, which is marketed under the name Sunlenca.

“But we need now a clear plan for rapid, equitable and affordable access to long-acting injectables, and for this we need to combine our efforts,” Turkova said. “We need strong community advocacy. From the pharmaceutical companies we need voluntary licensing — and not only for prevention but also for treatment. We need technology transfer to generic companies. We need targeted donor investment, accelerating generic development. And from researchers we need adult studies to include adolescents and pregnant women.”

Addressing HIV service gaps through young people

A panel of HIV leaders from around the world discussed the importance of empowering youth to prevent and treat HIV/AIDS at the International AIDS Society conference.

Adolescents and young people represent a growing population of HIV positive individuals. In 2022, 480,000 people ages 10 to 24 were diagnosed with HIV. Although this number has been cut almost in half in the last decade, numbers are still not low enough to reach the 2030 HIV goals, which aims to reduce new HIV cases worldwide by 90%. HIV testing in youths is especially important, say experts and advocates, because young people are more likely to engage in riskier behaviors.

When it comes to designing effective youth programs and projects, you must involve young people from the very beginning of the planning, said Lesley Gittings, Ph.D., an assistant professor at Western University in Ontario. “When young people are engaged early in program design, programs are way more relevant and effective,” Gittings said. “Young people are a unique group and as adults, we often don’t get it right.”

Rashida Ferrand is a clinical HIV specialist and professor at the London School of Hygiene and Tropical Medicine. As part of her research, which included an advisory board made up of young people, Ferrand and her colleagues distributed condoms with the phrase “have fun sex” on them to appeal to the age group.

One of the largest obstacles to engaging youth in HIV care is that people don’t fully understand what it means for them to participate, according to Tanyaradzwa Makotore, a DREAMS PrEP ambassador from Zimbabwe. “Sometimes people are just ticking boxes,” Makotore said. “An organization will send 10 young people to a conference, but when they get there, what exactly are they doing? Young people should be invited to places to fully participate.”

Grace Kamau, regional coordinator at the Africa Sex Workers Alliance explained how she and her colleagues reach out and support young women who come to their clinics. “You can lead a normal life with HIV, you can go to school. HIV does not affect your brain,” she said. “We let them know they can live normal lives on immunosuppressants.”

ViiV Healthcare will not continue trials of subcutaneous Cabenuva

A subcutaneous version of Cabenuva (cabotegravir and rilpivirine) has similar efficacy to the intramuscular injection in maintaining suppression of HIV, but many patients in a substudy of the phase 3 FLAIR trial found the self-injectable to be painful and led to nodules and reddening of the skin, according to results presented at a session at the International AIDS Society conference

“The sub q injections led to a higher incidence and longer duration of ISR [injection site reactions], resulting in lower acceptability of and satisfaction with sub q injections. As a result, further development of this treatment regimen for sub q self-administration will not be pursued,” said Ronald D’Amico, associate medical director at ViiV Healthcare, who presented the study during a session at the AIDS Conference.

Developed by ViiV Healthcare, Cabenuva is a long-acting therapy for patients 12 years and older with HIV to maintain virus suppression. It is approved by the FDA to be given as an intramuscular injection.

In the substudy, 93 patients received intramuscular injections during screening, three subcutaneous injections at day 1, week 4 and week 8. They returned to intramuscular injections at week 12 and week 16.

Although this was not a formal bioequivalence study, D’Amico said plasma exposures were comparable for intramuscular and subcutaneous administration. No participant experienced a suspected or confirmed virologic failure. But at week 9, 59% of 85 participants preferred the intramuscular injections, most commonly citing less injection site swelling and fewer nodules, and 34% of 85 participants preferred subcutaneous injection, most commonly citing convenience. The most common injection site reactions from the subcutaneous injection were pain (48%), nodules (34%) and redness (26%). Five participants withdrew because of injection site reactions from the subcutaneous version. There were no noninjection site reactions that led to withdrawal.