In June, we heard what could be this year’s biggest HIV breakthrough: a twice-yearly injection can prevent HIV infection. Findings from a second large study of the jab have now confirmed that it works, writes Elri Voigt in Spotlight.
The second of two pivotal studies of the six-monthly HIV prevention injection containing the antiretroviral drug lenacapavir has confirmed that the jab works remarkably well.
The first study, PURPOSE 1, found it was safe and highly effective at preventing HIV infection in women. The second, called PURPOSE 2, found the same for cisgender men, transgender men, transgender women and non-binary people who have sex with men assigned male at birth.
Interim findings from PURPOSE 2 were presented last week at the HIV Research for Prevention (HIVR4P) conference in Lima, Peru.
The researchers compared the safety and efficacy of lenacapavir injections every six months to a daily HIV prevention pill – a combination of emtricitabine and tenofovir disoproxil fumarate, called F/TDF. The results have not yet been published in a peer reviewed journal, but are expected to be soon, said Principal Investigator for PURPOSE 2 Dr Colleen Kelley, a professor of medicine at Emory University’s School of Medicine.
The new results come hot on the heels of findings from PURPOSE 1, previously reported on by Spotlight and published in the New England Journal of Medicine.
In the PURPOSE 1 study, none of the 2 134 people receiving the lenacapavir injection got HIV during the study. In PURPOSE 2, there were two HIV infections among the 2 179 people receiving the injection. These numbers are dramatically better than those for HIV prevention pills and for people in the communities where the study was done who were not receiving prevention injections or pills.
These findings mean the evidence is now in place for the manufacturer, Gilead Sciences, to file with regulatory authorities to register lenacapavir injections for HIV prevention.
Such registration is required before the jab can be marketed for prevention. Lenacapavir injections are already registered in some countries as a last resort treatment for HIV, but not yet in South Africa.
“Now that we have a comprehensive dataset across multiple study populations, Gilead will work urgently with regulatory, government, public health and community partners to ensure that, if approved, we can deliver twice-yearly lenacapavir for PrEP worldwide, for all those who want or need PrEP,” said Daniel O’Day, chairperson and CEO of Gilead.
Top line findings
The interim results presented at HIVR4P by Kelley showed that when compared with the background HIV incidence calculated in the study, lenacapavir reduced HIV infections by 96%. And when compared with the F/TDF prevention pill, the injection reduced HIV infections by 89%.
Among the 3 265 participants enrolled in the study, 11 people acquired HIV: two of the 2 179 people who were assigned to the lenacapavir arm and nine of the 1 086 participants assigned to the prevention pill arm. This translated to HIV incidence of 0.93 per 100 person years in the prevention pill arm compared with only 0.1 per 100 person years in the lenacapavir arm.
This was compared with the background incidence, which was determined when screening eligible participants for HIV. Out of 4 634 people screened for the study, 378 or 8.2% were diagnosed with HIV. Based on further laboratory testing, it was estimated that of those 378 people, 45 or 11.9% recently acquired HIV (classified as being within the last 120 days or so). This latter group provided the background HIV incidence, which was estimated to be 2.37 per 100 person years.
This is a novel study design, Kelley told Spotlight, because this calculation was used to estimate the HIV incidence that would have occurred in a placebo group without actually enrolling a placebo group.
“It’s no longer ethical to have a placebo group in HIV PrEP trials because we know that we have effective PrEP agents,” she said.
“Yet, it’s almost essential to have a placebo group when you design a clinical trial so that you can really say how effective your medication, your new agent is, compared with having nothing.”
When asked at a press conference about the two breakthrough infections in the lenacapavir arm, Kelley said the analysis for this was ongoing and would hopefully be available at a future conference and in a journal soon. She said that the two breakthrough infections in the lenacapavir arm were detected by routine testing during the study.
Kelley added that around 90% of participants in the two study arms were able to receive their injection on time. “So, we at least know that the injections were delivered in a timely fashion for almost all participants,” she said.
Whether or not the two infections occurred in people who had received the jabs on time and according to the study protocol will be closely watched as more study details is shared in the coming months.
To be enrolled in the study, participants had to meet several criteria. They had to be older than 16, never received HIV prevention injections before, weigh more than 35kg, have good kidney function, not have been tested for HIV in the past 12 weeks, and had to have been sexually active in the past 12 months.
All study participants were given a pill a day and an injection: those in the lenacapavir arm received two 1.5ml lenacapavir injections every six months and a daily placebo pill, while those in the prevention pill arm received the daily F/TDF pill and a placebo injection every six months.
The study was conducted across seven countries, with six sites in South Africa and others in Argentina, Brazil, Mexico, Peru, Thailand and the United States, according to study data on Gilead’s website.
Safety data
Overall, Kelley said lenacapavir was safe and well-tolerated despite some side effects, mainly related to the injections. A total of 43 people dropped out of the study due to side effects.
The most common adverse event was injection site reactions. There were more injection site reactions in the lenacapavir arm than in the prevention pill arm. A total of 29 people dropped out of the study because of these – 26 in the lenacapavir arm and three in the prevention pill arm (people in this study arm received placebo jabs).
The most common injection site reaction were subcutaneous nodules. These are harmless, usually invisible, small lumps under the skin. Nodules occur because lenacapavir is injected under the skin where it forms a drug depot. Injection site reactions and nodule size decreased with subsequent injections.
This side effect and trend of decreasing reactions was also noted in the PURPOSE 1 study. Other injection site reactions were pain and erythema, a type of skin rash.
There were no serious adverse events related to injection site reactions.
When injection site reactions are excluded, according to Kelley, the other adverse events were similar across both arms, with 74% of participants in each arm experiencing an adverse event. The majority were mild or moderate.
Seven participants in each study arm dropped out due to side effects that weren’t related to injection site reactions. Those who discontinued from the lenacapavir arm will be given prevention pills for a year. This is to protect these participants from potentially acquiring HIV when lenacapavir levels wane, and to reduce the risk of potential drug resistance developing.
There were a few serious adverse events, although Kelley told Spotlight she does not have any additional information on what these were. A serious adverse event is generally classified as something like hospitalisation, a life-threatening condition, an important medical event or adverse pregnancy outcome.
“Usually when we look at something like this, we look at the rates compared in the two arms of the study, and it was 3% in the LEN (lenacapavir) arm and 4% in the F/TDF arm, so they were equal, essentially the same in both.”
There were six deaths during the study, unrelated to the study drugs.
Next steps for lenacapavir
Now that the interim results have been announced, both studies have been unblinded and entered an open-label phase where participants can switch to or continue with the injection.
Professor Linda-Gail Bekker, CEO of the Desmond Tutu Health Foundation, recently said on a webinar hosted by the South African Health Technologies Advocacy Coalition, that study participants are now able to use the PrEP option they’d prefer – either oral PrEP or the injection. This means all participants will be able to access lenacapavir through the studies if they want to use it.
But it may be a while before anyone outside these studies can access lenacapavir as HIV prevention.
“This is an incredible intervention. Now we have to make sure everyone can get it. That’s going to be the most important next step, ensuring everyone who needs this drug has access,” Kelley said.
Gilead’s generic licensing agreement and pricing
The next steps for lenacapavir is that the process to allow for generic manufacturing has started. This month, Gilead released its voluntary licensing agreements with six generic companies for manufacturing cheaper versions of the drug.
Dr Andrew Gray, a senior lecturer in Pharmacology at the University of KwaZulu-Natal, said no South African firms have been included in the voluntary licences – four of them are in India, one in Pakistan, and one in Egypt.
“In essence, they (the generic companies) are allowed to sell their generic versions in a number of identified countries, specified by Gilead,” Gray said.
The agreement lists 120 countries, including South Africa.
Gilead itself will also be prioritising the registration of lenacapavir in 18 countries, which represent about 70% of the HIV burden in the countries named in the licence. The list includes South Africa, Uganda, and Botswana. Gilead says it will start filing for registration with regulatory authorities by year-end.
It will be important to see how quickly Gilead seeks regulatory approval for lenacapavir with the SA Health Products Regulatory Authority (SAHPRA), Gray said. Registration with SAHPRA will be required before the injection can be rolled in this country.
Some countries won’t be able to procure generics
Gilead was criticised for several omissions from the list of countries to which the generic manufacturers can sell, several of which have high HIV incidence. Some of those countries participated in PURPOSE 2, like Brazil, Argentina, Mexico and Peru.
A spokesperson from Gilead told Spotlight the manufacturer’s access policy included tailored approaches to ensure rapid and broad access of lenacapavir and it objectively considered the countries where a voluntary licence would provide the most benefit.
“Gilead’s voluntary licence primarily covers countries based on economic need and HIV burden, which are primarily low- and lower-middle income countries. The voluntary licence also covers certain middle-income countries with limited access to healthcare,” the spokesperson said.
Acknowledging that some middle-income countries do have a high HIV burden, Gilead is “exploring several innovative strategies to support access to LEN for PrEP (if approved), including tiered pricing, and are working to establish fast, efficient pathways to help reach people who need or want PrEP”.
“Ensuring access in middle-income and upper-middle income countries, including those in Latin America, is a priority. Planning for these countries, incorporating input from advocates and global health organisations, is ongoing,” the spokesperson added.
“Additionally, Gilead is committed to ensuring that individuals who participated in the PURPOSE studies have been offered, and will be able to stay on, open label lenacapavir until it is available in their country.”
The company’s decision to license generic manufacturers directly is at odds with earlier calls from several activist groups and UNAids to license via the UN-backed Medicines Patent Pool.
Pricing
It will also be important to see if Gilead will disclose a single exit price for the South African market, said Gray.
In its statement announcing the voluntary licensing agreement, Gilead said it would “support low-cost access to the drug in high-incidence, resource-limited countries through a two-part strategy: establishing a robust voluntary licensing programme and planning to provide Gilead-supplied product at no profit until generic manufacturers are able to fully support demand”.
It is too early to reveal a price for lenacapavir yet, Gilead told Spotlight.
Spotlight previously reported on research that estimated that if produced at sufficient volumes, the price of lenacapavir could be drastically reduced to levels considered affordable by South Africa. For instance, if enough volume were produced to supply 10m people with PrEP, the price for the injection could be as low as $40 per person per year.
At the moment, Gilead supplies lenacapavir for HIV treatment in wealthy countries for about $40 000 per person per year.
Gilead’s lenacapavir product will be the first to register in South Africa and will almost certainly be the only lenacapavir product available here for several years – because it is expected to take generic manufacturers a few years before they can start producing generic lenacapavir.
Based on calculations for other PrEP products, it seems unlikely the Department of Health would be willing to buy lenacapavir at a price significantly above R1 000 per person per year. The HIV prevention pill currently costs government around R800 per person per year.
Study details
Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women
Linda-Gail Bekker, Moupali Das, Quarraisha Abdool Karim et al.
Published in the NEJM on 24 July 2024-10-14
Abstract
Background
There are gaps in uptake of, adherence to, and persistence in the use of preexposure prophylaxis for human immunodeficiency virus (HIV) prevention among cisgender women.
Methods
We conducted a phase 3, double-blind, randomised, controlled trial involving adolescent girls and young women in South Africa and Uganda. Participants were assigned in a 2:2:1 ratio to receive subcutaneous lenacapavir every 26 weeks, daily oral emtricitabine–tenofovir alafenamide (F/TAF), or daily oral emtricitabine–tenofovir disoproxil fumarate (F/TDF; active control); all participants also received the alternate subcutaneous or oral placebo. We assessed the efficacy of lenacapavir and F/TAF by comparing the incidence of HIV infection with the estimated background incidence in the screened population and evaluated relative efficacy as compared with F/TDF.
Results
Among 5338 participants who were initially HIV-negative, 55 incident HIV infections were observed: 0 infections among 2134 participants in the lenacapavir group (0 per 100 person-years; 95% confidence interval [CI], 0.00 to 0.19), 39 infections among 2136 participants in the F/TAF group (2.02 per 100 person-years; 95% CI, 1.44 to 2.76), and 16 infections among 1068 participants in the F/TDF group (1.69 per 100 person-years; 95% CI, 0.96 to 2.74). Background HIV incidence in the screened population (8094 participants) was 2.41 per 100 person-years (95% CI, 1.82 to 3.19). HIV incidence with lenacapavir was significantly lower than background HIV incidence (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.04; P<0.001) and than HIV incidence with F/TDF (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.10; P<0.001). HIV incidence with F/TAF did not differ significantly from background HIV incidence (incidence rate ratio, 0.84; 95% CI, 0.55 to 1.28; P=0.21), and no evidence of a meaningful difference in HIV incidence was observed between F/TAF and F/TDF (incidence rate ratio, 1.20; 95% CI, 0.67 to 2.14). Adherence to F/TAF and F/TDF was low. No safety concerns were found. Injection-site reactions were more common in the lenacapavir group (68.8%) than in the placebo injection group (F/TAF and F/TDF combined) (34.9%); 4 participants in the lenacapavir group (0.2%) discontinued the trial regimen owing to injection-site reactions.
Conclusions
No participants receiving twice-yearly lenacapavir acquired HIV infection. HIV incidence with lenacapavir was significantly lower than background HIV incidence and HIV incidence with F/TDF.
See more from MedicalBrief archives:
Lenacapavir demonstrates efficacy in people with highly resistant HIV
Gilead inks deal for generic HIV drug supply to low-income nations
HIV drug trial success triumph for Professor Bekker
Twice-yearly anti-HIV jab shows total protection – African study