Long-acting injectables can be a good option for people with adherence challenges

IAS-USA guidelines now support cabotegravir / rilpivirine in this population
Dr Aadia Rana at CROI 2024. Photo by Roger Pebody.
Dr Aadia Rana at CROI 2024. Photo by Roger Pebody.

Antiretroviral therapy (ART) using cabotegravir and rilpivirine injections monthly or every other month can be an effective HIV treatment option for people who have difficulty maintaining viral suppression on daily pills due to suboptimal adherence, according to studies presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2024).

The LATITUDE trial gave people intensive support to achieve viral suppression on a daily oral regimen before switching to cabotegravir and rilpivirine injections, in accordance with the current label indication. Another study started the injections directly for people who had difficulty taking pills consistently. In addition, a case series suggests that injectable cabotegravir plus lenacapavir (Sunlenca) may also be a feasible option.

At CROI 2024, Dr Aadia Rana spoke to aidsmap's Roger Pebody about injectable treatment for people with adherence challenges.

“This study shows long-acting technology is safe and effective among the people with HIV who stand to benefit most from its use,” said lead investigator Professor Aadia Rana of the University of Alabama at Birmingham. “Offering an effective alternative for people who have struggled with taking daily ART could provide life-changing freedom from the stress of unsuppressed HIV.”

Injectables after pills

Modern ART regimens are highly effective and generally well tolerated, so treatment success often comes down to consistent use. Some people have difficulty maintaining good adherence because they forget to take their pills, don’t want to think about HIV every day, are concerned about having pill bottles that could reveal their HIV status or are in living situations where their pills could be lost or stolen.

“Only about 65% of people with HIV diagnosed in the US are estimated to be virally suppressed on daily oral tablets due to issues including mental health and substance use challenges, competing responsibilities and financial constraints and stigma,” Rana told reporters at a media briefing.

For some of these individuals, long-acting treatment may be a better option. Injectable formulations of the integrase inhibitor cabotegravir (Vocabria) and the NNRTI rilpivirine (Rekambys) comprise the first complete antiretroviral regimen that does not require daily pills. (In North America and Australia, the two drugs are marketed together as Cabenuva.) The treatment involves two intramuscular injections administered by a healthcare provider once monthly or every two months.

Phase III clinical trials showed that long-acting cabotegravir and rilpivirine work as well as daily pills for treatment-experienced people switching from a standard oral regimen with an undetectable viral load, as well as for those new to treatment who achieved viral suppression on a temporary oral regimen before switching to injections. However, these studies did not include people with unsuppressed virus or adherence challenges. Both the European Medicines Agency and the US Food and Drug Administration limited the approval of injectable cabotegravir and rilpivirine to people with viral suppression on a stable antiretroviral regimen, no history of treatment failure and no resistance to either drug.

The phase III LATITUDE trial (NCT03635788; ACTG A5359) focused on people who face challenges using oral treatment. The study enrolled 434 people at more that 30 US sites who either had poor virological response (persistent viral load above 200 despite oral ART for at least six months) or had been lost to clinical follow-up with ART non-adherence. They were screened to ensure that their HIV was not resistant to the study drugs and that they met other health and safety criteria.


virological suppression

Halting of the function or replication of a virus. In HIV, optimal viral suppression is measured as the reduction of viral load (HIV RNA) to undetectable levels and is the goal of antiretroviral therapy.


Refers to the mouth, for example a medicine taken by mouth.


In pharmacology, a medication which maintains its effects over a long period of time, such as an injection or implant.

middle income countries

The World Bank classifies countries according to their income: low, lower-middle, upper-middle and high. There are around 50 lower-middle income countries (mostly in Africa and Asia) and around 60 upper-middle income countries (in Africa, Eastern Europe, Asia, Latin America and the Caribbean).

low income countries

The World Bank classifies countries according to their income: low, lower-middle, upper-middle and high. While the majority of the approximately 30 countries that are ranked as low income are in sub-Saharan Africa, many African countries including Kenya, Nigeria, South Africa and Zambia are in the middle-income brackets. 

A majority (65%) were men, the median age was 40 years and 20% were age 30 or younger. Nearly two thirds were Black, 27% were White and 17% were Latino. People with active drug or alcohol use or unstable housing were included, and 14% had a history of injection drug use. About 14% had a high viral load (above 100,000) and the median CD4 count was quite low, at 270.

Participants first used a standard three-drug oral regimen for up to 24 weeks while receiving comprehensive adherence support and financial incentives to achieve viral suppression. Eligible participants with viral suppression (below 200) were then randomly assigned to either continue the same oral regimen or switch to cabotegravir and rilpivirine injections administered once monthly for a year.

As previously reported, the study was stopped early after a planned interim review found that the injectable regimen “demonstrated superior efficacy in maintaining viral load suppression compared to daily oral therapy in individuals with a history of ART adherence challenges,” according to a ViiV Healthcare news release.

Rana presented more detailed study results at CROI. A total of 294 eligible participants were randomised. Although they had to have viral suppression to meet the eligibility criteria, 17% in the cabotegravir and rilpivirine arm and 7% in the standard care arm had a viral load above 200 when they started the randomised treatment.

More than 90% of people assigned to cabotegravir and rilpivirine received their injections on time, while 3% had delayed injections and 3% missed injections. At 52 weeks, 24% of people on cabotegravir and rilpivirine and 39% of those on daily pills experienced regimen failure, meaning virological failure or treatment discontinuation.

This primary endpoint narrowly missed the threshold for statistical significance, but secondary endpoints favoured the injections. Only 7% of those who received cabotegravir and rilpivirine experienced virological failure compared with 25% who stayed on daily pills. Of these, two in each group had new resistance-associated mutations. Treatment-related failure rates, which included virological failure and discontinuation due to adverse events, were 10% and 26%, respectively. Further, 21% of injection recipients and 25% of standard care recipients permanently stopped treatment.

As seen in previous studies, cabotegravir and rilpivirine injections were safe and generally well tolerated. The overall rate of adverse events was similar in both treatment groups, Rana reported. More than half (57%) experienced injection site reactions including pain, tenderness or nodules, but only three had severe reactions and one discontinued due to a mild reaction.

“Considering all endpoints together, injectable cabotegravir and rilpivirine demonstrated superiority when compared to daily oral standard of care in people with HIV in the US who face barriers to adherence and have a prior history of virologic non-response or loss to clinical follow-up,” the she concluded. “These data support the use of long-acting injectables in this population.”

“This study is critically important because it shows that long-acting injectable HIV medications can provide substantial benefit to a broader population than those covered by the current regulatory approvals,” Rana said. “If guidelines were to recommend broader use, it would be expected to have a large impact on rates of new HIV infections, as most are transmitted by persons with HIV who are aware of their diagnosis but are not virally suppressed.”

Injectables without viral suppression

As noted, injectable cabotegravir and rilpivirine is only approved for people with viral suppression, so these study results do not apply to those who cannot get their HIV under control. Rana and colleagues recommended that future clinical trials should assess this regimen in “actively viraemic patients.”

After Rana’s presentation, Professor Monica Gandhi, medical director of the Ward 86 HIV clinic at Zuckerberg San Francisco General Hospital, pointed out that adherence-challenged patients by definition often do not have viral suppression and need new options.

To that end, Gandhi’s team conducted a pilot study of injectable cabotegravir and rilpivirine in the context of extensive support for people who were unable to maintain viral suppression due to adherence challenges. That study included patients at Ward 86, a safety-net HIV clinic that serves mostly low-income people, many of whom are dealing with substance use, mental health problems and unstable housing. At the 2022 International AIDS Conference, they reported initial results showing that 12 of 15 people (80%) with detectable HIV at baseline achieved viral suppression, some for the first time.

At CROI 2023, Gandhi reported results from a larger group of 133 people who started injectable cabotegravir and rilpivirine between June 2021 and November 2022. At the outset, 76 already had an undetectable viral load on their existing oral regimen, and all maintained viral suppression after switching to injections. What’s more, 55 of the 57 people (96%) who started with a detectable viral load were able to achieve viral suppression, comparable to response rates in the pivotal trials.

At an analysis presented at this year’s CROI, the Ward 86 team assessed the durability of response in a retrospective cohort study of 59 people who started long-acting cabotegravir and rilpivirine before 5 December 2023, had a baseline viral load of 50 or higher and had at least 56 weeks of follow-up time. This population differed from LATITUTDE participants, reflecting San Francisco’s HIV epidemic. Most (90%) were men, 48% were age 50 or older, nearly half had unstable housing and 61% used stimulants. Half had advanced immune suppression with a CD4 count below 200.

At 48 weeks, 81% met the primary endpoint of still being on cabotegravir and rilpivirine (defined as no discontinuations or injections given more than 14 days late) with viral suppression. Seventeen people had at least one injection more than seven days late and eight had injections more than 14 days late. Five people stopped the injections and resumed oral ART. Overall, 93% maintained viral suppression on cabotegravir and rilpivirine or another regimen. Two people (5%) experienced virological failure with resistance mutations despite on-time injections but regained viral suppression on alternative regimens (lenacapavir plus Biktarvy or cabotegravir plus lenacapavir). One had persistent low-level viral load even after adding lenacapavir. One stopped injections due to severe depression and two were lost to follow-up.

Based on this and other small studies, the International Antiviral Society­–USA (IAS-USA) recently released updated treatment guidelines, published 1 March in JAMA.

When supported by intensive follow-up and case management services, injectable cabotegravir and rilpivirine may be considered for people with viremia who are unable to take oral ART consistently, have a high risk of HIV disease progression and have HIV susceptible to both drugs “when no other treatment options are effective due to a patient’s persistent inability to take oral ART,” the new guidance states.

“People with HIV who have advanced HIV disease and can’t take oral ART (for whatever reason) are at high risk of opportunistic infections, cancers and death,” lead author Professor Paul Sax of Brigham and Women’s Hospital and Harvard Medical School said on X (formerly Twitter). “Injectable [cabotegravir and rilpivirine] can be literally lifesaving – which is why this change to the IAS-USA guidelines is so important.”

Cabotegravir plus lenacapavir

One limitation of long-acting cabotegravir and rilpivirine is that the regimen is less effective for people who have developed resistance to NNRTIs like rilpivirine. In another poster at CROI, Gandhi and colleagues described a case series of people treated with injectable cabotegravir plus lenacapavir.

As the sole HIV capsid inhibitor, lenacapavir remains effective against HIV that has developed resistance to other classes of antiretrovirals. It is currently approved for heavily treatment-experienced people with multidrug-resistant virus. Lenacapavir is administered by injection once every six months, but it has no equally long-acting partner, so it is typically combined with daily pills. The cabotegravir and lenacapavir combination has not been studied in clinical trials, but the regimen holds promise, especially for people in low- and middle-income countries where NNRTI resistance is more common.

Providers at Ward 86, the University of California San Diego’s Owen Clinic, MetroHealth in Cleveland and the University of Pennsylvania HIV Clinic used cabotegravir (monthly or every other month) plus lenacapavir (every six months after an oral loading dose) to treat people who had difficulty adhering to daily pills. The case series included 34 people. About three quarters were men and the median age was 47 years. More than half reported insecure housing, substance use or both.

The reasons for either adding lenacapavir to cabotegravir and rilpivirine (68%) or using lenacapavir and cabotegravir without rilpivirine (32%) were documented or suspected NNRTI resistance (59%), integrase inhibitor resistance (15%), a high viral load when starting or switching to long-acting injectables (18%) and continued viraemia on cabotegravir and rilpivirine alone (12%). While just 16 had viral suppression at baseline, all but two (94%) achieved a viral load below 75 after starting lenacapavir. Treatment was generally well tolerated, with 44% reporting mild or moderate injection site reactions.

“Long-acting ART is expanding in high-income settings but is not accessible in low- and middle-income countries. We are in a situation akin to 2001, when entire conferences were full of data on the promises of oral ART without access to these life-saving therapies worldwide; this inequity cannot be repeated for long-acting ART,” Gandhi told aidsmap. “The 2024 World Health Organization drug resistance report shows that resistance to NNRTIs is still prevalent, with rilpivirine resistance greater than 10% in some countries. We therefore need alternative long-acting ART regimens such as a combination of lenacapavir and cabotegravir which will work against NNRTI-resistant virus.”

“We wrote up this case series of individuals with mainly NNRTI-resistant virus on [lenacapavir and cabotegravir] to call for a larger trial of this combination in low- and middle-income countries,” she added. “The pharmaceutical companies who make each component have not worked together before, but advocacy seems to be working, and we will be initiating at least a small trial of this combination soon.”


Rana A et al. Long-acting injectable CAB/RPV is superior to oral ART in PWH with adherence challenges: ACTG A5359 [LATITUDE]. Conference on Retroviruses and Opportunistic Infections, Denver, abstract 212, 2024.

View the abstract on the conference website.

Hickey M et al. 24-week viral suppression in patients starting long-acting CAB/RPV without HIV viral suppression. Conference on Retroviruses and Opportunistic Infections, Denver, abstract 628, 2024.

View the abstract on the conference website.

Gandhi M et al. Case series examining the long-acting combination of lenacapavir and cabotegravir: call for a trial. Conference on Retroviruses and Opportunistic Infections, Denver, abstract 629, 2024.

View the abstract on the conference website.

Sax P et al. Updated treatment recommendation on use of cabotegravir and rilpivirine for people with HIV from the IAS-USA Guidelines Panel. JAMA. 1 March 2024.