A 79% reduction in HIV incidence was seen between two directly comparable groups in a whole-population analysis of people using PrEP (regular medication to prevent HIV) in Australia.

The findings were presented by Dr Nicholas Medland of the Kirby Institute, University of New South Wales, at the 31st Conference on Retroviruses and Opportunistic Infections (CROI 2024) in Denver, US, last week.

PrEP has been subsidised by the Australian government since 2018 and is available through its national health system, meaning it is low-cost and highly accessible.

Medland and colleagues designed an analysis based on a direct comparison of people eligible for PrEP: those who continue taking it and those who have been prescribed it but only filled one prescription. Using dispensing data for PrEP and HIV treatment (indicating an HIV diagnosis), they estimated the number of people in each group who acquired HIV between 2018 and 2023.

During the study period, 66,206 people were dispensed PrEP. While 19% received PrEP only once, the largest group (53%) received PrEP more than once, yet the proportion of total days covered by PrEP for this group was less than 60%, indicating low adherence. A third group (28%) were more adherent: they received PrEP more than once and the proportion of days covered by PrEP was over 60%.

There were 207 HIV diagnoses. Fifty-five per cent were in the low-adherence group, 30% in the group who received PrEP only once, and 15% in the high-adherence group.

Overall HIV incidence was low at 1.07 per 1000 person-years. However, incidence was very high for those who had also received treatment for hepatitis C, at 9.83 per 1000 person-years.

Compared to those who had only received PrEP once, incidence was 62% lower in the group that used it more than once but had low adherence. However, for the more adherent group, HIV incidence was 79% lower.

A programme in rural Kenya and Uganda that has already demonstrated that a dynamic, person-centred HIV prevention intervention results in substantial increases in the numbers of people covered by PrEP or PEP, has now shown the added benefits of offering a choice between PrEP pills and PrEP injections.

“Person-centred options and long-acting cabotegravir are needed to increase biomedical prevention coverage,” Dr Moses Kamya of Makerere University in Uganda told CROI 2024.

At last year’s conference, the research team presented results for the person-centred intervention. When services were offered in the usual way, a minority of people used oral PrEP or PEP (emergency treatment to prevent HIV). When services were optimised to provide choice and flexibility, uptake more than doubled.

The latest stage of the study included 984 people who were considered at risk of acquiring HIV. Half were randomly assigned to the intervention; the other half received standard care. PrEP injections (cabotegravir) were offered as an additional option, alongside oral PrEP, PEP and condoms.

In the standard-of-care arm, a form of biomedical HIV prevention was used 13% of the time. This rose to 70% in the intervention arm.

Over the 48 weeks of the study, over a quarter of participants in the intervention arm used at least two different prevention options. Oral PrEP was used by 53% of participants, injectable PrEP was used by 56%, while PEP was occasionally used (2%). Notably, of those who started injectable PrEP at the beginning of the study, 42% had not been using any form of HIV prevention in the previous month.

The intervention did not just increase HIV prevention coverage, it cut HIV incidence to zero. In the standard-of-care arm, seven people seroconverted during the study (incidence of 1.8% per year). In the intervention arm, there were no seroconversions.

In the next phase of the study, the dapivirine vaginal ring will be an additional option.

Several presentations at CROI 2024 addressed whether HIV is starting to develop resistance to the integrase inhibitor dolutegravir, one of the most widely used antiretrovirals in the world. In World Health Organization guidelines, dolutegravir is the cornerstone of first- and second-line HIV treatment.

Significant dolutegravir resistance is uncommon, but it has become more common, and certain groups, including children, seem more prone to it.

Dr George Bello of the International Training and Education Center for Health in Lilongwe, Malawi, presented a study involving 302 children aged 2-14, who had been on dolutegravir for more than nine months, and had a viral load of over 1000.

After adherence counselling, 169 children achieved viral suppression. The remaining 133 had drug resistance testing and three-quarters were found to have at least one resistance mutation, with 65.5% having resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and 42% to nucleoside reverse transcriptase inhibitors (NRTIs). Only 16% had significant integrase inhibitor (INSTI) mutations. Protease inhibitor (PI) mutations were rarer at 5%.

A second study hinting that children might be more at risk than adults came from Lesotho. This large cohort is mostly made up of adults and some patients who have high viral loads after switching from NNRTI-based regimens to the combination pill of tenofovir, lamivudine and dolutegravir (TLD) are eligible for resistance testing.

Of 15,299 who switched, 151 were eligible and 78 actually had a resistance test. Of these, only eight people (10%) had dolutegravir resistance, but two were boys aged nine and seven – 25% of those with dolutegravir resistance in a cohort in which less than 3% are children.

Two further studies looked at adults. In Kenya, 55 people who were on TLD and had viral loads over 200 had samples taken for resistance testing. Forty-four samples returned a valid resistance result and eight of these (14.5%) had dolutegravir resistance mutations.

In contrast, a study from Zambia and Malawi found only two people with significant dolutegravir resistance among 2833 people who had switched from TLD.

If people do experience treatment failure on second-line INSTIs, what treatment options do they have? A study from South Africa looked at people whose second-line PI-based regimens had failed. Of 355 people, 234 had resistance mutations to PIs. Of these, 133 switched to dolutegravir and 101 switched to boosted darunavir, regarded as a third-line PI.

Switching to boosted darunavir worked just as well as switching to dolutegravir. Eighty-nine per cent of people on dolutegravir and 92% of people on darunavir maintained viral undetectability at 12 months, despite having PI resistance mutations. This would appear to show potential for boosted darunavir to be a salvage therapy for people whose second-line INSTI regimens stop working.

A longer-acting formulation of cabotegravir may offer a PrEP and HIV treatment option that could be given once every four months, according to early study results.

Dr Kelong Han and colleagues at pharmaceutical company GSK evaluated the safety and pharmacokinetics of different cabotegravir formulations and administration methods in a phase I trial with 70 participants.

They first tested the approved 200mg/ml version of cabotegravir (CAB200) given by subcutaneous injection in the abdomen along with recombinant human hyaluronidase PH20 (rHuPH20), which allows for a larger injection volume. However, this was not well tolerated, and eight participants had severe injection site reactions. The company decided not to continue this dosing strategy.

In the next stage of the study, participants received a new ultra-long-acting formulation (CAB-ULA) without rHuPH20. A range of doses of CAB-ULA (800mg/2ml, 1200mg/3ml or 1600mg/3ml) were given by subcutaneous injection in the abdomen or intramuscular injection in the buttocks. CAB-ULA was better tolerated, especially when given by intramuscular injection.

The maximum concentration of CAB-ULA administered by subcutaneous injection was lower than that of intramuscular CAB-ULA, and both were lower than the approved intramuscular CAB200. Pharmacokinetic profiles were “flatter”, indicating slower absorption, according to Han. The half-life of subcutaneous CAB-ULA was longer than intramuscular CAB-ULA, and both were longer than intramuscular CAB200.

Pharmacokinetic modelling predicted that intramuscular CAB-ULA at a dose interval of at least four months would achieve higher drug exposure than intramuscular CAB200 given every two months.

Semaglutide, best known as a weight-loss medication, reduced liver fat build-up and metabolic dysfunction-associated steatotic liver disease (MASLD) in people with HIV, according to study results presented at CROI 2024.

MASLD, formerly known as non-alcoholic fatty liver disease (NAFLD), is responsible for a growing share of advanced liver disease worldwide. As the new name suggests, it is associated with obesity, type 2 diabetes and other metabolic abnormalities. Over time, the build-up of fat in the liver can lead to inflammation, liver fibrosis, cirrhosis and cancer.

Dr Jordan Lake of the University of Texas in Houston presented results from SLIM LIVER, a phase IIb trial to evaluate the effects of semaglutide on liver fat content in people with HIV.

The study enrolled 51 adults on suppressive antiretroviral therapy with a large waist circumference, insulin resistance or pre-diabetes, and MASLD (defined as at least 5% liver fat content by MRI imaging).

Participants self-administered subcutaneous injections of semaglutide once weekly for 24 weeks, increasing the dose over time until it reached 1mg. At six months, the mean absolute decline in liver fat was 4.2% while the mean relative decline was 31.3%. More than a quarter experienced complete MASLD resolution.

The reduction in liver fat was accompanied by significant improvements in weight (a median 7.8kg loss), waist circumference and fasting glucose and triglyceride levels.

Around 20% of participants did not respond to semaglutide, similar to the proportion in the general population.

There are currently no approved medical therapies for fatty liver disease, and management has relied on lifestyle changes such as weight loss and exercise. But Lake warned that semaglutide may not be effective against advanced disease. “It’s more of a way to either treat or prevent early disease, not a way to reverse existing liver disease,” she said.

Lifetime risk of acquiring HIV has decreased for Black gay and bisexual men in the US, from 1 in 2 from 2010 to 2014, to 1 in 3 from 2017 to 2021, according to data presented by researchers from the US Centers for Disease Control and Prevention (CDC). However, disparities between White and Black men persist and have widened over the past few years by some estimates, despite decreases in the numbers of new diagnoses for both groups.

Counselling about heart disease risk and statin use for women with HIV should highlight the similar levels of risk for men and women with HIV when communicating the results of the REPRIEVE study on the use of statins, one of the study’s investigators told CROI 2024 last week. Advice also needs to make women aware of how the symptoms of heart disease differ in women and men.

Switching to an integrase inhibitor around the time of the menopause was associated with accelerated weight gain in women with HIV when compared to pre-menopausal women with HIV, a retrospective cohort study in the US has found.

Dolutegravir did not increase the risk of high blood pressure during pregnancy in a large international study, Professor Risa Hoffman reported on behalf of the IMPAACT 2010 study team.