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HIV Glasgow Highlights for Europe
Innovations in HIV Care Across Europe: Highlights From HIV Glasgow 2024

Released: December 06, 2024

Expiration: December 05, 2025

Lene Ryom
Lene Ryom, MD, PhD, DMSc, DTMH
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Key Takeaways
  • Several promising long-acting treatment alternatives are currently under development.
  • These options are particularly beneficial for people with challenges such as adherence difficulties, fear of stigma, adverse drug reactions, and pill fatigue.

As highlighted by Dr Cissy Kityo in her opening remarks during the Monday morning session to kick off HIV Drug Therapy Glasgow 2024, Experience in the Implementation of Long-Acting Treatment, the evolution of antiretroviral treatment (ART) has been remarkable. Since the introduction of zidovudine monotherapy in 1987, treatment has progressed through decades of 3-drug combination ART to the current landscape, which offers numerous alternatives tailored to individual needs, particularly in resource-rich settings.

However, despite access to effective and durable daily oral ART, there is an increasing demand for treatment simplification due to factors such as stigma, pill fatigue, adverse drug reactions, polypharmacy and adherence challenges.

Meeting the Challenge of Long-Acting ART
Although long-acting (LA) cabotegravir (CAB) plus rilpivirine (RPV) demonstrates high efficacy in clinical trials and emerging real-world data, some challenges remain. These include the requirement for bimonthly injections by healthcare professionals, and a small but increased risk of failure in people with a combination of non-nucleoside reverse transcriptase inhibitor resistance, BMI greater than 30, and the A6 subtype, which is highly prevalent in Eastern Europe. In addition, issues such as RPV supply constraints and the need for cold storage show that there is room for some improvement in LA regimens. We can always aim higher!

Promising Data on Oral Once-Weekly ART 
An open-label 48-week phase II study presented data on the once-weekly oral combination of lenacapavir (LEN) and islatravir (ISL), extending findings from 24-week data earlier this year. Both LEN and ISL have long half-lives and have potency at low dosages, supporting the feasibility of an oral LA regimen.

In the study, 104 virologically supressed people stable for more than 6 months on bictegravir (BIC)/emtricitabine (FTC)/tenofovir alafenamide (TAF) were randomized to continue daily BIC/FTC/TAF or, after a loading dose, to switch to weekly oral LEN plus ISL. After 48 weeks, HIV viral load <50 copies/mL was observed in 94% of people on LEN plus ISL and 92% on BIC/FTC/TAF.

Although the absolute numbers were small, a fairly high proportion of participants (19%, n = 10) reported treatment-related adverse events (AEs) while receiving LEN plus ISL. These AEs were exclusively classified as grade 1-2, with nausea and dry mouth being the most common (both n = 2). No treatment-related AEs led to discontinuation. However, 1 person contracted acute hepatitis B (HBV) and was subsequently switched to a regimen active against both HIV and HBV.

Laboratory abnormalities were rare in both arms (n = 1-2) and were difficult to fully interpret owing to the small sample size. No significant differences in median or mean changes in body weight and BMI were reported between arms. However, weight changes are relatively rare events, and relying on median or mean values can mask outliers of interest among the majority with unchanged levels. A more detailed analysis of metabolic outliers would have been beneficial. If the reported relatively high rate of mild to moderate AEs was influenced by the open-label study design, further clarification of rates and type of AEs in larger study settings will be key for a more thorough safety evaluation.    

Adherence was high in both treatment arms, with 99% in the LEN plus ISL group and 98% in the BIC/FTC/TAF group. Study participants were offered optional text or email reminders to promote adherence. In real-world settings, long-term adherence to a once-weekly regimen will require careful implementation considerations with similar adherence support systems. The allowable window for missed doses was clarified during the discussion to be approximately 7 days, making the once-weekly administration somewhat less fragile.

LEN is a strong inducer of CYP3A, P-gp, and UGT1A1, with the potential for multiple drug–drug interactions and a requirement for dose adjustment for medications such as phosphodiesterase-5 inhibitors, certain statins, corticosteroids, and direct oral anticoagulants. Furthermore, LEN plus ISL cannot be used in people with HBV coinfection, making HBV vaccination a priority for those who are not immunized. As seen in the LA CAB plus RPV regulatory trials, people with the greatest need for these regimens, such as those with challenged adherence, were actively excluded, which I believe substantially limits external validity.

Future Phase III Trials
Nevertheless, these preliminary data are promising. Two phase III trials (ISLEND 1 and 2) will evaluate LEN plus ISL compared to BIC/FTC/TAF and standard ART, respectively, and their results are anticipated with great interest. If LEN plus ISL achieves regulatory approval as the first oral LA regimen, it will have far-reaching implications and likely broad public appeal for people with HIV in Europe and elsewhere. 

Case Series on LA LEN and CAB 
What insights can we gain on LA ART for people with adherence challenges? A case series involving 8 people (4 women and 4 men) with challenged adherence and resistance to RPV was presented, examining the use of LA LEN administered subcutaneously every 6 months combined with CAB administered intramuscularly every 2 months.

The median age of the cohort was 56 years (IQR 44-58), and all participants had extensive treatment histories. Over a minimum follow-up period of 6 months, no viral failures were reported, and there were no drug discontinuations or serious AEs. Injection-site reactions were commonly reported.

Although this case series and other similar small studies of LA LEN plus CAB seem promising, systematic evaluation in a clinical trial setting is necessary. The ACTG trial A5341 is planned to further investigate this combination, and larger trials are anticipated. 

Phase Ib Findings: LA ART and Broadly Neutralizing Antibodies 
Other promising early results included a phase Ib trial evaluating LA LEN combined with 2 broadly neutralizing antibodies (bNAbs), teropavimab and zinlirvimab (ZAB). This study focused on people who had been virologically supressed for more than 18 months. Data presented earlier this year at the Conference on Retroviruses and Opportunistic Infections (CROI) on bNAbs had been somewhat less encouraging regarding long-term efficacy and durability. However, the long half-lives of these antibodies, allowing for administration every 6 months, make them clinically appealing.

In the study presented at HIV Glasgow 2024, of the 32 participants, 21 were susceptible to both bNAbs, while 11 were susceptible to only one. Participants were randomized to receive either a high-dose or low-dose regimen of ZAB. By Week 26, no virologic failures were observed in the high-dose arm, but 3 failures occurred in the low-dose arm.

AEs were common in both arms (reported by approximately 80%-90% of participants) but were primarily limited to injection-site reactions. The methods for assessing susceptibility in routine clinical care and determining appropriate threshold levels remain unclear. A phase II trial with the high-dose regimen is planned and will provide further insights.

In addition, findings from a phase Ib trial of GS-1720, a once-weekly oral integrase strand transfer inhibitor, were also presentedregimen demonstrated a lack of emerging resistance and robust pharmacokinetics and pharmacodynamics.

Your Thoughts?  
These innovative strategies and regimens under development offer significant potential to expand future clinical management options, addressing the diverse needs of people with HIV.

What are your thoughts on the evolving HIV therapies of LA and once-weekly regimens to address adherence challenges and improve outcomes in HIV care? Get involved in the discussion by posting a comment below!