From the first HIV medication approval in 1987, treatment for HIV has come a long way. With the help of antiretroviral therapy (ART), most HIV patients can now lead a longer and healthier life. In 2022, according to the World Health Organisation (WHO), an average of 39.0 million people were living with HIV, and an estimated 630 000 people were dying from HIV globally [1]. The quest to find new and better treatment options continue as unmet needs such as drug resistance and ill compliance remain.
Novel Molecules for HIV
Lenacapavir (Sunlenca®)
In Dec 2022, Lenacapavir, in combination with other antiretroviral(s) (ARV), has been granted approval by the U.S. Food and Drug Administration (FDA) for the treatment of HIV-1 infection in heavily treatment-experienced (HTE) adults with multi-drug resistant (MDR) HIV-1 infection.
Efficacy
The phase II/III CAPELLA trial demonstrated that Lenacapavir maintained high rates of virologic suppression in heavily treatment-experienced individuals with multidrug-resistant HIV-1.
- Lenacapavir (n=24) achieved a significant viral load reduction of at least 0.5 log10 copies/mL from baseline compared with those randomly allocated to receive placebo (n=12) during the 14-day functional monotherapy period (88% vs. 17%, p<0.0001).
- Those who received lenacapavir achieved a statistically significant greater mean decrease in viral load than those who received placebo during the functional monotherapy period (-1.93 log10 copies/mL vs. -0.29 log10 copies/mL, p<0.0001).
Safety
Lenacapavir was generally well tolerated in CAPELLA, with one adverse event (AE) leading to study drug discontinuation at Week 52 and no serious adverse events related to lenacapavir.
The most common adverse events observed to date in the CAPELLA study were injection site reactions (63%), which were mostly mild or moderate in severity. The most common adverse events, excluding injection site reactions, were nausea and diarrhea (13% each) and COVID-19 (11%) [2].
Lenacapavir’s unique mechanism of action and its twice-yearly administration schedule make it a groundbreaking treatment option for adults with HIV with limited options for therapy and high unmet medical needs.
Currently, Lenacapavir, alone or in combination, is not approved by any regulatory authority outside of the United States, United Kingdom, Canada or the European Union for any use. Additional regulatory filings and decisions by regulatory authorities are anticipated to continue in 2023.
Islatravir
Developed by Merck/MSD, Islatravir is the highly potent NRTTI on hold since late 2021 due to safety concerns – an unexpected side effect that reduced CD4 counts.
Two discussions elucidated that the etiology is attributed to the elevated intracellular accumulation of Islatravir triphosphate, which can be effectively managed by administering reduced oral doses: 0.25mg on a daily basis and 2mg for weekly dosing [3,4].
Restarting Trials
Merck/MSD has started the Phase 2 clinical trial (NCT05052996) evaluating an investigational oral once-weekly combination treatment regimen of Islatravir and Lenacapavir in adults with HIV-1 infection who are virologically suppressed under an amended protocol with a lower dose of Islatravir (2mg weekly).
In addition, enrollment for the following trials commenced at the beginning of 2023 – one new phase III study will evaluate once-daily Islatravir plus Doravirine for previously untreated people with HIV, and two trials will test the combination as a switch option for treatment-experienced people with an undetectable viral load.
Novel Delivery Systems for HIV
Abacavir, Dolutegravir, and Lamivudine (Triumeq PD®)
The FDA approved Triumeq PD in March 2022, providing an age-appropriate, once-daily HIV regimen for pediatric HIV-1 patients weighing between 10 and 25 kg. This approval is a crucial step in closing the gap between HIV treatment options available for adults and children, as only 54% of children had access to HIV treatment compared to 74% of adults, according to UNAIDS [5].
This is the first dispersible single-tablet formulation of a fixed-dose combination of Abacavir, Dolutegravir, and Lamivudine. Clinically, this unique formulation lowers the minimum weight at which a child can be prescribed treatment from 40 kg to 14 kg. This development is expected to help meet the urgent needs of this vulnerable population, as most deaths among pediatric HIV patients occur in children under 5 years of age. The approval of Triumeq PD brings us one step closer to ensuring that no one living with HIV is left behind [6].
Cabenuva (Extended Release Cabotegravir and Rilpivirine)
FDA-approved in January 2021, Cabenuva is the first and only complete long-acting 2-drug combination HIV-1 treatment regimen for infected adults that is administered every other month or monthly by a healthcare professional.
Efficacy
Cabenuva was tested in 3 clinical studies, involving more than 2,200 undetectable adults who either switched or continued their HIV regimen.
- In 2 studies, people received once-monthly Cabenuva or continued their daily pill regimen
- In the other study, people received Cabenuva injections every other month or once a month
At Week 48 in all studies:
- 9 out of 10 people remained undetectable, whether they were on daily HIV pills or Cabenuva
- Less than 2% of people did not remain undetectable (primary endpoint)
Safety
Adverse effects reported were generally mild and self-limiting. The most common being injection-site reactions (75% to 83% of patients). Injection-site reactions lasted about 3 days and were mostly mild to moderate. They were also less reported the longer patients were on treatment. Overall, less than 4% of people on Cabenuva stopped treatment due to any side effect [7].
Slow-Release Bictegravir
The potential for a Bictegravir nano-drug delivery system (BIC NP) has been explored in several pharmacokinetic (PK) and animal studies.
The results from PK studies demonstrated enhanced PK properties of BIC NP such as:
- Slower clearance rate than free drug in solution.
- Enhanced BIC uptake compared to BIC solution [8]
Animal studies also showed a single intramuscular injection produced sustained drug levels above the protein-adjusted IC90 for more than seven months in rodents and for more than three months in macaques [9].
PreExposure prophylaxis (PrEP)
PrEP has emerged as a key strategy in the fight against HIV by preventing the acquisition of the virus altogether. One notable study, CAPRISA 018, is a phase I/II clinical trial study protocol to assess the safety, acceptability, tolerability and pharmacokinetics of a sustained-release Tenofovir alafenamide subdermal implant for HIV prevention in women. The trial will assess a novel sustained-release implant technology containing 110 mg of TAF for the prevention of HIV infection. It is anticipated to be completed in June 2024 [10].
Isolated studies have also highlighted the potential of novel delivery methods such as rectal or vaginal PrEP inserts. The promising technology for HIV prevention aims to improve medication efficacy, adherence and implementation in the long run. [11, 12]
The Significance of Long-Acting Systems
Potent long-acting (LA) antiretrovirals provide extended dosing intervals, which can help overcome the challenge of suboptimal drug adherence associated with daily oral dosing. As a result, the barrier to receiving effective medical therapy is further reduced.
The Big Picture
The advent of novel HIV medications represents a significant stride forward in enhancing the landscape of HIV management. These innovative therapeutic agents hold the potential to revolutionize patient care by addressing key challenges like treatment adherence and drug resistance.
By embracing cutting-edge technologies such as long-acting formulations and novel delivery systems, healthcare providers can address longstanding challenges of treatment adherence, convenience and even tailored dosage administration for special population groups.
With unique mechanisms of action and optimised dosing regimens, these novel ways of HIV treatment empower healthcare professionals with versatile tools to tailor interventions, minimize adverse effects, and maximize patient outcomes, thereby significantly reducing the global burden of HIV.
References:
- World Health Organization. HIV and AIDS. World Health Organization.
- Segal-Maurer S, et al. Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection. N Engl J Med. 2022;386(19):1793-1803.
- Squires KE et al. 92 Effect of islatravir on total lymphocyte and lymphocyte subset counts. Oral poster 192.
- Vargo R et al. Modeling to optimize islatravir QW dose in HIV virologically suppressed PWH. Poster abstract 497.
- UNAIDS. Global HIV & AIDS statistics — Fact sheet. 2021.
- ViiV Healthcare announces US FDA approval of Triumeq PD, the first dispersible single tablet regimen containing dolutegravir, a once-daily treatment for children living with HIV. ViiV Healthcare. [news release]. March 30, 2022.
- Cabenuva patient information leaflet
- Mandal S, et al. A potential long-acting bictegravir loaded nano-drug delivery system for HIV-1 infection: A proof-of-concept study. Antiviral Res. 2019 Jul;167:83-88.
- Nayan MU et al. Ultra-long-acting bictegravir nanoformulations. CROI 2023, Seattle. Poster abstract 540.
- Gengiah TN, et al. CAPRISA 018: a phase I/II clinical trial study protocol to assess the safety, acceptability, tolerability and pharmacokinetics of a sustained-release tenofovir alafenamide subdermal implant for HIV prevention in women. BMJ Open. 2022;12(1):e052880. Published 2022 Jan 6.
- Riddler SA et al. Safety and PK/PD of a tenofovir alafenamide/elvitegravir insert administered rectally. Oral abstract 164.
- Makarova M et al. Extended post-exposure protection against SHIV vaginal infection with TAF/EVG inserts. Poster abstract 990.
