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SHOBHA SHUKLA – CNS

Longstanding gender inequalities, discrimination and poverty deny many women and girls bodily and economic autonomy – which deprives them of control over their sexual health, and increase the risk of preventable infections like HIV. Women and girls are still disproportionately affected with HIV.

4000 missed opportunities to prevent HIV among young women and girls every week

In 2023, an estimated 1.9 million adolescent girls and young women aged 15–24 years were living with HIV, compared with 1.2 million adolescent boys and young men of the same age group. The estimated number of adolescent girls and young women aged 15–24 years who acquired HIV in 2023 was 210,000 —four times higher than the 2025 target of 50,000. This is equivalent to an estimated 4000 new HIV infections among adolescent girls and young women every week. Of these, 3100 infections were in sub-Saharan Africa alone.

In this dismal scenario it is somewhat heartening to see that the HIV prevention field is focussing on funding long-acting prevention technologies for women.

To achieve the Sustainable Development Goal of ending the AIDS epidemic by 2030, women must be able to choose among a range of HIV prevention options that address their different needs and preferences, at different stages of their lives and lived realities.

Her body, her choice

The importance of choice and access in combating the HIV epidemic was the dominant theme of the 5th HIV Research For Prevention Conference of International AIDS Society (HIVR4P) in Lima, Peru. Many clinical studies presented at the conference showed promising results of new HIV prevention tools made especially for women and young girls, which in addition to being safe and effective, will also be acceptable and affordable.

Long acting dapivirine vaginal ring for HIV prevention

The 3-months dapivirine vaginal ring is identical to the 1-month dapivirine vaginal ring (by way of its shape and size) except that it contains 100mg of dapivirine instead of 25 mg.

Just to recap, the monthly ring (developed by International Partnership for Microbicides and acquired by Population Council two years back), is the world’s first female-controlled, long-acting, non-systemic, microbicide product that substantially reduces the risk of getting infected with HIV. Thus, it is also referred to as Pre-Exposure Prophylaxis (PrEP) ring.

The dapivirine vaginal ring is a flexible silicon ring that slowly releases the HIV prevention drug dapivirine into the target cells and substantially reduces the risk of her getting infected with HIV. Any HIV-negative woman, who is at risk of acquiring the infection, can herself put the ring in her vagina, leave it in place for 1-month and then replace it by herself.

The ring is available as an alternative for women who are unable to take daily oral PrEP tablets. It received positive opinion from European Medicines Agency and a pre-qualification by the World Health Organization (WHO). It has been approved for use in eleven African countries and is available in six of them (Eswatini, Kenya, Lesotho, South Africa, Uganda and Zimbabwe) through implementation and pilot studies.

While research has shown that the monthly dapivirine vaginal ring is appealing to many women, a longer-lasting version will have a lower annual cost and may be more convenient to users.

3-months ring

Jeremy Nuttall of the Population Council’s Center for Biomedical Research, shared findings from a clinical study (IPM 054). This study of the 3-month extended-use dapivirine vaginal ring was recently completed. This study is a phase-1, open-label, randomised crossover study, which investigated the relative bioavailability of a 3-month (100mg) dapivirine vaginal ring and compared it with the 1-month (25mg) ring.

Of the 124 healthy women who enrolled, 104 have completed the study. Each participant used three consecutive 1-month rings, followed by single 3-month ring, or vice versa. Plasma vaginal fluid samples were taken regularly throughout the study period for drug-level measurement. Based on dapivirine concentrations in plasma after women used each type of ring, the study team determined that the 3-month ring is non-inferior and pharmaco-kinetically superior to the monthly one.

“These results show that the efficacy of 3-months ring is at least equal to that of the 1-month ring. While offering all benefits of 1-month vaginal ring, 3-months ring also means less number of rings per year – 4 rings in a year instead of 12 – which is a two-thirds reduction in number of rings and packaging materials required per year. The estimated cost is not more than US$ 16, which represents a 60% price reduction per year compared to 1-month ring,” said Nuttal.

Nuttal emphasized that the 3-months dapivirine vaginal ring will expand options and choice for women to protect their health and accelerate global efforts to end the HIV epidemic. By increasing convenience to women -in terms of fewer insertions and visits to the clinic, and lower costs – it is likely to increase acceptability and adherence, thus leading to increased effectiveness.

Population Council is preparing to seek regulatory approval for the 3-months ring. It is expected to enter the market by 2026 potentially replacing the 1-month ring providing a more convenient and cost-effective option to women. It represents yet another important prevention option for women.

Dual prevention pill

When it comes to health, people may have more than one disease prevention needs. Can one pill reduce the risk of HIV as well as act like a contraceptive and reduce risk of unplanned pregnancies?

The dual prevention pill, currently under development, is a single, co-formulated, daily oral pill containing oral pre-exposure prophylaxis (PrEP) and combined oral contraception that prevents both HIV and pregnancy. Since both the ingredients of dual prevention pill are already approved for individual use, their combination pill just needs to undergo bio-equivalence study to determine if they are as safe and effective in combination. A recently concluded bioequivalence study has demonstrated the active ingredients functioned in the body the same as when PrEP and oral contraception are taken separately.

Viatris, a manufacturer of generic antiretroviral HIV drugs and hormonal contraceptives, is developing the dual prevention pill as a bilayer tablet containing Tenofovir Disoproxil Fumarate (300mg) and Emtricitabine (200mg) (also referred to as TDF/FTC), and Levonorgestrel (0.15mg) and Ethinyl Estradiol (0.03mg) (also referred to as LNG/EE). A pack will contain 28 tablets – 21 combination tablets (with HIV prevention medicines and contraceptive) and 7 antiretroviral-only tablets, which will need to be taken to maintain protection against HIV during the last week of the month/ cycle.

The dual prevention pill is expected to be approved by regulators by late 2025 and could reach the market as early as 2026. It will become the first multipurpose prevention technology to go to the market since male and female condoms, and add to the contraceptive and HIV prevention toolbox.

Long-acting biodegradable hydrogel injectable system

Dr Melissa Peet, a scientist at CONRAD (a nonprofit research organisation affiliated with Eastern Virginia Medical School), presented data of a long-acting (LA) subcutaneous injectable hydrogel depot platform (currently in non-human primates studies)- a drug delivery system capable of both: either providing HIV prevention alone, or as multipurpose prevention technology for simultaneous protection against HIV and unplanned pregnancies.

It is biodegradable, provides lower injection volume and higher drug loading capacity, and may co-deliver two drugs with discretely controlled release profiles. Formulations containing 515 or 616mg/ml of micronised cabotegravir, and 359mg/ml of micronised dolutegravir and 67mg/ml of levonorgestrel were administered to rats to assess pharmacokinetics, drug-drug interactions, and injection site reactions for up to 3 months. Cabotegravir and dolutegravir are HIV antiretroviral medicines whereas levonorgestrel is a contraceptive one.

Both formulations showed high and sustained plasma concentrations. Dolutegravir and levonorgestrel plasma levels did not show drug-drug interactions and there were no observed safety signals in any formulations.

Peet and her team of researchers have now developed a silica-based hydrogel injectable platform loaded with high concentrations of cabotegravir  or dolutegravir and levonorgestrel, supporting subcutaneous administration and drug release for at least 3 months for protection against HIV and/or unplanned pregnancy.

Peet explained that, “The silica-based hydrogel matrix is composed of silicon micro-particles and water. Drug release is controlled by the silica erosion for the micro-encapsulated levonorgestrel and suspended antiretroviral drug. Silica is fully biodegradable – which means it does not need to be removed – and in this way it is different from silicon which is used to manufacture the silicon dapivirine vaginal ring. It is also capable of co-formulation with one or more drugs. It allows for subcutaneous injection in a low-dose volume. It is a stable suspension and does not require any cold chain storage.”

Additional studies are underway in non-human primates to better assess protective target drug concentrations and injection intervals. With the successful advancement of long-acting injectable cabotegravir for HIV prevention, development of a more clinically and regulatory congruent multipurpose prevention technology combining cabotegravir and levonorgestrel in this hydrogel gives hope.

Also, inserts of two antiretroviral medicines (tenofovir alafenamide or TAF and elvitegravir or EVG are stable, easy to manufacture, low-cost, acceptable, and show highly promising preclinical and clinical results for on-demand topical pre- or post-exposure HIV prevention.

Long-acting dissolving vaginal film for HIV prevention in women- the MATRIX way

The University of Pittsburgh and Magee-Women’s Research Institute (MWRI) is collaborating with the Population Council in the development of a monthly dapivirine vaginal film, as well as a dapivirine and levonorgestrel monthly vaginal film for the protection of both HIV and unplanned pregnancy.

This film when placed inside the vagina would begin to dissolve slowly on coming in contact with vaginal fluid, and release both dapivirine and levonorgestrel over the course of a month until the film completely dissolves and all drug has been delivered in the vagina. This means there would be nothing to remove or discard. The user would simply insert a new film for another month of discreet dual protection.

Similar to thin breath mint strips that dissolve in the mouth, vaginal films are products designed to dissolve after being inserted in the vagina.

Researchers anticipate conducting a first-in-human clinical study of the monthly dapivirine film in 2025 and depending on results, would follow with a clinical study of the combination film. Meantime, extensive laboratory and animal studies of the dual-purpose film are ongoing.

Given recent approvals and a promising pipeline, new biomedical HIV prevention tools for women have the potential to transform the HIV response and can help reach global goals to reduce new HIV infections by 90% by 2030 – but only if they become accessible to those who need them most.

The recently updated United Nations Resolution 60/2: Women, the Girl Child and HIV and AIDS adopted by governments at 68th session Commission on Status of Women (CSW) in March 2024 underscores the urgent need to prioritise the health and rights of adolescent girls and young women in the context of the global AIDS pandemic.