Promising data for multipurpose technologies to prevent HIV and pregnancy
Polly Clayden, HIV i-Base
Multipurpose technologies for prevention of HIV and pregnancy were the focus of a dedicated session at HIVR4P 2020. This included a antiretroviral and contraceptive vaginal rings as well as a study indicating preference for combined products from heterosexual couples. [1, 2, 3, 4]
Dapivirine and levonorgestrel ring
A combined anti-HIV and contraceptive vaginal ring achieved or exceeded dapivirine and levonorgestrel (DPV/LNG) plasma concentrations sufficient for HIV and pregnancy prevention with cyclic and continuous use. But concentrations in vaginal fluid dropped with periodic removal and it is unclear if HIV prevention efficacy will be maintained although contraceptive efficacy is expected. There was minimal toxicity and no differences in vaginal bleeding profiles between strategies.
The target product is a 90-day extended release vaginal ring – developed by International Partnership of Microbicides (IPM). The study was conducted by the University of Pittsburg.
The ring contains: DPV 200 mg (release rate approximately 440 mcg/day first month then 220 mcg/day) and LNG 320 mg (release rate approximately 120 mcg/day first month then 85 mcg/day).
This was a phase 1 study looking at the feasibility of periodic removal of the ring (which may depend on the rate of local DPV decline). Twenty-five HIV negative women were randomised to continuous vs cyclic (28 days in/2 days out) 90-day use of the ring. They were a median age 36 years, with BMI of 27 and 80% were white.
About a quarter of participants voluntarily removed the ring at least once. About three quarters experienced slippage and 40% full ring expulsion. For some this was a reoccurring issue – the ring is being reformulated to address this with a new clinical trial planned. Overall adherence to protocol was high at about 90%.
With continuous use, median Cmax for DPV 750 pg/mL (IQR 551 to 813) and AUC0–90 50471 pg*d/mL (IQR 44680 to 56279). As expected, in the cyclic group, the plasma concentrations dropped two days after ring removal but plasma DPV remained at target levels associated with previously demonstrated efficacy (25 mg DPV ring now with WHO prequalification).
LNG median Cmax was 1675 pg/mL (IQR 1341 to 2334) and ) and AUC0–90 79987 pg*d/mL (IQR 72633 to 93980). Again there was a drop in LNG concentrations in the cyclitic group but this remained in the range associated with contraceptive efficacy.
There was a steep drop in median concentrations for DPV and LNG in vaginal fluid. This was from about 100,000 ng/g to only about 10 ng/g over hours not days for DPV. Although drop in LNG was also pronounced, this is not expected to affect the contraceptive efficacy. But for DPV the implications are currently unknown – it is not clear whether concentrations in vaginal fluid, tissue or plasma are critically important for prevention of HIV.
There were 84 AEs, most were mild (80%) or moderate (29%). There was no difference in genitourinary AEs or grade 2 or higher AEs by arm. There was one grade 4 anaemia in the cyclitic arm judged related to study product in a participant who reported heavy vaginal bleeding. There were no differences in bleeding patterns between arms overall.
Tenofovir and levonorgestrel ring
TFV/LNG and TFV alone vaginal rings were shown to be safe when used by Kenyan women. Pharmacokinetic (PK) characteristics and markers of protection against HIV and pregnancy suggest the potential for clinical efficacy of these rings.
In this phase 2a study, 27 women were randomised 2:2:1 to use vaginal rings: tenofovir (TFV)/LNG (n=11); TFV alone (n=11); and placebo (n=5). Participants were a mean age of 24 (SD 4.7) and enrolled in Kisumu. Median days of ring use was 68 (IQR 36 to 90).
The most common AEs were headache and upper respiratory tract infection. The most common grade 2 AEs were bacterial vaginosis, upper respiratory tract infection and reduction in glomerular filtration rate. These were not judged to be product related.
Nine AEs (8 in TFV/LNG and 1 in TFV arms) were considered to be related to product use – all were related to menstrual bleeding changes and all resolved spontaneously.
TVF concentrations in cervicovaginal fluid (CVF) increased rapidly after insertion and declined on removal. Six hours after insertion TFV concentrations were: 1300 ng/swab in the TFV/LNG arm and 827 ng/swab in the TFV arm. Median steady state concentrations (reached within 24 hours) were: 70,550 ng/swab and 56,572 ng/swab in the respective arms.
TFV plasma concentrations were below quantification throughout period of vaginal ring use.
LNG serum concentrations also showed a quick upsurge after insertion, reaching 400 pg/mL within six hours. Median steady state concentration was 283 pg/mL (threshold for contraceptive effect: 200 pg/mL).
There was high anti-HIV activity in CVF among arms with TFV-containing rings vs placebo. There was also high anti-HSV activity in CVF with TFV-containing rings.
Tenofovir and levonorgestrel ring: CONRAD A15-138
Data from CONRAD A15-138 also suggested that a TFV/LNG vaginal ring was safe, acceptable and delivered high TFV concentrations locally with contraceptive efficacy.
This was a phase I study among HIV negative women, conducted in Norfolk, VA and the Dominican Republic, evaluating the safety, PK, pharmacodynamics (PD), and acceptability of CONRAD’s TFV/LNG ring following three months of continuous or interrupted use.
Participants were randomised to 1 of 4 study arms: TFV/LNG or placebo ring worn continuously for approximately 90 days or cyclically for 3 cycles of 28 days of use with 3 days removal then re-insertion. Forty women were randomised and completed all visits.
AEs were mild or moderate – there were no grade 3 or above AEs considered related to study product. There were no significant changes in cervicovaginal epithelium, immune cell populations or soluble immune and inflammatory markers from baseline.
The majority of participants reported either no change in their menstrual cycle or fewer/lighter bleeding days – there were no differences between arms.
Median vaginal fluid TFV concentrations were 546 to 3077 ng/mg throughout 90 days of use. Median TFV-DP tissue concentrations exceeded 1,000 fmol/mg within 72 hours of insertion. High levels remained through five days after removal.
Modelling showed at 1 and 3 months of use, vaginal fluid of women using TFV/LNG rings had significantly greater inhibitory activity against HIV in vitro compared to baseline and to placebo (p<0.01).
TFV/LNG ring users had mean serum LNG concentrations exceeding 200 pg/mL within 2 hours of insertion – these levels were not maintained in the cyclitic group.
The microdose of LNG caused changes in cervical mucus (CM), sperm penetration and ovulation compatible with contraceptive efficacy, while inducing acceptable changes in menstrual bleeding patterns.
Preference for combined products in the CUPID study
Heterosexual couples, both individually and jointly, showed high interest in products that combine HIV and pregnancy prevention in the CUPID study, conducted in Uganda and Zimbabwe .
Most research with users of future HIV prevention products has focused on women. The CUPID study looked at preferences for future technologies for pregnancy and HIV prevention and examines relationship-based issues to inform the development and use of these products. It was a multi-methods cross-sectional study started in January 2020.
This study found, of 400 couples (mean age: 26 years women and 31 years men), enrolled through March 2020, nearly all (91%) showed a preference for a dual vs single purpose product.
Benefits indicated included ease of using a 2-in-1 product; women liked to have the ability to present the product as just a contraceptive; and fewer clinic visits. Disadvantages included concerns that combined products might have more side effects; the need to switch methods when pregnancy is desired; and higher volume of drugs in the body.
The majority (73% Zimbabwe and 58% Uganda) of couples selected oral tablets as their ideal formulation, while 27% and 44% in Zimbabwe and Uganda respectively preferred a vaginally-delivered product (ring, insert or film).
Although most participants preferred longer-duration products (2 to 3 months), one-third indicated their ideal product would be monthly and 10% favoured on-demand.
All references are to the programme and abstracts for HIV Research for Prevention (HIVR4P) virtual conference.
https://virtual.hivr4p.org/media-452-oa06—multipurpose-prevention-technologies-mpts-for-prevention-of-hiv-and-pregnancy (Webcast – all presentations)
- Achilles S et al. Pharmacokinetics, safety, and vaginal bleeding associated with continuous versus cyclic 90-day use of dapivirine and levonorgestrel vaginal rings for multipurpose prevention of HIV and pregnancy. Oral abstract OA06.01.
- Mugo N et al.Randomised, placebo-controlled trial of safety, pharmacokinetics, and pharmacodynamics of 90-day intravaginal rings (IVRs) releasing tenofovir (TFV) with and without levonorgestrel (LNG) among women in Western Kenya.Oral abstract OA06.02.
- Thurman A et al. Randomised, placebo-controlled phase I trial of safety, pharmacokinetics, pharmacodynamics and acceptability of a multipurpose prevention vaginal ring containing tenofovir and levonorgestrel. Oral abstract OA06.03.
- Minnis A et al.Heterosexual couples’ preferences for dual-purpose prevention products for HIV and pregnancy prevention: the CUPID Study (MTN-045) in Uganda and Zimbabwe. Oral abstract OA06.04.