Safety, tolerability, and pharmacokinetics of an annual tenofovir alafenamide silicone subdermal implant in South African women: a two-part, randomised, placebo-controlled, double-blind, first-in-human, phase 1 trial.

BACKGROUND

Women in sub-Saharan Africa are at high risk for HIV acquisition. To overcome adherence challenges with daily oral pre-exposure prophylaxis we developed and tested the safety, tolerability, and pharmacokinetics of a novel long-acting tenofovir alafenamide implant.

METHODS

CAPRISA 018, a two-part, randomised, placebo-controlled, double-blind, first-in-human, phase 1 trial evaluated the safety, tolerability, and pharmacokinetics of an annual subdermal 110 mg tenofovir alafenamide silicone reservoir implant in HIV-negative women in Durban, South Africa. This trial was conducted at an urban research clinic. HIV negative women aged 18-40 years, clinically assessed to be in good health, non-pregnant, assessed to be at low HIV risk, able to provide written informed consent, using a non-barrier form of contraception even if not currently sexually active were eligible. Following an initial 4-week safety assessment of a single tenofovir alafenamide implant in a small group of participants (group 1), a second group of participants (group 2) were randomly assigned (1:1) to a 48-week assessment period of either one or two tenofovir alafenamide implants, with placebo implant comparator groups in a ratio of 4:1. An unmasked statistician generated the group 2 randomisation list using block randomisation and a uniform random number generator and assigned implants per the list using sealed, opaque, sequentially labelled envelopes. Local implant site reaction (ISR) adverse events, systemic adverse events, tolerability, and implant release were evaluated in all enrolees. Intracellular tenofovir diphosphate concentrations were also assessed. The trial was registered on the Pan African Clinical Trials Registry (PACTR201809520959443) and is closed to recruitment.

FINDINGS

From July 9, 2020, to May 31, 2022, 36 HIV-negative women aged 18-40 years were enrolled: six in group 1, followed by 30 randomly assigned in group 2 (12 assigned one active implant, three assigned one placebo implant, 12 assigned two active implants, and three assigned two placebo implants). Systemic adverse event rates were similar between tenofovir alafenamide and placebo implant recipients. Common local ISR adverse events in the 36 women included scarring (36 [100%]), induration (30 [83%]), and hyperpigmentation (29 [81%]). Non-procedure-related ISR adverse event incidence rate was 11·9 per person-year (95% CI 5·8-18·0) in women with tenofovir alafenamide and 2·9 per person-year (1·1-4·7) for placebo implants. Early implant removals occurred a median of 19 weeks (IQR 10-27) post-insertion in 11 (37%) of 30 women in group 2. Local ISR adverse event incidence was 27·4 per person-year (95% CI 11·9-42·9) in early removals and 12·3 (7·8-16·8) in scheduled removals (p=0·067). Implants individually released approximately 0·1 mg of tenofovir alafenamide per day. Median tenofovir diphosphate concentrations were 3·9 fmol per million cells (IQR 1·7-13·3) for one tenofovir alafenamide implant and 14·8 fmol per million cells (6·0-29·1) for two tenofovir alafenamide implants.

INTERPRETATION

Tenofovir alafenamide implants showed frequent local adverse events, often leading to early removal and inadequate drug release, halting further testing of this implant candidate for HIV prevention. Balancing high implant release rates while ensuring local tolerability remains a key challenge for the next generation of HIV prevention implants.

FUNDING

European and Developing Countries Clinical Trials Partnership, South African Medical Research Council, and South African Department of Science and Innovation and National Research Foundation.