The HIV PrEP and Microbicides Pipeline

July 2018
by Jeremiah Johnson

Since 2011, HIV prevention has undergone a true revolution. With three major studies (HPTN 052, PARTNER, and Opposites Attract) now showing zero new infections linked to an HIV positive person who has successfully suppressed their virus through antiretroviral treatment, it is now apparent that being “undetectable” means that a person living with HIV will not transmit the virus sexually. TDF/FTC pre-exposure prophylaxis (PrEP) continues to be a game changer, with an expanding body of literature demonstrating its essential role in driving down new infections. Most notably, a rapid scale-up of PrEP in Australia since 2016 has corresponded with a 35% decline in the number of new diagnoses in gay, bisexual, and other men who have sex with men in New South Wales and a 44% decline in the number of early infections in that same population. While youth continue to be left behind in the fight against HIV, the FDA’s recent approval of PrEP for adolescents is a long overdue and essential step toward protecting this vulnerable population from HIV infection.

While we have made tremendous strides, the revolution is far from over. Sustainably ending HIV as an epidemic for all affected communities will require even more options for prevention as we continue to advocate for a vaccine and a cure. Promising open label extension studies for the dapivirine vaginal ring– where researchers in the HOPE and DREAM studies estimate that they have both seen over a 50% decline in the number of new infections– provide hope that a better option for cisgender women is on the way. A regulatory application for the ring was also submitted to the European Medicines Agency in 2017. With several barriers to adherence for oral PrEP limiting the efficacy of that intervention for many individuals, the promise of long acting injectable cabotegravir– currently the focus of two phase III studies with results anticipated in late 2021 (MSM and transgender women) and early 2022 (cisgender women)– may eventually provide the option of injections every two months as opposed to daily pill taking. While funding cuts threaten to completely derail future possibilities for microbicide research, innovative products such as enemas containing tenofovir, rectal and vaginal gels, and multipurpose technologies that may one day protect individuals from other STIs and pregnancy in addition to HIV remain in the pipeline. Alternative oral PrEP regimens continue to be researched, most notably TAF/FTC (Gilead Inc.’s “Descovy”), however advocates will need to ensure that future PrEP and other preventive technologies are priced in a way that ensures access for marginalized populations around the world.

The following charts provide a quick snapshot of the PrEP and microbicides pipeline as of July 2018. We have mostly included interventions currently in clinical trials; other innovations such as long acting implants and microneedle array patches remain in preclinical development. Also of note, MK-8591, a long acting oral ARV that may only require weekly dosing for treatment, has also been shown to protect rhesus macaques against SHIV infection at weekly doses of 1.3 and 0.43 mg/kg, which would translate into weekly doses of less than 250 μg in humans. Clinical trials have not yet been announced for MK-8591 as PrEP but are anticipated.

Agent	Class/Type	Manufacturer/Sponsor	Delivery	Status
ORAL FORMULATIONS
TAF + FTC NCT02842086	NtRTI/NRTI	Gilead Sciences	Oral PrEP	Phase III
Gilead’s Phase III DISCOVER trial, evaluating safety and efficacy of F/TAF compared to TDF/FTC in MSM and TGW, projected to complete toward the end of 2020.
TAF + FTC NCT02904369	NtRTI/NRTI	CONRAD	Oral PrEP	Phase I (in cisgender women)
CONRAD’s Phase I exploratory pharmacokinetic and pharmacodynamic study of Oral F/TAF for the prevention of HIV acquisition. Clinical phases complete, result by end of 2018
F/TDF, Truvada F/TAF, Descovy	NtRTI/NRTI	CONRAD	Oral PrEP	Phase II
CONRAD’s Phase II evaluation of daily Truvada vs daily Descovy oral PrEP in African women. Estimated completion: 2021
Raltegravir Raltegravir + Lamivudine NCT03205566	INSTI INSTI/NRTI	Guy’s and St Thomas’ NHS Foundation Trust	Oral PrEP	Phase IV
Phase IV determining ex-vivo protection for genital tissue with a 7-day course of Raltegravir or Raltegravir+Lamivudine. Estimated study completion date: June 2018
Genvoya (EVG + COBI + FTC + TAF) NCT02985996	INSTI/NtRTI/NRTI	Emory University	Oral PrEP	Phase I
Phase I trial to determine the potential for Genvoya as a future PrEP regimen in MSM and TGW. Estimated study completion of September 2018.
LONG-ACTING FORMULATIONS
Cabotegravir NCT03164564 (Cisgender Women) NCT02720094 (MSM and Transgender Women)	INSTI	ViiV Healthcare	IM	Phase IIb/III (HPTN 083) Phase III (HPTN 084)
Phase III HPTN 084 study evaluating safety and efficacy of long-acting injectable cabotegravir (CAB LA) in HIV-uninfected cisgender women compared to oral TDF/FTC. Estimated study completion date: May 2022 Phase IIb/III HPTN 083 study evaluating safety and efficacy of long-acting injectable cabotegravir (CAB LA) in HIV-uninfected MSM and transgender women compared to oral TDF/FTC. Estimated study completion date: September 2021 Results from HPTN 077 pending on ClinicalTrials.gov, evaluating safety, tolerability, and PK of CAB LA at both 800mg and 600mg doses. Study follow up was extended following findings in the ECLAIR study that CAB LA persisted beyond 52 weeks in a minority of participants.

Agent	Class/Type	Manufacturer/Sponsor	Delivery	Status
MICROBICIDE RINGS, GELS, ENEMAS, FILMS, AND OTHER INSERTABLES
Dapivirine NCT03234400 (3 Month Vaginal Ring) MTN-026 and MTN-033 (Rectal Gel) NCT02858037 (HOPE) NCT02862171 (DREAM)	NNRTI	IPM (vaginal ring/gel/film); DAIDS/MTN (rectal gel)	Monthly vaginal ring	Phase IIIb
			3-month vaginal ring	Phase I
			Rectal gel	Phase I
Open label extensions of MTN-025 (HOPE) and IPM-032 (DREAM) continue to gather data on safety and adherence data on monthly vaginal rings. Hopeful early efficacy/adherence estimates presented at CROI 2018. Phase I MTN 036/IPM 047 launched to assess the potential for a three-month vaginal ring. Study estimated to complete in October 2018. Phase I MTN-026 and MTN-033 are the first studies to assess a rectal DPV gel in HIV-1 uninfected men and women.
Tenofovir NCT02235662	NtRTI	CONRAD	Vaginal ring	Phase I
2015 Phase 1 study evaluated the safety of the TFV/LNG intravaginal ring (IVR), TFV-only IVR, and placebo IVR, evaluated pharmacokinetics (PK) of TFV and LNG, evaluated pharmacodynamic (PD) surrogates of contraceptive efficacy of LNG, and acceptability of the IVRs. Product still in development.
TAF/Elvitegravir	NRTI/INSTI	CONRAD	Vaginal or Rectal Insert	Advanced preclinical;Phase 1
Tenofovir NCT02750540	NtRTI	Johns Hopkins University	Enema	Phase I
DREAM-01 is an early phase 1, open label, dose-escalation and variable osmolarity study to compare the safety, PK, PD, and acceptability of 3 formulations of a tenofovir (TFV) enema. Estimated study completion date of October 2018.
IQP-0528 NCT03082690	NNRTI	ImQuest U19	Rectal gel	Phase I
Phase I study looking at safety and PK for rectal use of IQP-0528, a DuoGel formulated for both rectal and vaginal use. Estimated study completion date: May 2018
Griffithsin NCT02875119 (Vaginal Gel)	Cell-viral fusion–blocking agent	U19 University of Louisville/University of Pittsburgh (Enema) Population Council (Vaginal Gel)	Enema	Phase I
The Population Council is set to begin a phase 1 study evaluating the safety of GRFT for vaginal use in the summer of 2018. Estimated study completion: August 2018. Favorable preclinical findings in mice and rhesus macaques were presented at CROI 2018. The PREVENT rectal microbicide program, operated by University of Louisville and University of Pittsburgh, will begin a clinical trial involving a griffithsin-based enema starting in mid 2019. Researchers have moved away from a gel formulation.
PC-1005 NCT03408899 (Rectal Gel)	NNRTI, ZA, CGN	Population Council/MTN	Rectal gel	Phase I
Phase I MTN-037 will evaluate the safety and PK of a rectal PC-1005 gel. PC-1005 is a multipurpose prevention microbicide to prevent HIV, HPV, and HSV-2 acquisition. Study set to begin in summer 2018 with an estimated completion of May 2019. A vaginal formulation previously being investigated by the Population Council is not presently in development.
DS003 NCT02877979	EI	IPM	Vaginal tablet
Phase 1 IPM-042 was a double-blind, randomized, placebo-controlled, dose escalation trial to evaluate the safety and PK of DS003 vaginal tablets administered to healthy HIV-negative women. Study completed in 2016, product still in development.
Dapivirine + DS003 In Development	NNRTI/EI	IPM	Vaginal ring	Preclinical
Darunavir In Development	PI	IPM	Vaginal ring	Preclinical
MULTIPURPOSE TECHNOLOGIES
Tenofovir + levonorgestrel NCT03279120	NtRTI/HC	CONRAD	Vaginal ring	Phase I
CONRAD: Multi-center, Phase I, 90-day safety, pharmacokinetic, and pharmacodynamics study of the tenofovir/levonorgestrel intravaginal ring (TFV/LNG IVR). (NCT03279120). Estimated completed date: Q3 2019 CDC and CONRAD are collaborating on a Phase IIa, 90-day safety, adherence, and acceptability study of intravaginal rings releasing tenofovir with and without levonorgestrel among women in western Kenya. Estimated completion: Q4 2019
Dapivirine + levonorgestrel NCT02855346	NNRTI/HC	IPM	Vaginal ring	Phase I
Phase 1 study evaluating PK and safety of a vaginal ring containing DPV and LNG. Study completed at the end of 2017, results expected in mid-2018.
MB66 NCT02579083	Anti-HIV + anti-HSV antibodies	LeafBio, Inc.	Vaginal film	Phase I
Phase 1 study evaluating the safety of a monoclonal antibody (MB66) vaginal insert to reduce transmission of HSV and HIV. Estimated study completion date of October 2018.

ABBREVIATIONS

CGN: carrageenan

COBI: cobicistat

EI: entry inhibitor

EVG: elvitegravir

FTC: emtricitabine

HC: hormonal contraception

HSV: herpes simplex virus

IM: intramuscular

IPM: International Partnership for Microbicides

MVC: maraviroc

MTN: Microbicide Trials Network

INSTI: integrase strand transfer inhibitor

NNRTI: non-nucleoside analogue reverse transcriptase inhibitor

NRTI: nucleoside analogue reverse transcriptase inhibitor

NtRTI: nucleotide analogue reverse transcriptase inhibitor

PI: protease inhibitor

PrEP: pre-exposure prophylaxis

TAF: tenofovir alafenamide

ZA: zinc acetate