An MD’s Roundup of New Data on Medications for HIV Presented at CROI 2016

Improving Access to Treatment
Improving Access to Treatment
Some treatment failures occur most often due to the need for a high level of adherence to daily medication.

Contemporary antiretroviral therapy (ART) offers many safe and effective options that durably suppress HIV replication and improve immune function. 

Still, some treatment failures occur most often due to the need for a high level of adherence to daily medication. Successful pre-exposure prophylaxis (PrEP) also requires rigorous adherence, and the only Food and Drug Administration (FDA)-approved regimen, a daily dose of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) fixed-dose combination, causes gastrointestinal upset, declines in renal function and bone mineral density in some individuals. Data on several medications and strategies targeting these unmet needs were presented at the 2016 Conference on Retroviruses and Opportunistic Infections (CROI) in Boston.

Long-Acting ART

For patients who struggle to maintain adherence to daily ART, long-acting agents, either injectable or oral, that allow infrequent dosing could be valuable. 

Rilpivirine (Janssen Pharmaceuticals), an approved non-nucleoside reverse transcriptase inhibitor (NNRTI) and cabotegravir (CAB, ViiV Healthcare), an investigational integrase strand-transfer inhibitor, are being developed in nanosuspension formulation for intramuscular injection. After induction with a 3-drug oral regimen, 32 weeks of intramuscular rilpivirine plus CAB dosed every 4 or every 8 weeks was shown to maintain HIV RNA suppression as well as continuation of the 3-drug regimen.1 

Long-acting CAB injection is also being development for PrEP. Phase 2a clinical data on the safety and tolerability of CAB injection in men judged to be at low risk of HIV was also reported.2 After a 4-week phase of daily oral use, participants received 3 injections consisting of 2 ml in both gluteals every 12 weeks of either CAB or saline placebo. Efficacy was not assessable in this study, but trough drug levels were lower than predicted, suggesting dosing every 8 weeks may be better for efficacy trials. In both studies, injection site pain was very common, and other types of injection site reactions (ISR) such as induration and pruritus were seen only with active drug injection, as was fever. Still, study withdrawal due to ISR was uncommon in both studies and participants overwhelmingly preferred injectable to oral therapy. These trials support the conduct of larger studies to further define the safety, tolerability, and establish the efficacy of long-acting injectable ART and PrEP.

Scientists from Merck presented data on the investigational nucleoside reverse transcriptase inhibitor (NRTI) MK-8591.3,4 Like other NRTIs, it is phosphorylated intracellularly to its active form, MK-8591-triphosphate, which has an extended half-life in human peripheral blood mononuclear cells. Administration of a single 10 mg oral dose for patients with HIV produced sustained HIV RNA reductions for at least 10 days. Studies of once-weekly dosing are planned. Development of an extended-release parenteral formulation is ongoing. Preliminary results from animal studies suggest therapeutic effects may be achievable for 6-12 months.

Pre-clinical studies of a completely novel antiretroviral with 3 mechanisms of entry inhibition were presented by scientists from Bristol-Myers Squibb.5 The agent is a biologic that contains an adnectin (engineered from human fibronectin) that binds CD4, another adnectin that binds gp p41 and a peptide that binds to a separate p41 site. All 3 are linked into a single molecule and bound to human serum albumin. The agent, dubbed a combinectin, has potent activity in vitro and in an animal model. There is no human data yet, but dosing once-weekly by subcutaneous injection is thought to be possible. This agent offers the possibility of a complete ART regimen with a single intermittently injected drug, but there are many hurdles to be cleared for this early stage investigational agent. ViiV HealthCare has acquired the rights to develop this drug. 

New drugs and strategies for PrEP

Some trials of oral or topical PrEP in women have shown poor results due to very low rates of adherence. Dapivirine (DPV) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that is not used systemically. 

To improve adherence, a dapivirine-eluting intravaginal ring that can be self-inserted and remains in place for one month was developed. Similar results were reported in two large efficacy trials conducted in African women.6,7 Compared to placebo, the DPV ring reduced HIV infection rates by 27% to 31%. 

The ring was somewhat more effective in women 21 years of age of more (37-56%) and ineffective in younger women. Estimates of adherence based on plasma DPV levels and by the amount of drug remaining in returned rings ranged from 82-84% and efficacy correlated with adherence. However, even in a subset of women with the lowest residual levels of DPV in returned rings, efficacy was only 65%. Information on drug resistance was not presented, but as noted in a third abstract,8 resistance to NNRTIs, including DPV is common in Africa, as it is worldwide. The drug-eluting ring may be a more acceptable alternative for high-risk women who will not adhere to oral or topical PrEP, but this product requires further optimization. Greater efficacy might be achieved from a higher dose, more complete drug release from the device or use of an alternate antiretroviral.

Maraviroc (MVC) is an approved antiretroviral that is safe and effective but not commonly used to treat HIV. Its unique mechanism of action is inhibition of the CCR-5 co-receptor necessary for HIV entry. Resistance among transmitted strains of HIV is rare. These features make it an attractive candidate for PrEP. 

A phase 2 trial conducted in at risk men having sex with men compared 3 MVC-containing regimens (MVC alone, MVC/FTC, MVC/TDF) to standard PrEP with TDF/FTC.9 About 100 participants were randomly assigned to each arm. Eight-four percent completed the 48 week study and adherence was around 80% based on plasma drug levels. There were no safety signals. Although there were 4 HIV infections in the MVC alone arm and one in the MVC/TDF arm, the study was not powered for efficacy, so it is not possible to conclude anything about the relative efficacy of MVC-based PrEP. Four of the 5 infections were associated with low or absent MVC levels. Additional data from a study in women may help determine the path forward for MVC-based PrEP.

Tenofovir alafenamide (TAF) Findings

TAF is a new prodrug of tenofovir. It has recently been approved as a component of two fixed-dose combination, single tablet regimens (Genvoya and Odefsey, Gilead Sciences). Compared to TDF, TAF achieves higher concentrations in lymphocytes of tenofovir diphosphate, the active form, with lower plasma concentrations.

 Published clinical trials have demonstrated that TAF has similar efficacy with less renal and bone adverse effects than TDF. Three CROI presentations provided 96-week safety data from clinical trials. These trials confirm that TAF is associated with fewer discontinuations for renal events and better preservation of estimate glomerular filtration rate, renal tubular function and bone mineral density.10,11  It appears safe in patients with estimated GFR 30-69 mL/min.12 TAF may also be a safer alternative to TDF for use in PrEP. Earlier research on TAF as PrEP showed excellent activity in an animal model.13 However, tenofovir levels in genital and rectal tissues are lower in women given a single dose of TAF compared with TDF.14  Whether or not this influences efficacy will need to be studied.


1.     Margolis DA, Gonzalez-Garciz J, Stellbrink HJ, et al. Cabotegravir+Rilpivirine as long-acting maintenance therapy: LATTE-2 week 32 results. Abstract 31LB.

2.     Markowitz M, Frank I, Grant R, et al. ÉCLAIR: Phase 2A safety and PK study of cabotegravir LA in HIV-uninfected men. Abstract 106.

3.     Grobler J, Friedman E, Barrett SE, et al. Long-acting oral and parenteral dosing of MK-8591 for HIV treatment or prophylaxis. Abstract 98.

4.     Friedman E, Schuermann D, Ruddet DJ, et al. A single monotherapy dose of MK-8591, a novel NRTI, suppresses HIV for 10 days. Abstract 437LB. 

5.     Krystal M, Wensel D, Sunet Y, et al. HIV-1 combination BMS-986197: A long-acting inhibitor with multiple modes of action. Abstract 97. 

6.      Baeten JM, Palanee-Phillips T, Brownet ER, et al. A phase III trial of the dapivirine vaginal ring for HIV‐1 prevention in women. Abstract 109LB. 

7.     Nel A, Kapiga S, Bekkeet LG, et al. Safety and efficacy of dapivirine vaginal ring for HIV-1 prevention in African women. Abstract 110LB. 

8.     Penrose KJ, Hamanishi KA, Gordon KC, et al. Frequent Dapivirine cross-resistance of HIV from 1st-line ART failures in S. Africa. Abstract 985. 

9.     Gulick R, Wilkin TJ, Chen Y, et al. HPTN 069/ACTG 5305: Phase II study of maraviroc-based regimens for HIV PrEP in MSM. Abstract 103.

10. Rijnders B,Post FA, Rieger A, et al. Longer-term renal safety of tenofovir alafenamide vs. tenofovir disoproxil fumarate. Abstract 682.

11. Wohl D, Thalme A, Finlay R, et al. Renal safety of tenofovir alafenamide in patients at high risk of kidney disease. Abstract 681.

12. Post FA, Tebas P, Clarke A, et al. Longer-term renal safety of tenofovir alafenamide in renal impairment. Abstract 680.

13. Massud I, Mitchell J, Babusis D, et al.  Chemoprophylaxis with oral FTC/TAF protects macaques from rectal SHIV infection. Abstract 107. 

14. Garret KL. Concentrations of TFV and TFVdp in female mucosal tissues after a single dose of TAF. Abstract 102LB.

All presented at: The Conference on Retroviruses and Opportunistic Infections 2016. Feb. 22-25, 2016. Boston.