The Antiretroviral Pipeline

March 2, 2015

The antiviral future holds great promise for people living with HIV: better-tolerated, less toxic, drugs are about to come to market, and we are about to see the introduction of drugs from 1 or 2 new classes.

No CROI would be complete without presentations of antiretroviral drugs in the pipeline. The 2015 CROI was no different, even if there were relatively few presentations on clinical trials comparing various drugs and combinations. Given the success of currently available combinations, most of the pharmaceutical industry effort in this area has gone into co-formulating existing drugs into single-tablet, fixed-dose products. Nevertheless, there are a few drugs in the pipeline. Here are the highlights:

  • There were several presentations on the new formulation of tenofovir. The current formulation (tenofovir disoproxil fumarate; TDF) is available as a single drug and in combination (co-formulated) with multiple other antiretroviral agents. The new formulation (tenofovir alafenamide; TAF) has been found to be substantially less nephrotoxic while also achieving higher intracellular concentrations (it is the intracellular levels, not serum levels, that matter for this class).
  • Stribild (TDF plus elvitagravir plus cobicistat plus emtricitabine), already on the market, was compared with TAF plus elvitegravir plus cobicistat plus emtricitabine in 1733 HIV-infected, previously antiretroviral-naive, persons, in 2 randomized, double-blind, studies.1 The new formulation was found to be non-inferior for efficacy to Stribild.
  • In a separate presentation involving the same 1733 study participants, TAF was found to have significantly fewer adverse effects on renal and bone health than did TDF.2 Expect to see the new formulation co-formulated with multiple other antiretrovirals in fixed-dose combinations within the next year.
  • Farther back in the pipeline, but exciting nevertheless, was the oral presentation of Bristol-Myers Sqibb’s second-generation HIV maturation inhibitor, BMS-955176.3 If successfully brought to market, it would be the first FDA-approved drug in this class. In the presented phase 2a (dose-finding) study, those participants randomized to receive the 40-mg once-daily dose achieved a 1.5 log drop in HIV RNA levels. Phase 2b (larger) trials are planned for 2015.
  • Another Bristol-Myers Squibb drug in development deserves mention: BMS-663068, a first-in-class HIV attachment inhibitor. A large, phase 3, trial is ongoing, enrolling “heavily treatment-experienced” (HTE) HIV-infected persons. In the US, the HTE group probably represents fewer than 5% of all HIV-infected persons. However, for individuals in this group, who have extensive resistance to multiple existing classes of antiretrovirals, this drug has the potential to restore maximal viral suppression when other regimens are failing because of developing drug resistance. Forty-eight–week results of a smaller, phase 2b trial were presented, showing comparable efficacy of BMS-663068 to ritonavir-boosted atazanavir, when each was combined with raltegravir and TDF.4
  • Cabotegravir is an HIV integrase strand transfer inhibitor (same class as raltegravir, elvitegravir, and dolutegravir) that is under development as both an oral and long-acting injectable product. Ninety-six–week results of the LATTE trial, comparing once-daily oral cabotegravir plus once-daily rilpilvirine with once-daily efavirenz plus once-daily TDF or Epzicom in HIV-infected persons previously antiretroviral-naive, were presented.5 Efficacy results of the two arms were comparable, and safety of cabotegravir was impressive (no serious adverse events attributable to the drug).

The future looks promising, as better-tolerated, less toxic drugs are about to come to market, and as we are about to see (within the next 2 years), the introduction of drugs from 1 or 2 new classes. Finally, it may be worth recalling that the first FDA-approved antiretroviral drug, zidovudine, became available in the US 28 years ago, in March 1987. We really have come a long way in less than one generation.


  • Wohl D, Pozniak A, Thompson M, et al. Tenofovir Alafenamide (TAF) in a Single-Tablet Regimen in Initial HIV-1 Therapy
. Abstract 113LB; 2015 CROI; Seattle; 23 – 26 February 2015.
  • Sax PE, Saag MS, Yin MT, et al. Renal and Bone Safety of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate. Abstract 113LB; 2015 CROI; Seattle; 23 – 26 February 2015.
  • Hwang C, Schürmann D, Sobotha C, et al. Antiviral Activity/Safety of a Second-Generation HIV-1 Maturation Inhibitor. Abstract 114LB; 2015 CROI; Seattle; 23 – 26 February 2015.
  • Thompson M, Lalezari J, Kaplan R, et al. Attachment Inhibitor Prodrug BMS–663068 in ARV-Experienced Subjects: Week 48 Analysis. Abstract 545; 2015 CROI; Seattle; 23 – 26 February 2015.
  • Margolis DA, Brinson CC, Smith GH, et al. Cabotegravir and Rilpivirine As 2-Drug Oral Maintenance Therapy: LATTE W96 Results. Abstract 554LB; 2015 CROI; Seattle; 23 – 26 February 2015.