New antiretrovirals: dolutegravir, entry inhibitor (BMS-663068) and tenofovir pro-drug (GS-7340)

Simon Collins, HIV i-Base

Studies on pipeline drugs in development included early results on:

  • Dolutegravir (formerly called GSK-572) from ViiV (GSK/Shionogi).
  • BMS-663068, an entry inhibitor from Bristol-Myers Squibb.
  • GS-7340, a new formulation of tenofovir from Gilead.

New integrase inhibitor: dolutegravir results in people with raltegravir resistance

Although raltegravir generally worked well in people with multiple drug resistance, especially when supported by new drugs like darunavir/r and etravirine in the background combinations, some people still developed integrase inhibitor resistance. These were generally people with few other treatment options who are now waiting for new drugs.

Joe Eron from University of Carolina presented results from a second open-label phase 2b study of dolutegravir in people with raltegravir resistance. [1]

The dose-response rates from the initial use of a 50 mg once-daily dose of dolutegravir supported increasing the dose to 50 mg twice-daily for this second cohort of experienced patients.

Baseline demographics included median (IQR): CD4 202 cells/mm3 (19–384); viral load 4.3 log copies/mL (3.9–4.8); age 47 (33–68); 75% male; duration on raltegravir 29 months (10–63). At baseline the median (range) fold change in susceptibility was >128 (0.8 to >128) to raltegravir and 2.7 (0.9 to 9.5) to dolutegravir. Baseline patterns of integrase-associated mutations were: N155H (n = 6); Y143H (n = 6); Q148+1 (n = 8); Q148+2 (n = 2); mixture (n = 1); other (n = 1).

The 50 mg twice-daily results included 24 people who added dolutegravir to their failing combination for 11 days (and dropped raltegravir if they were still taking it). To be included in the study people needed to have at least one additional drug that would be active, and this was added to dolutegravir on day 11 when the background combination was optimised, based on resistance test results.

Nearly all patients (23 out of 24) either reduced their viral load to less than 400 copies/mL or by at least 0.7 logs. The average (mean) drop in viral load at day 11 was –1.76 logs (SD 0.54) for study as a whole and –1.57 for people with integrase mutations (Q148 + others). This compared to –1.45 logs seen in the initial 50 mg once-daily study.

Safety data was available for a median 96 days (range 30–172) mainly included common grade 1 or 2 gastrointestinal events not related to dolutegravir. Grade 3 laboratory abnormalities were reported in 4 people (17%) with no discontinuations. One participant had two serious events judged unrelated to the study drug (demyelinating polyneuropathy and diabetes mellitus). No grade 4 events were reported.

The 50mg twice-daily dose has now been selected for phase 3 studies in people who have integrase inhibitor resistance to raltegravir or elvitegravir.

An oral entry inhibitor from BMS

The entry inhibitor in development from Bristol-Myers Squibb called BMS-663068 (BMS-068) is a prodrug of BMS-626529, active against gp120.

Richard Nettles from BMS reported results from a randomised open-label proof of concept study using BMS-068, in 50 people who were either antiretroviral naive (n=34) or experienced but off treatment for the previous eight weeks (n=16). Pharmacodynamic data was presented for 39 patients with an eligible IC50 <0.1µM. [2]

The study used five dose combinations using BMS 068 1200mg once-daily and either 600mg or 1200 mg twice-daily, with and without ritonavir boosting. Baseline demographics included median (range): CD4 432 cells/mm3 (206–921); viral load 4.4 log copies/mL (3.3–6.1); age 42 years (20–70).

After eight days most doses had reduced viral load by 1.6 logs (ranging from –1.22 to –1.78 in the intent to treat and –1.59 to –1.77 in the pharmacodynamic analysis). CD4 cell increases ranged from +28 to +106 after 8 days. All patients with an eligible IC50 achieved viral load reductions of at least 1 log.

The pharmacokinetic slide showed ritonavir to have a relatively modest impact on boosting BMS-068 and plasma levels of BMS-529 remaining 50-fold above median protein adjusted IC90 for twice-daily dosing and 9-fold above with one-daily arm (with ritonavir).

All adverse events were grade 1 or 2 and were similar in each arm (though there was not a control arm). The most frequent side effects included headache (22/50, 44%) and rash (8/50, 16%), mostly mild. There were no drug discontinuations.

Detailed results were also available in a separate poster which is available online. [3]

Drug levels suggested that ritonavir boosting may not be needed and phase 2b trials in treatment-experienced patients are planned to start later this year.

A new version of tenofovir in early studies

First antiviral efficacy results from a new formulation of tenofovir (called GS-7340) were presented by Andrew Zolopa from Stanford University and colleagues. [4]

This compound is designed to achieve higher levels of the active compound in specific tissues such as lymph nodes and target cells achieving higher intracellular levels of tenofovir diphosphate in BPMCs and higher potency compared to equivalent tenofovir doses, with lower plasma concentrations potentially reducing renal toxicity.

The double-blind active-controlled study randomised (1:1:1) 30 treatment-naive patients (CD4 >200; viral load >15,000) to either 50 mg or 150 mg of GS-7340 or to tenofovir 300 mg. After 14 days these three groups produced time weighted viral loads changes of –0.95 (±0.32), –1.07 (±0.14) and –0.54 (±0.32) log copies/mL respectively (primary efficacy endpoint). Mean viral load levels dropped by –0.95, –1.57 and –1.74 log copies/mL in the tenofovir, 50 mg and 150 mg arms respectively. Blood levels were lower (Cmax/AUC by 94%/88% with 50 mg and by 80%/58% with 150 mg) than the tenofovir group with PBMC levels approximately 30-fold higher.

There were no study discontinuation and no grade 3 or 4 events. Side effects reported were generally mild (nausea, headache).


Although these are early results, hopefully lower milligram compounds will be easily coformulated with other ARVs, and the the requirement for less active pharmaceutical ingredients will reduce prices in developing countries.

Although drug levels of the tenofovir prodrug were 6-15 fold higher higher in lymph tissue, spleen and bone marrow there were no increases in plasma, liver and renal tissue. As with tenofovir, the new formulation also does not penetrate the blood brain barrier.

Of interest, despite the improved pharmacokinetics, data presented at CROI in 2010 included a report that GS-7340 showed no protection when used as PrEP in animal studies. [5]


Unless mentioned otherwise, all references are to the Programme and Abstracts of the 18th Conference on Retroviruses and Opportunistic Infections, 28 February – 2 March 2011, Boston.

Webcasts are available at the following link:

  1. Eron J et al. DTG in subjects with HIV exhibiting RAL resistance: functional monotherapy results of VIKING study cohort II. 18th CROI, 27 February – –3 March 2011, Boston. Abstract 151LB.
  2. Nettles R et al. Pharmacodynamics, safety, and pharmacokinetics of BMS-663068: a potentially first-in-class oral HIV attachment inhibitor. 18th CROI, 27 February– – 3 March 2011, Boston. Oral abstract 49.
  3. Nowicka-Sans B et al. Antiviral Activity of a New Small Molecule HIV-1 Attachment Inhibitor, BMS-626529, the Parent of BMS-663068.18th CROI, 27 February– – 3 March 2011, Boston. Poster 518.
  4. Markowitz M et al. GS-7340 demonstrates greater declines in HIV-1 RNA than TDF during 14 days of monotherapy in HIV-1-infected subjects. 18th CROI, 27 February– – 3 March 2011, Boston. Oral abstract 152LB.
  5. Garcia-Lerma G et al. Efficacy of intermittent prophylaxis with tenofovir and emtricitabine against rectal SHIV transmission in macaques and relationship to systemic and mucosal drug levels. 17th CROI 2010. Oral abstract 83.

Links to other websites are current at date of posting but not maintained.