Advertisement covers CROI 2013

ARV Pipeline: Dolutegravir, TAF (GS-7340), MK-1439 and Cenicriviroc

March/April 2013

 1  |  2  |  Next > 

Promising compounds for new treatments that were discussed at CROI 2013 included the integrase inhibitor dolutegravir, a new version of tenofovir, a new NNRTI, a new CCR5 inhibitor and several long-acting formulations.


With two phase 3 studies completed, dolutegravir has already been submitted for regulatory assessment in both Europe and the U.S. As a once-daily drug with a low milligram dose and no requirement for boosting, dolutegravir may have advantages over other integrase inhibitors (INSTIs) including raltegravir and the recently approved elvitegravir (as a component of Quad/Stribild).

Interim 24 weeks results were presented from the ongoing international phase 3 SAILING study in 715 treatment-experienced (integrase-naive) patients randomised to either 50 mg dolutegravir once-daily or 400 mg raltegravir twice-daily, each plus matching placebo.1 Patients could use an additional two investigator-selected ARVs, at least one of which had to be fully sensitive. The background combinations were generally robust (PI/r plus tenofovir 40%, lopinavir/r only 10%, darunavir/r plus etravrine 10%).


At baseline, median CD4 count and viral load were approximately 200 cells/mm3 and 15,000 copies/mL, respectively, with approximately half of participants having resistance to three or more classes and a median six years prior ART. Approximately 30% were women, 50% white and 40% African American and 15% had HIV/HCV coinfection.

At week 24, the dolutegravir arm had greater viral suppression compared to raltegravir (79% vs 70% with VL <50 copies/mL; difference 9.7% [95%CI: +3.4, +15.9], p=0.003). However, this was in an analysis that adjusted for baseline viral load, phenotype sensitivity and use of darunavir without PI mutations. The differences were based on fewer discontinuations in the dolutegravir arm (14% vs 17%) and lower rates of virological failure (4% vs 7%). Side effects were broadly similar with few treatment discontinuations in each arm.

In patients with hepatitis B or C coinfection, IRIS-related liver complications were reported more frequently in the patients using dolutegravir (6 vs 3 patients).

The primary endpoint for the study will be results at week 48.

A second late-breaker poster reported that CSF levels of dolutegravir were similar to the unbound fraction in plasma and that this was above the IC50 for wild-type virus (0.2 ng/mL) indicating likely therapeutic levels. This was an open label, single arm intensive PK study in 13 men receiving doultegravir with abacavir/3TC.2

Baseline viral load in CSF and plasma were 3.64 and 4.73 log copies/mL, with 12/13 men achieving undetectable levels at week 16 (using <2 c/mL and <50 c/mL cut-off tests for CSF and plasma respectively). Levels the patients with detectable levels were 5 c/mL and 77 c/mL respectively.

A lack of interaction between dolutegravir and either methadone or combined oral contraceptives (ethinyl estradiol 0.035 mg and norgestimate 0.25 mg) was also reported in a poster showing two drug interaction studies in HIV negative volunteers.3

Tenofovir Alafenamide (TAF, GS-7340)

Several studies were presented on a new prodrug of tenofovir that was previously in development as GS-7340 and now has the generic compound name tenofovir alafenamide (abbreviated to TAF). At a 25 mg dose, TAF results in 7-fold greater intracellular levels of tenofovir with 90% lower plasma levels, compared to 300 mg formulation of tenofovir disoproxil fumerate (TDF).

Early clinical data on TAF compared to TDF in treatment-naive patients was shown in a late breaker oral presentation. Both formulations were included in single tablet, four-drug combinations with elvitegravir, cobicistat and FTC.4

This is an ongoing, double-blind phase 2 study in 170 patients randomised 2:1 to TAF or TDF formulations respectively. The 4-drug combination uses a 10 mg TAF dose as cobicistat boosts TAF by 2.4-fold.

This was a largely male (97%), white (67%) group in early infection. Baseline CD4 and viral load were approximately 400 cells/mm3 (15% were <200) and 40,000 copies/mL (17-28% were >100,000 copies/mL), respectively. Entry criteria included eGFR >70 mL/min, with median baseline levels at 115 mL/min, as with previous studies using cobicistat and tenofovir.

For the primary endpoint of virological suppression at 24 weeks, 87% vs 90% in the TAF vs TDF arms had viral load <50 copies/mL (weighted difference: -4.9%, 95%CI -15.7, +5.9, p=0.36). CD4 increases were similar (+163 vs +177 cells/mm3).

With efficacy expected to be high, the focus on side effects showed similar short-term results. The five side effects occurring in ≥10% of patients were: nausea (18% vs 12%), diarrhea (12% vs 12%), fatigue (12% vs 9%), headache (10% vs 10%), and upper respiratory tract infection (7% vs12%); any grade, TAF vs TDF.

Both arms had an increase in serum creatinine and reduction in eGFR related to use of cobicistat. These occurred by week 2 but then stablised to week 24, and were greater with TDF (-4.9 mL/min vs -11.8 mL/min, p = 0.032).

Mean (+/-SD) bone mineral density (BMD) was reduced less in the TAF arm for both spine [-0.8 (+/-3.4) vs -2.5 (2.5], p = 0.002 and hip [-0.3 (+/-1.8) vs -2.0 (+/-2.7)], p <0.001.

There were no cases of proximal renal tubulopathy or discontinuations for renal events.

MK-1439 -- a New NNRTI

First efficacy and safety data in HIV positive people were presented for a new NNRTI with the development name MK-1439 (from Merck) that has in vitro activity against common NNRTI drug resistant mutations (K103N, Y181C and G190A).5

This was a double-blind, placebo controlled, single-site, phase Ib study in 18 treatment-naive men randomised (1:1:1) to 25 mg (n=6), 200 mg (n=6) or placebo (n=3 for each placebo), taken once-daily for seven days as monotherapy. All participants started standard ART from day eight for 10 days to minimise risk of drug resistance during the washout phase.

Mean viral load reductions (90%CI) compared to placebo of -1.37 (-1.60, -1.14) and -1.26 (-1.51, -1.02) log copies/mL in the 25 and 200 mg arms, respectively, with non-significant differences between active doses at all time points.

A total of 21 non-serious side effects were reported in 13/18 participants, including headache (n=5), nausea (n=2), common cold (n=2) and sore throat (n=2). Night sweats, headache (at 200 mg) and loss of appetite (at 25 mg) were considered possibly related to MK-1439. The single serious event was a increase in LFT in one patient on day 7, judged related to acute HCV infection between screening and study entry.

Pharmacokinetic results were similar to those seen in HIV negative studies, with mean concentrations at 24 hours post dose that were 14-fold (25 mg dose) and 87-fold (200 mg dose) higher than the adjusted IC95 for wild-type virus (19 nM, in 50% serum).

Results from a phase 1a safety study in HIV negative people including multiple doses up to 750 mg for ten days were presented as a separate poster, reported a lack of significant interactions with or without food, and that at steady-state, a 12 mg dose produced 24-hour post dose drug levels that remained above the adjusted IC95 for wild-type virus.6 Other phase 1 studies in 140 HIV negative individuals included 14 young women and 12 elderly women, without reports of clinically relevant side effects, including rash or CNS events.

Phase 2b studies continue using 25, 50, 100 and 200 mg doses.

 1  |  2  |  Next > 

This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.

No comments have been made.

Add Your Comment:
(Please note: Your name and comment will be public, and may even show up in
Internet search results. Be careful when providing personal information! Before
adding your comment, please read's Comment Policy.)

Your Name:

Your Location:

(ex: San Francisco, CA)

Your Comment:

Characters remaining:

Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.


The content on this page is free of advertiser influence and was produced by our editorial team. See our content and advertising policies.