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Antiretroviral Studies at ICAAC 2014: Darunavir-Based FDC With TAF, Cobicistat, Doravirine, Stribild and Gel Formulation PrEP

October 1, 2014

The following summaries provide a brief overview of some of the antiretroviral studies presented at ICAAC 2014. For full details please see reports on NATAP.org, many of which include presentations slides.


Single Pill PI-based FDC Using Tenofovir Alafenamide Fumerate (TAF)

Week 48 results were presented comparing a single-pill fixed dose combination (FDC) that includes darunavir, cobicistat and FTC with tenofovir alafenamide (D/C/F+TAF; n=100), compared to separately dosed darunavir and cobicistat plus FTC/tenofovir DF (DRV+COB+TDF/FTC; n=50).1

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This was a phase II, randomised, placebo controlled study. The primary endpoint was virological suppression to <50 copies/mL at week 24, which was reported for 75% vs 74% in the TAF vs TDF arms [weighted difference: 3.3% (95%CI: -11.4%, +18.1%). At week 48, these rates were 77% vs 84% [weighted difference: -6.2 (95%CI: -19.9, +7.4), p=0.35].

Bone and renal markers suggested potential benefits for TAF. At 48 weeks, reductions in bone mineral density in both spine (-1.57% versus -3.62%, p=0.003) and hip (-0.84% vs -3.82, p<0.001) were significantly less with TAF than with TDF. Median reduction in eGFR was also less (-2.9% vs -10.6%, p=0.017). Median change in proximal tubular proteinuria rose significantly less with TAF than with TDF (+9% vs +54%, p=0.003).

As expected from earlier studies, plasma concentrations of tenofovir were significantly lower and intracellular concentrations approximately 6-fold higher using TAF compared to TDF.


Cobicistat vs Ritonavir to Boost Atazanavir

Extended follow-up continued to support non-inferiority for boosting atazanavir with cobicistat compared to ritonavir. Results were presented from a randomised, blinded, active-controlled phase III study in 700 treatment-naive patients.2

At 144 weeks, suppression to <50 copies/mL was 72% vs 74% (difference -2.1%, 95% CI -8.7% to 4.5%) in the cobicistat vs ritonavir groups respectively. This compared to 85% vs 87% (difference -2.2, [95%CI: -7.4% to 3.0%]) at week 48.

A single-arm study looked at switching ritonavir to cobicistat as the booster for either atazanavir or darunavir in 73 people who were on stable ART but who had a reduced renal function (defined as creatinine clearance [CrCl] 50 to 89 mL min).3

Almost half of study participants, 47%, had CrCl below 70 mL/min (median 71; range 42 to 98), and one third had proteinuria, 38% had hypertension, 18% had diabetes, and 3% had HIV-associated nephropathy.

Although 26% of people discontinued cobicistat (10% relating to side effects) there were no cases of proximal renal toxicity and no renal safety signal. The researchers concluded that cobicistat could be an option for this patient group. It was not clear from the presentation whether TDF was also used in this study.


Doravirine: 100 mg Dose Selected for New NNRTI

A phase II dose-ranging study of the NNRTI doravirine (MK-1439) in development at Merck, reported that once-daily dosing at 100 mg achieved target concentrations for both wild-type virus and against common NNRTI-associated mutaions (including K103N, Y181C and G190A).4

No correlation was seen between dose (at 25, 50, 100, and 200 mg) and either side effects or viral suppression at week 24 and the 100 mg dose will go forward for further development.


Stribild Response in Black Patients

A higher virological response rate was reported for black participants using Stribild compared to Atripla in a post-hoc analysis of the Gilead 102 study. Approximately 25-30% of participants in this phase III treatment-naive registrational study were black.5

At week 144, the percentage of black participants with viral suppression to <50 copies/mL was 78% vs 66% (difference, 12.4%; [95%CI: -0.1% to 25%]; p=0.052) in the Stribild vs Atripla arms respectively, a finding which fell short of statistical significance. The result was not explained by differences in baseline characteristics between the two combinations. However, differences in adherence (defined as taking >90% doses) was significant: 89% versus 76% in the Stribild vs Atripla arms respectively (p=0.023). Serious adverse event rates were similar (19% vs 18%), but grade 2 to 4 events (13% vs 35%), and side-effect related discontinuations (2% vs 11%, p=0.014) were both higher in the Atripla group.

By comparison, in non-black participants, rates of viral suppression <50 copies/mL were 81% vs 79% in the Stribild vs Atripla arms respectively.

These results are perhaps important for highlighting difficulties associated with Atripla, as CNS side effects were reported at higher rates compared to Stribild, but it is also important to note that this was a post-hoc analysis.


TDF/FTC Vaginal Ring Protects 6 of 6 Monkeys From Weekly SHIV Exposure

Intravaginal rings containing tenofovir and emtricitabine (TDF/FTC) in six pods protected 6 of 6 macaques from weekly exposure (for 16 weeks) to simian hybrid HIV (SHIV), while all animals not wearing a ring became infected.

It was estimated that a comparable ring for women would be able to provide a similar level of protection for a least one month.6


Tenofovir Suspension in Vaginal Gel Protects 10 of 10 Mice From HIV

A new TDF intravaginal gel protected 10 of 10 humanised mice from a single HIV challenge (4 hours after the gel) and they remained negative for four weeks. This new formulation uses a nanoparticle suspension of TDF that is liquid at room temperature but that becomes viscous at body temperature.

The three mice that were given an inactive gel all became infected.7


References

  1. Mills A et al. 48 Week study of the first PI-based single tablet-regimen (STR) darunavir/cobicistat/emtricitabine/tenofovir alafenamide versus cobicistat-boosted darunavir and emtricitabine/tenofovir disoproxil fumarate in treatment-naive adults. ICAAC 2014. September 5-9, 2014. Washington, DC. Abstract H-647c.
    Slides
    Report
  2. Gallant J et al. Cobicistat versus ritonavir as pharmacoenhancers of atazanavir in combination with emtricitabine/tenofovir DF -- phase 3 randomized, blinded, active-controlled trial, week 144 results.
    Slides
    Report
  3. McDonald C, Martorell C, Ramgopal M, et al. Efficacy And safety of switching the pharmacoenhancer from ritonavir to cobicistat in HIV patients with renal impairment who are virologically suppressed on a protease inhibitor containing regimen. ICAAC 2014. September 5-9, 2014. Washington, DC. Abstract H-1006.
    Slides
    Report
  4. Yee KL, Chatterjee M, Dockendorf M, et al. Pharmacokinetics of doravirine and exposure-response analysis: efficacy and safety implications. ICAAC 2014. September 5-9, 2014. Washington, DC. Abstract H-647b.
    Slides
    Report
  5. Hardy WD et al. Long-term efficacy and safety of E/C/F/TDF (STB) versus EFV/FTC/TDF (ATR) in HIV-1-infected treatment naive black and non-black subjects. 4th Interscience Conference on Antimicrobial Agents and Chemotherapy September 5-9, 2014 Washington DC, USA.
    Slides
    Report
  6. Smith JM et al. Complete protection in macaques from multiple simian-human immunodeficiency virus exposures with pod-intravaginal rings delivering an antiretroviral combination. ICAAC 2014. September 5-9, 2014. Washington, DC. Abstract H-998.
    Report
  7. Destache CJ, Date AA, Zhe Y, et al. Topical application of tenofovir TDF nanoparticles prevents HIV-1 vaginal transmission in humanized-BLT mice. ICAAC 2014. September 5-9, 2014. Washington, DC. Abstract H-997.
    Report and slides

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