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Novel ART Regimens
IAS 2017 Data Shed Light on the Potential Use of Investigational ART Coformulations

Released: September 11, 2017

Expiration: September 10, 2018

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In this HIV commentary series, we highlight the critical decision making that goes into selecting optimal patient management strategies with current therapies and evolving treatment options for HIV. This commentary highlights phase III data presented at the 2017 International AIDS Society (IAS) meeting in Paris on 2 investigational antiretroviral drugs—the novel INSTI bictegravir and the novel NNRTI doravirine—and discusses how these agents might fit into the HIV treatment landscape should they be approved.

Bictegravir: A Novel INSTI
INSTIs are currently the standard of care for first-line HIV therapy for the majority of patients. Three INSTIs are currently recommended by guidelines for the first-line treatment of HIV, but each has potential drawbacks.

  • A once-daily formulation of unboosted INSTI raltegravir has recently been FDA approved but requires multiple tablets, and raltegravir is not available in coformulated regimens with other ARVs.
  • Elvitegravir can be administered once daily as a single-tablet regimen with either tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF), but requires boosting with cobicistat.
  • Dolutegravir (DTG) is an unboosted INSTI with a high barrier to resistance and can be administered once daily as a single-tablet regimen. The coformulated DTG regimen contains abacavir (ABC), which some clinicians choose to avoid in patients with high cardiovascular disease risk. However, DTG can be dosed separately with other NRTIs.

Bictegravir (BIC) is a novel unboosted INSTI coformulated with emtricitabine (FTC) and TAF. At the 2017 IAS meeting, the results of 2 phase III trials (GS-1489 and GS-1490) that compared BIC/FTC/TAF with DTG-containing regimens as initial ART were presented. Both trials were randomized, double-blind, active-controlled trials that, in aggregate, enrolled nearly 1300 participants.

In both trials, BIC/FTC/TAF was noninferior to the DTG-containing regimen, either DTG/ABC/lamivudine (3TC) in GS-1489 or DTG + FTC/TAF in GS-1490 (Table). No resistance to any regimen component was detected across treatment arms in both studies. Treatment regimens were generally similar in terms of safety, with similar rates of discontinuations for adverse events observed with BIC/FTC/TAF and the respective DTG-containing regimens. Based on these data, it is anticipated that BIC/FTC/TAF will be FDA approved and become available for clinical use within the next year.

Table. Efficacy and Safety of BIC/FTC/TAF vs DTG-Containing Regimens

Doravirine: A Novel NNRTI
Two NNRTIs appear as part of alternative ART regimens in HIV treatment guidelines. Both are part of single-tablet, once-daily regimens, but each have potential drawbacks.

  • Efavirenz (EFV) use may be accompanied by CNS adverse events.
  • Rilpivirine must be taken with a meal and is only indicated for patients with lower viral loads. Moreover, coadministration with proton pump inhibitors is contraindicated, and concomitant antacids must be used with caution.

Doravirine (DOR) is a novel NNRTI that is administered once daily at a relatively low dose. Previously, the phase III DRIVE-FORWARD study demonstrated the noninferiority of DOR to ritonavir-boosted darunavir when each was paired with 2 NRTIs. The double-blind, active-controlled phase III DRIVE-AHEAD trial, the 48-week results of which were presented at IAS 2017, randomized 734 ART-naive participants to a fixed-dose combination of DOR/3TC/TDF or EFV/FTC/TDF. DOR/3TC/TDF was noninferior to EFV/FTC/TDF in terms of efficacy, with 84% and 81% of patients, respectively, achieving HIV-1 RNA < 50 copies/mL (treatment difference: 3.5%; 95% CI: -2.0% to 9.0%). Protocol-defined virologic failure occurred in 6% and 4% of patients, respectively, but no unexpected mutations were observed in the 1% to 3% with primary NRTI or NNRTI resistance. A significant reduction in neuropsychiatric adverse events (including dizziness, sleep disorders/disturbances, and altered sensorium) was observed for patients receiving DOR/3TC/TDF. Treatment with this regimen was also associated with significantly improved lipid parameters vs EFV/FTC/TDF. The chief potential disadvantage of the DOR-containing regimen may be its coformulation with TDF instead of TAF.

Clinical Implications
To place these results in clinical context and emphasize how these new agents alleviate potential challenges with already recommended or alternative options in their respective classes, here are the major takeaway messages:

  • BIC offers the possibility of a once-daily, coformulated, unboosted INSTI–based regimen with TAF in place of TDF.
  • DOR offers the possibility of an NNRTI-containing regimen coformulated with 3TC and TDF without any baseline HIV-1 RNA or food restrictions or evident CNS adverse events and minimal drug–drug interactions.

The role of these regimens in HIV treatment and endorsement by the various guideline panels await their formal approval and publication of clinical trial data. In addition, switch studies are under way for both BIC and DOR, with results expected before the end of next year.

Your Thoughts
Where do you see the investigational regimens discussed above fitting into the HIV treatment landscape? Please share your experiences and insights by joining the conversation in the comments box below.

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