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Investigational HIV Therapies
How Investigational Therapies May Fit Into the HIV Treatment Landscape

Released: April 10, 2017

Expiration: April 09, 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. With currently available antiretroviral therapy (ART) regimens, virologic suppression can be achieved in most patients with HIV. Despite this, ART can be improved; many current agents have numerous drug–drug interactions or may cause or exacerbate comorbid conditions in some patients. Some regimens must be taken twice daily or may not be available in single-tablet formulations. Long-acting injectable therapies are awaited but currently unavailable. This commentary highlights several agents under active investigation that may address some of the unmet needs in HIV treatment.

Bictegravir: A Novel INSTI
The novel integrase inhibitor, bictegravir, is dosed once daily without boosting because of its 18-hour half-life. A recent pharmacokinetic analysis showed that bictegravir has at least as few drug–drug interactions as the currently available integrase inhibitor dolutegravir. Of note, metformin exposure only modestly increased with coadministration of bictegravir. Because bictegravir is a substrate of both CYP3A4 and UGT1A1, inhibition of CYP3A4 alone (eg, voriconazole) did not substantially increase bictegravir levels. Similarly, mild induction (eg, rifabutin) did not substantially decrease bictegravir levels. The dose of bictegravir may have to be doubled, however, when coadministered with a powerful inducer such as rifampin, which reduced the bictegravir AUC by 75%. Finally, when coformulated at 50 mg with FTC/TAF, bictegravir achieved improved bioavailability vs the 75 mg used in single-agent dosing.

A double-blind phase II study randomized treatment-naive patients 2:1 to receive either bictegravir (n = 65) or dolutegravir (n = 33), each with FTC/TAF, and the matching placebo. Participants were predominantly male and healthy, with low percentages having HIV-1 RNA > 100,000 copies/mL or a CD4+ cell count ≤ 200 cells/mm3. Rates of overall virologic success were outstanding for both treatment arms: 97% with bictegravir vs 94% for dolutegravir at Week 24 and 97% with bictegravir vs 91% for dolutegravir at Week 48. No patient experiencing virologic failure developed clinically significant drug resistance in either treatment arm. One patient in the bictegravir arm with a history of allergic skin disease discontinued treatment at Week 24 for worsening urticaria; no treatment-related serious adverse events or cases of tubulopathy occurred in either arm (Table).

Table. Select Adverse Events Reported in Phase II Bictegravir + FTC/TAF Study
 
Going forward, 2 phase III studies in treatment-naive patients are currently enrolled to compare coformulated bictegravir/FTC/TAF with dolutegravir plus FTC/TAF or ABC/3TC. If phase III data confirm these encouraging phase II results, bictegravir will be the first unboosted integrase inhibitor to be coformulated with FTC/TAF and administered on a once daily schedule.

Doravirine: A Novel NNRTI
Doravirine is a novel NNRTI that is administered once daily at a relatively low dose, with a unique and potent resistance profile. It has few drug–drug interactions and a lower CNS adverse event profile vs efavirenz. A single-pill coformulation with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) is planned.

DRIVE-FORWARD was a fully powered, multicenter phase III noninferiority study wherein treatment-naive patients were randomized to receive either doravirine or darunavir (DRV)/ritonavir (RTV), each with 2 NRTIs (ie, FTC/TDF or abacavir ABC/lamivudine 3TC). The study was double blinded and placebo controlled such that each participant received 4 pills daily. In total, 84% of patients receiving doravirine achieved HIV-1 RNA < 50 copies/mL at Week 48 vs 80% receiving DRV/RTV, a difference that met protocol criteria for doravirine noninferiority. Only 1 noncompliant patient in the doravirine treatment group developed resistance vs none in the DRV/RTV group, and doravirine treatment was associated with an improved lipid profile from baseline to Week 48.

The good news is that doravirine is clearly as effective as DRV/RTV. Impressively, only 1 patient developed resistance, and the drug was very well tolerated. Unfortunately, doravirine was compared with boosted DRV, rather than an integrase inhibitor—the class that dominates both the DHHS and IAS-USA guidelines for first-line regimens.

Furthermore, doravirine will be coformulated with FTC/TDF, which may cause renal disease in some patients when administered long term and lowers bone mineral density more than tenofovir alafenamide (TAF). Advantages over nevirapine, efavirenz, rilpivirine, and etravirine are expected, but we must await results from other ongoing phase III studies in the first line and switch settings comparing doravirine/3TC/TDF with various combination regimens.

Additional Agents
Several other agents in late-stage clinical trial development have shown promise for treating patients with HIV. The once-daily, single-tablet DRV/COBI/FTC/TAF regimen demonstrated favorable results in a phase II trial in treatment-naive patients; 2 phase III trials are currently ongoing to further assess this agent in the first-line and switch settings.

A significant area of unmet need is in treating patients with multidrug-resistant virus. Ibalizumab, a monoclonal antibody to CD4 receptor that blocks postattachment HIV entry, was assessed in a single-arm phase III study enrolling heavily pretreated patients with multidrug-resistant virus and with HIV-1 RNA > 1000 copies/mL. At treatment Week 24, 43% of patients had HIV-1 RNA < 50 copies/mL. Fostemsavir, an HIV attachment inhibitor, has shown promise in a phase II study in treatment-experienced patients with HIV-1 RNA. Both agents are currently being further assessed in phase III trials in heavily treatment–experienced patients.

Your Thoughts
What do you see as the largest unmet needs in ART for HIV-infected patients? What investigational agents do you feel show the greatest promise for meeting these needs? I encourage you to post your thoughts in the comments section below.

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