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Which treatment regimens are recommended for rapid ART? Guidance from DHHS and IAS-USA are in agreement on 3 recommended regimens: bictegravir (BIC) coformulated with emtricitabine (FTC) and tenofovir alafenamide (TAF); dolutegravir (DTG) with either TAF of tenofovir disoproxil fumarate (TDF) plus lamivudine (3TC) or FTC; and boosted darunavir (DRV) with either TAF or TDF plus 3TC or FTC.[14,15] Regimens that are not recommended include NNRTI-based regimens and DTG/3TC due to the rate of transmitted resistance to agents in the NNRTI and NTRI classes. Regimens requiring abacavir are also not recommended without HLA-B*5701 screening results, which would not be available before rapid ART initiation at the time of diagnosis.
The foundation for recommending regimens comprising the second-generation INSTIs DTG and BIC is that clinical trial experience has shown that these drugs rarely select for resistance mutations among ART-naive or treatment-experienced patients.[16-20] DHHS recommends INSTI resistance testing only if a patient presents with viremia while receiving an INSTI or if there is reason to suspect that a patient has a rare instance of transmitted INSTI resistance. IAS-USA guidelines recommend against testing for transmitted INSTI resistance because the rate is extremely low—< 1% since the introduction of INSTIs in 2007.[14,21]
In addition, the risk of resistance to DRV is also quite low, even in patients with intermittent adherence. In one large study of more than 60,000 clinical samples, the proportion with ≥ 3 DRV mutations decreased from 2.9% in 2010 to 1.6% in 2017. This reiterates that DRV resistance is rare.
In the phase III GS-1489 and GS-1490 studies comparing BIC/FTC/TAF vs DTG plus FTC/TAF in treatment-naive patients, the preexisting INSTI resistance was low, at 1.3% in both studies. The primary INSTI mutation identified was T97A, which is an accessory mutation that occurs as a polymorphic mutation in approximately 1% to 4% of viruses from untreated persons living with HIV. T97A has minimal to no effect on INSTI susceptibility without the presence of additional mutations. Indeed, among the 12 total patients across both treatment groups who tested positive for baseline T97A, all achieved virologic suppression (HIV-1 RNA < 50 copies/mL) at Week 48.