Twice-daily versus once-daily antiretroviral therapy and coformulation strategies in HIV-infected adults: benefits, risks, or burden?

Figures & data

Table 1 Antiretroviral fixed-dose combinations

FDA-approved	Type
AZT/3TC	Dual NRTI
d4T/3TC*	Dual NRTI
ABC/3TC	Dual NRTI
TDF/FTC	Dual NRTI
TDF/3TC*	Dual NRTI
AZT/3TC/NVP*	NNRTI + dual NRTI
d4T/3TC/NVP*	NNRTI + dual NRTI
AZT/3TC/ABC	Triple NRTI
TDF/FTC/EFV	NNRTI + dual NRTI
TDF/3TC/EFV*	NNRTI + dual NRTI
LPV/r	Boosted PI
RPV/TDF/FTC	NNRTI + dual NRTI
Under study
Dolutegravir/ABC/3TC	Integrase inhibitor + dual NRTI
Elvitegravir/cobicistat/TDF/FTC	Boosted integrase inhibitor + dual NRTI
ATV + RTV (coblister)	Boosted PI

* Note: Fixed-dose combinations not available in the United States.

Abbreviations: 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; AZT, zidovudine; d4T, stavudine; EFV, efavirenz; FTC, emtricitabine; LPV/r, lopinavir/ritonavir; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; RPV, rilpiverine; RTV, ritonavir; TDF, tenofovir.

Table 2 Summary of recent studies comparing once-daily with twice-daily or three times daily HIV regimens

Reference	Study design/aim	Population	n	Adherence end point	Duration	Results
Wright et al^Citation41	Randomized trial to evaluate safety and antiviral activity of ENF QD versus BID	ENF-naïve, on an unchanged prestudy regimen for ≥28 days with VL ≥ 5000 copies/mL and prior experience or documented resistance to 3 classes of approved ARVs (PIs, NRTIs, and NNRTIs)	n = 61 QD: n = 30 BID: n = 31	Proportion of patients achieving HIV RNA < 400 copies/mL	48 weeks	At week 48, 23.3% of QD patients versus 22.6% of BID (P = 0.969) achieved HIV RNA < 400 copies/mL, and 13.3% and 22.6% (P = 0.323), respectively, achieved <50 copies/mL No significant differences in AEs were noted Adherence (95% of prescribed doses) was higher with ENF QD (80.0%) versus BID (58.1%)
Boyle et al^Citation19	Open-label, randomized, multicenter, Phase IIIB noninferiority study to evaluate BID+ regimen versus QD regimen	HIV-infected adult patients with VL < 50 copies/mL on a BID or more frequent ARV regimen	n = 320 QD: = 213 BID+: n = 107	Proportion of patients who maintained plasma HIV RNA < 50 copies/mL at week 48 after switching to QD arm versus patients in BID+ arm	48 weeks	QD arm was noninferior to BID+ arm in primary efficacy measure (proportion of patients who maintained suppression at week 48; QD arm, 80.0% versus BID+ arm, 75.8%) Adherence and treatment satisfaction significantly favored QD arm, in which 91.0% of patients preferred simpler regimen
Maitland et al^Citation16	Randomized open-label study comparing adherence, efficacy, and safety of immediate versus delayed switching from ABC + 3TC BID to ABC/3TC FDC Q	Single-center, open-label study in HIV-infected patients with VL < 50 copies/mL	94	Patient satisfaction measured by HIVTSQ questionnaire; adherence by MEMS caps	8 weeks	BID vs QD: treatment compliance 99.2% (90.7%–100%) versus 96.6% (60.0%–100%) (P = 0.017); dosing compliance 97.1% (64.3%–100%) versus 91.9% (33.3%–100%) (P = 0.016); and timing compliance 95.5% (53.8%–100%) versus 86.3% (4.3%–100%) (P = 0.006) Treatment satisfaction increased significantly at week 4 with ABC/3TC QD: 92% (82%–99%) versus 85% (75%–93%) (P = 0.004)
Zajdenverg et al^Citation27	Randomized controlled trial LPV/r tablet QD versus BID + NRTIs in ARV-experienced patients	ARV-experienced adult patients	599	Noncompliance (ingestion, correct dose, time of ingestion)	6 months	Through 24 weeks, QD dosing of LPV/r resulted in higher treatment compliance than BID dosing; <50 copies/mL and 100% <400 copies/mL
De Jesus et al^Citation23	Randomized controlled trial comparing EFV/TDF/FTC QD versus BID versus TID	ARV-naïve adults initiating ART	567	Adherence as measured by pill counts	6 months	Improved adherence with STR of EFV/TDF/FTC with QD versus BID or TID (P < 0.01, all comparisons)
Airoldi et al^Citation22	ADONE: prospective, multicenter, open-label, comparative study with within-patient analysis	Patients chronically treated with FTC + TDF + EFV or 3TC + TDF + EFV and with HIV-RNA < 50 copies/mL	202	Effect of simplification of ARV regimen on adherence	6 months	1 month after switch to FDR, adherence increased to 96.1% (baseline, 93.8%) (P < 0.01) and was 96.2% at 6 months. QOL improved over time from 68.8% to 72.7% (P = 0.042); QOL was significantly associated with adherence (P < 0.0001) During FDR use, mean CD4 count increased from 556 to 605 cells/mm^3 (P < 0.0001)
Bangsberg et al^Citation12	Prospective observational study assessing adherence and virologic response to EFV/FTC/TDF as STR	Homeless and marginally housed	658	Adherence and viral suppression versus historical controls from same cohort	6 months	Adherence was higher in EFV/FTC/TDF STR regimen compared with multiple-pill regimens (P = 0.006) after controlling for multiple confounders Viral suppression (HIV RNA < 50 copies/mL) was greater in EFV/FTC/TDF STR than multiple-pill regimens (69.2% versus 46.5%; P = 0.02) No difference in viral suppression after controlling for adherence
Gathe et al^Citation21	Randomized, double-blind, double-dummy study comparing efficacy and safety of NVP XR versus IR	ARV-naïve adults initiating ART	1011	Adherence as measured by pill counts	48 weeks	Week 48 virological responses were 81.0% (409/505) for NVP XR and 75.9% (384/506) for NVP IR. The adjusted difference in favor of NVP XR was 4.9% (95% CI: −0.1–10.0%) Mean adherence rates were 99.0% for NVP XR, and 97.6% for the NVP IR treatment groups.

Abbreviations: 3TC, lamivudine; ABC, abacavir; AE, adverse event; ARV, antiretroviral; ART, antiretroviral therapy; BID, twice daily; BID+, twice daily or greater; CI, confidence interval; EFV, efavirenz; ENF, enfuvirtide; FDC, fixed-dose combination; FDR, fixed daily regimen; FTC, emtricitabine; HAART, highly active antiretroviral therapy; HIVSQ, HIV Treatment Satisfaction Questionnaire; IR, immediate release; LPV/r, lopinavir/ritonavir; MEMS, Medication Event Monitoring System; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase; NPV, nevirapine inhibitor; PI, protease inhibitor; QD, once daily; QOL, quality of life; STR, single tablet regimen; TDF, tenofovir; VL, viral load; XR, extended-release.

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