This is a generic educational information sheet for 2 NRTI + 1 NNRTI regimens.


Regimens containing 2 NRTI + 1 NNRTI are well-supported in clinical trials, particularly when using EFV and RPV and DOR in treatment-naïve patients. TDF/FTC/EFV was historically a first line regimen for treatment naïve patients as a one pill once/daily regimen with excellent efficacy, but is increasingly considered an alternative to regimens anchored by INSTIs due to greater side effects. In some cases, 2NRTIs + 1NNRTI  may be considered in treatment experienced patients as well. For example, in virally suppressed patients, there is data to switch from EFV to RPV [1], boosted PI to RPV [2] [3]. In general, given the lower barrier to resistance among NNRTIs, a strategy of switching to NNRTI anchored regimens should be approached with caution in patients experiencing virologic failure (i.e. failing first line NNRTI regimen or failing first line PI regimen).

Recommendations for Treatment-Naïve Patients

DHHS: 1 NNRTI with 2 NRTIs is a recommended initial regimen in certain clinical situations, while an INSTI with 2 NRTIs is recommended for most patients with HIV.  Specific NRTI-based combinations discussed by DHHS include EFV + tenofovir/FTC (including TDF/FTC/EFV as a fixed dose combination), or tenofovir/FTC plus DOR (including TDF/3TC/DOR as a fixed dose combination), or, in patients with an HIV RNA <100,000 copies/mL and a CD4 count of > 200 cells/mm3, RPV +tenofovir/FTC. It is important to note that these regimens may be the preferred for some patients.

IAS: 2 NRTIs + 1 NNRTI is a recommended initial regimen for individuals in whom an INSTI is not an option, specifically EFV/TDF/3TC, and RPV/TAF/FTC or RPV/TDF/FTC.  In particular, EFV/TDF/FTC has the benefit of high efficacy in patients with baseline HIV Vl>100,000 and there is wide global availability and extensive experience; disadvantages include high rates of neuropsychiatric side effects.  RPV-containing regimens have low risk of rash and are the smallest single-pill regimens available, but have limitations in pts with high Vl or low CD4.

Recommendations for Treatment-Experienced Patients

DHHS: In virally suppressed patients, a ‘between class’ switch (e.g., from 2NRTI+PI) to this regimen (2 NRTIs + 1 NNRTI) may be considered where a switch would maintain viral suppression and where there is no resistance to any components in the regimen. Specifically, the DHHS discusses replacing a boosted PI with RPV within a regimen. A ‘within class’ switch that can be considered is switching from EFV to RPV, if there is an adverse event, as long as viral suppression is maintained and there is no drug resistance to RPV, because RPV offers a better safety profile, reduced dosing frequency, and lower pill burden. In cases of confirmed virologic failure, the DHHS does not currently discuss switching to an NNRTI + 2 NRTI regimen at this time. An ongoing phase 3 trial (DRIVE SHIFT) is studying effectiveness of switching to DOR/TDF/3TC. 

IAS: There is no explicit recommendation to switch to this type of regimen (2 NRTI + 1 NNRTI) in the IAS guidelines in the setting of treatment failure or for those that are virally suppressed. However, they suggest that when virally suppressed, there may be consideration for switching patients on older regimens to a variety of single-pill regimens, including RPV/FTC/TAF. Situations in which patients should be recommended a switch include use of old NRTIs as they have long-term toxic effects, or older drugs that have higher pill burdens and are more metabolically toxic. 

Other Considerations 


  • Can lead to renal and bone toxic effects due to high plasma tenofovir concentrations
  • High daily dose (as compared to TAF)
  • Similar rates of HIV suppression, resistance with virologic failure, and increases in CD4 cell count as TAF


  • Equivalent efficacy to TDF, with improved side effect profile and less impact on kidney function and on bone loss [4]
  • Should not be used in patients with CrCl<30


  • May see hypersensitivity reaction in patients who are not HLA-B*5701 negative


  • RPV based combination single pill regimens are among the smallest tablets
  • Approved for use in patients with pre-treatment viral loads <100,000 copies/mL and CD4 count >200 cells/mm3
  • Must be taken with a high-calorie meal (at least 390 kcal)
  • Contraindicated with PPIs, use with caution with H2 antagonists or antacids
  • Can prolong the QTc
  • Lowest risk of rash among NNRTI-based therapies, and low risk of metabolic adverse effects
  • Lower lipid effects than EFV, PIs, or EVG/c
  • Possible side effects include depressive disorders and suicidality


  • Lower rates of causing lipodystrophy than PI-based regimens; should consider switching to NNRTI-based regimen if experiencing PI-induced lipodystrophy


  • Can induce CNS toxicity (i.e. insomnia, abnormal dreams, nervousness)
  • Possible side effects include skin symptoms, fatigue, elevated transaminase levels, hypertriglyceridemia


  • Potential side effects include liver toxicity risks at higher CD4 levels, severe rash


  • Can be taken without regard to food
  • Does not appear to have the same CNS or psychiatric effects as EFV or RPV
  • May be suitable in patients considered high cardiac risk; less lipid effects than PI's EFV, or EVG/c
  • Available as a single tablet regimen once daily

Efficacy in Clinical Trials

Trial Name

Drugs Compared


Study Results



786 tx-naive

At week 48 TDF/FTC/RPV was noninferior to TDF/FTC/EFV (viral suppression of 86% versus 82%). TDF/FTC/RPV was more efficacious than TDF/FTC/EFV in persons with baseline HIV RNAs of ≤ 100,000  copies/ml (89% viral suppression versus 82%).  For participants with baseline HIV-RNAs between 100,000-500,000 copies/mL, the virologic failure rate in the TDF/FTC/RPV and TDF/FTC/EFV arms were 10% and 8.5% (not statistically significant). For those with a HIV RNA of ≥ 500,000 copies/mL it was 25% and 16% (not statistically significant). More emergent resistance occurred in the TDF/FTC/RPV arm (4% versus 1%). TDF/FTC/PRV had fewer discontinuations because of adverse events (2.5 vs 9%). These findings held at 96 weeks (overall viral suppression 78% for TDF/FTC/RPV versus 72% for TDF/FTC/EFV; higher efficacy of TDF/FTC/RPV in persons with HIV RNA <100,000 copies/mL [79% viral suppression versus 72%]; fewer discontinuations in the TDF/FTC/RPV group [3% versus 11%]) [5].


2 NRTIs plus RPV or EFV

1368 tx-naive

At week 48 the RPV arm was noninferior to the EFV arm (overall 84% viral suppression versus 82%).  Virologic failure occurred in 9% of patients in the RPV arm and 5% in the EFV arm. Discontinuation due to adverse events occurred in 3% of the RPV arm and 8% of the EFV arm. In participants with virologic failure, NNRTI and NRTI resistance was more frequently identified in the RPV arm. Also, in the RPV arm the rate of virologic failure was greater in those with pre-treatment CD4 counts <200 cells/mm3. These findings held at 96 weeks (overall viral suppression of 77% in both arms; viral suppression of 83% and 80% for persons with baseline HIV RNA <100,000 copies/mL; viral suppression of 60% versus 75% in persons with baseline HIV RNA levels of >500,000 copies/mL; 4% discontinuation due to adverse events in the RPV arm and 8% in the EFV arm; NNRTI and NRTI resistance was more frequently identified in the RPV arm in persons with virologic failure). [6] [7].


1 PI+2NRTIs vs. NVP+2NRTIs

106 tx-experienced (on PI-containing regimens)

At week 48, PI-sparing regimens, with NVP, were found to be an effective alternative for virally suppressed PI-experienced patients with lipodystrophy (HIV RNA levels were maintained in 79% of NVP-based patients and 77% of PI-based patients). Patients who switched to NVP had improved lipid profiles as compared to those who remained on PI-based regimens. NVP-based regimens were found to have an easier dosing schedule, higher adherence, and better QOL [8].


2NRTI/EFV/ETV-placebo vs 2NRTI/ETV/EFV-placebo

38 tx-experienced

Patients who switched to an ETV-based regimen after experiencing CNS side effects after 12 weeks on an EFV-based regimen were found to have a decrease in neurological side effects while maintaining virological suppression[9].

ACTG 5202

2 NRTIs plus EFV or ATV/r

463 tx-naive

EFV was comparable to ATV/r with respect to virological response when each was given with either TDF/FTC or ABC/3TC [10].

GS 102

FTC/TDF/EFV was non-inferior to EVG/c/TDF/FTC

700 tx-naive

At 144 weeks, EFV was non-inferior with respect to study discontinuation [11].



833 tx-naive

At 48 weeks, a DTG-based regimen was superior to EFV with regards to viral suppression[12]



49 tx-experienced

100% of patients on RPV/FTC/TDF remained virally suppressed at weeks 12 and 24. At week 48, 93.9% of patients remained suppressed. Switching from EFV/FTC/TDF to RPV/FTC/TDF was found to be safe and effective for patients who are virally suppressed [1].


RPV/FTC/TDF vs baseline PI/r+2NRTIs

476 tx-experienced

RPV/FTC/TDF was found to be noninferior at week 24, with 93.7% of the RPV/FTC/TDF group maintaining viral suppression, while 89.9% of the PI/r+2NRTI group maintained viral suppression. The switch maintained virologic suppression and had a low risk of virologic failure, with improvements in total cholesterol, LDL, and triglycerides [2].


Baseline regimen (SBR) vs EFV/FTC/TDF

300 tx-experienced

At 48 weeks, EFV/FTC/TDF was found to be noninferior to SBR with 89% of the EFV/FTC/TDF group and 88% of the SBR group maintaining viral suppression [3].



566 tx-naive

At 48 weeks, RAL was noninferior to EFV. At 4 and 5 years, RAL was superior to EFV, in part because of more frequent discontinuations due to adverse events in the EFV group [13] [14][15].



728 tx naive

At 48 weeks, there was non-inferiority of the DOR regimen (viral load<50) compared to the EFV regimen (84% vs 81%) [16]. At week 96, 78% vs 74% achieved virologic suppression. No additional resistance was seen in DOR at 96 weeks., and DOR had a favorable neuropsychiatric and lipid profile.


 DOR vs DRV/r plus backbone (TDF/FTC) or (ABC/3TC) 

 769 tx naive

At 48 weeks non-inferiority of DOR (viral load <50) 84% vs 80% compared to DRV regimen[17]. At 96 weeks, a higher proportion achieved suppression (73%) than DRV/r (66%), with improvements in LDL (-14mg/dl) comparing arms. There were few (2 individuals, 1%) emergent resistant virus in the DOR group[18].

1.         Mills AM, Cohen C, Dejesus E, Brinson C, Williams S, Yale KL, et al. Efficacy and safety 48 weeks after switching from efavirenz to rilpivirine using emtricitabine/tenofovir disoproxil fumarate-based single-tablet regimens. HIV Clin Trials. 2013;14(5):216-23.

2.         Palella FJ, Jr., Fisher M, Tebas P, Gazzard B, Ruane P, Van Lunzen J, et al. Simplification to rilpivirine/emtricitabine/tenofovir disoproxil fumarate from ritonavir-boosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA-suppressed participants. AIDS. 2014;28(3):335-44.

3.         Dejesus E, Young B, Morales-Ramirez JO, Sloan L, Ward DJ, Flaherty JF, et al. Simplification of antiretroviral therapy to a single-tablet regimen consisting of efavirenz, emtricitabine, and tenofovir disoproxil fumarate versus unmodified antiretroviral therapy in virologically suppressed HIV-1-infected patients. J Acquir Immune Defic Syndr. 2009;51(2):163-74.

4.         Sax PE, Zolopa A, Brar I, Elion R, Ortiz R, Post F, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr. 2014;67(1):52-8.

5.         Cohen C, Wohl D, Arribas JR, Henry K, Van Lunzen J, Bloch M, et al. Week 48 results from a randomized clinical trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate vs. efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV-1-infected adults. AIDS. 2014;28(7):989-97.

6.         Cohen CJ, Molina JM, Cassetti I, Chetchotisakd P, Lazzarin A, Orkin C, et al. Week 96 efficacy and safety of rilpivirine in treatment-naive, HIV-1 patients in two Phase III randomized trials. AIDS. 2013;27(6):939-50.

7.         Nelson MR, Elion RA, Cohen CJ, Mills A, Hodder SL, Segal-Maurer S, et al. Rilpivirine versus efavirenz in HIV-1-infected subjects receiving emtricitabine/tenofovir DF: pooled 96-week data from ECHO and THRIVE Studies. HIV Clin Trials. 2013;14(3):81-91.

8.         Ruiz L, Negredo E, Domingo P, Paredes R, Francia E, Balague M, et al. Antiretroviral treatment simplification with nevirapine in protease inhibitor-experienced patients with hiv-associated lipodystrophy: 1-year prospective follow-up of a multicenter, randomized, controlled study. J Acquir Immune Defic Syndr. 2001;27(3):229-36.

9.         Waters L, Fisher M, Winston A, Higgs C, Hadley W, Garvey L, et al. A phase IV, doubleblind, multicentre, randomized, placebo-controlled, pilot study to assess the feasibility of switching individuals receiving efavirenz with continuing central nervous system adverse events to etravirine. AIDS. 2011;25(1):65-71.

10.       Daar ES, Tierney C, Fischl MA, Sax PE, Mollan K, Budhathoki C, et al. Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1. Ann Intern Med. 2011;154(7):445-56.

11.       Wohl DA, Cohen C, Gallant JE, Mills A, Sax PE, Dejesus E, et al. A randomized, double-blind comparison of single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF versus single-tablet regimen efavirenz/emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: analysis of week 144 results. J Acquir Immune Defic Syndr. 2014;65(3):e118-20.

12.       Walmsley S, Baumgarten A, Berenguer J, Felizarta F, Florence E, Khuong-Josses M-A, et al. Brief Report: Dolutegravir Plus Abacavir/Lamivudine for the Treatment of HIV-1 Infection in Antiretroviral Therapy-Naive Patients: Week 96 and Week 144 Results From the SINGLE Randomized Clinical Trial. J Acquir Immune Defic Syndr. 2015;70(5):515-9.

13.       Rockstroh JK, DeJesus E, Lennox JL, Yazdanpanah Y, Saag MS, Wan H, et al. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK. J Acquir Immune Defic Syndr. 2013;63(1):77-85.

14.       DeJesus E, Rockstroh JK, Lennox JL, Saag MS, Lazzarin A, Zhao J, et al. Efficacy of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: week-192 overall and subgroup analyses from STARTMRK. HIV Clin Trials. 2012;13(4):228-32.

15.       Lennox JL, DeJesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009;374(9692):796-806.

16.       Orkin C, Squires KE, Molina JM, Sax PE, Wong WW, Sussmann O, et al. Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate is Non-inferior to Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-naive Adults With Human Immunodeficiency Virus-1 Infection: Week 48 Results of the DRIVE-AHEAD Trial. Clin Infect Dis. 2019;68(4):535-44.

17.       Molina JM, Squires K, Sax PE, Cahn P, Lombaard J, DeJesus E, et al. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV. 2018;5(5):e211-e20.

18.       Molina JM, Squires K, Sax PE, Cahn P, Lombaard J, DeJesus E, et al. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 96-week results of a randomised, double-blind, non-inferiority, phase 3 trial. Lancet HIV. 2020;7(1):e16-e26.