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


This regimen consists of 1 INSTI paired with 1 NNRTI. These individual drugs are more often used in tandem with 2 NRTIs. Efficacy for the combination of these classes has been previously inferred based on studies of DTG/RPV, a combination that is discussed in the DHHS guidelines [1], under the section of simplification strategies. There is limited research to support use of this type of regimen except in the case of patients with viral suppression. The U.S. Food and Drug Administration recently approved Cabenuva (cabotegravir and rilpivirine, injectable formulation) as a complete regimen for the treatment of HIV-1 infection in adults to replace a current antiretroviral regimen in those who are virologically suppressed on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine. This is the first FDA-approved injectable, complete regimen for HIV-infected adults that is administered once a month. The FDA also approved Vocabria (cabotegravir, tablet formulation), which should be taken in combination with oral rilpivirine (Edurant) for one month prior to starting treatment with Cabenuva to ensure the medications are well-tolerated before switching to the extended-release injectable formulation. Current guidelines do not yet discuss usage of INSTI + NNRTI for naïve patients. DTG/RPV now comes coformulated (Juluca) as a one pill/once daily regimen, while most combinations of INSTI + NNRTI would represent two separate pills (except injectable cabotegravir/rilpivirine).

Recommendations in treatment-naïve patients

DHHS (Dec 2019): This type of regimen is not discussed as an option for initial treatment in the guidelines. However, both INSTI-based and NNRTI-based regimens are recommended for initial treatment for most people or in certain clinical situations when combined with 2NRTI's. 

IAS-USA (2018): This type of regimen is not discussed in the IAS guidelines for treatment naïve patients. However, both INSTI-based and NNRTI-based regimens are recommended for initial treatment.

Recommendations in treatment-experienced patients

DHHS (Dec 2019): DTG+RPV is now discussed as a 2-drug simplification strategy in patients that are virally suppressed. DHHS guidelines now state that, "DTG plus RPV can be a reasonable option when the use of NRTIs is not desirable and when resistance to either DTG or RPV is not expected." This type of regimen is not discussed in the guidelines for treatment-experienced patients in cases of virologic failure.

IAS-USA (2018): The IAS guidelines recommend switching from 3-drug regimens to certain 2-drug regimens (including DTG/RPV) in the setting of viral suppression, patients with no prior virologic failure or transmitted drug resistance. It is mentioned that longer-term follow-up is needed to confirm the durability of these strategies).

Other Considerations: DTG/RPV is now available coformulated.


  • Dosed once daily (oral), once monthly or once every other month (Long acting injectable).  
  • The long-acting injectable formulation likely will require an oral lead-in (induction) phase to ensure that the medication is tolerated before the long-acting intramuscular formulation is given. 
  • Remains present in the plasma at detectable but sub-therapeutic levels for many months after an intramuscular injection


  • Smallest tablet among the single-pill regimens (oral).
  • Approved for use in treatment naive patients with pre-treatment viral loads <100,000 copies/mL and CD4 count >200 cells/mm3 [1].There are no current guidelines or listed restrictions in DHHS guideliens when used in conjunction with DTG in the context of virally suppressed patient.
  • Must be taken with a high-calorie meal (at least 390 kcal) (oral).
  • Contraindicated with PPIs, use with caution with H2 antagonists or antacids (oral).
  • Can prolong the QTc (oral and IM).
  • Lowest risk of rash among NNRTI-based therapies, and low risk of metabolic adverse effects
  • Possible side effects include depressive disorders and suicidality


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


  • Must be taken with a meal
  • Possible side effects include skin symptoms, fatigue, elevated transaminase levels, hypertriglyceridemia


  • 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


  • Lowest risk of resistance with virological failure among INSTIs
  • Relatively few drug interactions
  • Can be taken with or without food (but not with polyvalent ions, which may be found in antacids, laxatives, and mineral supplements)
  • May raise serum creatinine 
  • Possible side effects include insomnia, headache, and (rarely) hypersensitivity reaction
  • Use caution in women of childbearing age, based on limited reports of neural tube defects[2].


  • Must be taken twice daily, although a once daily dose has shown similar efficacy in a recent trial, but there is not enough data to recommend this [1].
  • Should not be taken with polyvalent cations, which may be found in antacids, laxatives, and mineral supplements
  • Possible side effects include creatine kinase elevation, myositis, rhabdomyolysis, and (rarely) severe skin reactions and systemic hypersensitivity reactions.

Efficacy in Clinical Trials






PI and/or NRTI-based regimens vs RAL + ETR

25 tx-experienced

In a prospective cohort study, virologically suppressed patients on PI or NRTI regimens who expressed concerns due to unwanted side effects were switched to an RAL+ETR regimen. The regimen was wel- tolerated and maintained viral suppression at 48 weeks and the regimen can be considered a well-tolerated potential regimen in certain patients who had difficulty with both PI and NRTI therapy [3].






SWORD 1 and 2

DTG/RPV vs prior combination ART

1024 participants virally suppressed and no history of treatment failure

In a randomized control trial evaluating the strategy of switching from stable ARV regimens to DTG/RPV, at week 48, ~95%  of patients assigned to both groups (486/513 for DTG/RPV, 485/511 in combination ART) had viral loads < 50 copies/ml[4].





In an observational cohort at eight centers in Italy, 132 subjects were followed for median of 24 months on DTG + RPV.  Most were switched to this regimen for simplification (53%) or toxicity (35%), and nearly half had RT mutations and nearly half had PI mutations, and majority were virally suppressed at time of starting on to DTG +RPV.  At 24 weeks, all but one individual appeared virally suppressed [5].


Open label study of DTG/RPV

38 Heavily experienced with history of treatment failure

Three patients discontinued the new regimen due to gastrointestinal toxicity, DDI with omeprazole, and physician’s decision, one case each. There were no virological failures: HIV-RNA remained below 37copies/mL in 100% (38/38) at week 4 and 100% (35/35) at week 48. CD4 count remained stable after switching; median 707.7 cells/mm3 at week 48 (95%CI 591.7-823.6, P=0.99). We observed a statistically improvement in total cholesterol and triglycerides with no changes in HDL and LDL-cholesterol. All total bilirubin, ALT, AST, GGT and alkaline phosphatase decreased (P<0.05). CKD-EPI eGFR decreased from 85 to 76 mL/min/1.73m² (95% CI 5.1-16.6, P=0.0002) at week 4 and maintained stable until week 48[6].



104 participants treatment experienced

A total of 104 participants were included, who switched for the following reasons: toxicity/intolerance (42.3%), convenience (27.8%), and drug interactions (17.3%). 82 (78.8%) with virologic suppression and 22 (21.1%) without virologic suppression (8 virologic failure and 14 restarting ART).Prior regimens are protease inhibitor (56.7%), integrase strand transfer inhibitor (26.9%), and non-nucleoside reverse transcriptase inhibitor (16.3%). Efficacy at 24 weeks was 88.4% (intention to treat) and 96.8% (per protocol).  No patient discontinued due to adverse events [7].







CAB/RPV (Oral) vs

243 tx-naive

A double-blind randomized control trial of treatment naïve patients that were initially randomly allocated in a 1:1:1:1 ratio to oral cabotegravir 10 mg, 30 mg, 60 mg, or oral efavirenz with 2 NRTIs for 24 weeks of induction. At week 24, after the switch to dual maintenance therapy, 82% (149/156) in the cabotegravir plus rilpivirine group had HIV RNA below 50 copies/mL as compared to 71% (44/62) in the efavirenz group. Patients who were virologically suppressed by week 24 received a two-drug maintenance regimen consisting of their randomly allocated cabotegravir dose plus oral rilpivirine 25 mg or continued efavirenz plus NRTIs for an additional 72 weeks. After 72 weeks of maintenance therapy, the proportion with HIV RNA below 50 copies/mL was 76% in the combined cabotegravir arms versus 63% in the efavirenz arm. Cabotegravir plus rilpivirine provided antiviral activity similar to efavirenz plus dual NRTIs until the end of week 96[8].



286 with viral suppression after oral induction

After a 20-week induction period on oral cabotegravir plus abacavir-lamivudine, patients with viral suppression were randomized to continue their oral regimen (ABC/3TC/CAB) or initiate IM CAB/RPV arms (4 or 8 weeks) of the study. Among 309 enrolled patients, 286 were randomly assigned: 115 to each of the 4-week and 8-week groups and 56 to the oral treatment group. Viral suppression was maintained at 32 weeks in 51 (91%) of 56 patients in the oral treatment group, 108 (94%) of 115 patients in the 4-week group, and 109 (95%) of 115 patients in the 8-week group. At week 96, viral suppression was maintained in 47 (84%) of 56 patients receiving oral treatment, 100 (87%) of 115 patients in the 4-week group, and 108 (94%) of 115 patients in the 8-week group. The two-drug combination of injectable long-acting cabotegravir plus rilpivirine every 4 weeks or every 8 weeks was as effective as daily three-drug oral therapy at maintaining HIV-1 viral suppression through 96 weeks[9]. Participants in the 4-week and 8-week LA injectable groups were significantly more satisfied with treatment than participants in the oral maintenance group at Week 96[10].


CAB/RPV (LA) vs ABC/DTG/3TC (Oral)

283 with viral suppression after oral induction

Randomized trial in which adults with HIV-1 infection who had not previously received antiretroviral therapy were given 20 weeks of daily oral induction therapy with ABC/DTG/3TC. Participants who had an HIV-1 RNA level of less than 50 copies per milliliter after 16 weeks were randomly assigned (1:1) to continue the current oral therapy or switch to oral cabotegravir plus rilpivirine for 1 month followed by monthly injections of long-acting cabotegravir plus rilpivirine. At 48 weeks, 93.6% of patients who received long acting CAB/RPV after oral induction had an HIV-1 RNA level of <50 copies/mL;93.3% of patients who continued to receive oral ABC/DTG/3TC had an HIV-1 level of <50 copies/mL[11]. At Week 96, with no further cases of virologic failure and similar safety outcomes compared with the week 48 results. Preliminary data shows the strong preference for LA CAB plus RPV injectable treatment over oral ABC/DTG/3TC was also maintained at Week 96 [12].


CAB/RPV (LA) vs Current Oral ART

308 with viral suppression after oral induction

In this randomized noninferiority trial involving patients with virologic suppression for at least 6 months while taking standard oral ARV therapy, participants were randomized (1:1) to either continue their oral therapy or switch to monthly intramuscular injections of long-acting CAB/RPV. .At 48 weeks, 92.5% of patients who received long acting CAB/RPV after oral induction had an HIV-1 RNA level of <50 copies/mL. 95.5% of patients who continued to receive oral ART had an HIV-1 level of <50 copies/mL[13]. Monthly injections of long-acting cabotegravir and rilpivirine were noninferior to continuation of oral therapy (INSTI, NNRTI, or PI) for maintaining HIV-1 suppression.


CAB/RPV LA q4 weeks vs q8 weeks

1045 participants with virologic suppression

Preliminary data suggests that at 48 weeks, every-8-week LA CAB plus RPV dosing met the primary endpoint of noninferiority to every-4-week LA CAB plus RPV dosing for the outcome of virologic failure (HIV-1 RNA ≥ 50 copies/mL). The every-8-week dose interval had a comparable safety profile to every-4-week dosing. Unsurprisingly, participants preferred the every-8-week dosing regimen—94% of those who had previously received every-4-week dosing preferred every-8-week dosing [14].

1.         ClinicalInfo. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Clinicalinfo.hiv.gov; 2019.

2.         ClinicalInfo. Recommendations Regarding the Use of Dolutegravir in Adults and Adolescents with HIV who are Pregnant or of Child-Bearing Potential. 2018.

3.         Monteiro P, Perez I, Laguno M, Martinez-Rebollar M, Gonzalez-Cordon A, Lonca M, et al. Dual therapy with etravirine plus raltegravir for virologically suppressed HIV-infected patients: a pilot study. J Antimicrob Chemother. 2014;69(3):742-8.

4.         Llibre JM, Hung CC, Brinson C, Castelli F, Girard PM, Kahl LP, et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. Lancet. 2018;391(10123):839-49.

5.         Capetti AF, Sterrantino G, Cossu MV, Orofino G, Barbarini G, De Socio GV, et al. Switch to Dolutegravir plus Rilpivirine Dual Therapy in cART-Experienced Subjects: An Observational Cohort. PLoS One. 2016;11(10):e0164753.

6.         Díaz A. CJ, Dronda F., Gómez-Ayerbe C., Vivancos M., Bañón S., et al. Dolutegravir plus rilpivirine in suppressed heavily pretreated HIV-infected patients.  21st International AIDS Conference; Durban, South Africa: International AIDS Society; 2016.

7.         Gantner P, Cuzin L, Allavena C, Cabie A, Pugliese P, Valantin MA, et al. Efficacy and safety of dolutegravir and rilpivirine dual therapy as a simplification strategy: a cohort study. HIV Med. 2017;18(9):704-8.

8.         Margolis DA, Brinson CC, Smith GHR, de Vente J, Hagins DP, Eron JJ, et al. Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial. Lancet Infect Dis. 2015;15(10):1145-55.

9.         Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, Eron JJ, Yazdanpanah Y, Podzamczer D, et al. Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial. Lancet. 2017;390(10101):1499-510.

10.       Murray M, Pulido F, Mills A, Ramgopal M, LeBlanc R, Jaeger H, et al. Patient-reported tolerability and acceptability of cabotegravir + rilpivirine long-acting injections for the treatment of HIV-1 infection: 96-week results from the randomized LATTE-2 study. HIV Res Clin Pract. 2019;20(4-5):111-22.

11.       Orkin C, Arasteh K, Gorgolas Hernandez-Mora M, Pokrovsky V, Overton ET, Girard PM, et al. Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection. N Engl J Med. 2020;382(12):1124-35.

12.       al. OCOSPPe. LONG-ACTING CABOTEGRAVIR + RILPIVIRINE FOR HIV TREATMENT: FLAIR WEEK 96 RESULTS.  Conference on Retroviruses and Opportunistic Infections; Boston, Massachusetts: CROI; 2020.

13.       Swindells S, Andrade-Villanueva JF, Richmond GJ, Rizzardini G, Baumgarten A, Masia M, et al. Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression. N Engl J Med. 2020;382(12):1112-23.

14.       Overton ET, Richmond GJ, Rizzardini G, Jaeger H, Orrell C, Nagimova F, et al. CABOTEGRAVIR + RILPIVIRINE EVERY 2 MONTHS IS NONINFERIOR TO MONTHLY: ATLAS-2M STUDY.  Conference on Retroviruses and Opportunistic Infections; Boston, Massachusetts: CROI.