1. Home
  2. Resources
  3. 1 INSTI 1 NNRTI

1 INSTI 1 NNRTI

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

 

Overview

This regimen consists of a two-drug regimen using 1 INSTI paired with 1 NNRTI. 

Efficacy for the combination of these classes has been previously inferred based on studies of DTG/RPV and CAB/RPV, combinations that are discussed in the DHHS and IAS-USA guidelines [1, 2], under the respective sections on simplification strategies in persons with virologic suppression. There is limited research to support use of this type of regimen in treatment naïve or experienced patients with detectable viremia [3, 4]. Consequently, current guidelines do not yet discuss usage of INSTI+NNRTI for persons that are not virologically suppressed.

 

DTG/RPV now comes coformulated (Juluca) as a one pill/once daily regimen, while most combinations of INSTI + NNRTI would represent two separate pills.  A long-acting formulation of CAB/RPV (Cabenuva) is also available consisting of monthly or every 2 month injections, after an optional oral lead-in phase. These regimens overall are generally most appropriate in persons without HBV, have achieved sustained virologic suppression for at least 3 to 6 months, and whose HIV is susceptible to both ARV drugs in the new regimen, and in whom adherence is expected to be good. 

 

When initiating CAB/RPV, ‘Caution is warranted in the presence of HIV-1 A6/A1 subtype’, per the European EMA product information [5]. This precaution stems from data from the FLAIR trial in which 3 of 4 subjects with confirmed virologic failure (CVF) were from Russia and had Subtype.  In ATLAS, all three subjects with VF receiving CAB/RPV had subtype A, A1 or AG. In post-hoc analysis of pooled data, HIV-1 subtype A6/AI (associated with integrase L74I polymorphism) were significantly associated with increased risk of CVF [6]. Consequently, current EMA product information suggests, “Before starting the regimen, it should be taken into account that multivariable analyses indicate that a combination of at least 2 of the following baseline factors may be associated with an increased risk of virological failure: archived rilpivirine resistance mutations, HIV-1 subtype A6/A1, or BMI ≥30 kg/m2”[5, 7].

 

Recommendations in treatment-naïve patients

DHHS (2022): This type of regimen is explicitly not recommended in ART-naïve patients for initial therapy due to lack of data demonstrating efficacy. 

 

IAS-USA (2022): This type of regimen is not recommended in the IAS-USA guidelines for treatment naïve patients. 

 

Recommendations in treatment-experienced patients

 

Treatment simplification, suppressed

DHHS (Dec 2022): DTG/RPV and CAB/RPV are included as a 2-drug simplification strategy in patients that are virally suppressed. Per DHHS guidelines, “Growing evidence indicates that some two-drug regimens are effective in maintaining virologic control in patients who initiated therapy and achieved sustained virologic suppression for at least 3 to 6 months with three-drug regimens, provided their HIV is susceptible to both ARV drugs in the new regimen. However, because none of the two-drug regimens discussed below meet the standard of care for HBV treatment, these regimens are not recommended for individuals with HBV coinfection, unless the patient is also on a specific anti-HBV active regimen (e.g., entecavir).” Two Phase 3 trials (SWORD-1 and SWORD-2) demonstrated noninferiority of DTG/RPV compared to continuing a first or second ARV regimen in persons with suppressed HIV viral load and without resistance to DTG or RPV. 

 

Based on the ATLAS, ATLAS-2M, FLAIR, and LATTE trials, the Panel recommends that “separate monthly or every 2-month IM injections of long-acting CAB and RPV can be used to replace an existing oral ARV regimen in people with HIV with sustained viral suppression for 3 to 6 months (optimal duration is not defined).” The Panel also notes that oral lead-in therapy with CAB/RPV is optional and can be done based on a discussion between the patient and provider. Finally, the Panel states that “Criteria for use should include individuals who have good adherence and engagement in care, with no baseline resistance to either medication, no prior virologic failures; who do not have active or occult HBV infection (unless the patient also is receiving an HBV active regimen [e.g., entecavir]); who are not pregnant or planning on becoming pregnant; and who are not receiving medications with significant drug interactions with oral (during lead-in or bridging therapy) or injectable CAB or RPV.”

 

 IAS-USA (2022): Per the IAS-USA guidelines, “Persons with suppressed virus and no history of transmitted or acquired HIV drug resistance can generally switch therapy to any of the recommended initial regimens and maintain viral suppression. Recently, there has been increased interest in 2-drug strategies as a way of reducing drug exposure. Most data supporting this strategy come from prospective randomized trials of persons with no history of treatment failure switching to DTG/3TC or DTG/RPV. These studies demonstrated ongoing viral suppression comparable to continued 3-drug treatment, without evidence of loss of virologic control. In addition, InSTI resistance was not observed in these studies, although NNRTI resistance occurred in 1% of participants receiving DTG/RPV.”  The guidelines also discuss switches to long acting CAB/RPV. In persons with no history of treatment failure and no known or suspected resistance to either drug, injectable cabotegravir and rilpivirine, given either every 1 or 2 months, was noninferior to continued oral ART. Those interested in non-oral options for ART because of privacy, stigma, or convenience reasons will usually have greater satisfaction with cabotegravir and rilpivirine than continued oral ART. Cabotegravir plus rilpivirine injections can be started after an oral lead-in to ensure tolerability or, alternatively, without an oral cabotegravir plus rilpivirine lead-in based on patient preference”

 

Treatment Experienced, Viremic

In light of the lack of recommendation for usage in viremic patients, HIVASSIST ranks 1 INSTI + 1 NNRTI regimens lower than many alternatives by assigning a high base score. However, there may be some situations where long-acting injectable regimens are considered based on other considerations. For example, the Ward 86 study evaluated the efficacy of every 4-week CAB/RPV-LA in patients with and without viral suppression in a diverse urban clinic that serves publicly insured patients with high levels of marginal housing and stimulant use [3]. The study included 15 patients who started injectable CAB/RPV with detectable viremia, (median CD4 cell count, 99 cells/mm3; mean log10 viral load, 4.67 with standard deviation 1.16). Of these 15 patients, 12 (80%; 95% CI, 55%–93%) achieved and maintained viral suppression, including one patient with a baseline N155H mutation. For the 3 patients who did not achieve viral suppression, all had a 2-log decline by a median of 22 days.

 

Additional considerations: 

Hepatitis B: CAB, DTG, and RPV are not active against hepatitis B. Therefore, switching from a TAF/TDF containing regimen to CAB/RPV or DTG/RPV should not be done in persons with chronic hepatitis B infection without the addition of treatment for hepatitis B. 

Prior Use of CAB-LA as PrEP: For a person who had exposure to CAB-LA as PrEP, an INSTI-containing regimen should not be initiated unless an INSTI genotypic resistance-test result is available and shows no INSTI-resistance mutations. 

Pregnancy: There is insufficient data for use of either regimen in pregnancy or around the time of conception. CAB/RPV and DTG/RPV should not be initiated during pregnancy. People who become pregnant while on CAB/RPV should switch to a preferred or alternative 3 drug regimen (DHHS 2022). People who become pregnant on DTG/RPV and who are stable on DTG/RPV should be counseled on the lack of safety data and, if they continue, should have their HIV RNA monitored more frequently (IAS-USA 2022). 

 

Specific medication considerations:

 

Cabotegravir

  • CAB is a novel INSTI and structural analogue of DTG.  Dosed once daily (oral), once monthly or once every other month (Long acting injectable).  
  • The long-acting injectable formulation includes an optional 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

Dolutegravir

  • 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

Raltegravir

  • 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.

 

Rilpivirine

  • 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 guidelines 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

Efavirenz

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

Etravirine

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

Doravirine

  • 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

 

 

Efficacy in Clinical Trials

Trial Regimen Population Result
Monteiro et al. (2014) 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 well- 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 [8].

 

DTG/RPV

Trial Regimen Population Result
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[9].

 
TivEdO   DTG/RPV 132 treatment experienced patients  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 [10].
 Diaz. et al. (2016) 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[11].
DORIVIR DTG/RPV 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 [12].

 

CAB/RPV

Trial Regimen Population Result
LATTE CAB/RPV (Oral) vs
EFV+2NRTIs		 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[13].
LATTE-2 CAB/RPV (LA,IM) vs ABC/3TC/CAB (Oral) 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[14]. 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[15].
FLAIR 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[16]. 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 [17].
ATLAS 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[18]. Monthly injections of long-acting cabotegravir and rilpivirine were noninferior to continuation of oral therapy (INSTI, NNRTI, or PI) for maintaining HIV-1 suppression.
ATLAS-2M 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 [19].
Christopoulous et al. (2023) CAB/RPV LA n=51; n=24 with viral suppression; some with history of treatment failure 51 patients initiated LAI-ART, with 39 receiving at least 2 follow-up injections by database closure (median age, 46 years; 90% cisgender men, 61% non-White, 41% marginally housed, 54% currently using stimulants). Of 24 patients who initiated injections with viral suppression (median CD4 cell count, 706 cells/mm3), 100% (95% confidence interval [CI], 86%-100%) maintained viral suppression [3].
D’Amico et al. (2023) CAB/RPV LA N=35; n=28 with viremia, n=7 viral suppression; some with history of treatment failure Compassionate use of CAB/RPV with need for parenteral therapy, no primary resistance mutations to CAB or RPV. Some received oral CAB/RPV lead-in, some directly started injection. 16 of 28 and 6/7 achieved or maintained virologic suppression, respectively. N=7 discontinued for incomplete virologic response; of these, 6 had detectable viremia at initiation. Majority of these developed new NRTI and INSTI mutations [4]. 

Did we forget a study or make an error?  If so, please click on the "feedback" tab and provide details and comments.

 

 Full Update 2/14/2024

 

 

REFERENCES

 

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

2.         Gandhi RT, Bedimo R, Hoy JF, et al. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2022 Recommendations of the International Antiviral Society-USA Panel. JAMA 2023; 329(1): 63-84.

3.         Christopoulos KA, Grochowski J, Mayorga-Munoz F, et al. First Demonstration Project of Long-Acting Injectable Antiretroviral Therapy for Persons With and Without Detectable Human Immunodeficiency Virus (HIV) Viremia in an Urban HIV Clinic. Clin Infect Dis 2023; 76(3): e645-e51.

4.         D'Amico R, Cenoz Gomis S, Moodley R, et al. Compassionate use of long-acting cabotegravir plus rilpivirine for people living with HIV-1 in need of parenteral antiretroviral therapy. HIV Med 2023; 24(2): 202-11.

5.         Agency EM. Vocabria/cabotegravir Product Information. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/vocabria#product-information-section. 

6.         Jeffrey JL, St Clair M, Wang P, et al. Impact of Integrase Sequences from HIV-1 Subtypes A6/A1 on the In Vitro Potency of Cabotegravir or Rilpivirine. Antimicrob Agents Chemother 2022; 66(3): e0170221.

7.         Cutrell AG, Schapiro JM, Perno CF, et al. Exploring predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: a multivariable analysis. AIDS 2021; 35(9): 1333-42.

8.         Monteiro P, Perez I, Laguno 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.

9.         Llibre JM, Hung CC, Brinson C, 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.

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

11.       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.

12.       Gantner P, Cuzin L, Allavena C, 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.

13.       Margolis DA, Brinson CC, Smith GHR, 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.

14.       Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, 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.

15.       Murray M, Pulido F, Mills A, 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.

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

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

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

19.       al. OERGRGe. CABOTEGRAVIR + RILPIVIRINE EVERY 2 MONTHS IS NONINFERIOR TO MONTHLY: ATLAS-2M STUDY. Conference on Retroviruses and Opportunistic Infections. Boston, Massachusetts: CROI.