1 INSTI 1 NRTI

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

Overview

Use of 1 NRTI + 1 INSTI regimens is becoming supported by emerging evidence for using this regimen as in ART naive patients and as a treatment simplification strategy for virologically suppressed patients without prior treatment failure or resistance. It offers potential  cost or toxicity advantages over 3-drug regimens.  Dual-treatment studies of 1 NRTI + 1 INSTI have primarily included DTG + Lamivudine ( which is available in the US as coformulated DTG/3TC).   Within HIVASSIST we prioritized DTG/3TC when considering INSTI + NRTI dual ART regimens.  Given the lower barrier to resistance with RAL, we considered its usage to be less preferred and should be done with caution as part of two-drug regimens. 

In particular, Dolutegravir/Lamivudine is a two-drug combination tablet approved for therapy in treatment-naive patients.   Potential advantages of this option for first-line therapy include avoidance of the NRTI’s tenofovir and abacavir in patients with significant renal insufficiency, cardiovascular disease, or positive HLA-B*5701 testing.  In Dec 2019, DHHS guidelines were updated to include DTG/3TC as a 'recommended initial regimen for most people with HIV’ as the first 2 drug regimen for this purpose and is listed alongside INSTI +2 NRTI for this indication (except for individuals with HIV RNA>500,000, HBV coinfection, or when starting before HIV genotypic resistance testing is available).  Among treatment experienced, suppressed patients, DTG/3TC has also been found to be an effective maintanence strategy (TANGO, as well as smaller trials; see table below). 

More comprehensive information can be found from the National HIV Curriculum: https://www.hiv.uw.edu/page/treatment/drugs/dolutegravir-lamivudine

Recommendations for treatment-naïve patients

DHHS (Dec 2019): DTG+3TC is listed as an initial regimen for most people with HIV(AI), except for individuals with HIV RNA >500,000 copies/mL, HBV coinfection, or in whom ART is to be started before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available.  DTG/3TC was non-inferior to a three drug regimen of DTG+TDF/FTC, and no treatment emergennt resistance was seen in either the two or three drug group.  There are now data that some INSTI-based regimens that include TAF may result in greater weight gain, but the clinical significance is still uknown. Do not use in individuals with concomitant HBV infection. Effectiveness for other INSTI + NRTI combinations has to be inferred, but should be considered with caution as other combinations have not been studied. 

IAS-USA (2018): IAS-USA guidelines were last updated before publication of the GEMINI trials and may be updated in future iterations. In the 2018 guidance, they suggested that initial 2-drug regimens should only be considered in the rare situations in which a patient cannot take ABC, TAF, or TDF; IAS-USA 2018 guidance does acknowledge the promising PADDLE trial results, but considers the trial to be too small to make a formal recommendation of this regimen for treatment-naïve patients. IAS-USA recommends DTG over RAL among INSTI drugs, as DTG has been found to be noninferior to RAL in treatment-naïve patients, whereas it was found to be superior to RAL in treatment-experienced patients.

HIVASSIST: Within HIV-ASSIST, DTG/3TC is ranked 1 for treatment-naive patients with Vl that are known and <500,000, along with other combinations of 2NRTI+1 INSTI.  Situations in which it might be preferred could include those in which there are comedications that have drug-interactions with other Recommended regimens, or in situations where NRTIs such as Tenofovir are less preferred (which may include presence of some comorbidities such as renal disease or osteoporosis).  Data is still emerging on defining scenarios in which dual-drug therapy is preferred over traditional three drug regimens.

Recommendations for Treatment-Experienced Patients

DHHS (Dec 2019): In virally suppressed patients, the DHHS guidelines discuss the results of the TANGO study along with several others (e.g, Lamidol trial) evaluating DTG+3TC as a maintenance strategy in suppressed patients with no history of NRTI, INSTI, or PI resistance. They indicate that there is growing evidence that some two drug regimens are effective in maintaining virologic control; none are recommended in patients with HBV coinfection.  As with ART-naive patients, patients with no resistance mutation or history of virologic failure can likely switch to any regimen that has been shown to be highly effective in ART-naive patients (presumably including DTG/3TC).  In cases of confirmed virologic failure, the DHHS recommends that patients be put on a regimen with at least two to three active drugs and does not specifically discuss this regimen.

IAS-USA (2018): The IAS-USA does not specifically recommend this regimen for treatment-experienced patients in cases of confirmed virologic failure. However, in virally suppressed patients, they recommend considering switching patients on older regimens to a variety of simplified regimens (i.e. from use of old NRTIs as they have long-term toxic effects, or older PIs that have higher pill burdens and are more metabolically toxic), but do not specifically recommend any 2 drug regimens.

HIVASSIST:  A combination of 1 INSTI + 1 NRTI (as coformulated DTG/3TC) is considered an acceptable/prioritized option for usage in patients who are virologically suppressed > 6 months, and have no history of treatment failure or resistance.  Among individuals who have experienced treatment failure and are currently viremic, HIV-ASSIST algorithms downgrade dual drug regimens with 1 INSTI+1 NRTI as the regimen has not been studied in such situations, and also for potential concerns that there could be unrecognized NRTI resistance.

Other Considerations: It is important to note that dolutegravir-lamivudine is not adequate treatment for hepatitis B coinfection.

DTG

  • Lowest risk of resistance with virological failure among INSTIs
  • Relatively few drug interactions
  • Use caution in women of childbearing age, based on limited reports of neural tube defects [1]
  • 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
  • DTG, RAL, or RPV-based regimens may be advantageous in patients with high cardiac risk 

Efficacy in Clinical Trials

Trial Name

Regimen

Population

Study Results

PADDLE

DTG+3TC (1 arm)

20 tx-naive

At week 48, 90% (18 of 20) achieved viral suppression. The combination was well tolerated through week 48, and all adverse events were reported in the first week of therapy [1].

ANRS 167 LAMIDOL

DTG+3TC

104 tx-experienced

101/104 (97%) of patients who switched from triple ART to DTG+3TC maintained therapeutic success through 40 weeks of dual therapy [2].

ACTG A5353

DTG+3TC

120 tx-naive

At week 24, 90% had HIV RNA<50copies/ml (with similar response in those with high and low baseline VL). Three participants with suboptimal adherence experienced virologic failure, one with INSTI mutation [3].

GEMINI

DTG+3TC vs TDF/FTC+DTG

719 vs 722 tx-naive, with viral load <500,000

At week 48, 91% and 93% were virally suppressed in the 2 drug and 3 drug arms, respectively, in the pooled analysis of GEMINI 1 and 2, and met non-inferiority margin [4]. In prespecified secondary analyses at 96 weeks, HIV-1 RNA < 50 copies/mL achieved by 86.0% of patients receiving dual therapy vs 89.5% receiving triple-drug ART [5].

ASPIRE

DTG+3TC (n=44) vs 3 drug ART (n=45)

44 vs 45 suppressed patients with no hx of failure or known NRTI or INSTI mutations and no HBV

At week 24 and 48, 93 vs 91% and 91 vs 89% were suppressed for the DTG+3TC vs 3-drug ART regimens, respectively [6].

TANGO

DTG/3TC vs TAF-based regimen

369 vs 372 tx-experienced

In this non-inferiority study of virologically suppressed patients, at week 48, 368/369 (99.7%) in the DTG/3TC arm had HIV-1 RNA <50 copies/mL vs 370/372 (99.5%) in the TAF-based regimen arm; DTG/3TC was non-inferior to a TAF based 3 drug regimen in maintaining suppression with no virologic failure or emergent resistance reported with DTG/3TC [7].

1.         Figueroa M. SO, Patterson P., Gun A., Rolon M., Cahn P. Dolutegravir-lamivudine as initial therapy in HIV-infected, ARV naive patients: first results of the PADDLE trial.  15th European AIDS Conference; Barcelona, Spain2015.

2.         Joly V, Burdet C, Landman R, Vigan M, Charpentier C, Katlama C, et al. Dolutegravir and lamivudine maintenance therapy in HIV-1 virologically suppressed patients: results of the ANRS 167 trial (LAMIDOL). J Antimicrob Chemother. 2019;74(3):739-45.

3.         Nyaku AN, Zheng L, Gulick RM, Olefsky M, Berzins B, Wallis CL, et al. Dolutegravir plus lamivudine for initial treatment of HIV-1-infected participants with HIV-1 RNA <500 000 copies/mL: week 48 outcomes from ACTG 5353. J Antimicrob Chemother. 2019;74(5):1376-80.

4.         Cahn P, Madero JS, Arribas JR, Antinori A, Ortiz R, Clarke AE, et al. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): results from two multicentre, randomised, , phase 3 trials. Lancet. 2019;393(10167):143-55.

5.         Mascolini M. Week-96 Potency of Dolutegravir/3TC in GEMINI Trials of First-Line ART - "Durable efficacy of dolutegravir (DTG) plus lamivudine (3TC) in antiretroviral treatment-naive adults with HIV-1 infection--96-week results from the GEMINI studies" IAS Conference on HIV Science; Mexico City2019.

6.         Taiwo BO, Marconi VC, Berzins B, Moser CB, Nyaku AN, Fichtenbaum CJ, et al. Dolutegravir Plus Lamivudine Maintains Human Immunodeficiency Virus-1 Suppression Through Week 48 in a Pilot Randomized Trial. Clin Infect Dis. 2018;66(11):1794-7.

7.         Wyk Jv, Ajana F, Bisshop F, Wit SD, Osiyemi O, Sogorb JP, et al. Efficacy and Safety of Switching to Dolutegravir/Lamivudine Fixed-Dose 2-Drug Regimen Versus Continuing a Tenofovir Alafenamide-Based 3- or 4-Drug Regimen for Maintenance of Virologic Suppression in Adults With HIV-1. Clin Infect Dis. 2020;71(8):1920-9.