This is a generic educational information sheet for 1 NRTI + 1 INSTI regimens.
Overview
Dual-treatment studies of 1 NRTI + 1 INSTI have primarily included DTG + 3TC (co-formulated in the United States as DOVATO). Potential advantages of this option for first-line therapy include avoidance of the NRTIs tenofovir and abacavir in patients with significant renal insufficiency, cardiovascular disease, or unknown/positive HLA-B*5701 testing. This combination 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 maintenance 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 (2022): DTG/3TC is currently 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. In the GEMINI trial, DTG/3TC was found to be non-inferior to a three-drug regimen of DTG+TDF/FTC, and no treatment emergent resistance was seen in either the two or three drug group [1]. However, the Panel cautions that DTG/3TC should not be used in patients with concomitant HBV infection without additional HBV coverage (eg with entecavir). 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 (2022): Based on the results of the GEMINI trial, the IAS-USA now recommends DTG/3TC the only initial 2-drug antiretroviral therapy option among treatment naïve patients (along with two other regimens: BIC/TAF/FTC and DTG+TXF/XTC). However, the IAS-USA only recommends this regimen if HIV RNA is <500,000, if HBV coinfection is present, and if genotype, HIV RNA, and HBV serology are available.
HIVASSIST: Within HIV-ASSIST, DTG/3TC has the same base score for treatment-naive patients with viral loads that are known or <500,000 as other combinations of 2NRTI+1 INSTI. Situations in which it might be preferred 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).
Recommendations for Treatment-Experienced Patients
DHHS (Dec 2023): The DHHS Panel currently recommends DTG/3TC as a maintenance strategy among virologically suppressed patients with no history of NRTI or PI resistance. DHHS guidelines also note that DTG+ emtricitabine (FTC) as an option if switching from a stable three-drug regimen to a two-drug regimen, if no history of prior virologic failure or resistance to these two drugs. Among treatment experienced patients exhibiting virologic failure, the Panel recommends that drug-resistance testing – including INSTI resistance testing -- guide ARV regimen design. However, even for patients with virologic failure and no INSTI resistance mutations, the Panel does not currently recommend 1 INSTI + 1 NRTI. Instead, they recommend either 1) a boosted PI+2NRTIs, 2) 1 INSTI + 2 NRTIs, 3) or a boosted PI plus DTG.
IAS-USA (2022): Based on the results of the SALSA and TANGO trials, the IAS-USA suggests that virologically suppressed patients without a history of transmitted or acquired HIV resistance can switch to any of the initial ARV regimens – including DTG/3TC -- and maintain viral suppression [2-4]. Furthermore, the IAS-USA comments that retrospective studies of baseline samples in the trials of DTG/3TC showed no adverse effect from archived resistance mutations, including M184V [4, 5]. With regard to resistance testing, the Society suggests that, unless there is a documented or suspected history of treatment failure, pro-viral resistance testing is not required prior to switching to 2-drug therapy for patients who are virologically suppressed. However, for patients exhibiting virologic failure, the IAS-USA recommends using genotype resistance testing (including proviral testing for RNA levels less than 500 copies/mL) to guide treatment, even if a patient acknowledges poor medication adherence.
HIVASSIST: A combination of 1 INSTI + 1 NRTI 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 penalize 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.
Antacids/Laxatives: DTG absorption may be reduced when coadministered with polyvalent cations. DTG should therefore be taken at least 2 hours before or 6 hours after cation-containing antacids or laxatives are taken. Alternatively, DTG and supplements containing calcium or iron can be taken simultaneously with food.
Hepatitis B coinfection: All patients should be tested for the presence of chronic HBV prior to switching to an INSTI+NRTI regimen. Because it does not contain tenofovir, DTG/3TC is not adequate treatment for chronic hepatitis B coinfection. For patients with chronic hepatitis B who are switching off a tenofovir-based regimen to, it is important to add additional HBV coverage (eg with entecavir) to prevent hepatitis B reactivation.
Liver disease: DTG/3TC is not currently recommended in patients with severe hepatic impairment (Child-Pugh Score C).
Pregnancy: In the January 2024 DHHS Perinatal HIV Clinical Guidelines, while the panel categorizes DTG-based regimens as preferred, they should be accompanied by a dual-backbone NRTI. Thus DTG/3TC or other 1 INSTI + 1 NRTI regimens are not recommended. IAS-USA (2022) additionally does not recommend in pregnancy for treatment initiation. If someone is taking a 2-drug regimen, including DTG/3TC during pregnancy, counseling is recommended regarding uncertain safety during pregnancy with monitoring of HIV RNA more frequently.
Prior Exposure to CAB (as PrEP): For patients with prior 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.
Renal impairment: Since 3TC needs dose adjustment with CrCl<30, fixed dose combination mediations such as DOVATO cannot be used in patients with renal impairment and CrCl<30, including those on dialysis. However, the DHHS Panel does state that the individual component drugs can be used if the 3TC
Tuberculosis treatment: For patients who are taking rifampin for tuberculosis treatment, IAS-USA Guidelines (2022) do not recommend use of DTG/3TC due to drug-drug interactions and inadequate data.
Dolutegravir (DTG)
- Lowest risk of resistance with virological failure among INSTIs
- Relatively few drug-drug interactions
- Use caution in women of childbearing age, based on limited reports of neural tube defects
- 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
- DTG, RAL, or RPV-based regimens may be advantageous in patients with high cardiac risk
Lamivudine (3TC) or Emtricitabine (FTC)
- Both 3TC and FTC have activity against hepatitis B but are insufficient for HBV treatment when used alone due to the emergence of resistance. Discontinuation of FTC or 3TC can precipitate a flare in HBV if no other HBV-active drugs are in the regimen.
- The dose of FTC or 3TC should be adjusted in patients with creatinine clearance (CrCl) <50 mL/min.
- No significant drug interactions have been identified with FTC.
- Both FTC and 3TC select for the M184V mutation when viral suppression is suboptimal.
Efficacy in Clinical Trials
| Trial Name | Regimen | Population | Study Results |
| SALSA (2023) | DTG+3TC | 493 tx-experienced patients | At week 48, 1 (0.4%) participant in the DTG/3TC group and 3 (1.2%) in the current ARV group had HIV-1 RNA of 50 copies/mL or greater (Snapshot, ITT-E population), demonstrating noninferiority of DTG/3TC to current ARV (adjusted difference, −0.8%; 95% confidence interval [CI], −2.4%, 0.8%) [2]. |
| STAT (2021) | DTG/3TC for an initial test and treat strategy | 131 enrolled (5 with HBV coinfection, 1 M184V). 111 w/ available data | At 24 wks, 102/111 (92%) virologically suppressed (HIV-1 RNA <50 copies/mL), 7(5%) were LOF, ARVs adjusted if/after HBV co-infection was identified; 2 SAEs identified (1 SSTI and 1 Strep bacteremia) [6]. |
| RESPOND Cohort (2021) | Switch to a 2-drug or 3-drug regimen | 248 tx-experienced pts switched to DTG + 3TC; n=1088 total on other 2-drug regimen | 1088 ARV experienced individuals started a 2-drug regimen (2DR); most common was DTG+3TC (n=248). N=8703 started a 3-drug regimen (3DR). No difference in composite severe clinic event (AIDS, CVD, non-AIDS defining cancer, ESLD, ESRD, death) between 2DR and 3DR. Virologic and immunologic outcomes (6 & 12 months) were similar [7]. |
| ART-PRO (2020) | DTG+3TC | 41 tx-experienced patients, 21 with 3TC resistance mutations | At week 48, 92·7% of participants (38/41) had fewer than 50 HIV-1 RNA copies per mL. There were no cases of virologic failure. Three participants with historical lamivudine resistance were prematurely discontinued from the study (2 protocol violations, one adverse event). Ten participants (4 in the group with historical lamivudine resistance) had a transient viral rebound, all resuppressed on dolutegravir plus lamivudine [8]. |
| TANGO (2020; 2022) | DTG/3TC vs TAF-based regimen | 369 vs 372 tx-experienced | A total of 741 participants received study treatment (DTG/3TC, n = 369; TAF-based regimen, n = 372). At week 144, the proportion of participants with an HIV-1 RNA level ≥50 copies/mL (primary end point, Snapshot; intention-to-treat-exposed population) after switching to DTG/3TC was 0.3% (1 of 369) versus 1.3% (5 of 372) for those continuing TAF-based regimens, demonstrating noninferiority (adjusted treatment difference, -1.1 [95% confidence interval, -2.4 to .2), with DTG/3TC favored in the per-protocol analysis (adjusted treatment difference, -1.1 [-2.3 to -.0]; P = .04) [3, 4]. |
| ANRS 167 LAMIDOL (2019) | 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 [9]. |
| ACTG A5353 (2019) | 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 [10]. |
| GEMINI-1 & GEMINI-2 (2019) | 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 [1]. |
| ASPIRE (2019) | 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 [11]. |
| PADDLE (2017) | 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 [12]. |
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Last Full Update 2/20/2024
REFERENCES
1. Cahn P, Madero JS, Arribas JR, 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): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet 2019; 393(10167): 143-55.
2. Llibre JM, Brites C, Cheng CY, et al. Efficacy and Safety of Switching to the 2-Drug Regimen Dolutegravir/Lamivudine Versus Continuing a 3- or 4-Drug Regimen for Maintaining Virologic Suppression in Adults Living With Human Immunodeficiency Virus 1 (HIV-1): Week 48 Results From the Phase 3, Noninferiority SALSA Randomized Trial. Clin Infect Dis 2023; 76(4): 720-9.
3. Osiyemi O, De Wit S, Ajana F, et al. Efficacy and Safety of Switching to Dolutegravir/Lamivudine Versus Continuing a Tenofovir Alafenamide-Based 3- or 4-Drug Regimen for Maintenance of Virologic Suppression in Adults Living With Human Immunodeficiency Virus Type 1: Results Through Week 144 From the Phase 3, Noninferiority TANGO Randomized Trial. Clin Infect Dis 2022; 75(6): 975-86.
4. van Wyk J, Ajana F, Bisshop F, et al. Efficacy and Safety of Switching to Dolutegravir/Lamivudine Fixed-Dose 2-Drug Regimen vs Continuing a Tenofovir Alafenamide-Based 3- or 4-Drug Regimen for Maintenance of Virologic Suppression in Adults Living With Human Immunodeficiency Virus Type 1: Phase 3, Randomized, Noninferiority TANGO Study. Clin Infect Dis 2020; 71(8): 1920-9.
5. Wang R, Wright J, Saggu P, et al. Assessing the Virologic Impact of Archived Resistance in the Dolutegravir/Lamivudine 2-Drug Regimen HIV-1 Switch Study TANGO through Week 144. Viruses 2023; 15(6).
6. Rolle CP, Berhe M, Singh T, et al. Dolutegravir/lamivudine as a first-line regimen in a test-and-treat setting for newly diagnosed people living with HIV. AIDS 2021; 35(12): 1957-65.
7. Greenberg L, Ryom L, Neesgaard B, et al. Clinical Outcomes of 2-Drug Regimens vs 3-Drug Regimens in Antiretroviral Treatment-Experienced People Living With Human Immunodeficiency Virus. Clin Infect Dis 2021; 73(7): e2323-e33.
8. De Miguel R, Rial-Crestelo D, Dominguez-Dominguez L, et al. Dolutegravir plus lamivudine for maintenance of HIV viral suppression in adults with and without historical resistance to lamivudine: 48-week results of a non-randomized, pilot clinical trial (ART-PRO). EBioMedicine 2020; 55: 102779.
9. Joly V, Burdet C, Landman R, 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.
10. Nyaku AN, Zheng L, Gulick RM, 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.
11. Taiwo BO, Marconi VC, Berzins B, 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.
12. Cahn P, Rolon MJ, Figueroa MI, Gun A, Patterson P, Sued O. Dolutegravir-lamivudine as initial therapy in HIV-1 infected, ARV-naive patients, 48-week results of the PADDLE (Pilot Antiretroviral Design with Dolutegravir LamivudinE) study. J Int AIDS Soc 2017; 20(1): 21678.