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This is a generic educational information sheet for 2 NRTIs + 1 INSTI regimens.


Dual NRTI regimens in combination with an INSTI (i.e. RAL, EVG/c, and DTG) are well-studied and supported in literature. General recommendations by both DHHS and IAS are that treatment-naïve patients initiate treatment with 2 NRTIs and one more active ARV drug (i.e. 1 INSTI, 1 boosted PI, or NNRTI). This type of regimen is also recommended for treatment-experienced patients for both patients who are virally suppressed and those who have experienced virologic failure.

Recommendations in treatment-naïve patients

DHHS: "Recommended as initial regimens for most" treatment-naïve patients. The guidelines specifically recommend the following regimens: DTG/ABC/3TC for patients who are HLA-B*5701 negative, DTG + TDF/FTC or TAF/FTC, EVG/c/TAF/FTC, EVG/c/TDF/FTC, and RAL + TDF/FTC or TAF/FTC. RAL + ABC/3TC is "recommended as an iniitial regimen in certain clinical situations" for patients who are HLA-B*5701 negative and have viral load<100,000. Patients with pre-existing psychiatric conditions should be monitored closely when started on INSTI-based regimens as these have been associated wtih adverse neuropsychiatric effects.

IAS: Recommended as initial regimens for treatment-naïve patients. The specific 2 NRTI + 1 INSTI regimens that are recommended are DTG/ABC/3TC, DTG+TAF/FTC, EVG/c/TAF/FTC, RAL+TAF/FTC.

Recommendations in treatment-experienced patients

DHHS: In virally suppressed patients, within-class switches from RAL to EVG/c or DTG may be considered if the switch will improve QOL and maintain viral suppression. Between-class switches that can be considered include replacing an NNRTI or boosted PI with an INSTI.

In cases of confirmed virologic failure, the DHHS does not discuss switching to a regimen of 2 NRTIs + 1 INSTI specifically, but recommends considering a switch to a non-PI-based regimen with more than two fully active agents in cases of poor tolerability or interactions that result in the virologic failure of a PI-based regimen.

IAS: In virally suppressed patients, switching from an older regimen to a simpler single-pill regimen (i.e. DTG/ABC/3TC, EVG/c/FTC/TAF, or EVG/c/FTC/TDF) may be considered as long as the patient has no resistance or mutations that would result in virologic failure.

In cases of virologic failure, the IAS does not have any specific recommendations, but notes that in treatment-experienced patients, DTG was found to be superior to RAL and EVG was found to be noninferior to RAL.

Other Considerations


  • 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


  • Must be taken with food (but not with polyvalent ions, which may be found in antacids, laxatives, and mineral supplements)
  • Contraindicated in pregnancy
  • May raise serum creatinine and reduce estimated CrCl
  • Interacts with many other drugs
  • Possible side effects include diarrhea, nausea, headache, and fatigue


  • 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 
  • Largest tablet among co-formulated single-pill regimens 
  • Possible side effects include insomnia, headache, and (rarely) hypersensitivity reaction


  • 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 [2]
  • Should not be used in patients with CrCl<30
  • TAF/FTC is the dual-NRTI base recommended for patients with HIV/HBV coinfection


  • May see hypersensitivity reaction in patients who are not HLA-B*5701 negative
  • Dosing does not need to be adjusted for patients with renal insufficiency


Efficacy in Clinical Trials

Trial Name

Drugs Compared


Study Results



833 tx-naive

At week 48, the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter was significantly higher in the ABC/3TC/DTG group than in the TDF/FTC/EVF group (88% vs. 81%).  Was due primarily to discontinuations because of adverse events (2% in the ABC/3TC/DTG group and 10% in the TDF/FTC/EVF group). At week 144, ABC/3TC/DTG remained superior (71% vs 63% viral suppression) [3] [4] [5]



575 tx-naive women

At 48 weeks, 87% of the women in the TDF/FTC/EVG/c group achieved viral suppression, vs. 81% of the women in the TDF/FTC+ATV/r group. 5 women in the in the TDF/FTC/EVG/c group discontinued due to adverse events, compared to 19 women in the TDF/FTC+ATV/r group[6].


2 NRTIs plus DRV/r or DTG

484 tx-naive

At 48 weeks, DTG outperformed DRV/r (viral suppression 90% vs 83%, respectively). Discontinuation due to adverse effects was higher in the DRV/r group than the DTG group (2% vs 4%, respectively), which contributed to the difference in the response rate. DTG continued to outperform DRV/r at 96 weeks (viral suppression 80% vs 66%) [7][8]

ACTG A5257

ATV/r vs DTV/r vs RAL + TDF/FTC

1809 tx-naive

At 96 weeks, RAL and DRV/r were found to be equally tolerable, while ATV/r was found to be less tolerable, leading to more discontinuation by patients on ATV/r-based regimens. RAL was superior to both PIs in combined virologic efficacy and tolerability, while DRV/r was superior to ATV/r. RAL has a more favorable lipid profile (lower increases in total cholesterol, triglycerides, and LDLc)  as compared to ATV/r and DRV/r, but the long-term clinical significance of the results need to be further evaluated[9][10].



715 tx-experienced

 At week 48, 71% of patients on the DTG-based regimen were virally suppressed as comparted to 64% of patients on the RAL-based regimen. Fewer patients experienced virological failure in the DTG group. DTG, taken once daily, was well-tolerated and more effective than twice daily RAL[11].


2 NRTIs plus DTG or RAL

822 tx-naive

At 48 and 96 weeks, once-daily DTG was non-inferior to twice-daily RAL (88% vs 85% viral suppression at 48 weeks, and 81% vs 76% at 96 weeks), with a similar safety profile[12] [1]



164 tx-naive, 24% with VL ≥100,000

After 96 weeks, there was no difference in virologic response between the ABC/3TC and TDF/FTC groups when RAL was given as the third drug [13].



433 tx-experienced

At week 48, 93.8% of patients who were switched to EVG/c/TAF/FTC maintained viral suppression, whereas 87.1% of patients in the non-switch group who remained on 1 PI/r + TDF/FTC. The study notes that the disparity in suppression between regimens was due to patients in the no-switch group discontinuing the treatment for non-virological reasons and that both are effective treatments for maintaining virologic suppression. There were also noted to be increased side effects (increased serum creatinine, nausea) in the switch group, but they did have lower rates of diarrhea and bloating [14].


ABC/DTG/3TC vs current ART

553 tx-experienced

At week 24, switching to ABC/DTG/3TC from current ART regimen was found to be noninferior to remaining on current ART (85% switched vs 88% remained virally suppressed). At week 48, 83% of the early-switch group remained virologically suppressed, while 92% of the late-switch group were virally suppressed. ABC/DTG/3TC found to be noninferior to continuing current ART and should be considered as an option when switching virally suppressed patients[15]



495 tx-naive women

At 48 weeks, ABC/3TC/DTG was superior in terms of virologic suppression (82% vs 71%). There were fewer virological nonresponses and fewer discontinuations due to adverse events in the ABC/3TC/DTG arm [16]



1733 tx-naive

TAF/FTC/EVG/c was non-inferior to TDF/FTC/EVG/c (92% viral suppression in the TAF group and 90% in the TDF group) Patients given TAF/FTC/EVG/c had significantly smaller mean serum creatinine increases than those given TDF/FTC/EVG/c (0·08 vs 0·12 mg/dL), significantly less proteinuria (median % change -3 vs 20), and a significantly smaller decrease in bone mineral density at spine (mean % change -1·30 vs -2·86) and hip (-0·66 vs -2·95) at 48 weeks [17].



757 tx-naive

At 48 weeks, TDF/FTC/EVG/c was non-inferior to TDF/FTC/EFV (88% viral suppression vs. 84%). Proportions of patients discontinuing drugs for adverse events did not differ substantially (4% in the TDF/FTC/EVG/c group vs 5% in the TDF/FTC/EFV group). Similar findings were also seen at 96 weeks (84% viral suppression vs. 82%) and 144 weeks ( 80% viral suppression vs. 75%)  [18] [19] [20].



708 tx-naive

At 48 weeks, TDF/FTC/EVG/c was non-inferior to TDF/FTC+ATV/r (90% viral suppression vs. 87%, respectively).   Proportions of patients discontinuing drugs for adverse events did not differ substantially (4% of TDF/FTC/EVG/c vs 5% of TDF/FTC+ATV/r). Similar findings were also seen at 96 weeks (83% viral suppression vs. 82%) and 144 weeks (78% viral suppression vs. 75%)  [21] [22] [23].



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 [23][24][25].

Study 103


350 tx-naive

At 144 weeks, FTC/TDF/EVGc demonstrated durable efficacy and improved safety [22].


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