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This is a generic educational information sheet for 2 NRTI + 1 PI regimens.


Dual NRTI regimens in combination with ATV, DRV, or LPV are well-studied and supported in the literature, but there is less evidence in favor of use of FPV, SQV, or TPV.  However, it is a reasonable extrapolation from clinical trial evidence that these “other” PIs might also work acceptably in combination with 2 NRTIs. General recommendations by both the DHHS and IAS are that treatment-naïve patients initiate treatment with 2 NRTIs and one more active ARV drug (i.e. 1 boosted PI, INSTI, or NNRTI). Many experts recommend boosted PI-based regimens as secondline treatments for patients because of their high barrier to resistance.

Recommendations for Treatment-Naïve Patients

DHHS: Boosted PI and 2 NRTIs is a recommended initial regimen in certain clinical situations. When choosing among PIs, DRV is generally recommended over ATV. Boosted DRV + tenofovir/FTC has the highest recommendeation among regimens for its tolerability, toxicity profile, ease of use, and durable virologic efficacy. When selecting a PI, consider avoiding ATV in patients with chronic kidney disesae as it has been associated with worsened disease in some observational studies. For patients with high cardiac risk, an ATV-based regimen may be preferred over DRV or other PIs is it has not been shown to ahve the same increased risk of cardiovascular events that other PIs have. Older PI's including LPV have been removed from treatment recommendations. Among NRTI backbones, tenofovir/FTC is preferred. ABC/3TC may be considered if HLA-B*5701 is negative. The combination of boosted ATV + ABC/3TC can be considered if HLA-B*5701 and HIV RNA < 100,000 copies/mL.

IAS: Recommended for treatment-naïve patients in which an INSTI is not an option. The recommended 2 NRTI + 1 boosted PI regimens are boosted DRV + TAF or TDF/FTC or ABC/3TC, EFV/TDF/FTC, or RPV/TAF or TDF/FTC.

Recommendations for Treatment-Experienced Patients

DHHS: In cases of virologic failure, patients who fail an NNRTI-based regimen are recommended to consider a switch to either a boosted PI + NRTIs regimen or an INSTI due to the failure often being a result of NNRTI resistance, rather than NRTI resistance. In virally suppressed patients, switching to a regimen of 2 NRTIs + 1 boosted PI may only be considered as a within-class regimen to reduce pill burden, improve the safety profile of the drugs or reduce the dosing frequency; for example, switching from a ritonavir-boosted PI to a cobicistat-boosted PI. The DHHS does not recommend a between-class switch to a boosted PI if the drugs in their current regimen are fully active.

IAS: There is no explicit recommendation to switch to this type of regimen in the IAS guidelines. However, they recommend to consider switching patients on older regimens to a variety of single-pill regimens, including RPV/FTC/TDF. Situations in which patients should be recommended a switch include use of old NRTIs as they have long-term toxic effects, or older PIs that have higher pill burdens and are more metabolically toxic than DRV or ATV.

Other Considerations 


  • Must be taken with food
  • Low risk of resistance with virologic failure, even with intermittent adherence
  • PI booster (ritonavir) interacts with many other drugs
  • Possible side effects include rash, severe rash with fever, and elevated transaminases
  • Caution advised when administering to patients with severe sulfonamide allergy


  • Must be taken with food
  • High barrier to resistance
  • PI booster (cobicistat) interacts with many other drugs 
  • Cobicistat inhibits active tubular secretion of creatinine, which can increase serum creatinine without an effect on renal glomerular function
  • Possible side effects include diarrhea, nausea, and headache
  • Efficacy is inferred from studies of DRV/r


  • Relatively high rates of gastrointestinal adverse effects and hyperlipidemia
  • Higher pill burden than other PI-based regimens


  • 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 [1]
  • Should not be used in patients with CrCl<30


  • 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


2 NRTIs + DRV/c (single arm)

313, 95% tx-naive

At week 48, 81% achieved viral suppression, while 5% discontinued treatment because of adverse events [2].

Study 115

DRV/c vs. DRV/r

62 tx-naive

DRV/c is bioequivalent to DRV/r in healthy volunteers [3].


ABC/3TC+DRV/r (single arm)

67, 48% tx-naive

At 48 weeks, 79% achieved viral suppression [4].


TDF/FTC plus DRV/r or LPV/r 

689 tx-naive

At 92 weeks, DRV/r was superior to LPV/r with respect to virological response. Among participants with baseline HIV RNA levels >100,000 copies/mL, virologic response rates were lower in the LPV/r arm than in the DRV/r arm [5].


2 NRTIs plus DRV/r or DTG

488 tx-naive

At week 96, virologic suppression was significantly greater among those who received DTG. The excess failure observed in the DRV/r group was related to a higher rate of virologic failure among those with a viral load >100,000 copies/mL and more drug discontinuations in the DRV/r group [6].

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[7][8].



878 tx-naive

Virological suppression with FPV/r was found to be noninferior to LPV/r in combination with ABC/3TC at 48 weeks with similar rates of discontinuation due to adverse effects between the two cohorts[9].


SQV/r vs LPV/r

337 tx-naive

SQV/r was noninferior to LPV/r when each were combined in a treatment regimen with 3TC/TDF over 48 weeks in terms of virological suppression. Comparatively, SQV/r offered an improved triglyceride profile [10]


TPV/r vs CPI-ritonavir

3384 tx-experienced

TPV/r with an optimized background regimen was found to provide better virological and immunological responses over 48 weeks in patients with previous antiretroviral exposure as compared to regimens with other PIs[11]


2 NRTIs + DRV/c (single arm)

313, 95% tx-naive

At week 48, 81% achieved viral suppression, while 5% discontinued treatment because of adverse events [2].



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%)  [12] [13] [14].



575 tx-naive women

At 48 weeks, EVG/c/TDF/FTC had superior efficacy, in part because of a lower rate of treatment discontinuation. 87% of participants on EVG achieved viral suppression, with fewer adverse events and incidents of virological failure than in the ATV group [15].

Study 103


350 tx-naive

At 144 weeks, FTC/TDF/EVGc demonstrated durable efficacy and improved safety [13].


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