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


There are several FDA approved NRTI’s and PI’s.  In general, regimens anchored by 2 NRTIs (e.g., TAF/FTC, TDF/FTC, ABC/3TC) in combination with newer PIs (such as ATV, DRV, or LPV ) are well-studied and supported in the literature for treatment naïve and experienced patients. DRV/c/TAF/FTC is now available coformulated in a single pill once/daily regimen. We note that when BID dosing for the DRV component is required (i.e. in the setting of DRV mutations), it must be used in combination with ritonavir.

Previously, such regimens were considered a preferred regimen in treatment guidelines.  However, all PIs (with the exception of ATV) must be combined with a pharmacologic booster, cobicistat or ritonavir, which can have substantial drug interactions; PIs also may have more side effects than INSTIs. Consequently, the combination of 2NRTI with PIs are now considered a regimen recommended only in some clinical situations for treatment naïve patients in DHHS guidelines (2019).

Among regimens combining these classes, HIVASSIST prioritize the usage of DRV with either cobicistat or ritonavir in combination with TAF or TDF and 3TC or FTC. 

Owing to higher toxicity and lower barriers to resistance, HIVASSIST considered the usage of other/older PIs other than Darunavir and Atazanavir, and NRTIs other than ABC/3TC, or the combination of TAF or TDF with 3TC or FTC to be less favored.

*There is evidence from bioequivalence or relative bioavailability studies that TAF can be substituted for TDF without loss of efficacy and with an improved side effect profile, particularly less impact on kidney function and on bone loss[1]. As such, TAF, an oral prodrug of TDF, is now included (since 2016) as a component of several recommended regimens and first line therapy in both DHHS and IAS-USA guidance. TAF is FDA approved for use in patients with estimated CrCl as low as 30mL/min. It should be noted that some guidelines (UK) continue to recommend TDF over TAF except for specific reasons such as bone or renal complications; there is emerging evidence of an association of TAF and weight gain.

+DRV/c was found to be bioequivalent to DRV/r in healthy volunteers[2].  Based on the results of the study, efficacy of DRV/c has been extrapolated from DRV/r data. Therefore, many experts may consider use of DRV/c despite the limited supporting data from clinical trials due to the reduced pill burden. Use of DRV/c is discussed in both the DHHS and IAS guidelines for use in treatment-naïve and treatment-experienced patients. Cobicistat inhibits active tubular secretion of creatinine, which can increase serum creatinine without an effect on renal glomerular function.

Recommendations for Treatment-Naïve Patients

DHHS (2019): 2NRTI + 1 PI are no longer preferred regimens in most patients (DHHS now recommends certain 2 NRTI + 1 INSTI or 1NRTI+1 INSTI for most patients). TAF/FTC/DRV/c; TAF or TDF plus 3TC or FTC with DRV/r or ATV/boosted; or ABC/3TC with DRV/boosted in HLA B*5701 negative patients, are "recommended as an initial regimen in certain clinical situations" for treatment-naive patients, because these regimens have durable virologic efficacy.   

IAS-USA (2018): 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.

HIVASSIST(2020):  Regimens containing 2 NRTI + 1 PI are ranked below the currently recommended regimens (NRTI and INSTI based regimens) for treatment naïve patients. We prioritized DRV/b* (either cobicistat or ritonavir) with TAF/FTC above usage of ATV/b and other NRTI backbones. 

For treatment naive patients TAF/FTC + DRV/b was ranked similar to TDF/XTC/DOR and RPV/TAF/FTC within HIVASSIST algorithms, consistent with DHHS guidelines[3-5].  While current guidelines do not offer preferences between such regimens and dual drug regimens involving a PI (PI+3TC, PI+INSTI), we ranked 2NRTI+1 PI ahead of such dual regimens given the longer track record and current evidence base. See tables below.

*/b refers to usage of a pharmacologic booster

Recommendations for Treatment-Experienced Patients

DHHS (2019): In cases of virologic failure, currently guidelines discuss several options based on the failing regimen.  Guidelines suggest a Boosted PI plus 2 NRTI is a possible switch option after failure of a NNRTI, INSTI, or PI anchored regimen (with 2 NRTI).  In the case of failing an NNRTI plus NRTI initial regimen, there are at least three large RCTs suggesting a PI with 2 NRTI may be effective[6-8].  In the setting of prior PI+NRTI failure, current data suggests that patients will have either no resistance or limited resistance (e.g., to 3TC or FTC). Guidelines acknowledge a lack of data on regimens after failing INSTI based regimens, but list 2 NRTIs plus boosted PI as an option to consider.

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-USA (2018): 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. 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.

HIVASSIST: HIVASSIST algorithms prioritize usage of 2 NRTIs+ PIs after NNRTI failure, consistent with current evidence and DHHS guidelines (2019).  When failing a boosted PI + NRTI regimen, several studies have shown limited resistance to XTC (ARTEMIS study[9, 10]).  A systematic review has suggested that maintaining the same regimen, with improved adherence, may be effective[11]. PI resistance in this setting are also relatively rare[9, 10].  As such, our algorithm prioritizes continuing the PI based regimen (i.e. 2 NRTI + PI in some cases), or switching to a non-PI regimen with at least 2 fully active agents.We also prioritized switching to PI based regimens (either with NRTI or INSTI) after INSTI failure and emergence of INSTI mutations given the relatively high barrier of resistance, provided the regimen had more than 2 active drugs.  In patients that are already virally suppressed, HIVASSIST did not prioritize or penalize regimens switching to 2NRTI+1PI.  Existing evidence for viral simplification strategies have suggested that switching from a PI based regimen to NNRT and to INSTIs can be considered in order to improve lipid profiles, minimize drug interactions, or reduce dosing frequency(see Table). Consequently, HIVASSIST algorithms prioritize each of these strategies (note no changes are made to base-case rankings for 2 NRTI+INSTI given such regimens carry the top HIVASSIST rank even in non-suppressed patients).

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

TREATMENT NAÏVE (not all are listed, and focus is on DRV regimens. BOLDED studies were particularly important to ranking of 2NRTI+PI relative to NNRTI and INSTI regimens)

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 [12]

Study 115

DRV/c vs. DRV/r

62 tx-naive

DRV/c is bioequivalent to DRV/r in healthy volunteers[2]


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

67, 48% tx-naive

At 48 weeks, 79% achieved viral suppression[13]


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 [4, 9]


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[14]

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[15, 16]

ACTG 5202

2 NRTIs plus EFV or ATV/r

463 tx-naive patients

EFV was comparable to ATV/r with respect to virological response when each was given with either TDF/FTC or ABC/3TC[3]



769 Tx Naïve

 At week 96, a higher proportion of the doravirine group (277 [73%] of 383) achieved an HIV-1 RNA concentration of less than 50 copies per mL than did of the darunavir group (248 [66%] of 383; difference 7·1%, 95% CI 0·5-13·7). Responses were similar regardless of baseline characteristics. Treatment-emergent resistance to any study drug occurred in two (1%) of 383 participants in the doravirine group and one (<1%) of 383 in the ritonavir-boosted darunavir group. Significant differences were seen between treatment groups in mean changes from baseline in LDL cholesterol (-14·6 mg/dL, 95% CI -18·2 to -11·0) and non-HDL cholesterol (-18·4 mg/dL, -22·5 to -14·3).[17]

Comparison with INSTI+PI


TDF/FTC + LPV/r vs LPV/r + RAL

206 tx-naive

The LPV/r + RAL regimen was found to be noninferior to the regimen of LPV/r + TDF/FTC in both safety and efficacy. Viral suppression at 48 weeks 83% in RAL group vs 85% in TDF/FTC+LPV/r group[18]



94 tx-naive

Similar rates of viral suppression at 24 weeks, but higher incidence of hyperbilirubinemia and RAL resistance development[19]



112 tx-naive

26% virologic failure by 48 weeks, with integrase resistance in 5 participants, particularly in those with baseline viral load>100,000[20]



68 tx-naive

DRV/r+RAL was less effective than DRV/r+TDF/FTC (62.5% of RAL subjects and 83.7% of TDF/FTC subjects were responders (VL<48 copies/mL) at week 48) but better for bone health. However, the proportions of patients achieving VL<200 copies/mL were similar: 72.5% and 86.0%[21]

ANRS143/NEAT 100

DRV/r+RAL vs


805 tx-naive

DRV/r+RAL was noninferior for the primary endpoint of time to treatment failure (17.8%vs 13.8% at 96 weeks); planned subgroup analysis showed RAL arm was inferior for those with CD4<200.[22]



LPV/r + NRTI backbone vs LPV/r + RAL

541 tx-experienced

At 48 weeks, a regimen of LPV/r+RAL was found to be noninferior to a regimen of LPV/r+2 NRTIs, given that 223 (83%) of patients in the LPV/r + RAL group and 213 (81%) of patients in the control group were virally suppressed[6]


PI monotherapy vs 2 NRTI+LPV/r vs LPV/r + RAL

1277 tx-experienced

PI+INSTI regimen had 64% viral suppression and was noninferior to a 2NRTI+PI regimen that had 60% viral suppression[7] 


LPV/r+RAL vs LPV/r+2 or 3 NRTI

515 tx experienced

Patients viremic on NNRTI based regimen randomized to the two arms and followed at 24 and 48 weeks.  By 48 weeks, probability of failure was 10.3% in RAL+LPV/r arm vs 12.4% in the NRTI+PI arm, indicating non-inferiority but not superiority.[23] 



60 tx-experienced

At week 48, both arms of the study were found to have similar levels of sustained viral suppression; 92% of the LPV/r + RAL patients and 88% of the sHAART patients [24]



109 tx-experienced

At 24 weeks 94.6% of patients on the ATV/r+TDF/FTC regimen maintained viral suppression, while 80.6% of patients on the ATV/r+RAL regimen-maintained suppression. At 48 weeks, 86.5% of ATV/r+TDF/FTC and 69.4% of ATV/r+RAL patients maintained virologic suppression. The ATV/r+RAL group was noted to have lower adherence and higher treatment discontinuation along with a higher virologic rebound rate as compared to ATV/r+TDF/FTC[25] 


DTG+2NRTI vs LPV/r+2NRTI post NNRTI failure

627 Tx experienced, failing NNRTI

At week 48, 261 (84%) of 312 in DTG arm compared to 219 (70%) in LPV achieved suppression (superior) (p<0·0001).[26]


LPV/r + 2 NRTIs vs DRV/r + 2 NRTIs

595 tx-experienced

At 96 weeks, a greater number of DRV/r patients were virologically suppressed, showing that DRV/r is noninferior to LPV/r. Response to DRV/r was found to be 60.4%, as opposed to 55.2% in LPV/r patients. Virological failure with DRV/r was 13.8%, nearly half of that of LPV/r, which was 25.6%. There were similar rates of discontinuation due to adverse events with both regimens. There was less diarrhea with patients on DRV/r as well as an improved lipid profile, as compared to LPV/r[27]



Participants of RCTS experiencing VF after PI+2 NRTI

Of 209 participants, only 1 participant had major PI-associated treatment-emergent mutations at first-line VF. The most common treatment approach after VF (66%) was to continue the same regimen. The virologic suppression rate 24 weeks after VF was 64% for these participants, compared with 72% for those who changed regimens (P = .19).[11] 


DRV BID/r+OBR vs Control PI/b_+OBR

155 Tx experienced with PI mutation

At week 48, 67 of 110 (61%) darunavir-ritonavir patients compared with 18 of 120 (15%) of control PI patients had viral load reductions of 1 log10 copies per mL or greater from baseline (primary endpoint; difference in response rates 46%, 95% CI 35%-57%, p<0.0001). 56% vs 46% vs 26% suppressed using DRV (1,2, 3+ mutations), compared to 17%,7%, 3% using other PI (for 1,2,3+mutations respectively).[28, 29]


PI/r anchor regimen vs DTG anchor regimen (+2NRTI)

415 Tx experienced, suppressed, w Framingham >10%

89% were men, 87% >50 years, 74% with Framingham score more than 10%, with a median CD4 cell count of 617 cells per μl and suppressed viremia for a median of 5 years.

At week 48, treatment success 93.1% in DTG group and 95.2% in PI/r group (noninferiority demonstrated). There were four virological failures with DTG and one with PI/r with no emergent resistance mutations. Total cholesterol and other lipid fractions (except high-density lipoprotein cholesterol) improved significantly (P < 0.001) in the DTG group regardless of PI/r at baseline[30].


BIC/TAF/FTC vs PI/b regimens

577 Tx experienced, GFR>50, suppressed

At 48 weeks 2% in BIC and 2% in PI/b had Vl>50 (non-inferior). 1% and <1% in the respective groups discontinued treatment because of adverse events. Incidence of adverse events was similar in both arms, though headache was more common w BIC[31]



476 Tx suppressed on PI

Noninferiority at week 24: HIV-1 RNA <50 copies/ml, 93.7% of RPV/FTC/TDF versus 89.9% of PI/r +two NRTIs (difference 3.8%,). At week 48, 89.3% of switch group maintained virologic suppression. High rates of suppression were maintained with RPV/FTC/TDF regardless of participant's pre-antiretroviral HIV-1 RNA level. Overall development of resistance mutations after switching to RPV/FTC/TDF was low. Decreases in total cholesterol, low-density lipoprotein (LDL), and triglycerides were significantly greater among RPV/FTC/TDF recipients than those in the protease inhibitor+RTV+ two NRTIs group.[32]


OLDER PI regimens or comparators



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[33]


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 [34]


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[35]


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[12]



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%)[36-39] 



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 [40]

Study 103


350 tx-naive

At 144 weeks, FTC/TDF/EVGc demonstrated durable efficacy and improved safety[39]



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[41]



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[42]

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