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


This type of regimen consists of one boosted PI with one NNRTI and is considered to be an NRTI-sparing regimen. This combination of drugs is more often used in tandem with either 2 NRTIs or a single NRTI. However, there has been some promising research for this type of regimen and some experts believe that it may have potential as an alternative for patients who are having toxicity issues when taking NRTIs [1].

Recommendations in treatment-naïve patients

DHHS: The DHHS guidelines do not discuss this type of regimen for treatment-naïve patients. However, both PI-based and NNRTI-based regimens are recommended for initial treatment.

IAS: The IAS guidelines do not discuss this type of regimen for treatment-naïve patients. However, both PI-based and NNRTI-based regimens are recommended for initial treatment.

Recommendations in treatment-experienced patients

DHHS: The DHHS guidelines do not discuss this type of regimen in great detail, but in cases of virologic failure of an NNRTI plus NRTI regimen, a regimen consisting of a second-generation NNRTI (ETR) combined with a boosted PI can be considered. The guidelines also mention that there is promising data that a boosted PI with one other drug will reduce viral load in most patients, both treatment-naïve and treatment-experienced.

IAS: The IAS guidelines do not specifically recommend any regimens for treatment-experienced patients in both cases of virologic failure or suppression and do not discuss this type of regimen for treatment-experienced patients. 

Other Considerations


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


  • 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


  • Lower rates of causing lipodystrophy than PI-based regimens; should consider switching to NNRTI-based regimen if experiencing PI-induced lipodystrophy


  • Smallest tablet among the single-pill regimens
  • Approved for use in patients with pre-treatment viral loads <100,000 copies/mL and CD4 count >200 cells/mm3
  • Must be taken with a high-calorie meal (at least 390 kcal)
  • Interacts with many other drugs
  • Contraindicated with PPIs, use with caution with H2 antagonists or antacids
  • Can prolong the QTc
  • Lowest risk of rash among NNRTI-based therapies, and low risk of metabolic adverse effects
  • Possible side effects include depressive disorders and suicidality


  • Can induce CNS toxicity (i.e. insomnia, abnormal dreams, nervousness)
  • Possible side effects include skin symptoms, fatigue, elevated transaminase levels, hypertriglyceridemia


  • Potential side effects include liver toxicity risks at higher CD4 levels, severe rash

Efficacy in Clinical Trials







60 tx-experienced

The DRV/r+RPV regimen was non-inferior to a standard triple therapy regimen over 48 weeks in terms of virological response. The dual therapy had a more favorable side effect profile for bone density, and was not any different with respect to lipid profile or renal function. This regimen can be considered as an alternative for patients who are experiencing NRTI-related toxicity [1].


LPV/r+2 NRTIs vs EFV+2 NRTIs vs EFV+LPV/r

757 tx-naïve

At week 96, 89% of patients in the EFV group, 77% in the LPV/r group, and 83% in the NRTI-sparing group had fewer than 50 copies of plasma HIV-1 RNA per ml. Virologic failure was more likely in patients on the LPV/r regimen than either the EFV or NRTI-sparing regimens, but the NRTI-sparing regimen was more likely to result in drug resistant mutations than the other two groups [2].


LPV/r+NVP vs LPV/r+2 NRTIs

31 tx-experienced

At 48 weeks, NVP+LPV/r was found to be as effective and as safe as standard-of-care ART. Use of NVP+LPV/r is thought to possibly reduce mitochondrial toxicity as well as lipid abnormalities associated with taking LPV/r [3].


LPV/r+NVP vs LPV/r+2 NRTIs

67 tx-experienced

At 48 weeks, it was found that switching to an NRTI-sparing regimen resulted in an improvement in mitochondrial conditions, unlike the mitochondrial toxicity sometimes seen with NRTIs. Given the results of the study, it is thought that there may be a correlation between reduced mitochondrial toxicity and clinical improvement in lipodystrophy [4].



65 tx-naïve and 21 NNRTI-naive

At 48 weeks, a regimen of LPV/r+EFV was found to have a high rate of virologic response, given an increase in the proportion of patients with a viral load <400 copies/ml to 97%. Researchers concluded that the regimen should be studied alongside more traditional NRTI-based regimens [5].

1.         Maggiolo F, Di Filippo E, Valenti D, Serna Ortega PA, Callegaro A. NRTI Sparing Therapy in Virologically Controlled HIV-1 Infected Subjects: Results of a Controlled, Randomized Trial (Probe). J Acquir Immune Defic Syndr. 2016;72(1):46-51.

2.         Riddler SA, Haubrich R, DiRienzo AG, Peeples L, Powderly WG, Klingman KL, et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med. 2008;358(20):2095-106.

3.         Negredo E, Moltó J, Burger D, Côté H, Miró O, Ribalta J, et al. Lopinavir/ritonavir plus nevirapine as a nucleoside-sparing approach in antiretroviral-experienced patients (NEKA study). J Acquir Immune Defic Syndr. 2005;38(1):47-52.

4.         Negredo E, Miró O, Rodríguez-Santiago B, Garrabou G, Estany C, Masabeu A, et al. Improvement of mitochondrial toxicity in patients receiving a nucleoside reversetranscriptase inhibitor-sparing strategy: results from the Multicenter Study with Nevirapine and Kaletra (MULTINEKA). Clin Infect Dis. 2009;49(6):892-900.

5.         Allavena C, Ferré V, Brunet-François C, Delfraissy J-F, Lafeuillade A, Valantin M-A, et al. Efficacy and tolerability of a nucleoside reverse transcriptase inhibitor-sparing combination of lopinavir/ritonavir and efavirenz in HIV-1-infected patients. J Acquir Immune Defic Syndr. 2005;39(3):300-6.