1 INSTI 1 PI 1 NNRTI

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

Overview

This type of regimen contains 1 NNRTI, 1 INSTI, and 1 PI. This type of regimen is thought to be a good choice for “salvage therapy” to treat patients who are infected with multidrug-resistant HIV, as shown in one study[1]. Some experts recommend this type of regimen for patients with various mutations that result in multiclass drug resistance, and have used this type of regimen with success.

Recommendations in Support of 1 NNRTI + 1 INSTI + 1 PI

Treatment-naïve patients

DHHS: The DHHS guidelines do not mention this type of regimen for treatment-naïve patients because naïve patients are generally started on an initial regimen that consists of 2 NRTIs with either an INSTI, NNRTI, or boosted PI. A component of this regimen, DRV/r+RAL, which is 1 boosted PI + 1 INSTI is recommended as an “other” regimen for patients who require an NRTI-sparing regimen.

IAS: The IAS guidelines do not discuss this type of regimen for treatment-naïve patients. However, the guidelines recommend an initial treatment regimen of at least 2-3 fully active agents. Furthermore, INSTI-based, PI-based and NNRTI-based regimens are all recommended for initial treatment.

Treatment-experienced patients

DHHS: This type of regimen is not specifically discussed in the guidelines. However, in cases of confirmed virologic failure, the guidelines discuss the potential success of regimens that contain 3 active drugs as well as the increasing data that shows that a

pharmacokinetically enhanced PI plus one other active drug or several partially active drugs will effectively reduce viral load in most patients.” This type of regimen is not discussed in cases of viral suppression.

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. The guidelines recommend addressin adherence and drug interactions prior to switching a patient’s regimen in cases of suspected virologic failure.

Recommendations in Support of 1 INSTI + 1 PI

Treatment-naïve patients

DHHS: Recommended as an “other” regimen for treatment-naïve patients in cases when an NRTI (ABC, TAF, TDF) cannot be used. Based on trial data, the DHHS acknowledges that this type of regimen has some potential disadvantages and may be less effective with patients who have high viral loads or low CD4 counts[2]. DHHS recommends that a regimen of DRV/r + RAL be considered for use only in patients with HIV RNA <100,000 copies/uL and CD4 cell counts >200 cells/mm3 who cannot take ABC, TAF, or TDF.

IAS: Only recommended in situations where patients cannot take ABC, TAF, or TDF because it may be less effective in patients with CD4 cell counts below 200µ/L or HIV RNA levels above 100,000 copies/mL.

Treatment-experienced patients

DHHS: In virally suppressed patients, DHHS discusses the possibility of switching patients to a regimen of DRV/r + RAL, but acknowledges the lack of data to support the switch. The DHHS does not currently recommend switching to a regimen of ATV/r + RAL due to higher rates of virologic failure and discontinuation that was seen in patients who switched from ATV/r + TDF/FTC to ATV/r + RAL[3].

In cases of confirmed virologic failure, DHHS recommends considering a regimen of a boosted PI + 1 INSTI after a patient has failed a regimen of an NNRTI with NRTIs. DHHS also recommends considering 1 boosted PI with an INSTI in patients who do not have an INSTI resistance after failing an INSTI + 2 NRTI regimen. This regimen may also be considered in cases of virologic failure of second-line regimens, as long as the virus is susceptible to INSTIs.

IAS: The IAS does not specifically recommend any regimens for treatment-experienced patients in cases of both virologic failure or suppression. However, IAS does recommend a regimen of 1 PI + 1 INSTI as an alternative regimen for treatment-experienced patients.

Recommendations in Support of 1 PI + 1 NNRTI

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.

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.

Recommendations in Support of 1 INSTI + 1 NNRTI

Treatment-naïve patients

DHHS: This type of regimen is not discussed as an option for initial treatment in the guidelines. However, both PI-based and NNRTI-based regimens are recommended for initial treatment.

IAS: This type of regimen is not discussed in the IAS guidelines. However, both PI-based and NNRTI-based regimens are recommended for initial treatment.

Treatment-experienced patients

DHHS: This type of regimen is not discussed in the guidelines for treatment-experienced patients in cases of virologic failure or suppression.

IAS: The IAS guidelines do not specifically recommend any regimens for treatment-experienced patients in both cases of virologic failure or suppression. This type of regimen is not discussed in the guidelines.

Other Considerations

DRV/r

Must be taken with food
High barrier to resistance
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

DRV/c

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

LPV/r

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

RAL

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 [4].
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

EVG/c

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

DTG

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

NNRTI

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

RPV

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

EFV

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

NVP

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

Efficacy in Clinical Trials

Trial	Regimen	Population	Result
ANRS139/TRIO	RAL+ETR+DRV/r vs. optimized background therapy without any fully active agents	103 tx-experienced	In a cohort of 103 treatment experienced patients infected with multidrug resistant HIV with plasma levels >1000 copies/ml, 90% of patients at 24 weeks had an HIV level of <50 copies/ml with the drug combination of RAL+ETR+DRV/r. At week 96, the triple drug regimen was shown to have sustained efficacy and was recommended by researchers to be considered an option for patients who have multiclass drug resistance[1].
Tivista	DRV/r+DTG (1 arm)	113 tx-experienced	At week 48, the combination of DTG and DRV/r provided a high rate of viral suppression (98.1%), with only one dropout due to drug toxicity [5].
PROGRESS	TDF/FTC + LPV/r vs LPV/r + RAL	206 tx-naive	Viral suppression at 48 weeks 83% in RAL group vs 85% in TDF/FTC+LPV/r group (non-inferior) [6]
SPARTAN	RAL + ATV vs TDF/FTC+ATV/r	94 tx-naive	Similar rates of viral suppression at 24 weeks, but higher incidence of hyperbilirubinemia and RAL resistance development[3]
ACTG A5262	DRV/r + RAL	112 tx-naive	26% virologic failure by 48 weeks, with integrase resistance in 5 participants, particularly in those with baseline viral load>100,000 [7]
RADAR	DRV/r+ RAL vs TDF/FTC+DRV/r	68 tx-naive	62.5% of RAL subjects and 83.7% of TDF/FTC subjects were responders (VL<48 copies/mL) at week 48 (p = 0.045; chi-square test). The proportions of patients achieving VL<200 copies/mL were similar: 72.5% and 86.0% (p = 0.175) [8].
ANRS143/NEAT 100	DRV/r+RAL vs TDF/FTC+DRV/r	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 [2].
SECOND-LINE	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 [9].
EARNEST	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[10].
KITE	LPV/r + RAL vs sHAART	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 [11].
N/A	ATV/r+RAL vs ATV/r+TDF/FTC	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[12]
N/A	PI and/or NRTI-based regimens vs RAL + ETR	25 tx-experienced	In a prospective cohort study, virologically suppressed patients on PI or NRTI regimens who expressed concerns due to unwanted side effects were switched to an RAL+ETR regimen. The regimen was well tolerated and maintained viral suppression at 48 weeks and the regimen can be considered a well-tolerated potential regimen in certain patients who had difficulty with both PI and NRTI therapy [13].
ONCEMRK	RAL 1200mg QD vs RAL 400mg BID	802 tx-naive	In a clinical trial of patients receiving RAL either 1200 mg once daily (QD) or 400 mg twice daily (BID) the once daily regimen was found to be noninferior at 48 weeks. 89% of patients receiving QD RAL and 88% of patients receiving BID RAL achieved viral suppression, and there were numerically higher rates of serious adverse events and discontinuations in patients receiving BID[14].
PROBE	RPV+DRV/r vs cART		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 [15].
N/A	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[16].
NEKA	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[17]
MULTINEKA	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 [18].
N/A	LPV/r+EFV	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[19].

1. Yazdanpanah Y, Fagard C, Descamps D, Taburet AM, Colin C, Roquebert B, et al. High rate of virologic suppression with raltegravir plus etravirine and darunavir/ritonavir among treatment-experienced patients infected with multidrug-resistant HIV: results of the ANRS 139 TRIO trial. Clin Infect Dis. 2009;49(9):1441-9.

2. Raffi F, Babiker AG, Richert L, Molina JM, George EC, Antinori A, et al. Ritonavir-boosted darunavir combined with raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults infected with HIV-1: 96 week results from the NEAT001/ANRS143 randomised non-inferiority trial. Lancet. 2014;384(9958):1942-51.

3. Kozal MJ, Lupo S, DeJesus E, Molina JM, McDonald C, Raffi F, et al. A nucleoside- and ritonavir-sparing regimen containing atazanavir plus raltegravir in antiretroviral treatment-naive HIV-infected patients: SPARTAN study results. HIV Clin Trials. 2012;13(3):119-30.

4. Raffi F, Jaeger H, Quiros-Roldan E, Albrecht H, Belonosova E, Gatell JM, et al. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2013;13(11):927-35.

5. G. S. Dolutegravir plus Ritonavir-Boosted Darunavir in Highly cARTExperienced

Subjects. 14th European Meeting on HIV and Hepatitis; Rome2016.

6. Reynes J; Lawal A; Pulido F ea. Examination of noninferiority, safety, and tolerability of lopinavir/ritonavir and raltegravir compared with lopinavir/ritonavir and tenofovir/ emtricitabine in antiretroviral-naïve subjects: the progress study, 48-week results. HIV Clin Trials. HIV Clin Trials. 2011;12(5):255-67.

7. Nyaku AN, Zheng L, Gulick RM, Olefsky M, Berzins B, Wallis CL, 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.

8. Bedimo RJ, Drechsler H, Jain M, Cutrell J, Zhang S, Li X, et al. The RADAR study: week 48 safety and efficacy of RAltegravir combined with boosted DARunavir compared to tenofovir/emtricitabine combined with boosted darunavir in antiretroviral-naive patients. Impact on bone health. PLoS One. 2014;9(8):e106221.

9. Boyd MA, Kumarasamy N, Moore CL, Nwizu C, Losso MH, Mohapi L, et al. Ritonavir-boosted lopinavir plus nucleoside or nucleotide reverse transcriptase inhibitors versus ritonavir-boosted lopinavir plus raltegravir for treatment of HIV-1 infection in adults with virological failure of a standard first-line ART regimen (SECOND-LINE): a randomised, open-label, non-inferiority study. Lancet. 2013;381(9883):2091-9.

10. Hakim JG, Thompson J, Kityo C, Hoppe A, Kambugu A, Oosterhout JJv, et al. Lopinavir plus nucleoside reverse-transcriptase inhibitors, lopinavir plus raltegravir, or lopinavir monotherapy for second-line treatment of HIV (EARNEST): 144-week follow-up results from a randomised controlled trial. Lancet Infect Dis. 2018;18(1):47-57.

11. Ofotokun I, Sheth AN, Sanford SE, Easley KA, Shenvi N, White K, et al. A switch in therapy to a reverse transcriptase inhibitor sparing combination of lopinavir/ritonavir and raltegravir in virologically suppressed HIV-infected patients: a pilot randomized trial to assess efficacy and safety profile: the KITE study. AIDS Res Hum Retroviruses. 2012;28(10):1196-206.

12. van Lunzen J, Pozniak A, Gatell JM, Antinori A, Klauck I, Serrano O, et al. Brief Report: Switch to Ritonavir-Boosted Atazanavir Plus Raltegravir in Virologically Suppressed Patients With HIV-1 Infection: A Randomized Pilot Study. J Acquir Immune Defic Syndr. 2016;71(5):538-43.

13. Monteiro P, Perez I, Laguno M, Martinez-Rebollar M, Gonzalez-Cordon A, Lonca M, et al. Dual therapy with etravirine plus raltegravir for virologically suppressed HIV-infected patients: a pilot study. J Antimicrob Chemother. 2014;69(3):742-8.

14. Pedro Cahn M, Sax PE, Squires K, Molina J-M, Ratanasuwan W, Rassool M, et al. Raltegravir (RAL) 1200 mg Once Daily (QD) is Non-Inferior to RAL 400 mg Twice Daily (BID), in

Combination with Tenofovir/Emtricitabine, in Treatment-Naïve HIV-1 Infected Subjects: Week 48 Results. J Acquir Immune Defic Syndr. 2018;78(5):589-98.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.