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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][4].

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.

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.

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[5].
  • 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 [6].

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)[7]

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[8]

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)[9].

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[10].

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[11].

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[12].

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[4]

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].

 

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