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1 INSTI 1 NNRTI 1 NRTI

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

Overview

1 INSTI + 1 NNRTI + 1 NRTI regimens are generally regimens of 3 active drugs that are not routinely used in treatment-naïve or treatment-experienced patients and are only used in specific circumstances. These regimens are not widely discussed in either the DHHS or IAS guidelines. However, given promising results of various clinical trials with other 3-drug regimens, some experts are starting to consider use of this type of regimen more for patients who are experiencing multidrug-resistant HIV.

Recommendations in support of 1 INSTI + 1 NNRTI + 1 NRTI

Treatment-naïve Patients

DHHS: This type of regimen is not discussed as an option for initial treatment in the guidelines. However, along with NRTIs, INSTI-based regimens are recommended as initial treatment for most patients with HIV and NNRTI-based regimens are recommended as initial treatment in certain clinical situations.

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

Treatment-experienced Patients

DHHS: This type of regimen is not specifically discussed in the guidelines. However, in cases of confirmed virologic failure, the guidelines recommend starting patients on regimens that contain at least 2-3 fully active agents. The guidelines also mention that there is increasing data that patients who are on at least 3 active drugs achieve a more sustained and improved virologic response as opposed to patients who have fewer active drugs in their regimens. 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 addressing adherence and drug interactions prior to switching a patient’s regimen in cases of suspected virologic failure.

Recommendations in Support of 1 NRTI + 1 INSTI

Treatment-naïve Patients

DHHS: Given the promising results of the PADDLE study, a regimen of 1 NRTI + 1 INSTI, specifically with 3TC + DTG, can be considered[1].

IAS: Initial 2-drug regimens are only recommended for consideration in the rare situations in which a patient cannot take ABC, TAF, or TDF. Given that there are not any adequately-powered studies of initial therapy for 1 NRTI + 1 INSTI regimens, efficacy of these regimens is inferred from other clinical trials. IAS does acknowledge the promising PADDLE trial results, but considers the trial to be too small to make a formal recommendation of 1 NRTI + 1 INSTI regimens for treatment-naïve patients[1]. IAS recommends DTG over RAL among INSTI drugs, as DTG has been found to be noninferior to RAL in treatment-naïve patients, whereas it was found to be superior to RAL in treatment-experienced patients.

Treatment-experienced Patients

DHHS: In virally suppressed patients, the DHHS discusses the promising results of the PADDLE study, and states that there is currently a clinical trial underway testing the possibility of this type of regimen, specifically with 3TC + DTG, for use as a maintenance regimen in virally suppressed patients who have no NRTI, INSTI, or PI resistance. In cases of confirmed virologic failure, the DHHS recommends that patients be put on a regimen with at least two to three active drugs and does not discuss a regimen of 1 INSTI + 1 NRTI in the guidelines.

IAS: The IAS does not specifically recommend this regimen for treatment-experienced patients in cases of confirmed virologic failure. However, in virally suppressed patients, they recommend considering switching patients on older regimens to a variety of simplified regimens (i.e. from use of old NRTIs as they have long-term toxic effects, or older PIs that have higher pill burdens and are more metabolically toxic), but do not specifically recommend any 2 drug regimens.

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 INSTI-based and NNRTI-based regimens are recommended for initial treatment.

IAS: This type of regimen is not discussed in the IAS guidelines. However, both INSTI-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

NNRTI           

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

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

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[2].
  • 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

TDF

  • 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

TAF

  • Equivalent efficacy to TDF, with improved side effect profile and less impact on kidney function and on bone loss [3]
  • Should not be used in patients with CrCl<30

ABC

  • 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

Regimen

Population

Result

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 wel- 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 [4].

PADDLE

3TC+DTG (1 arm)

20 tx-naive

At week 48, 90% (18 of 20) achieved viral suppression. The combination was well tolerated through week 48, and all adverse events were reported in the first week of therapy [1].

ANRS 167 LAMIDOL

DTG+3TC

104 tx-experienced

101/104 (97%) of patients who switched from triple ART to DTG+3TC maintained therapeutic success through 40 weeks of dual therapy [unpublished; Joly V, et al CROI 2017 Abstract 458][5]   

 

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