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1 INSTI 1 PI 1 NRTI

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

Overview

1 NRTI + 1 INSTI + 1 PI 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, use of a similar regimen has been studied as a simplification strategy in virally suppressed patients with multiclass drug resistance without INSTI resistance[1].

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

Treatment-Naïve Patients

DHHS: This type of regimen is not discussed for treatment-naïve patients in the guidelines. However, various combinations of 1 INSTI + 2 NRTIs are recommended as the initial regimen for most people with HIV, and 1 boosted PI + 2 NRTIs are recommended as the initial regimen in certain clinical situations.

IAS: This type of regimen is not discussed by the IAS for treatment-naïve patients. However, both 2 NRTIs + 1 INSTI and 2 NSTIs + 1 boosted PI regimens are recommended initial regimens and regimens of 1 PI + 1 INSTI (specifically DRV/r + RAL). 

Treatment-Experienced Patients

DHHS: The DHHS does not specifically discuss this type of regimen for treatment-experienced patients in cases of virologic failure or suppression. However, a similar drug regimen, DRV + EVG/c/TAF/FTC, is discussed as a simplification strategy for virally suppressed patients who have resistance to at least 2 ARV drug classes without INSTI resistance, given promising results[1]. The DHHS states that the regimen has potential to be a good option for simplification of patients who have complicated rescue regimens, but that there is not enough evidence to support the regimen beyond special circumstances without an additional clinical trial.

IAS: This type of regimen is not discussed by the IAS for treatment-experienced patients, in cases of both virologic failure or suppression.

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[2].

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[2]. 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 to consider 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 NRTI + 1 PI

Treatment-naïve patients

DHHS: 1 boosted PI + 3TC (1 NRTI) is considered to be a reasonable option when regimens containing TDF, TAF, or ABC are either contraindicated. This type of regimen is thought to be able to achieve virologic suppression in ART-naïve individuals without baseline mutations as well as patients with sustained viral suppression. The DHHS specifically recommends to consider a regimen of LPV/r+3TC as an “other” regimen in cases when TDF, TAF, and ABC cannot be used.

IAS: Initial 2-drug regimens have limitations and are only recommended in cases where they offer cost or toxicity advantages over 3-drug regimens. The IAS mentions that LPV/r + 3TC (lamivudine) was found to be noninferior to LPV/r + 2 NRTIs in one study and can be considered as a possible regimen[3].

Treatment-experienced patients

DHHS: In virally suppressed patients, the DHHS notes that switching to a regimen of a boosted PI plus 3TC can be considered as it has been seen to maintain viral suppression in patients with sustained viral suppression. Specifically, they recommend considering regimens of LPV/r + 3TC and ATV/r + 3TC, and consider a regimen of DRV/r + 3TC to be promising, as there is a recently completed study[4]. In cases of virologic failure, the DHHS does not currently discuss a regimen of a single NRTI with a boosted PI. However, the guidelines recommend considering a regimen of 1 boosted PI with 2 NRTIs.

IAS: The IAS does not specifically recommend any regimens for treatment-experienced patients in cases of both virologic failure or suppression. However, 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 than DRV or ATV).

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[5]. 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[6][7].

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.

Other Considerations

DRV/r

  • 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

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
  • Efficacy is inferred from studies of DRV/r

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. A once daily dose has shown similar efficacy in a recent trial but there is not enough data to recommend this[8][9].
  • 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 [10]
  • 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

Regimens

Participants

Results

 N/A

TAF/FTC/EVG/c+DRV vs baseline regimen

 135 suppressed on DRV, with >=2 class resistance

 At 24 weeks 94% vs 91% in the EVG/c+DRV arm and baseline regimen arms maintained viral suppression, respectively. [1]

N/A

EVG/c + PI/r + 3rd drug vs RAL + PI/r + 3rd drug

(3rd drug usually TDF or another NRTI; PI/r usually DRV/r)

351 tx-experienced

At week 48, 59% of the EVG group maintained viral suppression, while 57.8% of the RAL group maintained viral suppression. At week 96, 47.6% of the EVG group and 45% of the RAL group maintained viral suppression. Lower efficacy of each regimen was seen in patients who did not have previous resistance or baseline mutations. [11]

IV ATLASM

ATV/r+3TC vs ATV/r+2NRTI

266 tx-experienced

90% of patients who switched to ATV/r + 3TC maintained virologic suppression vs. 80% of patients who remained on ATV/r +2NRTI[12].

SALT

ATV/r+3TC vs ATV/r+2NRTI

286 tx-experienced

The dual-treatment regimen was found to be noninferior to the triple-treatment regimen. At week 48, 112 (84%) of the dual-treatment group had virological response versus 105 (78%) in the triple-treatment group. Treatment discontinuations were also less frequent in the dual-treatment group as compared to the triple-treatment group [13].

GARDEL

LPV/r+3TC vs 2NRTI+LPV/r

426 tx-naive

At week 48, 189 patients (88.3%) in the dual-therapy group and 169 (83.7%) in the triple-therapy group had viral suppression[14].

OLE

LPV/r+3TC vs LPV/r+2NRTI

250 tx-experienced

The dual-treatment group was found to be noninferior to the triple-treatment group as 110 (86.6%) of triple-treatment patients responded to treatment versus 108 (87.8%) of dual-treatment patients [3].

 N/A

DRV/r+3TC

94 tx-experienced

In a retrospective analysis of patients with at least six months of virological suppression switched to 3TC plus DRV/r demonstrated continued virological suppression with a favorable safety profile[4]

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 [15].

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)[16]

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[6]

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[17]

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)[18]

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.[5]

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[19].

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[20]

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[21].

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 [2].

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][22]  

 

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