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1 INSTI 1 PI

ARVs: 

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

Overview

1 PI + 1 INSTI regimens have several possible combinations and are recommended for consideration in patients who need an NRTI-sparing regimen for both treatment-naïve patients or as a second-line regimen for treatment-experienced patients. There are several possible combinations; most studied with clinical trial evidence are DRV/r+RAL and LPV/r+RAL. However, many experts’ most commonly preferred regimen is DRV/r or DRV/c + DTG, based on extrapolated data and more recent clinical trial results[1].

Recommendations in treatment-naïve patients

DHHS: Recommended as an “other” regimen for treatment-naïve patients. However in patients for whom ABC, TAF, and TDF cannot be used and whose HIV RNA is <100,000 copies/uL and CD4 cell counts >200 cells/mm3, DRV/r + RAL is suggested as a regimen to consider. 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].

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.

Recommendations in 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.

Other Considerations

There are different considerations depending on the specific drug regimen. Given the poor tolerability of LPV/r, and the BID dosing of RAL, we have prioritized other regimens (for which efficacy is inferred, or supported only by limited experience) above these regimens. Greatest priority is given to DRV/r + DTG or DRV/c + DTG.

DRV/r

  • Must be taken with food
  • High barrier to resistance
  • PI booster (ritonavir) nteracts 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

 

Efficacy in Clinical Trials

Trial

Drugs Compared

Population

Result

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 [1].

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[4]

N/A

DRV/r or c plus DTG

60

Retrospective chart review of 60 patients on DTG/b+DRV followed for median 444 days.  59/60 reached viral suppression at some point. 100% (46) patients with baseline suppression at time of switch maintained, compared to 11/14 (79%) without baseline suppression. ABSTRACT 1766 IDweek 2018.

 

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