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1 INSTI 1 PI

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

 

Overview

1 PI + 1 INSTI regimens have several possible combinations and may be considered in patients who need an NRTI-sparing regimen for both treatment-naïve patients and 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. While some data has suggested that 1PI+1INSTI is inferior to regimens containing 2NRTI+1PI (particularly with high viral load), these studies were generally done with RAL (an earlier generation INSTI with lower barrier to resistance) as the INSTI. Within HIVASSIST, we generally prioritized DRV/boosted +DTG as the favored combination of INSTI + PI based on the high barrier to resistance and available scientific evidence.

 

 

Note: DRV/c was found to be bioequivalent to DRV/r in healthy volunteers. Based on the results of the study, efficacy of DRV/c has been extrapolated from DRV/r data. Therefore, many experts may consider use of DRV/c despite the limited supporting data from clinical trials due to the reduced pill burden. Use of DRV/c is discussed in both the DHHS and IAS-USA guidelines for use in treatment-naïve and treatment-experienced patients. Cobicistat inhibits active tubular secretion of creatinine, which can increase serum creatinine without an effect on renal glomerular function. 

 

 

Recommendations in treatment-naïve patients

DHHS (Dec 2019): 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[1]

 

IAS-USA (2018): 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.

 

HIVASSIST: Regimens containing 1 INSTI 1 PI are generally ranked below regimens with 2NRTI+ 1 INSTI, as well as below those with 2 NRTI+ 1 PI, both of which have more clinical trial data to support their usage in treatment naïve patients.

 

Recommendations in treatment-experienced patients

DHHS (Dec 2019): 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. DHHS also mentions the use of boosted DRV with DTG is “only recommended if there are no other alternative options”. 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[2, 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-USA (2018): The IAS does not specifically recommend any regimens for treatment-experienced patients in cases of both virologic failure and suppression. However, IAS does recommend a regimen of 1 PI + 1 INSTI as an alternative regimen for treatment experienced patients.

 

HIVASSIST: We considered the available evidence and guidelines regarding dual therapy with INSTIs (e.g., DTG/RPV, DTG/3TC) to suggest that a regimen containing a fully active INSTI+ PI is likely to be effective at maintaining virologic suppression, but considered the strength of evidence to be less than that of other INSTI dual therapy regimens (in the setting of no treatment failure or resistance).  There is emerging data on the usage of this strategy in heavily treatment experienced patients for maintainence of suppression, particularly after multi-class resistance and prioritized this combination (with or without additional agents) in such settings.[4-8]. We prioritized the combination of INSTI+PI[9-11] following NNRTI failure based on available clinical trial data and DHHS recommendations. Similarly based on the DHHS guidelines we prioritized regimens containing 1 INSTI+1 PI following virologic failure with INSTI based regimens (note DTG is dosed BID in most such situations), though the guidelines acknowledge there is a lack of clinical trial data to guide selection in individuals who have failed INSTI anchored regimens. 

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 above these regimens. Greatest priority is given to DRV/r + DTG or DRV/c + DTG.

AZT

  • Association with insulin resistance
  • Bone marrow suppression can be seen with long term use
  • GI intolerance is seen more often than with other NRTIs
  • High-level resistance with multiple TAMs leads to broad NRTI cross-resistance 

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

  • 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
  • Use caution in women of childbearing age, based on limited reports of neural tube defects. DHHS recommends documenting negative pregnancy test prior to initiation[19].

Efficacy in Clinical Trials

Treatment Naïve Patients

Trial

Regimen

Population

Result

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)[12]

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 [2]

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 [13]

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)[14]

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[14]

 

Trial

Regimen

Population

Result

DUALIS

bDRV+DTG vs bDRV +2NRTI

263 tx-experienced,

Suppressed

Randomized, open label study of 263 patients with viral suppression on booster DRV+ 2NRTI. Fifty percent of patients were randomized to receive boosted DRV + DTG, 50% were randomized to continue boosted DRV + 2 NRTI therapy. At week 48, 86.3% (n=113/131) switching to two-drug therapy and 87.9% (n=116/132) continuing 3-drug therapy had HIV-RNA < 50cps/mL [4]

Tivista

DRV/r+DTG (1 arm)

113 tx-experienced,

65 suppressed,

49 detectable

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. 83% had NRTI mutations, 81% had PI mutations, and 11% had INSTI mutations. [15]

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].

SELECT

LPV/r+RAL vs LPV/r+2 or 3 NRTI

515 tx experienced

Patients viremic on NNRTI based regimen randomized to the two arms and followed at 24 and 48 weeks.  By 48 weeks, probability of failure was 10.3% in RAL+LPV/r arm vs 12.4% in the NRTI+PI arm, indicating non-inferiority but not superiority.[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[16]

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 [3]

N/A

DRV/r or c plus DTG

60 tx experienced

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.[5]

N/A

DRV/c+DTG

31 tx-experienced

Retrospective study. Among 13 patients who switched to DRV/c+DTG owing to treatment failure, the proportion of patients in whom the viral loads were suppressed to less than 50 copies/mL increased from 0% at baseline to 45% at 4 weeks, 50% at 12 weeks, 50% at 24 weeks, and 66.7% at 48 weeks. In non-treatment failure patients (18 patients), the levels of viral suppression and CD4+ T cells were maintained[17]

N/A

DRV/r+DTG

130 tx experienced

In an observational cohort at eight centers in Italy, 130 subjects were followed for median of 56 months on DRV/r+DTG.  Most were switched to this regimen for simplification (44.6%) or toxicity (16.9%), and at baseline, 118 subjects had documented resistance to 1 to 5 antiretroviral classes. At 56 weeks, Those with undetectable viral load increased from 38.5% to 76.2%[6]

NA

DRV/r+DTG

76 tx experienced

30 failing

Retrospective analysis at 4 Polish treatment centers with 48 week results.  Therapy was discontinued in 6 patients.  6 patients with detectable viremia, of which only 1 had Vl>200 copies.  Total cholesterol increased compared to prior to switch; there was no change in lipid parameters when comparing those not previously on TDF regimens.  Proteinuria declined from 13 to 7%.[8]

NA

DRV/b+DTG

50 Tx suppressed

50 patients on stable ART and undetectable for 6 months, irrespective of prior VF were switched to DTG+DRV/b.  93% had baseline NRTI RAMS, 72% with NNRTI RAMS, 27% with PI RAMS, 16% with DRV RAMS, and no one had INSTI RAMS.  After 25 months 49/50 (98%) maintained Vl <50. Total cholesterol and LDL increased 9mg/dl, CD4 remained stable[7]

Darunavir Outcomes Study

DRV+other ARV

108 Tx experienced

Prospective cohort study of 3 class ARV experienced patients after 2006 in whom DRV was used.  Mean prior exposure to 10.5 ARVs. 64% achieved 48 week Vl<400.  Those with DRV/r+RAL were more likely to achieve 48 week Vl<400 among highly treatment experienced patients (80%)[18]

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2. 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 clinical trials 2012; 13(3):119-130 PMID 22592092 https://doi.org/10.1310/hct1303-119

3. 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):538-543.PMC4804741  PMID 26605505 https://doi.org/10.1097/QAI.0000000000000904

4. Spinner C. KT, Schneider J., Cordes C., Heiken H., Stellbrink H., et al. A switch to dolutegravir in combination with boosted darunavir is safe and effective in

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5. Hawkins KL, Montague BT, Rowan SE, Beum R, McLees MP, Johnson S, et al. Boosted darunavir and dolutegravir dual therapy among a cohort of highly treatment-experienced individuals. Antivir Ther 2019; 24(7):513-519 PMID 31538963 https://doi.org/10.3851/IMP3330

6. Capetti AF, Sterrantino G, Cossu MV, Orofino G, Barbarini G, De Socio GV, et al. Switch to Dolutegravir plus Rilpivirine Dual Therapy in cART-Experienced Subjects: An Observational Cohort. PLoS One 2016; 11(10):e0164753.PMC5065232  PMID 27741309 https://doi.org/10.1371/journal.pone.0164753

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8. Jablonowska E, Siwak E, Bociaga-Jasik M, Gasiorowski J, Kalinowska A, Firlag Burkacka E, et al. Real-life study of dual therapy based on dolutegravir and ritonavir-boosted darunavir in HIV-1-infected treatment-experienced patients. PLoS One 2019; 14(1):e0210476.PMC6336297  PMID 30653541 https://doi.org/10.1371/journal.pone.0210476

9. Group S-LS, Boyd MA, Kumarasamy N, Moore CL, Nwizu C, Losso MH, 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):2091-2099 PMID 23769235 https://doi.org/10.1016/S0140-6736(13)61164-2

10. Paton NI, Kityo C, Hoppe A, Reid A, Kambugu A, Lugemwa A, et al. Assessment of second-line antiretroviral regimens for HIV therapy in Africa. N Engl J Med 2014; 371(3):234-247 PMID 25014688 https://doi.org/10.1056/NEJMoa1311274

11. La Rosa AM, Harrison LJ, Taiwo B, Wallis CL, Zheng L, Kim P, et al. Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, non-inferiority study. The lancet HIV 2016; 3(6):e247-258.PMC4914044  PMID 27240787 https://doi.org/10.1016/S2352-3018(16)30011-X

12. Reynes J, Lawal A, Pulido F, Soto-Malave R, Gathe J, Tian M, et al. Examination of noninferiority, safety, and tolerability of lopinavir/ritonavir and raltegravir compared with lopinavir/ritonavir and tenofovir/ emtricitabine in antiretroviral-naive subjects: the progress study, 48-week results. HIV clinical trials 2011; 12(5):255-267 PMID 22180523 https://doi.org/10.1310/hct1205-255

13. Taiwo B, Zheng L, Gallien S, Matining RM, Kuritzkes DR, Wilson CC, et al. Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naive HIV-1-infected patients (ACTG A5262). Aids 2011; 25(17):2113-2122.PMC3515052  PMID 21857490 https://doi.org/10.1097/QAD.0b013e32834bbaa9

14. 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.PMC4149560  PMID 25170938 https://doi.org/10.1371/journal.pone.0106221

15. Capetti AF, Sterrantino G, Cossu MV, Cenderello G, Cattelan AM, De Socio GV, et al. Salvage therapy or simplification of salvage regimens with dolutegravir plus ritonavir-boosted darunavir dual therapy in highly cART-experienced subjects: an Italian cohort. Antivir Ther 2017; 22(3):257-262 PMID 27661787 https://doi.org/10.3851/IMP3095

16. 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):1196-1206.PMC3448110  PMID 22364141 https://doi.org/10.1089/AID.2011.0336

17. Lee SA, Kim SW, Chang HH, Jung H, Kim Y, Hwang S, et al. Effectiveness, Safety, and Tolerability of a Switch to Dual Therapy with Dolutegravir Plus Cobicistat-Boosted Darunavir in Treatment-Experienced Patients with Human Immunodeficiency Virus. Infect Chemother 2018; 50(3):252-262.PMC6167504  PMID 30270584 https://doi.org/10.3947/ic.2018.50.3.252

18. Willig JH, Aban I, Nevin CR, Ye J, Raper JL, McKinnel JA, et al. Darunavir outcomes study: comparative effectiveness of virologic suppression, regimen durability, and discontinuation reasons for three-class experienced patients at 48 weeks. AIDS Res Hum Retroviruses 2010; 26(12):1279-1285.PMC3011996  PMID 20961276 https://doi.org/10.1089/aid.2010.0059

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