1 INSTI 1 PI 2 NRTI

This is a generic educational information sheet for 2 NRTI + 1 INSTI + 1 PI regimens.

Overview

2 NRTI + 1 INSTI + 1 PI regimens are generally regimens of 3-4 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-USA guidelines. However, use of a similar regimen has been studied as a simplification strategy in virally suppressed patients with multiclass drug resistance without INSTI resistance1.

Recommendations in Support of 2 NRTI + 1 INSTI + 1 PI

Treatment-Naïve Patients

DHHS (2019): 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-USA (2018): This type of regimen is not discussed by the IAS-USA 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) are recommended in some instances 

HIV-ASSIST: Within HIV-ASSIST, we assess regimens across several domains including likelihood of achieving virologic suppression (and improved clinical outcomes), and tolerability (e.g., side effects, pill burden, drug interactions, etc).  While not formally studied for treatment naïve patients, we extrapolate the likelihood of achieving virologic suppression (assuming all drugs are active) based on the available data for regimens containing “2NRTI and 1 INSTI” and regimens containing “2 NRTIs and 1 PI”.  Consequently, we consider the likelihood of virologic suppression with this regimen to be comparable to “3 drug” regimens. However, given the lack of data to suggest a benefit to treatment intensification in terms of immunologic, virologic, or clinical outcomes, we ranked this regimen lower for treatment naïve patients and penalized usage of ‘4 active drug’ regimens in suppressed patients2-4.  

Treatment-Experienced Patients

DHHS (2019): The DHHS does not specifically discuss these types of regimens generically for treatment-experienced patients in cases of virologic failure or suppression. However, a 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 results1. 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-USA (2018): This type of regimen is not discussed by the IAS for treatment-experienced patients, in cases of both virologic failure or suppression.

HIV-ASSIST:  HIV-ASSIST assesses regimens with this drug combination on the basis of active drugs in the regimen. As with treatment-naïve patients, HIV-ASSIST penalizes usage of a 4 drug regimen when all 4 drugs are fully active, as there is little evidence for treatment intensification (i.e. more than 3 drugs).  However, this regimen may be considered in the event that there is some underlying resistance conferring partial or full resistance to some of the drug components.  In treatment experienced, viremic patients, DHHS guidelines currently advocate constructing regimens with at least two and potentially three active drugs.  Owing to the fact that the M184V mutation (which confers resistance to 3TC and FTC) can hypersensitize the activity of tenofovir, it is not uncommon for some clinicians to consider inclusion of 3TC or FTC in a treatment regimen (i.e. an NRTI) despite resistance.  Given 3TC and FTC often come coformulated with tenofovir, regimens with 2NRTI + INSTI + PI, often include this combination as the 2 NRTI component. In this scenario, a regimen with 2 NRTI + INSTI +PI typically has between 2 and 3 active drugs.

Overall, we infer and extrapolate the effectiveness of 2NRTI + INSTI + PI, partially from the available data on the component regimens.  Below, we include clinical trial information available for subcomponents of this 4 drug strategy. 

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 this10,15.
  • 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 loss58
  • 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

Usage of 4 drug regimens

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

TREATMENT NAÏVE DTG or BIC (2NRTI + INSTI)

Trial Name

Drugs Compared

Participants

Study Results

SINGLE

ABC/3TC/DTG vs. TDF/FTC/EFV

833 tx-naive

At week 48, the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter was significantly higher in the ABC/3TC/DTG group than in the TDF/FTC/EVF group (88% vs. 81%).  Was due primarily to discontinuations because of adverse events (2% in the ABC/3TC/DTG group and 10% in the TDF/FTC/EVF group). At week 144, ABC/3TC/DTG remained superior (71% vs 63% viral suppression).5,6

FLAMINGO

2 NRTIs plus DRV/r or DTG

484 tx-naive

At 48 weeks, DTG outperformed DRV/r (viral suppression 90% vs 83%, respectively). Discontinuation due to adverse effects was higher in the DRV/r group than the DTG group (2% vs 4%, respectively), which contributed to the difference in the response rate. DTG continued to outperform DRV/r at 96 weeks (viral suppression 80% vs 66%)7,8

SPRING-2

2 NRTIs plus DTG or RAL

822 tx-naive

At 48 and 96 weeks, once-daily DTG was non-inferior to twice-daily RAL (88% vs 85% viral suppression at 48 weeks, and 81% vs 76% at 96 weeks), with a similar safety profile9,10

ARIA

ABC/3TC/DTG vs. TDF/FTC+ATV/r

495 tx-naive women

At 48 weeks, ABC/3TC/DTG was superior in terms of virologic suppression (82% vs 71%). There were fewer virological nonresponses and fewer discontinuations due to adverse events in the ABC/3TC/DTG arm11 

Trial 1490

TAF/FTC/BIC vs. TAF/FTC/DTG

657 tx-naive

At week 96, HIV-1 RNA less than 50 copies per mL was achieved by 269 (84%) of 320 participants in the bictegravir group and 281 (86%) of 325 in the dolutegravir group (difference -2·3%, 95% CI -7·9 to 3·2), demonstrating non-inferiority of the bictegravir regimen compared with the dolutegravir regimen.12

Trial 1489

TAF/FTC/BIC vs. ABC/3TC/DTG

631 tx-naive

At week 96, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to dolutegravir, abacavir, and lamivudine, with 276 (88%) of 314 participants in the bictegravir group versus 283 (90%) of 315 participants in the dolutegravir group achieving HIV-1 RNA less than 50 copies per mL (difference -1·9%; 95% CI -6·9 to 3·1).13

TREATMENT EXPERIENCED DTG or BIC (2NRTI + INSTI)

Trial Name

Drugs Compared

Participants

Study Results

NEAT022

PI/r anchor regimen vs DTGanchor regimen (+2NRTI)

415 Tx experienced, suppressed, w Framingham >10%

89% were men, 87% >50 years, 74% with Framingham score more than 10%, with a median CD4 cell count of 617 cells per μl and suppressed viremia for a median of 5 years. 

At week 48, treatment success 93.1% in DTG group and 95.2% in PI/r group (noninferiority demonstrated). There were four virological failures with DTG and one with PI/r with no emergent resistance mutations. Total cholesterol and other lipid fractions (except high-density lipoprotein cholesterol) improved significantly (P < 0.001) in the DTG group regardless of PI/r at baseline.14

SAILING

2 NRTIS + DTG or RAL

715 tx-experienced

 At week 48, 71% of patients on the DTG-based regimen were virally suppressed as comparted to 64% of patients on the RAL-based regimen. Fewer patients experienced virological failure in the DTG group. DTG, taken once daily, was well-tolerated and more effective than twice daily RAL15

STRIIVING

ABC/DTG/3TC vs current ART

553 tx-experienced

At week 24, switching to ABC/DTG/3TC from current ART regimen was found to be noninferior to remaining on current ART (85% switched vs 88% remained virally suppressed). At week 48, 83% of the early-switch group remained virologically suppressed, while 92% of the late-switch group were virally suppressed. ABC/DTG/3TC found to be noninferior to continuing current ART and should be considered as an option when switching virally suppressed patients16

NA

BIC/TAF/FTC vs DTG/ABC/3TC

563 Tx experienced, suppressed

At 48 weeks, switching to BIC regimen was non-inferior to remaining on DTG/ABC/3TC: three (1%) of 282 in the bictegravir group had HIV-1 RNA of 50 copies per mL or higher at week 48 versus one (<1%) of 281 participants in the dolutegravir group (difference 0·7%, 95·002% CI -1·0 to 2·8; p=0·62).17

NA

BIC/TAF/FTC vs current ART

472 Tx experienced, suppressed women

Switching to BIC regimen was non inferior to continuing current ART, 1.7% vs 1.7% experienced HIV RNA >50 copies at week 48, and no individual developed treatment emergent resistance18. 

NA

BIC/TAF/FTC vs PI/b regimens

577 Tx experienced, GFR>50, suppressed

At 48 weeks 2% in BIC and 2% in PI/b had Vl>50 (non-inferior). 1% and <1% in the respective groups discontinued treatment because of adverse events. Incidence of adverse events was similar in both arms, though headache was more common w BIC19

ART-PRO

DTG/3TC single arm

41 Tx suppressed patients

Participants excluded if there were 3TC resistance mutations at baseline proviral genotyping.  Suppressed patients  were switched to DTG/3TC and followed. To assess minority variants, proviral next gen sequencing was done. 71% of individuals had M184V or K65R over a 5% threshold. Suppression was maintained in all individuals, despite historical 3TC resistance and detection of archived 3TC resistance on next gen sequencing.20  

NA

ABC/3TC/DTG

154 Tx suppressed on PI/b switched to ABC/3TC/DTG and had M184V

Observational study of 154 patients who were switched and followed. During 12 mo of f/u 3 patients had Blips (under 200 copies, followed by suppression). No patient experienced virological failure21. 

NA

ABC/3TC/DTG; M184V

1626 observational study of treatment suppressed

Analysis of impact of M184V on VF.  137 had M184V/I documented.  VF was 29.8/1000 person-years among those with M184V vs. 13.6/1000 without M184V. Propensity score weighting suggested M184V/I was not assocted with VF or composite endpoint (HR 1.27, 0.35-4.59). Median follow up was 288.5.  Longer term data is likely needed; VF was relatively uncommon, but in this short f/u was not associated VF22.

NA, ARCA group

DTG+2NRTI

588 Tx suppressed switching to DTG+2NRTI

588 with a median 37 mo of viral suppression, of whom 148 (25.2%) had at least one previous NRTIs resistance mutation. In the multivariable model no association was observed between NRTIs mutations and VF. Duration of  suppression before switch resulted associated with a lower risk of VF (for 1 month increase, adjusted Hazard Ratio 0.98, 95%CI 0.96-0.99; p=0.024). Previous NRTIs mutations appeared to have no impact on the risk of VF in patients switched to DTG+2NRTIs, whereas a longer interval on a controlled viremia decreased significantly the risk of VF23.

Study 1878 and 1844 subanalysis

BIC/TAF/FTC

543 with historical or proviral genotypes

40% (217/543) had >=1 pre-existing primary resistance in protease, reverse transcriptase and/or integrase. Pre-switch NRTI resistance in 16% (89/543) of BIC/FTC/TAF-treated participants, with M184V or M184I detected by proviral genotyping in 10% (54/543). At week 48, 98% (561/570) BIC/FTC/TAF-treated participants versus 98% (213/217) with pre-existing resistance and 96% (52/54) with archived M184V/I had HIV-1 RNA <50 copies/mL. No BIC/FTC/TAF-treated participants developed treatment-emergent resistance to study drugs.24

DAWNING

DTG+2NRTI vs LPV/r+2NRTI post NNRTI failure

627 Tx experienced, failing NNRTI

At week 48, 261 (84%) of 312 in DTG arm compared to 219 (70%) in LPV achieved suppression (superior) (p<0·0001).25

2NRTI + PI, TREATMENT NAÏVE (not all are listed, and focus is on DRV regimens. BOLDED studies were particularly important to ranking of 2NRTI+PI relative to NNRTI and INSTI regimens)

Trial Name

Drugs Compared

Participants

Study Results

N/A

2 NRTIs + DRV/c (single arm)

313, 95% tx-naive

At week 48, 81% achieved viral suppression, while 5% discontinued treatment because of adverse events 26

Study 115

DRV/c vs. DRV/r

62 tx-naive

DRV/c is bioequivalent to DRV/r in healthy volunteers27

N/A

ABC/3TC+DRV/r (single arm)

67, 48% tx-naive

At 48 weeks, 79% achieved viral suppression28

ARTEMIS

TDF/FTC plus DRV/r or LPV/r 

689 tx-naive

At 92 weeks, DRV/r was superior to LPV/r with respect to virological response. Among participants with baseline HIV RNA levels >100,000 copies/mL, virologic response rates were lower in the LPV/r arm than in the DRV/r arm 29,30

FLAMINGO

2 NRTIs plus DRV/r or DTG

488 tx-naive

At week 96, virologic suppression was significantly greater among those who received DTG. The excess failure observed in the DRV/r group was related to a higher rate of virologic failure among those with a viral load >100,000 copies/mL and more drug discontinuations in the DRV/r group7

ACTG A5257

ATV/r vs DTV/r vs RAL + TDF/FTC

1809 tx-naive

At 96 weeks, RAL and DRV/r were found to be equally tolerable, while ATV/r was found to be less tolerable, leading to more discontinuation by patients on ATV/r-based regimens. RAL was superior to both PIs in combined virologic efficacy and tolerability, while DRV/r was superior to ATV/r. RAL has a more favorable lipid profile (lower increases in total cholesterol, triglycerides, and LDLc)  as compared to ATV/r and DRV/r, but the long-term clinical significance of the results need to be further evaluated31,32

ACTG 5202

2 NRTIs plus EFV or ATV/r

463 tx-naive patients

EFV was comparable to ATV/r with respect to virological response when each was given with either TDF/FTC or ABC/3TC33 

DRIVE-FORWARD

DOR vs DRV/r+2NRTI

769 Tx Naïve

 At week 96, a higher proportion of the doravirine group (277 [73%] of 383) achieved an HIV-1 RNA concentration of less than 50 copies per mL than did of the darunavir group (248 [66%] of 383; difference 7·1%, 95% CI 0·5-13·7). Responses were similar regardless of baseline characteristics. Treatment-emergent resistance to any study drug occurred in two (1%) of 383 participants in the doravirine group and one (<1%) of 383 in the ritonavir-boosted darunavir group. Significant differences were seen between treatment groups in mean changes from baseline in LDL cholesterol (-14·6 mg/dL, 95% CI -18·2 to -11·0) and non-HDL cholesterol (-18·4 mg/dL, -22·5 to -14·3).34

Comparison with INSTI+PI

PROGRESS

TDF/FTC + LPV/r vs LPV/r + RAL

206 tx-naive

The LPV/r + RAL regimen was found to be noninferior to the regimen of LPV/r + TDF/FTC in both safety and efficacy. Viral suppression at 48 weeks 83% in RAL group vs 85% in TDF/FTC+LPV/r group35

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 development36

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>100,00037

RADAR

DRV/r+ RAL vs TDF/FTC+DRV/r

68 tx-naive

DRV/r+RAL was less effective than DRV/r+TDF/FTC (62.5% of RAL subjects and 83.7% of TDF/FTC subjects were responders (VL<48 copies/mL) at week 48) but better for bone health. However, the proportions of patients achieving VL<200 copies/mL were similar: 72.5% and 86.0%38

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<200.39

2 NRTI + PI TREATMENT EXPERIENCED PATIENTS:

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 suppressed40

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 suppression41 

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.42  

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 43

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/FTC44 

DAWNING

DTG+2NRTI vs LPV/r+2NRTI post NNRTI failure

627 Tx experienced, failing NNRTI

At week 48, 261 (84%) of 312 in DTG arm compared to 219 (70%) in LPV achieved suppression (superior) (p<0·0001).25

TITAN

LPV/r + 2 NRTIs vs DRV/r + 2 NRTIs

595 tx-experienced

At 96 weeks, a greater number of DRV/r patients were virologically suppressed, showing that DRV/r is noninferior to LPV/r. Response to DRV/r was found to be 60.4%, as opposed to 55.2% in LPV/r patients. Virological failure with DRV/r was 13.8%, nearly half of that of LPV/r, which was 25.6%. There were similar rates of discontinuation due to adverse events with both regimens. There was less diarrhea with patients on DRV/r as well as an improved lipid profile, as compared to LPV/r45

Review

2NRTI+PI

Participants of RCTS experiencing VF after PI+2 NRTI

Of 209 participants, only 1 participant had major PI-associated treatment-emergent mutations at first-line VF. The most common treatment approach after VF (66%) was to continue the same regimen. The virologic suppression rate 24 weeks after VF was 64% for these participants, compared with 72% for those who changed regimens (P = .19).46 

POWER 1,2

DRV BID/r+OBR vs Control PI/b_+OBR

155 Tx experienced with PI mutation

At week 48, 67 of 110 (61%) darunavir-ritonavir patients compared with 18 of 120 (15%) of control PI patients had viral load reductions of 1 log10 copies per mL or greater from baseline (primary endpoint; difference in response rates 46%, 95% CI 35%-57%, p<0.0001). 56% vs 46% vs 26% suppressed using DRV (1,2, 3+ mutations), compared to 17%,7%, 3% using other PI (for 1,2,3+mutations respectively).47,48

NEAT022

PI/r anchor regimen vs DTG anchor regimen (+2NRTI)

415 Tx experienced, suppressed, w Framingham >10%

89% were men, 87% >50 years, 74% with Framingham score more than 10%, with a median CD4 cell count of 617 cells per μl and suppressed viremia for a median of 5 years. 

At week 48, treatment success 93.1% in DTG group and 95.2% in PI/r group (noninferiority demonstrated). There were four virological failures with DTG and one with PI/r with no emergent resistance mutations. Total cholesterol and other lipid fractions (except high-density lipoprotein cholesterol) improved significantly (P < 0.001) in the DTG group regardless of PI/r at baseline14.

NA

BIC/TAF/FTC vs PI/b regimens

577 Tx experienced, GFR>50, suppressed

At 48 weeks 2% in BIC and 2% in PI/b had Vl>50 (non-inferior). 1% and <1% in the respective groups discontinued treatment because of adverse events. Incidence of adverse events was similar in both arms, though headache was more common w BIC19

NA

RPV/FTC/TDF vs PI/b+2NRTI

476 Tx suppressed on PI

Noninferiority at week 24: HIV-1 RNA <50 copies/ml, 93.7% of RPV/FTC/TDF versus 89.9% of PI/r +two NRTIs (difference 3.8%,). At week 48, 89.3% of switch group maintained virologic suppression. High rates of suppression were maintained with RPV/FTC/TDF regardless of participant's pre-antiretroviral HIV-1 RNA level. Overall development of resistance mutations after switching to RPV/FTC/TDF was low. Decreases in total cholesterol, low-density lipoprotein (LDL), and triglycerides were significantly greater among RPV/FTC/TDF recipients than those in the protease inhibitor+RTV+ two NRTIs group.49

INSTI +PI 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)35

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 36

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 37

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)38

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 <20038

INSTI + PI (Treatment Experienced)

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 50

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. 51

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 suppressed40 

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 suppression41.

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.42  

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 patients43

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 44

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.52

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 maintained53

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%54

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%.55

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 stable56

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%)57

1.         Huhn GD, Tebas P, Gallant J, et al. A Randomized, Open-Label Trial to Evaluate Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Plus Darunavir in Treatment-Experienced HIV-1-Infected Adults. J Acquir Immune Defic Syndr. 2017;74(2):193-200.

2.         Joly V, Fagard C, Grondin C, et al. Intensification of antiretroviral therapy through addition of enfuvirtide in naive HIV-1-infected patients with severe immunosuppression does not improve immunological response: results of a randomized multicenter trial (ANRS 130 Apollo). Antimicrob Agents Chemother. 2013;57(2):758-765.

3.         Dinoso JB, Kim SY, Wiegand AM, et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 2009;106(23):9403-9408.

4.         Yilmaz A, Verhofstede C, D'Avolio A, et al. Treatment intensification has no effect on the HIV-1 central nervous system infection in patients on suppressive antiretroviral therapy. J Acquir Immune Defic Syndr. 2010;55(5):590-596.

5.         Walmsley S, Baumgarten A, Berenguer J, et al. Brief Report: Dolutegravir Plus Abacavir/Lamivudine for the Treatment of HIV-1 Infection in Antiretroviral Therapy-Naive Patients: Week 96 and Week 144 Results From the SINGLE Randomized Clinical Trial. J Acquir Immune Defic Syndr. 2015;70(5):515-519.

6.         Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013;369(19):1807-1818.

7.         Molina JM, Clotet B, van Lunzen J, et al. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study. The lancet HIV. 2015;2(4):e127-136.

8.         Clotet B, Feinberg J, van Lunzen J, et al. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet. 2014;383(9936):2222-2231.

9.         Raffi F, Rachlis A, Stellbrink HJ, et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet. 2013;381(9868):735-743.

10.       Raffi F, Jaeger H, Quiros-Roldan E, et al. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2013;13(11):927-935.

11.       Orrell C, Hagins DP, Belonosova E, et al. Fixed-dose combination dolutegravir, abacavir, and lamivudine versus ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate and emtricitabine in previously untreated women with HIV-1 infection (ARIA): week 48 results from a randomised, open-label, non-inferiority, phase 3b study. The lancet HIV. 2017;4(12):e536-e546.

12.       Stellbrink HJ, Arribas JR, Stephens JL, et al. Co-formulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial. The lancet HIV. 2019;6(6):e364-e372.

13.       Wohl DA, Yazdanpanah Y, Baumgarten A, et al. Bictegravir combined with emtricitabine and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial. The lancet HIV. 2019;6(6):e355-e363.

14.       Gatell JM, Assoumou L, Moyle G, et al. Switching from a ritonavir-boosted protease inhibitor to a dolutegravir-based regimen for maintenance of HIV viral suppression in patients with high cardiovascular risk. Aids. 2017;31(18):2503-2514.

15.       Cahn P, Pozniak AL, Mingrone H, et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet. 2013;382(9893):700-708.

16.       Trottier B, Lake JE, Logue K, et al. Dolutegravir/abacavir/lamivudine versus current ART in virally suppressed patients (STRIIVING): a 48-week, randomized, non-inferiority, open-label, Phase IIIb study. Antivir Ther. 2017;22(4):295-305.

17.       Molina JM, Ward D, Brar I, et al. Switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir plus abacavir and lamivudine in virologically suppressed adults with HIV-1: 48 week results of a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. The lancet HIV. 2018;5(7):e357-e365.

18.       Kityo C, Hagins D, Koenig E, et al. Switching to Fixed-Dose Bictegravir, Emtricitabine, and Tenofovir Alafenamide (B/F/TAF) in Virologically Suppressed HIV-1 Infected Women: A Randomized, Open-Label, Multicenter, Active-Controlled, Phase 3, Noninferiority Trial. J Acquir Immune Defic Syndr. 2019;82(3):321-328.

19.       Daar ES, DeJesus E, Ruane P, et al. Efficacy and safety of switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from boosted protease inhibitor-based regimens in virologically suppressed adults with HIV-1: 48 week results of a randomised, open-label, multicentre, phase 3, non-inferiority trial. The lancet HIV. 2018;5(7):e347-e356.

20.       De Miguel R, Rial-Crestelo D, Dominguez-Dominguez L, et al. Dolutegravir plus lamivudine for maintenance of HIV viral suppression in adults with and without historical resistance to lamivudine: 48-week results of a non-randomized, pilot clinical trial (ART-PRO). EBioMedicine. 2020;55:102779.

21.       Jary A, Marcelin AG, Charpentier C, et al. M184V/I does not impact the efficacy of abacavir/lamivudine/dolutegravir use as switch therapy in virologically suppressed patients. J Antimicrob Chemother. 2020;75(5):1290-1293.

22.       Olearo F, Nguyen H, Bonnet F, et al. Impact of the M184V/I Mutation on the Efficacy of Abacavir/Lamivudine/Dolutegravir Therapy in HIV Treatment-Experienced Patients. Open forum infectious diseases. 2019;6(10):ofz330.

23.       Giacomelli A, Lai A, Franzetti M, et al. No impact of previous NRTIs resistance in HIV positive patients switched to DTG+2NRTIs under virological control: Time of viral suppression makes the difference. Antiviral research. 2019;172:104635.

24.       Andreatta K, Willkom M, Martin R, et al. Switching to bictegravir/emtricitabine/tenofovir alafenamide maintained HIV-1 RNA suppression in participants with archived antiretroviral resistance including M184V/I. J Antimicrob Chemother. 2019;74(12):3555-3564.

25.       Aboud M, Kaplan R, Lombaard J, et al. Dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with HIV-1 infection in whom first-line therapy has failed (DAWNING): an open-label, non-inferiority, phase 3b trial. Lancet Infect Dis. 2019;19(3):253-264.

26.       Tashima K, Crofoot G, Tomaka FL, et al. Phase IIIb, open-label single-arm trial of darunavir/cobicistat (DRV/COBI): Week 48 subgroup analysis of HIV-1-infected treatment-nave adults. J Int AIDS Soc. 2014;17(4 Suppl 3):19772.

27.       Gilead. Package Insert. 2017. http://www.gilead.com/~/media/Files/pdfs/medicines/hiv/tybost/tybost_pi.pdf  ;

https://www.prezcobix.com/sites/www.prezcobix.com/files/prescribing-information-prezcobix.pdf.

28.       Trottier B, Machouf N, Thomas R, et al. Abacavir/lamivudine fixed-dose combination with ritonavir-boosted darunavir: a safe and efficacious regimen for HIV therapy. HIV clinical trials. 2012;13(6):335-342.

29.       Orkin C, DeJesus E, Khanlou H, et al. Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naive patients in the ARTEMIS trial. HIV Med. 2013;14(1):49-59.

30.       Lathouwers E, De Meyer S, Dierynck I, et al. Virological characterization of patients failing darunavir/ritonavir or lopinavir/ritonavir treatment in the ARTEMIS study: 96-week analysis. Antivir Ther. 2011;16(1):99-108.

31.       Lennox JL, Landovitz RJ, Ribaudo HJ, et al. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med. 2014;161(7):461-471.

32.       Ofotokun I, Na LH, Landovitz RJ, et al. Comparison of the metabolic effects of ritonavir-boosted darunavir or atazanavir versus raltegravir, and the impact of ritonavir plasma exposure: ACTG 5257. Clin Infect Dis. 2015;60(12):1842-1851.

33.       Daar ES, Tierney C, Fischl MA, et al. Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1. Ann Intern Med. 2011;154(7):445-456.

34.       Molina JM, Squires K, Sax PE, et al. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 96-week results of a randomised, double-blind, non-inferiority, phase 3 trial. The lancet HIV. 2020;7(1):e16-e26.

35.       Reynes J, Lawal A, Pulido F, 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.

36.       Kozal MJ, Lupo S, DeJesus E, 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.

37.       Taiwo B, Zheng L, Gallien S, 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.

38.       Bedimo RJ, Drechsler H, Jain M, 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.

39.       Raffi F, Babiker AG, Richert L, et al. Ritonavir-boosted darunavir combined with raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults infected with HIV-1: 96 week results from the NEAT001/ANRS143 randomised non-inferiority trial. Lancet. 2014;384(9958):1942-1951.

40.       Group S-LS, Boyd MA, Kumarasamy N, 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.

41.       Paton NI, Kityo C, Hoppe A, et al. Assessment of second-line antiretroviral regimens for HIV therapy in Africa. N Engl J Med. 2014;371(3):234-247.

42.       La Rosa AM, Harrison LJ, Taiwo B, 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.

43.       Ofotokun I, Sheth AN, Sanford SE, 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.

44.       van Lunzen J, Pozniak A, Gatell JM, 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.

45.       Banhegyi D, Katlama C, da Cunha CA, et al. Week 96 efficacy, virology and safety of darunavir/r versus lopinavir/r in treatment-experienced patients in TITAN. Curr HIV Res. 2012;10(2):171-181.

46.       Zheng Y, Hughes MD, Lockman S, et al. Antiretroviral therapy and efficacy after virologic failure on first-line boosted protease inhibitor regimens. Clin Infect Dis. 2014;59(6):888-896.

47.       Arasteh K, Yeni P, Pozniak A, et al. Efficacy and safety of darunavir/ritonavir in treatment-experienced HIV type-1 patients in the POWER 1, 2 and 3 trials at week 96. Antivir Ther. 2009;14(6):859-864.

48.       Clotet B, Bellos N, Molina JM, et al. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet. 2007;369(9568):1169-1178.

49.       Palella FJ, Jr., Fisher M, Tebas P, et al. Simplification to rilpivirine/emtricitabine/tenofovir disoproxil fumarate from ritonavir-boosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA-suppressed participants. Aids. 2014;28(3):335-344.

50.       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

suppressed patients with HIV - a subanalysis of the dualis study.;. 2020. https://www.croiconference.org/abstract/virologic-outcomes-by-resistance-category-and-pretreatment-in-the-dualis-study/.

51.       Capetti AF, Sterrantino G, Cossu MV, 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.

52.       Hawkins KL, Montague BT, Rowan SE, et al. Boosted darunavir and dolutegravir dual therapy among a cohort of highly treatment-experienced individuals. Antivir Ther. 2019;24(7):513-519.

53.       Lee SA, Kim SW, Chang HH, 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.

54.       Capetti AF, Sterrantino G, Cossu MV, et al. Switch to Dolutegravir plus Rilpivirine Dual Therapy in cART-Experienced Subjects: An Observational Cohort. PLoS One. 2016;11(10):e0164753.

55.       Jablonowska E, Siwak E, Bociaga-Jasik M, 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.

56.       Navarro J, Santos JR, Silva A, et al. Effectiveness of Once/Day Dolutegravir Plus Boosted Darunavir as a Switch Strategy in Heavily Treated Patients with Human Immunodeficiency Virus. Pharmacotherapy. 2019;39(4):501-507.

57.       Willig JH, Aban I, Nevin CR, 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.

58. Sax PE, Zolopa A, Brar I, Elion R, Ortiz R, Post F, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr. 2014;67(1):52-8. PubMed Google Scholar