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1 INSTI 2 NRTI

ARVs: 

This is a educational information sheet for 2 NRTIs + 1 INSTI regimens.

 

Overview

Regimens containing one INSTI (i.e. RAL, EVG/c, and DTG, BIC) combined with 2 NRTI are well-studied and supported in literature.  Current recommendations by DHHS (2019) and IAS-USA (2018) suggest that an INSTI + 2NRTI are “Recommended as an initial regimen” in most treatment naïve patients.  DTG with TAF/FTC or TDF/FTC, and BIC/TAF/FTC, and DTG/ABC/3TC are considered the preferred regimens within HIVASSIST for treatment naïve patients.  EVG/c/TAF/FTC and EVG/c/TDF/FTC are also available coformulated, but have the disadvantage of including an INSTI with a lower barrier to resistance and inclusion of a booster which can have drug interactions.  Consequently, EVG/c regimens are no longer preferred in most instances.  While RAL containing regimens (with TAF/FTC or TDF/FTC) are still recommended regimens for most people with HIV, RAL containing regimens are ranked lower within HIVASSIST owing to a lower barrier to resistance and the potential for treatment emergent virus after failure.

In most instances, regimens recommended for treatment naïve patients are also considered to be likely to be effective and durable in suppressed patients without a history of treatment failure or resistance.  When individuals fail these regimens as initial therapy, it is often an issue with adherence and cases of emergent INSTI resistance has been relatively uncommon when DTG or BIC is used as the INSTI.  Among these regimens, BIC/TAF/FTC and DTG/ABC/3TC are available as single pill once daily coformulated regimens.  We note that there is some emerging data that usage of some INSTIs including DTG, particularly in combination with TAF could be associated with weight gain; the clinical significance of these findings is not yet known. This type of regimen is also recommended for treatment-experienced patients for both patients who are virally suppressed and those who have experienced virologic failure.

Pregnancy/Child-bearing potential:  Most NRTIs are considered safe and effective during pregnancy without concerns for teratogenicity.  Among commonly used NRTIs, ABC has good PK at standard doses; TDF has lower AUC in 3rd trimester, but trough is considered adequate; there is insufficient PK data to recommend for or against TAF during pregnancy.  ABC/3TC and DTF/FTC are considered the preferred dual-nrti backbones Among INSTIs, EVG concentrations are lowered and is not recommended. BIC has insufficient data to recommend.  RAL is considered a preferred INSTI during pregnancy.  In prior guidelines, because of concerns related to neural tube defects and DTG usage, DHHS recommended against usage in pregnancy and in those of childbearing potential trying to conceive; data presented later in 2019 suggests that the risk was lower than seen with preliminary data and DTG can now be considered. For individuals of childbearing potential, a pregnancy test should be performed and providers should discuss risks and benefits of DTG around the time of conception. DTG is considered an alternative rather than preferred option for women trying to conceive rather than preferred. Of note, DTG is considered a preferred regimen during any trimester of pregnancy (no increased risk of NTDs among mothers initiated DTG during pregnancy).

Recommendations in treatment-naïve patients

 

DHHS(2019): "Recommended as initial regimens for most" treatment-naïve patients. The guidelines specifically recommend the following regimens: DTG/ABC/3TC for patients who are HLA-B*5701 negative, DTG + TDF/FTC or TAF/FTC, BIC/TAF/FTC, and RAL + TDF/FTC or TAF/FTC.

 

EVG/c/TAF/FTC, EVG/c/TDF/FTC, are "recommended as an iniitial regimen in certain clinical situations"

 

Patients with pre-existing psychiatric conditions should be monitored closely when started on INSTI-based regimens as these have been associated wtih adverse neuropsychiatric effects.

 

IAS-USA (2018): Recommended as initial regimens for treatment-naïve patients. The specific 2 NRTI + 1 INSTI regimens that are recommended are DTG/ABC/3TC, DTG+TAF/FTC, EVG/c/TAF/FTC, RAL+TAF/FTC.

 

HIVASSIST: We considered BIC/TAF/FTC, DTG+TAF/FTC, and DTG/ABC/3TC to be the top ranked regimens (along with DTG/3TC) for treatment naïve patients. 

 

 

Recommendations in treatment-experienced patients

DHHS 2019: In virally suppressed patients, within-class switches from RAL to EVG/c or DTG; EVG/c, DTG, or RAL to BIC may be considered if the switch will improve QOL and maintain viral suppression. Between-class switches that can be considered include replacing an NNRTI or boosted PI with an INSTI. (see trials below).  There is some data that switching to INSTI from PI has led to improved lipid parameters.

 

In cases of confirmed virologic failure, the DHHS discusses switching to a regimen of 2 NRTIs + 1 INSTI after NNRTI failure, noting that “DTG plus 2 NRTI (at least one of which is active) can be an option after failure of a fairst line NNRTI-based therapy (AI).  2 NRTI + 1 INSTI is also discussed as an option following failure of a boosted PI based regimen.

 

IAS-USA(2018): In virally suppressed patients, switching from an older regimen to a simpler single-pill regimen (i.e. DTG/ABC/3TC, EVG/c/FTC/TAF, or EVG/c/FTC/TDF) may be considered as long as the patient has no resistance or mutations that would result in virologic failure.

In cases of virologic failure, the IAS does not have any specific recommendations, but notes that in treatment-experienced patients, DTG was found to be superior to RAL and EVG was found to be noninferior to RAL.

 

HIVASSIST:  Given the effectiveness of most INSTI +2 NRTI regimens in treatment naïve patients, we considered these same regimens to be acceptable as part of switch strategies in suppressed patients without a history of treatment failure or resistance.  Given the effectiveness of DTG/3TC in maintaining suppression as a dual-drug regimen, we considered pairing an INSTI with 2 NRTIs to be likely to achieve maintanence of suppression even in the setting of a history of treatment failure or some NRTI resistance, provided there are at least 2 active drugs in the regimen, but did not rank such regimens as highly as other switch strategies in individuals without a history of treatment failure.

 

We note that there is emerging data on the usage of INSTI + 1 or 2 NRTI for maintaining suppression in individuals despite a history of resistance

[1-5] . We considered such an approach to be more robust when accompanied by longer period of virologic suppression at the time of switch [4] .  In general we considered DTG regimens to be preferred in treatment experienced patients with a history of failure over other INSTIs including BIC owing to less data of using BIC/TAF/FTC in this setting.

 

Among individuals experiencing viremia or virologic failure, we considered there to be several lines of evidence in support of using 2NRTI+1 INSTI, with and without resistance.  In the GEMINI studies, treatment naïve ( viremic ) patients, individuals received DTG/3TC (i.e. INSTI + 1 NRTI) and were able to achieve virologic suppression comparable to 3 drug regimens, suggesting that there is likely biological plausibility for the usage of INSTI+2 NRTI, provided there are at least 2 active drugs in the regimen.  

 

Furthermore, in the DAWNING study among individuals failing NNRTI regimens, DTG plus 2 NRTI (in which at least one was active) was superior to LPV/r + 2 NRTI

[6] .  Consistent with DHHS guidelines, we prioritized usage of such regimens after NNRTI failure and after PI failure [6] .

 

In situations when a person has failed an INSTI based regimen, current guidelines note that data suggests that treatment emergent virus may be unlikely with newer INSTIs. In such situations, we considered 2NRTI+DTG to be a regimen to be considered. In the context of INSTI mutations, we noted that guidelines suggest using etiher BID DTG+2 NRTI or a boosted PI based regimen; within HIVASSIST we prioritized PI based regimens over INSTI based regimens in the setting of INSTI mutations.

 

 

Other Considerations

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[1].
  • 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 co-formulated single-pill tablet with ABC/3TC/DTG 
  • Possible side effects include insomnia, headache, and (rarely) hypersensitivity reaction
  • See above discussion of usage in pregnancy

 

BIC

·        BIC levels can be reduced when administered with polyvalent cations. 

·        BIC blocks tubular secretion of Cr, and can raise Cr by ~0.1mg/dl but does not affect GFR

 

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 [2]
  • Should not be used in patients with CrCl<30
  • TAF/FTC is the dual-NRTI base recommended for patients with HIV/HBV coinfection

 

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

 

TREATMENT NAÏVE DTG or BIC

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).

[7, 8]

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%)

[9, 10]

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 profile

[11, 12]

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 arm

[13]  

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.

[14]

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).

[15]

 

TREATMENT EXPERIENCED DTG or BIC

Trial Name

Drugs Compared

Participants

Study Results

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 baseline.

[16]

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 RAL

[17]

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 patients

[18]

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).

[19]

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 resistance

[20] .

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 BIC

[21]

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.

[1]  

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 failure

[2] .

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 VF

[3] .

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 VF

[4] .

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.

[5]

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).

[6]

 

 

 

EVG/c or RAL studies

Trial Name

Drugs Compared

Participants

Study Results

WAVES

TDF/FTC/EVG/c vs. TDF/FTC+ATV/r

575 tx-naive women

At 48 weeks, 87% of the women in the TDF/FTC/EVG/c group achieved viral suppression, vs. 81% of the women in the TDF/FTC+ATV/r group. 5 women in the in the TDF/FTC/EVG/c group discontinued due to adverse events, compared to 19 women in the TDF/FTC+ATV/r group

[22]

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 evaluated

[23, 24]

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 profile

[11, 12]

SPRING-2

ABC/3TC+RAL vs. TDF/FTC+RAL

164 tx-naive, 24% with VL ≥100,000

After 96 weeks, there was no difference in virologic response between the ABC/3TC and TDF/FTC groups when RAL was given as the third drug 11

STRATEGY-NNRTI

NNRTI+TDF/FTC vs EVG/c/TAF/FTC

439 tx-experienced

At week 48, 93% of the patients who were switched to the EVG/c/TAF/FTC maintained viral suppression, whereas 88% of patients in the non-switch group who remained on 1 NNRTI + TDF/FTC maintained viral suppression, with similar safety profiles. Coformulated EVG/c/TAF/FTC determined to be a suitable alternative to patients who are on an NNRTI + TDF/FTC regimen or those who want to modify/simplify their regimen

[25]

STRATEGY-PI

PI/r+TDF/FTC vs EVG/c/TAF/FTC

433 tx-experienced

At week 48, 93.8% of patients who were switched to EVG/c/TAF/FTC maintained viral suppression, whereas 87.1% of patients in the non-switch group who remained on 1 PI/r + TDF/FTC. The study notes that the disparity in suppression between regimens was due to patients in the no-switch group discontinuing the treatment for non-virological reasons and that both are effective treatments for maintaining virologic suppression. There were also noted to be increased side effects (increased serum creatinine, nausea) in the switch group, but they did have lower rates of diarrhea and bloating

[26]

GS-US-292-0104/0111

TAF/FTC/EVG/c vs TDF/FTC/EVG/c

1733 tx-naive

TAF/FTC/EVG/c was non-inferior to TDF/FTC/EVG/c (92% viral suppression in the TAF group and 90% in the TDF group) Patients given TAF/FTC/EVG/c had significantly smaller mean serum creatinine increases than those given TDF/FTC/EVG/c (0·08 vs 0·12 mg/dL), significantly less proteinuria (median % change -3 vs 20), and a significantly smaller decrease in bone mineral density at spine (mean % change -1·30 vs -2·86) and hip (-0·66 vs -2·95) at 48 weeks

[27]

GS-US-236-0102

TDF/FTC/EVG/c vs. TDF/FTC/EFV

757 tx-naive

At 48 weeks, TDF/FTC/EVG/c was non-inferior to TDF/FTC/EFV (88% viral suppression vs. 84%). Proportions of patients discontinuing drugs for adverse events did not differ substantially (4% in the TDF/FTC/EVG/c group vs 5% in the TDF/FTC/EFV group). Similar findings were also seen at 96 weeks (84% viral suppression vs. 82%) and 144 weeks ( 80% viral suppression vs. 75%)

[28-30]   

GS-236-0103

TDF/FTC/EVG/c vs. TDF/FTC+ATV/r

708 tx-naive

At 48 weeks, TDF/FTC/EVG/c was non-inferior to TDF/FTC+ATV/r (90% viral suppression vs. 87%, respectively).   Proportions of patients discontinuing drugs for adverse events did not differ substantially (4% of TDF/FTC/EVG/c vs 5% of TDF/FTC+ATV/r). Similar findings were also seen at 96 weeks (83% viral suppression vs. 82%) and 144 weeks (78% viral suppression vs. 75%)

[30]  

STARTMRK

TDF/FTC plus EFV or RAL

566 tx-naive

At 48 weeks, RAL was noninferior to EFV. At 4 and 5 years, RAL was superior to EFV, in part because of more frequent discontinuations due to adverse events in the EFV group

[31-33]  

Study 103

FTC/TDF/EVGc vs. FTC/TDF/ATVr

350 tx-naive

At 144 weeks, FTC/TDF/EVGc demonstrated durable efficacy and improved safety. High rates of virologic success (HIV-1 RNA <50 copies/mL) in both groups were maintained at week 144: EVG/COBI/FTC/TDF: 77.6% (274/353) vs ATV + RTV + FTC/TDF: 74.6% (265/355) (difference: 3.1%; 95% CI: −3.2% to 9.4%) 

[34]

BENCHMRK

Optimized background +/- RAL

699 tx experienced with triple class resistance with failing regimen

Suppression of HIV-1 RNA to a level below 50 copies per milliliter was achieved at week 16 in 61.8% of the raltegravir recipients, as compared with 34.7% of placebo recipients, and at week 48 in 62.1% as compared with 32.9%

[35]

 

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Last updated June 25, 2020

 

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2. Jary A, Marcelin AG, Charpentier C, Wirden M, Le MP, Peytavin G, 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 PMID 32065630 https://doi.org/10.1093/jac/dkaa019

3. Olearo F, Nguyen H, Bonnet F, Yerly S, Wandeler G, Stoeckle M, 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.PMC6778427  PMID 31660328 https://doi.org/10.1093/ofid/ofz330

4. Giacomelli A, Lai A, Franzetti M, Maggiolo F, Di Giambenedetto S, Borghi V, 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 PMID 31629714 https://doi.org/10.1016/j.antiviral.2019.104635

5. Andreatta K, Willkom M, Martin R, Chang S, Wei L, Liu H, 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.PMC6857193  PMID 31430369 https://doi.org/10.1093/jac/dkz347

6. Aboud M, Kaplan R, Lombaard J, Zhang F, Hidalgo JA, Mamedova E, 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 PMID 30732940 https://doi.org/10.1016/S1473-3099(19)30036-2

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8. Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutierrez F, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med 2013; 369(19):1807-1818 PMID 24195548 https://doi.org/10.1056/NEJMoa1215541

9. Molina JM, Clotet B, van Lunzen J, Lazzarin A, Cavassini M, Henry K, 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 PMID 26424673 https://doi.org/10.1016/S2352-3018(15)00027-2

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