1 INSTI 2 NRTI | HIV-ASSIST

This is a generic 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 (2022) and IAS-USA (2022) 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 are considered the preferred regimens within HIVASSIST for treatment naïve patients. DTG/ABC/3TC continues to be recommended in DHHS (2022) guidance, but ABC containing regimens are no longer preferred in IAS-USA guidance owing to "concerns about its association with cardiovascular disease, risk of abacavir hypersensitivity, burden of HLA B*B5701 testing, and no substantial advantage over DTG/3TC." 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, and have a higher HIVASSIST 'weighted score'. Similarly RAL containing regimens (with TAF/FTC or TDF/FTC) are regimens that can be 'recommended in certain clinical situations' according to DHHS (2022) guidelines; RAL containing regimens are ranked lower within HIVASSIST owing to a lower barrier to resistance and the potential for treatment emergent virus after failure.

Within HIVASSIST algorithms, in most instances, regimens recommended for treatment naïve patients are also considered to 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. Some regimens with 2NRTI and 1 INSTI are also recommended for treatment-experienced patients in patients who are virally suppressed and those who have experienced virologic failure; it should be noted that BIC has a high barrier to resistance similar to DTG, but there is limited clinical trial data in the setting of treatment failure, particularly with any INSTI resistance and is generally not recommended by DHHS guidelines and is not FDA approved in such settings. Notably HIVASSIST assess a penalty for BIC containing regimens in such situations where there is a history of INSTI failure or resistance to component drugs.

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. When combined with DTG, the efficacy and toxicity of TAF/FTC and TDF/FTC are considered similar in the treatment of pregnant women, but TAF/FTC is associated with fewer adverse birth outcomes and less risk of insufficient weight gain in pregnancy (DHHS 2022). ABC/3TC and TDF/FTC and TAF/FTC or TXF+3TC are considered the preferred dual-nrti backbones (DHHS 2022, IAS-USA 2022). 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. DHHS updated guidance (2020) now considers DTG a preferred ARV during any trimester of pregnancy and during pre-conception but emphasizes counseling and informed decision-making. In particular they state, "The use of DTG at conception and in very early pregnancy has been associated with a small but statistically significant increase in the risk of NTDs; this information should be discussed with patients to ensure informed decision-making." https://clinicalinfo.hiv.gov/en/guidelines/perinatal/whats-new-guidelines. Overall, DTG/ABC/3TC as a fixed dose combination, or DTG plus preferred dual-NRTI backbone are the preferred initial treatment, except in those with acute/recent HIV with a history of CAB/RPV exposure for PrEP.

Recommendations in treatment-naïve patients

DHHS (2022): 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, and BIC/TAF/FTC.

RAL + TDF/FTC or TAF/FTC, EVG/c/TAF/FTC, EVG/c/TDF/FTC, are recommended as an initial 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 with adverse neuropsychiatric effects.

IAS-USA (2022): Recommended as initial regimens for treatment-naïve patients. The specific 2 NRTI + 1 INSTI regimens that are recommended are BIC/TAF/FTC, DTG+TAF/FTC or DTG + TDF/FTC or DTG +TDF/3TC.

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. Due to the reduced preference for ABC, DTG/ABC/3TC has a slightly lower ranking than the other regimens.

Recommendations in treatment-experienced patients

DHHS 2021: 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 quality of life with a lower pill burden and will 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 first 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(2022): In virally suppressed patients, switching from an older regimen to any of the recommended initial regimens (e.g., 2NRTI + 1 INSTI) is generally considered acceptable. The guidelines also note the potential to switch to 2 drug strategies (not covered in this educational sheet) in persons with no history of treatment failure such as DTG/3TC and DTG/RPV. The most recent guidelines also indicate emerging data has demonstrated the safety of switching to dTG plus 2NRTIs or BIC/TAF/FTC, even in settings of likely or proven NRTI resistance. In the 2SD study in Kenya, persons on 2^nd line drugs were randomized to a boosted PI or DTG plus NRTIs, and the INSTI based strategy was non-inferior. The guidelines also note that similar results have been sween with switches to BIC/FTC/TAF in persons with resistant virus. Preexisting M184V/I did not have effect on efficacy in this setting.

In cases of virologic failure, the IAS-USA recommends DTG plus 2 NRTIs (with ≥ 1 active NRTI determined by genotype testing) in the setting of initial treatment failure with an NNRTI; they note that although not studied in virologic failure, BIC/FTC/TAF should have similar activity to DTG plus TXF/XTC.

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 maintenance 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 or may retain activity after failing RAL^[7]. 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 either BID DTG+2 NRTI^[8] 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.
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 virologic 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 weight gain, 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 [bib]157[/bib]
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%) 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).^{[9, 10]}
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%)^{[11, 12]}
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^{[13, 14]}
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^[15]
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.^[16]
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).^[17]
Trial 1475	BIC/TAF/FTC versus DTG + TAF/FTC	125 tx-naive	At week 24, BIC/TAF/FTC and DTG + TAF/FTC both showed high efficacy. 63/65 (96.9%) in the bictegravir group had HIV-1 RNA loads of less than 50 copies/ml compared with 31/33 (93.9%) in the dolutegravir group (weighted difference 2.9%, 95% CI -8.5 to 14.2; p=0.50).^[18]

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.^[19]
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^[20]
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^[21]
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).^[22]
1961	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^[23].
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^[24]
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]
VIKING	DTG BID + >=1 active drug	Tx experienced, INSTI resistant virus	69% of subjects achieved <50 c/ml at week 24. DTB BID was effective in this highly treatment experienced population.^[8]
--	DTG activity	39 failing RAL based regimen	DTG retained activity against isolates failing RAL-based therapy for variants containing Y143, N155 resistance. Q148 plus additional mutations had more reduced DTG susceptibility.^[7]
NADIA	DTG +TDF/3TC vs DTG +ZDV/3TC vs DRV/r +TDF/3TC vs DRV/r +ZDV/3TC	464 tx-experienced	DTG in combination with NRTIs was effective in treatment experienced patients, including those with extensive NRTI resistance (no predicted NRTI activity). TDF noninferior to ZDV.^[25]

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^[26]
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^{[27, 28]}
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^{[13, 14]}
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^[29]
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^[30]
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^[31]
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%)^[32-34]
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%)^[34]
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^[35-37]
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%) ^[38]
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%^[39]

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1. De Miguel R, Rial-Crestelo D, Dominguez-Dominguez L, Montejano R, Esteban-Cantos A, Aranguren-Rivas P, 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.

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.

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.

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.

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.

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.

7. Underwood MR, Johns BA, Sato A, Martin JN, Deeks SG, Fujiwara T. The activity of the integrase inhibitor dolutegravir against HIV-1 variants isolated from raltegravir-treated adults. J Acquir Immune Defic Syndr 2012; 61(3):297-301.

8. Castagna A, Maggiolo F, Penco G, Wright D, Mills A, Grossberg R, et al. Dolutegravir in antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study. J Infect Dis 2014; 210(3):354-362.

9. Walmsley S, Baumgarten A, Berenguer J, Felizarta F, Florence E, Khuong-Josses MA, 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.

10. 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.

11. 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.

12. Clotet B, Feinberg J, van Lunzen J, Khuong-Josses MA, Antinori A, Dumitru I, 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.

13. Raffi F, Rachlis A, Stellbrink HJ, Hardy WD, Torti C, Orkin C, 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.

14. Raffi F, Jaeger H, Quiros-Roldan E, Albrecht H, Belonosova E, Gatell JM, 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.

15. Orrell C, Hagins DP, Belonosova E, Porteiro N, Walmsley S, Falco V, 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.

16. Stellbrink HJ, Arribas JR, Stephens JL, Albrecht H, Sax PE, Maggiolo F, 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.

17. Wohl DA, Yazdanpanah Y, Baumgarten A, Clarke A, Thompson MA, Brinson C, 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.

18. Sax PE, DeJesus E, Crofoot G, Ward D, Benson P, Dretler R, et al. Bictegravir versus dolutegravir, each with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection: a randomised, double-blind, phase 2 trial. The lancet HIV 2017; 4(4):e154-e160.

19. Gatell JM, Assoumou L, Moyle G, Waters L, Johnson M, Domingo P, 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.

20. Cahn P, Pozniak AL, Mingrone H, Shuldyakov A, Brites C, Andrade-Villanueva JF, 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.

21. Trottier B, Lake JE, Logue K, Brinson C, Santiago L, Brennan C, 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.

22. Molina JM, Ward D, Brar I, Mills A, Stellbrink HJ, Lopez-Cortes L, 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.

23. Kityo C, Hagins D, Koenig E, Avihingsanon A, Chetchotisakd P, Supparatpinyo K, 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.

24. Daar ES, DeJesus E, Ruane P, Crofoot G, Oguchi G, Creticos C, 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.

25. Paton NI, Musaazi J, Kityo C, Walimbwa S, Hoppe A, Balyegisawa A, et al. Dolutegravir or Darunavir in Combination with Zidovudine or Tenofovir to Treat HIV. N Engl J Med 2021; 385(4):330-341.

26. Squires K, Kityo C, Hodder S, Johnson M, Voronin E, Hagins D, et al. Integrase inhibitor versus protease inhibitor based regimen for HIV-1 infected women (WAVES): a randomised, controlled, double-blind, phase 3 study. The lancet HIV 2016; 3(9):e410-e420.

27. Lennox JL, Landovitz RJ, Ribaudo HJ, Ofotokun I, Na LH, Godfrey C, 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.

28. Ofotokun I, Na LH, Landovitz RJ, Ribaudo HJ, McComsey GA, Godfrey C, 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.

29. Pozniak A, Markowitz M, Mills A, Stellbrink HJ, Antela A, Domingo P, et al. Switching to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of non-nucleoside reverse transcriptase inhibitor with emtricitabine and tenofovir in virologically suppressed adults with HIV (STRATEGY-NNRTI): 48 week results of a randomised, open-label, phase 3b non-inferiority trial. Lancet Infect Dis 2014; 14(7):590-599.

30. Arribas JR, Pialoux G, Gathe J, Di Perri G, Reynes J, Tebas P, et al. Simplification to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of ritonavir-boosted protease inhibitor with emtricitabine and tenofovir in adults with virologically suppressed HIV (STRATEGY-PI): 48 week results of a randomised, open-label, phase 3b, non-inferiority trial. Lancet Infect Dis 2014; 14(7):581-589.

31. Sax PE, Wohl D, Yin MT, Post F, DeJesus E, Saag M, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet 2015; 385(9987):2606-2615.

32. Wohl DA, Cohen C, Gallant JE, Mills A, Sax PE, Dejesus E, et al. A randomized, double-blind comparison of single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF versus single-tablet regimen efavirenz/emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: analysis of week 144 results. J Acquir Immune Defic Syndr 2014; 65(3):e118-120.

33. Sax PE, DeJesus E, Mills A, Zolopa A, Cohen C, Wohl D, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet 2012; 379(9835):2439-2448.

34. Zolopa A, Sax PE, DeJesus E, Mills A, Cohen C, Wohl D, et al. A randomized double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr 2013; 63(1):96-100.

35. Rockstroh JK, DeJesus E, Lennox JL, Yazdanpanah Y, Saag MS, Wan H, et al. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK. J Acquir Immune Defic Syndr 2013; 63(1):77-85.

36. DeJesus E, Rockstroh JK, Lennox JL, Saag MS, Lazzarin A, Zhao J, et al. Efficacy of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: week-192 overall and subgroup analyses from STARTMRK. HIV clinical trials 2012; 13(4):228-232.

37. Lennox JL, DeJesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 2009; 374(9692):796-806.

38. Clumeck N, Molina JM, Henry K, Gathe J, Rockstroh JK, DeJesus E, et al. A randomized, double-blind comparison of single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: analysis of week 144 results. J Acquir Immune Defic Syndr 2014; 65(3):e121-124.

39. Steigbigel RT, Cooper DA, Kumar PN, Eron JE, Schechter M, Markowitz M, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med 2008; 359(4):339-354.