1 INSTI 1 PI 2 NRTI | HIV-ASSIST

2 NRTI 1 INSTI 1 PI

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 resistance[1]. Within HIV-ASSIST, we extrapolate from data on usage of 2NRTI+ 1 INSTI, 2NRTI+1PI, and 1PI + 1 INSTI (i.e. subcomponents of this 4 drug regimen).

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 patients[2-4].

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 results[1]. 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.

Among individuals experiencing viremia or virologic failure, we considered there to be several lines of evidence in support of using 2NRTI+1 INSTI and 2 NRTI+1 PI, as well as 1INSTI + 1PI, 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 + 1 PI, 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[5]. Consistent with DHHS guidelines, we prioritized usage of such regimens after NNRTI failure and after PI failure[5].

HIVASSIST algorithms also prioritize usage of 2 NRTIs+ PIs [and therefore +/- INSTI] after NNRTI failure, consistent with current evidence and DHHS guidelines (2019). When failing a boosted PI + NRTI regimen, several studies have shown limited resistance to XTC (ARTEMIS study[6, 7]). A systematic review has suggested that maintaining the same regimen, with improved adherence, may be effective[8]. PI resistance in this setting are also relatively rare[6, 7]. As such, our algorithm prioritizes continuing the PI based regimen (i.e. 2 NRTI + PI in some cases), or switching to a non-PI regimen with at least 2 fully active agents.We also prioritized switching to PI based regimens (either with NRTI or INSTI) after INSTI failure and emergence of INSTI mutations given the relatively high barrier of resistance, provided the regimen had more than 2 active drugs.

Finally, we considered the available evidence and guidelines regarding dual therapy with INSTIs (e.g., DTG/RPV, DTG/3TC) to suggest that a regimen containing a fully active INSTI+ PI is likely to be effective at maintaining virologic suppression as well, but considered the strength of evidence to be less than that of other INSTI dual therapy regimens (in the setting of no treatment failure or resistance). There is emerging data on the usage of this strategy in heavily treatment experienced patients for maintainence of suppression, particularly after multi-class resistance and prioritized this combination (with or without additional agents) in such settings.[9-13]. We prioritized the combination of INSTI+PI[14-16] with or without additional agents following NNRTI failure based on available clinical trial data and DHHS recommendations. Similarly based on the DHHS guidelines we prioritized regimens containing 1 INSTI+1 PI following virologic failure with INSTI based regimens (note DTG is dosed BID in most such situations), though the guidelines acknowledge there is a lack of clinical trial data to guide selection in individuals who have failed INSTI anchored regimens.

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[17]. 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[18] or a boosted PI based regimen; within HIVASSIST we prioritized PI based regimens over INSTI based regimens in the setting of INSTI mutations.

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 this[bib]122[/bib][bib]151[/bib].
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 loss [bib]157[/bib]
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).[19, 20]
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%)[21, 22]
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[23, 24]
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[25]
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.[26]
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).[27]

TREATMENT EXPERIENCED DTG or BIC (2NRTI + INSTI)

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.[28]
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[29]
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[30]
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).[31]
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[32].
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[33]
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.[34]
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[35].
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[36].
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[37].
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.[38]
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).[5]
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.[18]
--	DTG activity	39 failing RAL based regimen	DTG retained activity against isolates failing RAL-based therapy for variants containing Y143, N155 resistnace. Q148 plus additional mutations had more reduced DTG susceptibility.[17]

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 [39]
Study 115	DRV/c vs. DRV/r	62 tx-naive	DRV/c is bioequivalent to DRV/r in healthy volunteers[40]
N/A	ABC/3TC+DRV/r (single arm)	67, 48% tx-naive	At 48 weeks, 79% achieved viral suppression[41]
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 [6, 42]
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 group[21]
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[43, 44]
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/3TC[45]
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).[46]
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 group[47]
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[48]
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[49]
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%[50]
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.[51]

2NRTI + 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 suppressed[14]
EARNEST	PI monotherapy vs 2 NRTI+LPV/r vs LPV/r + RAL	1277 tx-experienced	PI+INSTI regimen had 64% viral suppression and was noninferior to a 2NRTI+PI regimen that had 60% viral suppression[15]
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.[16]
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 [52]
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[53]
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).[5]
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/r[54]
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).[8]
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).[55, 56]
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[28].
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[33]
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.[57]

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)[47]
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 [48]
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 [49]
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)[50]
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[50]

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 [9]
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. [58]
SECOND-LINE	LPV/r + NRTI backbone vs LPV/r + RAL	541 tx-experienced	At 48 weeks, a regimen of LPV/r+RAL was found to be noninferior to a regimen of LPV/r+2 NRTIs, given that 223 (83%) of patients in the LPV/r + RAL group and 213 (81%) of patients in the control group were virally suppressed[14]
EARNEST	PI monotherapy vs 2 NRTI+LPV/r vs LPV/r + RAL	1277 tx-experienced	PI+INSTI regimen had 64% viral suppression and was noninferior to a 2NRTI+PI regimen that had 60% viral suppression[15].
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.[16]
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[52]
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 [53]
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.[10]
N/A	DRV/c+DTG	31 tx-experienced	Retrospective study. Among 13 patients who switched to DRV/c+DTG owing to treatment failure, the proportion of patients in whom the viral loads were suppressed to less than 50 copies/mL increased from 0% at baseline to 45% at 4 weeks, 50% at 12 weeks, 50% at 24 weeks, and 66.7% at 48 weeks. In non-treatment failure patients (18 patients), the levels of viral suppression and CD4+ T cells were maintained[59]
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%[11]
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%.[13]
NA	DRV/b+DTG	50 Tx suppressed	50 patients on stable ART and undetectable for 6 months, irrespective of prior VF were switched to DTG+DRV/b. 93% had baseline NRTI RAMS, 72% with NNRTI RAMS, 27% with PI RAMS, 16% with DRV RAMS, and no one had INSTI RAMS. After 25 months 49/50 (98%) maintained Vl <50. Total cholesterol and LDL increased 9mg/dl, CD4 remained stable[12]
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%)[60]

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