1 PI 2 NRTI | HIV-ASSIST

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

Overview

There are several FDA approved NRTI’s and PI’s. In general, regimens anchored by 2 NRTIs (e.g., TAF/FTC, TDF/FTC, ABC/3TC) in combination with newer PIs (such as ATV, DRV, or LPV ) are well-studied and supported in the literature for treatment naïve and experienced patients. DRV/c/TAF/FTC is now available coformulated in a single pill once/daily regimen. We note that when BID dosing for the DRV component is required (i.e. in the setting of DRV mutations), it must be used in combination with ritonavir.

Previously, such regimens were considered a preferred regimen in treatment guidelines. However, all PIs (with the exception of ATV) must be combined with a pharmacologic booster, cobicistat or ritonavir, which can have substantial drug interactions; PIs also may have more side effects than INSTIs. Consequently, the combination of 2NRTI with PIs are now considered a regimen recommended only in some clinical situations for treatment naïve patients in DHHS guidelines (2019).

Among regimens combining these classes, HIVASSIST prioritize the usage of DRV with either cobicistat or ritonavir in combination with TAF or TDF and 3TC or FTC.

Owing to higher toxicity and lower barriers to resistance, HIVASSIST considered the usage of other/older PIs other than Darunavir and Atazanavir, and NRTIs other than ABC/3TC, or the combination of TAF or TDF with 3TC or FTC to be less favored.

*There is evidence from bioequivalence or relative bioavailability studies that TAF can be substituted for TDF without loss of efficacy and with an improved side effect profile, particularly less impact on kidney function and on bone loss[1]. As such, TAF, an oral prodrug of TDF, is now included (since 2016) as a component of several recommended regimens and first line therapy in both DHHS and IAS-USA guidance. TAF is FDA approved for use in patients with estimated CrCl as low as 30mL/min. It should be noted that some guidelines (UK) continue to recommend TDF over TAF except for specific reasons such as bone or renal complications; there is emerging evidence of an association of TAF and weight gain.

+DRV/c was found to be bioequivalent to DRV/r in healthy volunteers[2]. Based on the results of the study, efficacy of DRV/c has been extrapolated from DRV/r data. There is additional data from the EMERALD study in which a study regimen of DRV/c/TAF/FTC was non-inferior to DRV/r/TAF/FTC at 48 weeks[3]. Use of DRV/c is discussed in both the DHHS and IAS guidelines for use in treatment-naïve and treatment-experienced patients. Cobicistat inhibits active tubular secretion of creatinine, which can increase serum creatinine without an effect on renal glomerular function. Note that some drug interactions with cobicistat may differ from those with ritonavir.

Recommendations for Treatment-Naïve Patients

DHHS (2019): 2NRTI + 1 PI are no longer preferred regimens in most patients (DHHS now recommends certain 2 NRTI + 1 INSTI or 1NRTI+1 INSTI for most patients).

TAF/FTC/DRV/c;

TAF or TDF plus 3TC or FTC with DRV/r or ATV/boosted;

or ABC/3TC with DRV/boosted in HLA B*5701 negative patients, are "recommended as an initial regimen in certain clinical situations" for treatment-naive patients, because these regimens have durable virologic efficacy.

IAS-USA (2018): Recommended for treatment-naïve patients in which an INSTI is not an option. The recommended 2 NRTI + 1 boosted PI regimens are boosted DRV + TAF or TDF/FTC or ABC/3TC, EFV/TDF/FTC, or RPV/TAF or TDF/FTC.

HIVASSIST(2020): Regimens containing 2 NRTI + 1 PI are ranked below the currently recommended regimens (NRTI and INSTI based regimens) for treatment naïve patients. We prioritized DRV/b* (either cobicistat or ritonavir) with TAF/FTC above usage of ATV/b and other NRTI backbones.

For treatment naive patients TAF/FTC + DRV/b was ranked similar to TDF/XTC/DOR and RPV/TAF/FTC within HIVASSIST algorithms, consistent with DHHS guidelines[4-6]. While current guidelines do not offer preferences between such regimens and dual drug regimens involving a PI (PI+3TC, PI+INSTI), we ranked 2NRTI+1 PI ahead of such dual regimens given the longer track record and current evidence base. See tables below.

*/b refers to usage of a pharmacologic booster

Recommendations for Treatment-Experienced Patients

DHHS (2019): In cases of virologic failure, currently guidelines discuss several options based on the failing regimen. Guidelines suggest a Boosted PI plus 2 NRTI is a possible switch option after failure of a NNRTI, INSTI, or PI anchored regimen (with 2 NRTI). In the case of failing an NNRTI plus NRTI initial regimen, there are at least three large RCTs suggesting a PI with 2 NRTI may be effective[7-9]. In the setting of prior PI+NRTI failure, current data suggests that patients will have either no resistance or limited resistance (e.g., to 3TC or FTC). Guidelines acknowledge a lack of data on regimens after failing INSTI based regimens, but list 2 NRTIs plus boosted PI as an option to consider.

In virally suppressed patients, switching to a regimen of 2 NRTIs + 1 boosted PI may only be considered as a within-class regimen to reduce pill burden, improve the safety profile of the drugs or reduce the dosing frequency; for example, switching from a ritonavir-boosted PI to a cobicistat-boosted PI. The DHHS does not recommend a between-class switch to a boosted PI if the drugs in their current regimen are fully active.

IAS-USA (2018): There is no explicit recommendation to switch to this type of regimen in the IAS guidelines. However, they recommend to consider switching patients on older regimens to a variety of single-pill regimens. Situations in which patients should be recommended a switch include use of old NRTIs as they have long-term toxic effects, or older PIs that have higher pill burdens and are more metabolically toxic than DRV or ATV.

HIVASSIST: HIVASSIST algorithms prioritize usage of 2 NRTIs+ PIs 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[10, 11]). A systematic review has suggested that maintaining the same regimen, with improved adherence, may be effective[12]. PI resistance in this setting are also relatively rare[10, 11]. 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. In patients that are already virally suppressed, HIVASSIST did not prioritize or penalize regimens switching to 2NRTI+1PI. Existing evidence for viral simplification strategies have suggested that switching from a PI based regimen to NNRT and to INSTIs can be considered in order to improve lipid profiles, minimize drug interactions, or reduce dosing frequency(see Table). Consequently, HIVASSIST algorithms prioritize each of these strategies (note no changes are made to base-case rankings for 2 NRTI+INSTI given such regimens carry the top HIVASSIST rank even in non-suppressed patients).

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

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[1]
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

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 [13]
Study 115	DRV/c vs. DRV/r	62 tx-naive	DRV/c is bioequivalent to DRV/r in healthy volunteers[2]
N/A	ABC/3TC+DRV/r (single arm)	67, 48% tx-naive	At 48 weeks, 79% achieved viral suppression[14]
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 [5, 10]
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[15]
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[16, 17]
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[4]
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).[18]
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[19]
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[20]
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[21]
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%[22]
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.[23]

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[7]
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[8]
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.[24]
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 [25]
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[26]
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).[27]
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[28]
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).[12]
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).[29, 30]
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[31].
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[32]
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.[33]
EMERALD	DRV/c/TAF/FTC vs DRV/r/TAF/FTC	1141 suppressed patients	The study regimen was non-inferior to the control for virological rebound cumulative through week 48 (19 [2·5%] of 763 patients in the study group vs eight (2·1%) of 378 patients in the control group; difference 0·4%, 95% CI -1·5 to 2·2; p<0·0001). No resistance to any study drug was observed. [3]

OLDER PI regimens or comparators

KLEAN	FPV/r+ABC/3TC vs LPV/r+ABC/3TC	878 tx-naive	Virological suppression with FPV/r was found to be noninferior to LPV/r in combination with ABC/3TC at 48 weeks with similar rates of discontinuation due to adverse effects between the two cohorts[34]
GEMINI	SQV/r vs LPV/r	337 tx-naive	SQV/r was noninferior to LPV/r when each were combined in a treatment regimen with 3TC/TDF over 48 weeks in terms of virological suppression. Comparatively, SQV/r offered an improved triglyceride profile [35]
RESIST	TPV/r vs CPI-ritonavir	3384 tx-experienced	TPV/r with an optimized background regimen was found to provide better virological and immunological responses over 48 weeks in patients with previous antiretroviral exposure as compared to regimens with other PIs[36]
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[13]
GS-236-0103	TDF/FTC/EVG/c vs. ATV/r + TDF/FTC	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%)[37-40]
WAVES	EVG/c/TDF/FTC vs. ATV/r + TDF/FTC	575 tx-naive women	At 48 weeks, EVG/c/TDF/FTC had superior efficacy, in part because of a lower rate of treatment discontinuation. 87% of participants on EVG achieved viral suppression, with fewer adverse events and incidents of virological failure than in the ATV group [41]
Study 103	FTC/TDF/EVGc vs. FTC/TDF/ATVr	350 tx-naive	At 144 weeks, FTC/TDF/EVGc demonstrated durable efficacy and improved safety[40]
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[42]
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[43]

Did we forget a study or make an error? If so, please click on the "feedback" tab and provide details and comments.

Last Updated 6/10/2020

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

2. Gilead. Package Insert. In; 2017.

3. Orkin C, Molina JM, Negredo E, Arribas JR, Gathe J, Eron JJ, et al. Efficacy and safety of switching from boosted protease inhibitors plus emtricitabine and tenofovir disoproxil fumarate regimens to single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide at 48 weeks in adults with virologically suppressed HIV-1 (EMERALD): a phase 3, randomised, non-inferiority trial. The lancet HIV 2018; 5(1):e23-e34.

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

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

6. Molina JM, Andrade-Villanueva J, Echevarria J, Chetchotisakd P, Corral J, David N, et al. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr 2010; 53(3):323-332.

7. Group S-LS, Boyd MA, Kumarasamy N, Moore CL, Nwizu C, Losso MH, et al. Ritonavir-boosted lopinavir plus nucleoside or nucleotide reverse transcriptase inhibitors versus ritonavir-boosted lopinavir plus raltegravir for treatment of HIV-1 infection in adults with virological failure of a standard first-line ART regimen (SECOND-LINE): a randomised, open-label, non-inferiority study. Lancet 2013; 381(9883):2091-2099.

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

9. Bunupuradah T, Chetchotisakd P, Ananworanich J, Munsakul W, Jirajariyavej S, Kantipong P, et al. A randomized comparison of second-line lopinavir/ritonavir monotherapy versus tenofovir/lamivudine/lopinavir/ritonavir in patients failing NNRTI regimens: the HIV STAR study. Antivir Ther 2012; 17(7):1351-1361.

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

11. Stebbing J, Nathan B, Jones R, McKenna A, Powles T, Bower M, et al. Virological failure and subsequent resistance profiles in individuals exposed to atazanavir. Aids 2007; 21(13):1826-1828.

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

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

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

15. 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.

16. 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.

17. 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.

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

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

20. Kozal MJ, Lupo S, DeJesus E, Molina JM, McDonald C, Raffi F, et al. A nucleoside- and ritonavir-sparing regimen containing atazanavir plus raltegravir in antiretroviral treatment-naive HIV-infected patients: SPARTAN study results. HIV clinical trials 2012; 13(3):119-130.

21. Taiwo B, Zheng L, Gallien S, Matining RM, Kuritzkes DR, Wilson CC, et al. Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naive HIV-1-infected patients (ACTG A5262). Aids 2011; 25(17):2113-2122.

22. Bedimo RJ, Drechsler H, Jain M, Cutrell J, Zhang S, Li X, et al. The RADAR study: week 48 safety and efficacy of RAltegravir combined with boosted DARunavir compared to tenofovir/emtricitabine combined with boosted darunavir in antiretroviral-naive patients. Impact on bone health. PLoS One 2014; 9(8):e106221.

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

24. La Rosa AM, Harrison LJ, Taiwo B, Wallis CL, Zheng L, Kim P, et al. Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, non-inferiority study. The lancet HIV 2016; 3(6):e247-258.

25. Ofotokun I, Sheth AN, Sanford SE, Easley KA, Shenvi N, White K, et al. A switch in therapy to a reverse transcriptase inhibitor sparing combination of lopinavir/ritonavir and raltegravir in virologically suppressed HIV-infected patients: a pilot randomized trial to assess efficacy and safety profile: the KITE study. AIDS Res Hum Retroviruses 2012; 28(10):1196-1206.

26. van Lunzen J, Pozniak A, Gatell JM, Antinori A, Klauck I, Serrano O, et al. Brief Report: Switch to Ritonavir-Boosted Atazanavir Plus Raltegravir in Virologically Suppressed Patients With HIV-1 Infection: A Randomized Pilot Study. J Acquir Immune Defic Syndr 2016; 71(5):538-543.

27. 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.

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

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

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

31. 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.

32. 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.

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

34. Eron J, Jr., Yeni P, Gathe J, Jr., Estrada V, DeJesus E, Staszewski S, et al. The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial. Lancet 2006; 368(9534):476-482.

35. Walmsley S, Avihingsanon A, Slim J, Ward DJ, Ruxrungtham K, Brunetta J, et al. Gemini: a noninferiority study of saquinavir/ritonavir versus lopinavir/ritonavir as initial HIV-1 therapy in adults. J Acquir Immune Defic Syndr 2009; 50(4):367-374.

36. Hicks CB, Cahn P, Cooper DA, Walmsley SL, Katlama C, Clotet B, et al. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet 2006; 368(9534):466-475.

37. DeJesus E, Rockstroh JK, Henry K, Molina JM, Gathe J, Ramanathan S, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet 2012; 379(9835):2429-2438.

38. 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.

39. Rockstroh JK, DeJesus E, Henry K, Molina JM, Gathe J, Ramanathan S, et al. A randomized, double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus coformulated emtricitabine and tenofovir DF for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr 2013; 62(5):483-486.

40. 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.

41. 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.

42. 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.

43. 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.