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Switch Strategies in Virally Suppressed Patients

ART regimens in patients that are virologically suppressed confers risks including emergence of resistance (i.e. risk of virologic failure), or new toxicities. A central goal of switching ART regimens is to maintain viral suppression, without jeopardizing future treatment options [1].  One should consider prior documented resistance mutations, which are likely to persist in the viral reservoir.  A commercially available test can help to detect archived mutations, but its sensitivity and clinical utility is unknown.

Potential reasons to switch

  • Improve adherence (e.g., simplified regimens with fewer drugs, reduced pill burden or dosing frequency, minimize food requirements)

  • Improve tolerability (i.e. avoid toxicities of current regimen)

  • Mitigate Comorbidities

  • Avoid significant current or future drug-drug interactions

Evidence for Switching ART in patients that are virologically suppressed

The data from switch studies suggests that one should consider the drug class(es) of regimens to which a person is being switched, along with the number of agents in the future regimens, and prior treatment and resistance history.

There is some data to support simplifying to multi-drug regimens (including fixed dosed combinations) which contain an INSTI and/or PI.  In some instances, there is data to support 2 drug (class) regimens, but in other situations such strategies have been less successful (e.g., PI + EI). Strategies to simplify to monotherapy with INSTI or boosted PI have found success in niche circumstances, but data is lacking to recommend this strategy broadly.

General considerations

Our algorithm attempts to incorporate information about why a person may be considering a switch from a suppressive regimen.  We attempt to balance the evidence base for simplification of regimen, with maintenance of a similarly constructed regimen

Score Modification Rule
Remaining on the current regimen when virally suppressed

First, irrespective of our ‘base-rank’ for an individuals regimen (for naive patients), we apply a score of ‘1’ for the individual’s current regimen as its new 'base-rank'.  This strategy gives some acknowledgement to the fact that the patient has already reached virologic success, and any change comes with risks for side effects or change in adherence such that remaining on the current regimen may be a preferrable strategy. However, we then apply other rules (mutation penalties, comorbidities) including rules to penalize regimens with less than two active drugs. (see below)

"Similar" regimens with equal or better pill burden and number of active drugs

When a regimen has equal or better pill burden, and equal or better Active Drugs (with at least 2 active drugs), AND is a "similar" regimen (1 class different for 2 or 4 ARV containing regimens, or same class for 3 ARV regimens), then apply a base score of 1 to that regimen.  

This rule was developed based on the available evidence that has generally found 'within-class' switches (usually for adverse events or safety profile of newer drugs, dosing frequency, lower pill burden) to result in maintained viral suppression. While multiple permutations of within-class switches have been studied, we restricted the rule to additionally having provision for similar or improved pill burden and activity.  Thus, the algorithm will continue to recommend staying on a current suppressive regimen over a switch within class that leads to greater pill burden. Comorbidity or other side effect penalties are assessed separately. 

Treatment intensification in a virally suppressed patient

HIVASSIST assesses a number of regimens with 4 drugs.  In general, these regimens have a base-rank of 3.5 or lower. They are likely to lead to virologic suppression, but have little role in treatment naive paitents. There role is largely restricted to cases with treatment failure or extensive resistance.  Given some of the other algorithm rules listed on this page, these regimens (e.g., TAF/FTC/EVG/c+DRV, TAF/FTC/BIC+DRV/c, etc) may have their base-rank modified to 1-1.5 based on data for components of these regimens that are likely to maintain suppression.  

However, tere is little evidence to support treatment intensification to 4 active drugs in a patient that is virally suppressed. A discussion of treatmetn intensification can be found here:

As such, we penalize all regimens with 4 active drugs.

In some situations, a person may be already suppressed on a regimen that only contains 2 active drugs (e.g., suppressed on TAF/FTC+DTG with an M184V).  In these circumstances, some 4 drug regimens that have similar pill burden and greater number of active drugs could be considered. However, based on expert opinion and consideration of avoiding unnecessary exposure to extra drug classes, we have applied a modest penalty in these scenarios (i.e. with prior resistance) to all 4 drug regimens.  Nonetheless, we also acknowledge that there may be emerging evidence in support of this scenario (see section on TAF/FTC/EVG/c+DRV in patients with prior multi-class failure).

Regimens with fewer than three active drugs

Increasingly there is data on dual-therapy for maintaining viral suppression, which is listed in other portions of this page (See sections on INSTI's and PI's).

In general, dual therapy regimens have appeared promising when including DTG from the INSTI class or DRV/r from PI class.  While data is lacking, we have extrapolated this to include BIC which appears to have higher barrier to resistance and similar potency to DTG.

For other regimens, our algorithms continue to prioritize regimens with 3 active drugs when one of those drugs is not a fully active DRV, DTG or BIC. We apply a penalty when a regimen has 2-2.5 or 2.5-3 active drugs (scaled).

There is less data on regimens with less than 2 active drugs, and relatively strong data advocating against monotherapy. Please see sections on PI or INSTI monotherapy elsewhere on this page. In the absence of more data we have penalized regimens with less than 2 active drugs

Switching for ART toxicities or side effects

Score Modification Rule
Switching for CNS toxicity

If EFV is in the current suppressive regimen, we consider it to be the likely offending agent.  There are clinical data in this setting of switching to 2NRTI + NVP [2], 2 NRTI + ETR [3], RAL [4], TAF/FTC/EVG/c [5], 2 NRTI + RPV [6].  We have extrapolated the data for RAL and EVG/c to DTG containing regimens as well.

Switching for dyslipidemia or cardiovascular toxicities/comorbidities

If ABC is in the regimen, we consider the potential for its contribution to the dyslipidemia. There are clinical data to support a switch to TDF/FTC in this setting (and we extrapolate this to include TAF) [7] [8].

If ritonavir-boosted PI is in the regimen, we consider its potential for contribution to dyslipidemia. There is data to support switch from LPV/r to ATV/r in this setting. There is also data to support switch from LPV/r to RAL [9], which we extrapolate to include DTG and other INSTIs.

Switching for diarrhea
If ritonavir boosted PI is in the regimen,we consider its potential for contribution to diarrhea. This was more frequent with LPV/r. There is data in this setting to switch to RAL(9), TDF/FTC/EVG/c [10], TDF/FTC/RPV [11], and ETR containing regimens [12]. As such, we prioritize these regimens.

 Switching or Simplifying to INSTI based regimens

Score Modification Rule
Switching to 3-drug fixed-dose combination regimens (2 NRTI + 1 INSTI)

Based on the data below, we generally considered a switch to ABC/3TC/DTG or TAF/FTC/BIC or TAF/FTC/EVG/c or TAF/FTC+DTG to be an acceptable option, and apply a base rank of 1.0 to these regimens when a person is virally suppressed. We considered it less desirable (SWITCHMRK below) to switch from PI regimens to RAL regimens (acknowledging that in subgroup analysis, those without background history of failure had similar rates of suppression to LPV/r).  

 

 

DTG/ABC/3TC, from heterogenous pre-enrollment regimens

 

 

STRIIVING Study[13]:  553 suppressed patients were randomized to switch pre-enrollment regimen to fixed dose ABC/3TC/DTG or remain on their pre-enrollment regimen. Subjects were HIV-1-positive men and women ≥18 years of age who had achieved and maintained virological suppression (HIV-1 RNA <50 copies/ml) on an ART regimen that had been stable for ≥6 months prior to screening. The inclusion criteria required that subjects have achieved plasma HIV-1 RNA level <50 copies/ml within 6 months of starting an initial ART regimen with no plasma HIV-1 RNA level >200 copies/ml following initial suppression. Patients had no history of dual therapy and no history of treatment failure. Subjects were randomly assigned to switch to ABC/DTG/3TC once daily for 48 weeks (early-switch group) or continue current ART for 24 weeks and then switch to ABC/DTG/3TC (late-switch group). At week 24, 85% and 88% of subjects who switched to ABC/DTG/3TC or remained on current ART, respectively, were virologically suppressed At week 48, 83% and 92% were virologically suppressed in the early- and late-switch groups, respectively. Adverse events were reported more frequently with ABC/DTG/3TC (66%) than with current ART (47%) by week 24, and in the late-switch group, 60% of subjects reported adverse events post-switch. Pharmacokinetic data supported immediate switch. HIV Treatment Satisfaction Questionnaire scores improved in participants switching to ABC/DTG/3TC versus current ART.  Note, that background resistance mutations was not provided.

We applied a CHANGE BASE SCORE TO 1.0 for this regimen IF NO HISTORY OF TREATMENT FAILURE.

EVG/c/TAF/FTC or EVG/c/TDF/FTC, from heterogenous

  • Open label phase III GS109, unpublished data (IDweek 2015), randomized patients with virologic suppression (including a subset that were on TDF/FTC + ATV) receiving EVG/c/FTC/TDF whose eGFR was > 50 mL/min to continue, or switch to EVG/c/FTC/TAF. There was similar virologic efficacy at 48 weeks (98% in the switch arm and 97% in the continuation arm), with improvements in Cr, proteinuria, and Bone Mineral Density in the arm receiving TAF [14].
  • In the GS-112 study 242 patients who were virally suppressed were enrolled with CrCl 30-69 ml/min to switch to EVG/c/TAF/FTC. Through 48 weeks no significant change in CrCl was observed. 92% maintained HIV-1 RNA <50 copies/ml. Significant improvements in proteinuria, albuminuria, and tubular proteinuria were observed. Hip and bone mineral density significantly increased from baseline to week 48.
  • In a study to simplify from 2 NRTI + RAL BID, to fixed dose EVG/c/TDF/FTC. 48 patients were enrolled. Ninety-six percent of participants cited regimen simplification as the reason to enroll in the switch study. At week 48, all assessed study participants remained viro-logically suppressed (HIV-1 RNA<50 copies/mL) and maintained high CD4 cell count (median, 751 cells/mL) and stable eGFR (median, 100.5 mL/min).
  • Data support switching to fixed dosed INSTI regimen, from a NNRTI regimen.  In the STRATEGY: NNRTI study(5), 439 participants were randomized to no switch vs switch to EVG/c/TDF/FTC. At week 48, 271 (93%) of 290 participants in the switch group and 126 (88%) of 143 participants in the no-switch group maintained plasma viral loads below 50 copies per mL (difference 5·3%, 95% CI -0·5 to 12·0; p=0·066).There was no treatment-emergent resistance in either group.
  • Data support switching to fixed dosed INSTI regimen, from a PI regimen. In the STRATEGY:PI study(10) 433 participants were randomly to switch EVG/c/TDF/FTC, or remain on a boosted PI regimen. At week 48, 272 (93·8%) of 290 participants in the switch group maintained a viral load of less than 50 copies per mL, compared with 121 (87·1%) of 139 in the no-switch group (difference 6·7%, 95% CI 0·4-13·7; p=0·025). The statistical superiority of the simplified regimen was mainly caused by a higher proportion of participants in the no-switch group than in the switch group discontinuing treatment for non-virological reasons; virological failure was rare in both groups (two [1%] of 290 vs two [1%] of 139). We did not detect any treatment-emergent resistance in either group.
  • Additional support for simplification from PI to INSTI comes from the WAVES study, evaluating switching to EVG/c/TAF/FTC in women [15] [16]. This study evaluated TDF/FTC+ATV/r with TDF/FTC/EVG/c in 575 treatment naive patients, with primary endpoint at 48 weeks. 212 women that met viral suppression then either continued ATV/r or switched to TAF/FTC/EVG/c. An additional 48 weeks later, 94% were suppressed in the TAF/FTC/EVG/c arm compared to those that stayed on the PI. Switching led to improvements in spinal and hip bone mineral density, but did also have greater lipid increased compared to the TDF/FTC+ATV/r regimen.

2 NRTI + RAL, from 2 NRTI + LPV/r

  • 2 NRTI + RAL The SWITCHMARK 032 and 033 studies are good examples of the challenges of switching from regimens with high barriers to resistance, to lower barriers to resistance in the setting of archived mutations.  Both studies randomized patients w 2 NRTI + LPV/r to remaining or switching to 2NRTI + RAL, and were stopped early because the RAL arm failed to show non-inferiority. A post hoc analysis suggested that the subgroup without history of virologic failure had similar efficacy as the LPV/r arm. [9].
  • 2NRTI +RAL: SPIRAL [17] study randomized 273 patients with suppressed viral load for 6 months on a stable boosted-PI regimen to continue PI or switch to RAL.  Few were taking boosted DRV (most were LPV/r or ATV/r).   After 48 weeks, 124 (89%) of 149 patients in the raltegravir arm had an HIV RNA level less than 50 copies/mL compared with 116 (87%) of 134 in the ritonavir-boosted PI group (meeting criteria for non-inferiority). SPIRAL did not identify prior virologic failure or NRTI resistance mutations as risk factors for virologic failure.  SPIRAL patients also had improvements in lipid parameters, cardiovascular biomarkers and bone mineral density compared to boosted PI
  • ABC/3TC/DTG, to TAF/FTC/BIC Study 380-1844: Randomized phase III trial of patients suppressed on ABC/3TC/DTG with eFGFR>50, no active HBV, and no known resistance to study drugs randomized to stay or switch to BIC/FTC/TAF. At 48 weeks there was no treatment emergent resistance, and 94% vs 95% were virologically suppressed, respectively.  (Molina JM CROI 2018, Abstract O22)

Suppresseive INSTI or PI based regimen, to TAF/FTC/BIC

  • Randomized trial in Uganda, Russia, Thailand, US, DR among Women randomized to stay on baseline regimen of EVG/c/FTC/(TAF or TDF)(95%) or ATV/r+FTC/TDF(5%).  At 48 weeks 85% suppressed on baseline ART vs 96% on BIC/FTC/TAF. (Kityo et al. CROI 2018 Abstract 500)

Simplifying to DRV + EVG/c/TAF/FTC, from regimens with multi-class mutations

Early data suggests this may be an effective strategy; Consequently when there is multi-class resistance, we prioritized regimens that included EVG/c, DTG, or BIC (extrapolated data) with 2NRTI's and a boosted DRV.

Unpublished data (IDweek 2015):  Virally suppressed patients with baseline ≥2 ARV class mutations, but no INSTI mutations and no DRV mutations, were randomized to continue current regimen vs EVG/c/FTC/TAF plus DRV. At 48 weeks, 94% of patients on EVG/c/FTC/TAF + DRV maintained Vl <50 copies/mL vs 76% on their baseline regimen.[18]

Simplifying to DTG + NRTI

There is some evidence from treatment naïve patients that DTG + 3TC may be effective.  We considered the data to be sufficient to Apply a Base-Rank of 1.2 to regimens that included DTG plus an NRTI +/- an additional ARV.  While data is more limited, we also applied a base rank of 1.5 to scenarios of DTG+ an additional unspecified ARV. 

18 of 20 patients receiving 3TC/DTG dual therapy for initial treatment of HIV achieved virological suppression at week 48 in the PADDLE study, results of which were presented at EACS 2015.  

In the ANRS 167 LAMIDOL study, an open Label single arm study of switching from suppressive Triple ART to  DTG+3TC. Patients had to have viral suppression for greater than or equal to 2 years on first line ART with less than 2 ART modifications and have CD4>200.  101/104 maintained suppression at 48 weeks. There were 3 virologic failures, none with INSTI resistance.[19]  

The GEMINI studies (see education sheet for DTG+3TC) have suggested that DTG_3TC may be an acceptable regimen in patients that are newly initiating ARV's. We extrapolate this data to infer that this regimen may therefore be acceptable when already virally suppressed.

--Unresolved question: whether this regimen would be effective in patients with baseline 3TC resistance. 

  • In a retrospective analysis of the Antiertroviral Resistance Cohort Analysis Database (N=436), outcomes were assessed among those with HIV Vl<=50, who were switching to 3TC +PI/r (36% DRV, 24%ATV, 10% LPV+3TC) or 3TC+INSTI (29% DTG+3TC), and had M184V in hisotoric genotypes. At 3 years of follow up, there was no difference in risk of VF comparing those with and without M184V (p=.323), though higher amount of viral blips with M184V compared to without M184V(90% free of VB without M184V vs 79.8% free with M184V). (Gagliardini CROI 2018 Abstract 498)
Simplifying to DTG + NNRTI
  • There are two  phase III RCTS (SWORD1 and SWORD 2) that evaluated the strategy of switching from stable ARV regimens (2NRTIs + etiher PI, INSTI or NNRTI) to DTG plus RPV.  516 participants were randomized to dolutegravir-rilpivirine and 512 to continue with current regimen. At week 48, in the pooled analysis  95% of participants had viral loads lower than 50 copies per mL in each group (486 of 513 in the dolutegravir-rilpivirine group vs 485 of 511 in the current regimen group) and showed non-inferiorityThe most common adverse events were nasopharyngitis (49 [10%] for dolutegravir-rilpivirine vs 50 [10%] for CAR) and headache (41 [8%] vs 23 [5%]). More participants taking dolutegravir-rilpivirine (17 [3%]) reported adverse events leading to withdrawal than did participants taking CAR (three [<1%]).[20][21]
  • In an observational cohort at eight centers in Italy, 132 subjects were followed for median of 24 months on DTG + RPV.  Most were switched to this regimen for simplification (53%) or toxicity (35%), and nearly half had RT mutations and nearly half had PI mutations, and majority were virally suppressed at time of starting on to DTG +RPV.  At 24 weeks, all but one individual appeared virally suppressed [22].
  • In an open label cohort study switching virologically suppressed patients with multiple previous treatment failures to once daily RPV/DTG was found to be safe and effective through week 48. CD4 cell count remained stable after the switch, and the regimen was associated with improved liver function tests, improved lipid profile, and stable kidney function at 48 weeks [23].
  • Cabotegravir plus RPV: Latte I and II.  [24][25] These studies of long acting injectable cabotegravir have suggested that this regimen may be acceptable for maintance or simplification in patients that are virally suppressed.

 

We have applied a base-score change to 1.2 for DTG/RPV, if there is no history of treatment failure.  Otherwise, DTG+one other active drug is modified to a 1.5. 

 

New DHHS guidelines suggest that DTG/RPV may be an acceptable regimen in patients with virologic suppression without history of treatment failure.  As such, we assign a 'base-score' of 1.2 (preferred regimen) for DTG/RPV in suppressed patients without prior treatment experience or failure.  Given lack of data (but emerging data) on this regimen in patients with history of treatment failure, we prioritize it but not to the same degree  in such cases (base score of 2.0).  

Simplifying to DTG Monotherapy 

Pending more data, avoid DTG monotherapy, particularly if there is a history of INSTI exposures.

  • Unpublished, presented EACS 2015: Spanish study of 33 patients with suppression for at least 12 months on PI (67%) regimen, or NNRTI regimen (27%), or INSTI (6%) regimen, being simplified due to either comorbidities, drug interactions, side effects, or other resistance. 32/33 maintained virologic suppression at 24 weeks.
  • Unpublished, presented EACS 2015: Cohort study of 28 patients in Paris with long term virological suppression, and naïve or without history of failure to INSTI, were switched to DTG monotherapy.  3/28 experienced viral failure (all of whom had prior exposures to INSTI).
  • Dolumono study[26]:  In this rerospective single center cohort study, 31 patients on suppressive ART were switched to DTG monotherapy (with no known piror INSTI resistance or failure).  Prior ART included NNRTI, PI, or INSTI regimens (32%, 6%, and 61% respectively).  At 24 weeks, 94% had HIV RNA <50 copies/ml (all suppressed except 2).  One of those two developed a new INSTI mutation (Q148H//G140S).  
  •  DOMONO study was a multicenter Dutch randomized trial of 104 patients of DTG QD compared to continued ART in patients virally suppressed for at least 6 months (51 immediate switch, 53 delayed switch).  At week 24, dolutegravir monotherapy was non-inferior to combination ART, with VL> 200 copies per mL in 2% (1/50)  in the immediate switch group and in no patients in the delayed switch group . Eight (8%) of the 95 patients who remained on dolutegravir monotherapy had virological failure; all had therapeutic plasma concentrations of dolutegravir. In three (38%) of the eight patients, mutations associated with resistance were detected in the integrase gene. According to a predefined stopping rule, detection of these mutations led to premature study discontinuation..[27]

Switching or Simplifying to PI based regimens

Score Modification Rule
Switching to PI/r + 3TC, or INSTI+3TC, or PI + XXX

There is evidence that a boosted PI with 3TC/FTC can maintain viral suppression in ART naïve patients without baseline resistance, and in patients with viral suppression. There is also emerging evidence for other 3TC based dual therapies. We considered this evidence to be nearly on par with the evidence for a INSTI + 3TC, but felt data was stronger for DTG+3TC (or other ARV). We assigned a Base-Rank of 1.4 to regimens of DRV/r +NRTI, and 1.2 if switching from 2 NRTI+PI to PI +XTC.

ATV/r + 3TC, from ATV/r + 2 NRTI

  • The phase IV ATLASM study (Unpublished, EACS 2015), randomized virally suppressed patients receiving 2 NRTI + ATV/r to continue or switch to 3TC+ATV/r.  At 48 weeks, 90% switching maintained virologic suppression vs. 80% remaining on 2 NRTI + ATV/r.
  • The SALT trial randomly assigned 286 patients (143 [50%] to each group) with prior viral suppression, and no history of treatment failure or resistance, to 3TC+ATV/r vs 2NRTI+ ATV/r. At week 48 in the per-protocol population, 112 (84%) of 133 patients had virological response in the dual-treatment group versus 105 (78%) of 135 in the triple-treatment group (difference 6% [95% CI -5 to 16%), showing non-inferiority at the prespecified level. Treatment discontinuations were less frequent in the dual-treatment group (three [2%]) than in the triple-treatment group (ten [7%]; p=0·047) [28].

 

DRV/r + 3TC

  • In a retrospective analysis of 94 patients with at least six months of virological suppression (without evidence of resistance to 3TC or DRV) switched to 3TC plus DRV/r demonstrated continued virological suppression with a favorable safety profile [29].
  • In the DUAL-GESIDA trial [30] who were suppressed on a boosted DRV regimen, with no history of DRV mutations, were randomized to continue or transition to DRV/r+3TC. At 48 weeks, 88.9% participants in the dual therapy arm had HIV RNA below 50 copies/mL compared with 92.7% in those that continued baseline regimen (not statistically significant)

LPV/r + 3TC

  • The OLE study randomized 250 patients that were virally suppressed to continue 2NRTI+LPV/r (127 [51%] patients) or switch to dual treatment with 3TC+LPV/r (123 [49%] patients). 110 (86·6%) of 127 patients in the triple-treatment group responded to treatment versus 108 (87·8%) of 123 in the dual-treatment group, meeting the criteria for non-inferiority [31].

3TC based Dual therapy, despite M184V

 

  • In a retrospective analysis of the Antiertroviral Resistance Cohort Analysis Database (N=436), outcomes were assessed among those with HIV Vl<=50, who were switching to 3TC +PI/r (36% DRV, 24%ATV, 10% LPV+3TC) or 3TC+INSTI (29% DTG+3TC), and had M184V in hisotoric genotypes. At 3 years of follow up, there was no difference in risk of VF comparing those with and without M184V (p=.323), though higher amount of viral blips with M184V compared to without M184V(90% free of VB without M184V vs 79.8% free with M184V). (Gagliardini CROI 2018 Abstract 498)

PI plus second drug

  • In a multi center observational retrospective study of 376 individuals with virologic suppression on triple drug therapy, were simplified to PI + XXX (RAL, ETR, 3TC, or Tenofovir).  Mean followup was 73 weeks, and 10% developed failure. Using DRV/r was associated with lower risk of failure. [32]. Most common second drug was RAL.
  • Retrospective study of 131 heavily treatment experienced individuals who were simplified from their baseline regimen to PI+(TDF, RAL, or ETR).  Only 1.5% virologic failure at median of 14 months[33]
  • Retrospective study of 221 experienced patients were simplified to DRV/r + (RAL, MVC or ETR).  Prior to swtich only 39% were suppressed. High rates of virologic failure (34% at 2 years).  Lower failure rates if already virally suppressed (13% vs 25%). [34]
Switching to PI +INSTI
  • The combination of a boosted PI with an INSTI (DRV/r plus RAL) has been studied in ART-naive patients. At week 96, DRV/r plus RAL was noninferior to DRV/r plus TDF/FTC based on the proportion of patients achieving viral suppression. However, in patients with low pretreatment CD4 T lymphocyte counts (<200 cells/mm3) and high viral loads (>100,000 copies/mL), DRV/r plus RAL was inferior to DRV/r plus TDF/FTC.  The efficacy of this regimen in virally suppressed patients is not known. Raffi F, Babiker AG, Richert L, et al. Ritonavir-boosted darunavir combined with raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults infected with HIV-1: 96 week results from the NEAT001/ANRS143 randomised noninferiority trial [35].

  • KITE study:  60 HIV infected adults with plasma HIV-1 RNA <50 copies/ml were randomized to continue their NRTI based therapy or to start on LPV/r + RAL. At 48 weeks 92% of the LPV/r/RAL arm and 88% of the sHAART had HIV-RNA < 50 copies/ml. There were no serious adverse events in either arm. There were no differences between arms in bone mineral density, total body fat composition, creatinine clearance, or CD4 T cell counts at week 48.

  • In the HARNESS study, virologically suppressed patients switched to a regimen consisting of ATV/r plus RAL or ATV/r plus TDF/FTC. This regimen switch was associated with higher rates of virologic failure and treatment discontinuations than switching to ATV/r plus  TDF/FTC. A regimen consisting of ATV/r plus RAL cannot currently be recommended [36].

  • In an observational cohort in Italy, 113 patients on DTG + DRV/r were followed, most of whom had baseline NRTI mutations, and PI mutations (12 also had INSTI mutations). The percentage of viremic patients declined from baseline to week 24 from 43% to 6% [22].

  • In an observational study, 82 individuals simplified from 2NRTI's plus boosted PI to DRV/r+RAL dual therapy.  At 48 weeks, 93% acheived virologic suppression in the intent to treat analysis, and 98% in the per protocol analysis. Main reason for switch was NRTI toxicity.  There were reductions in tubulra proteinuria, TG values, and increase in phosphoremia. 
Simplifying to PI Monotherapy

The DHHS guidelines recommend against simplification to a boosted PI monotherapy regimen. A systematic review has suggested lower rates of long term side effects, but there may be an increased risk of virologic failure.[37]In a meta-analysis of 2303 patients in 13 randomized trials, HIV suppression was lower in the PI/r monotherapy arm comared with triple therapy arm[38]

  • Monet: 256 patients with a viral load of < 50 HIV-1 RNA currently on suppressive ART (57% on PI regimen) for at least 6 months were switched to either DRV/r monotherapy or DRV/r plus two NRTI’s. By week 144, viral suppression was was 69% vs. 75% in the DRV/r monotherapy and triple therapy arms [difference= -5.9%; 95% confidence interval (CI) -16.9%, +5.1%]; by a strict ITT analysis (switches not considered failures), viral suppression was 84% vs. 83.5%. There was non-inferiority in strict ITT, but not in TLOVR (switch=failure) analysis.[39].  Those who experienced virologic rebound after switch to monotherapy, were likely to suppress if reintensified with NRTI backbone.[40]
  • In the MONOI-ANRS 136 trial of maintenance monotherapy in patients with suppressed HIV RNA viremia. 225 patients were randomized to receive DRV/r monotherapy or DRV/r triple drug regimen. TAt week 96, in intent-to-treat analysis, 91/103 patients (88%, 95% CI 81-94) allocated to the darunavir/ritonavir monotherapy arm and 87/104 patients (84%, 95% CI 75-90) allocated to the darunavir triple-therapy arm achieved an HIV-1 viral loadNo resistance emerged to protease inhibitors and the two groups did not differ in the number of serious adverse events.[41]
  • PROTEA: RCT  of patients suppressed on first line ARV's, switch to DRV monotherapy (137) or DRV+2NRTI (136).  In the primary efficacy analysis, the percentage of patients with HIV-1 RNA < 50 copies/mL by week 96 [intent to treat (ITT)] was lower in the DRV/r monotherapy arm (103 of 137 patients; 75%) than in the triple therapy arm (116 of 136 patients; 85%) [difference -10.1%; 95% confidence interval (CI) -19.5, -0.7%]. In the switch-included analysis, monotherapy was noninferior to triple therapy. In a post hoc analysis, for patients with nadir CD4 count ≥ 200 cells/μL, rates of HIV-1 RNA suppression were 82 of 96 patients (85%) in the DRV/r monotherapy arm and 88 of 106 patients (83%) in the triple therapy arm. No treatment-emergent primary protease inhibitor mutations were detected in either arm.[42]
  • PIVOT: Pragmatic randomized trail in the UK of patietns suppressed for at least 24 weeks, randomized to continue current regimen (Ongoing Therapy, OT), vs boosted DRV or LPV monotherapy. Virologic rebound occurred in 35% of those on Monotherapy, vs. 3.2% in those on OT.  All patients had resuppression if reinitiated on triple therapy. But one or more future drug options had been lost in two participants (Kaplan-Meier estimate 0·7%) in the OT group and six (2·1%) in the PI-mono group: difference 1·4% (-0·4 to 3·4); non-inferiority shown. [43]
  • Of 529 patients virologically suppressed who switched to a boosted protease inhibitor monotherapy individuals with less than 1 year of prior sustained virological suppression were more likely to experience virological failure on boosted protease inhibitor monotherapy (BPIMT) for a duration of 12-23 months and 24 months or more. Rates of failure were similar for BPIMT with lopinavir-ritonavir or darunavir-ritonavir, but increased for BPIMT with atazanavir-RTV [44].
  • In another study 131 HIV-1 infected patients who switched to a maintenance dual antiretroviral regimen containing a boosted PI were followed for a median of 14 months. Virological failure rate was 90.1%. Two patients had virological failure and 11 discontinued treatment due to side effects or were lost to follow-up [33]

Switching or Simplifying to NNRTI based regimens

Score Modification Rule
Switching to RPV based regimens from EFV or boosted PI regimens

Switching from EFV to RPV

A phase 2b, open-label, multicenter study evaluated the efficacy and safety of switching from EFV/FTC/TDF (≥3 months duration) to RPV/FTC/TDF. At weeks 12 and 24, all 49 dosed subjects remained suppressed on RPV/FTC/TDF. At week 48, 46 (93.9%) subjects remained suppressed and virologic failure occurred in 2/49 (4.1%) subjects with no emergence of resistance [6].

Switching from a boosted PI to RPV

In an RCT of switching from 2NRTI +PI/r in virally suppressed patients to TDF/FTC/RPV, primary objective of noninferiority at week 24 was met(11): 93.7% of RPV/FTC/TDF versus 89.9% of protease inhibitor+RTV+ Through week 48, 89.3% of participants in the immediate 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 [11]

Switching from boosted PI or NNRTI therapy to EFV/TDF/FTC
The A1266-073 study randomized suppressed patients on NNRTI or PI based therapy to stay on their regimens or switch to TDF/FTC/EFV, and found that switching to TDF/FTC/EFV was non-inferior with regards to virologic suppression, and had benefits of improvements in TG and quality of life measurements [45].

Switching or Simplifying to EI based regimens

Score Modification Rule
Switching to a Boosted PI + Maraviroc, from Boosted PI + 2 NRTI 
Not recommended.  In the MARCH study [46], patients with R5 tropic virus, who were virally suppressed on 2NRTI + 1 PI/r, were randomized to MVC + PI/r.  Patients switched to the MVC + PI/r regimen had lower rates of maintaining viral suppression (84%) , compared to 98% who continued on the 2 NRTI + 1  PI regimen.