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Accounting for a Non-suppressed Viral Load

We incorporate the following score modifications if a patient is noted to have a non-suppressed viral load. [1]

We exclude EFV-containing regimens if there is a history (or current use) of EFV and the patient is not virally suppressed. We add a further penalty for NNRTI-containing regimens if the patient has a history of non-EFV NNRTI use and is not currently virally suppressed if there are less than two fully-active non-NNRTI drugs in the regimen (see below). 

NRTI Rules

Score Modification Rule
We penalized ABC/3TC + (NNRTI or PI) if the viral load was high or unknown
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Score Modification Rule
With history of treatment failure on NNRTIs, we penalized regimens with insufficient additional drugs with high barrier of resistance with concurrent use of an NNRTI
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We prioritized switching to 2 NRTI + PI +/- another ARV or 2 NRTI + INSTI +/- another ARV after treatment failure on an NNRTI regimen

In patients failing NNRTI therapy, there are clinical trial data to support the usage of: a)PI + NRTI or b)PI + INSTI. While this data is primarily for 2NRTI + LPV/r, or LPV/r + RAL, we have extrapolated to include other PIs (Baheyngyi et al) and INSTIs that may be better tolerated and with easier dosing schedules.

1)In the SECOND-LINE trial of 541 patients that had failed a first line NNRTI-based regimen, patients received either LPV/r + NRTI backbone (control) vs LPV/r + RAL, and both had comparable rates of viral suppression at 48 weeks (83% vs 81%)[2]  

2)Similar results were observed in the EARNEST trial(Paton et al., 2014) of 1277 patients failing first line NNRTI based regimens in sub-Saharan Africa; patients received PI monotherapy vs 2NRTI + LPV/r vs LPV/r + RAL. PI monotherapy did not meet criteria for non-inferiority, but the alternative regimens were non-inferior to each other, with 60% viral suppression and 64% viral suppression in the 2NRTI+PI and PI+INSTI arms, respectively[3]

3)Similar results were again seen in the phase III SELECT trial of 515 patients failing NNRTI based regimens, where LPV/R + RAL was non-inferior to LPV/R +NRTI[4]

4)In the STAR study[5] of 195 patients failing NNRTI-based regimens, many of them with M184V, TDF/3TC+LPV/r was superior with respect to viral suppression (83%) at 48 weeks, compared to LPV/r monotherapy.

6)Some experts would avoid a strategy of using less than 3 active drugs in this setting, except when including a boosted PI.

7) Evidence against the usage of NRTI + INSTI comes from the SWITCHMARK[6] study in which patients that were virally suppressed on a boosted PI that had their PI switched to RAL experienced more viral rebound (Viral suppression 84%) compared to those that stayed on a boosted PI (91%).  Whether this finding applies to DTG is unknown. These data suggest that a boosted PI +NRTI may be able to lead to adequate viral suppression even with compromised NRTI backbones, whereas perhaps a compromised background is not optimal when pairing NRTI with some INSTI such as RAL in viremic patients.In the SPIRAL study and VIKING-3 studies, DTG appeared to lead to viral suppression in a large proportion of patients that had multi class resistance.

We prioritized switching to PI + INSTI +/- another ARV after treatment failure on an NNRTI regimen
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We penalized switching to 2 NRTI + ETR +/- another ARV after treatment failure on an NNRTI regimen

5)Combining NRTIs with other NNRTI’s in patients failing first line NNRTI regimens has been shown to have suboptimal responses. Ruxrunghtam et al showed that in patients experiencing NNRTI failure, receipt of NRTI + ETR had lower rates of virological responses at week 12 compared to a strategy of NRTI + PI[7] 

We penalized 2 NRTI + RPV if the viral load was high or unknown

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PI Rules

Score Modification Rule
We prioritized remaining on 2 NRTI + PI +/- another ARV or switching to 2 NRTI + INSTI +/- another ARV after treatment failure on an PI regimen

When failing a boosted PI based regimen, failure is often due to poor adherence, drug-drug interactions, or drug-food interactions.

When failing a boosted PI + NRTI regimen, several studies have shown limited resistance to XTC (Lathouwers 2011, Stebbing 2007).  A systematic review has suggested that maintaining the same regimen, with improved adherence, may be effective (Zheng 2014). PI reseistance in this setting are also relatively rare (Daar 2011, Orkin 2013, Molina 2010).  As such, our algorithm prioritizes continuing the PI based regimen, or switching to a non-PI regimen with at least 2 fully active agents.


Score Modification Rule
We prioritized switching to 2 NRTI + PI +/- another ARV or PI + DTG +/- another ARV after treatment failure on an INSTI regimen
There is currently limited data on managing patients with first line failure of 2NRTIs + 1 INSTI.  In patients receiving 2NRTI + RAL, or 2NRTI + EVG/c, there may be emergent resistance to XTC and possibly the INSTI, but may retain sensitivity to DTG[8][9][10].  Failing in this scenario is often due to poor adherence.  DHHS guidance suggests that one can likely extrapolate based on NNRTI failure datea, suggesting that a boosted PI plus NRTI, or a PI plus INSTI (assuming no INSTI resistance) can be considered.  
We penalized INSTI + PI if the viral load was high or unknown
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Active Drug Rules

Score Modification Rule
In treatment experienced patients with detectable viral loads, we severely penalized regimens with ≤ 1 active drugs and moderately penalized regimens with > 1 but < 2 active drugs. We slightly penalized regimens with ≥ 2 but < 3 active drugs and prioritized regimens with 3 or more active drugs.
Overall, the goal of treatment in ART experienced patients experiencing virologic failure is to establish virologic suppression (DHHS Guidelines 2016).  DHHS panel recommends that "at least 2, and preferably three full active agents" should be included, in which a "fully active agent is one that is expected to have uncompromised activity on the basis of the patient’s treatment history and drug-resistance testing results and/or the drug’s novel mechanism of action"
We additionally prioritized two drug regimens that contained fully active DTG or DRV
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