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Accounting for a Non-suppressed Viral Load

 

Individuals with a Non-Suppressed Viral Load includes those that are Treatment Naive and Treatment experienced.  By default, HIVASSIST considers the user inputted scenario to be one of Treatment Naive patients if no regimens are entered in the Treatment History or Current Treatment boxes.  When there is a Current Treatment along with a detectable viral load, HIVASSIST interprets the scenario to represent a case of treatment failure.  Please see Methodology related to Mutations regarding HIVASSIST assumptions about the potential for undetected or archived resistance.  In the base-case scenario (i.e. no specific options selected), HIVASSIST produces results calibrated to the current DHHS and IAS-USA guidelines for 'Recommended Regimens in most scenarios' for Treatment Naive patients. 

HIVASSIST further assesses a number of additional 'rules' based on the literature related to the management of treatment-experienced patients.  These 'score modifications' are outlined below.

NRTI Rules

Score Modification Rule
We penalized ABC/3TC + (NNRTI or PI) if the viral load was high or unknown. We penalized NRTI backbone regimens in the context of known TAMS and less active drugs

Based on clinical trial data, we prioritized the usage of tenofovir with XTC over ABC/3TC except if paired with INSTI

Thymidine Associated Mutations can compromise the activity of some NRTIs.  In heavily treatment experienced patients HIVASSIST conservatively considers the possibility that not all TAMS may be evident on available genotypes.  Consequently, in addition to mutation penalties, we included penalization of regimens with a compromised NRTI backbone further when part of regimens with fewer active drugs with the consideration that any observed NRTI activity may not be fully representative of underlying resistance.  We penalized such regimens more heavily if there was evidence of TAM pathway 1 mutations compared to pathway 2.

NNRTI Rules

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
Given the low barrier to resistance, we penalized all NNRTI containing regimens after a history of NNRTI treatment failure, unless there were at least 2 fully active other drugs.
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 or c)2NRTI + 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)INSTI+PI or 2NRTI +PI:  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%)[1]  

2)2NRTI+PI or PI+INSTI:  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[2]

3)PI+INSTI: 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[3]

4)2NRTI+PI:  In the STAR study[4] 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[5] 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.

8)2NRTI+INSTI: In the DAWNING randomized trial in 13 countries, participants failing first line ARV regimens containing NNRTI were randomized to DTG or LPV/r anchored therapy with 2 NRTI.  At week 48, 84% vs 70% of indivdiuals achieved virologic suppression in the DTG and LPV/r arms respectively.  There were also more favorable adverse event profiles in the DTG arms. [6]

 

 

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

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%)[1]  

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[2]

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[3]

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

Given the low barrier to resistance, and recommendations against usage of RPV based regimens with high viral loads, we penalize regimens containing 2 NRTI+RPV for treatment naive and experienced patients with viral load>100,000

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 (ARTEMIS study[8][9], [10]).  A systematic review has suggested that maintaining the same regimen, with improved adherence, may be effective [11]. PI resistance in this setting are also relatively rare ([12], [9], [13]).  As such, our algorithm prioritizes continuing the PI based regimen, or switching to a non-PI regimen with at least 2 fully active agents.

INSTI Rules

Score Modification Rule
We prioritized switching to 2 NRTI + PI +/- another ARV or PI + DTG +/- another ARV after treatment failure on an INSTI regimen; We penalize usage of BIC given lack of data in the setting of prior INSTI failure

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[14][15][16].  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.  In the absence of data on usage of BIC/TAF/FTC after treatment failure, we penalized this regimen in the setting of prior failure on an INSTI regimen

Also, see section on INSTI+PI below.

We penalized INSTI + PI if the viral load was high or unknown
  • In the NEAT001/ANRS143 (N = 805) trial of Naive patients, DRV/r plus RAL was noninferior to TDF/FTC+DRV/r, but had lower efficacy in patients with high HIV-1 RNA/low CD4+ cell counts.
  • Efficacy in Clinical Trials

    Trial Name

    Drugs Compared

    Participants

    Study Results

    Tivista

    DRV/r+DTG (1 arm)

    113 tx-experienced

    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 [17].

    Other Evidence in support of 1 INSTI + 1 PI:

    Trial

    Regimen

    Population

    Result

    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[18]

    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[19]

    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[20]

    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%[21]

    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.[22]

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 2019).  DHHS panel recommends that "ideally, a new ARV regimen should contain at least two, and preferably three, fully active drugs, which should be selected after considering the patient’s ART history and current and previous resistance test results and whether an ARV drug with a new mechanistic action is available (AI). When constructing a salvage regimen, it is more important to consider drug potency and viral susceptibility based on cumulative genotype data than the number of component drugs."  

In general, we prioritized drugs with higher barrier to resistance (DTG, DRV), and escalated penalties for fewer active drugs in individuals with a history of treatment failure.  We note the OPTION to further augment these penalties in individuals with intermittent adherence--when these options are selected, HIVASSIST prioritizes inclusion of regimens with more active drugs.  

 

SALVAGE: In situations where there is multi-class resistance, we considered the inclusion of drugs with partial or no activity. The guidelines note that partially active drugs may be used when no other options are available. In such situations, there may be benefit to even partial reduction in viral load.  Studies have suggested that even partial virologic suppression can have clinical benefit in terms of delayed disease progression.  In general, we did not consider there to be sufficient data to suggest inclusion of a resistant NNRTI.  We allowed inclusion of boosted PI's and INSTIs and some NRTIs in such situations.  

Among regimens with fewer active drugs, we prioritized those that contained fully active DRVDTG, or BIC

In the DAWNING trial, 627 patients failing first line NNRTI regimens (> 6 months) with at least one active NRTI were randomized to 2WHO recommended NRTIs + DTG VS. 2NRTI's +LPV/RTV.  WHO recommend ZDV + 3TC after failure of first-line TDF + 3TC or FTC; TDF + 3TC or FTC after first-line ZDV or d4T + 3TC.At Week 24, DTG+2NRTIs was superior to LPV/r+2NRTIs, with 82%  and 69%, respectively, achieving HIV-1 RNA <50 c/mL (p<0.001). The difference was mainly driven by lower rates of Snapshot virologic non-response in the DTG group. 56% (347/624) of subjects received WHO-recommended second-line NRTIs, and their response rates within each arm were higher than those for subjects who did not. Regardless of WHO-recommended NRTI use, response rates were higher with DTG versus LPV/r-based regimens (Table).  In this analysis, there were no treatment-emergent primary integrase-strand transfer inhibitor or NRTI resistance mutations in the DTG group through the randomisation phase.

In a Swedish cohort of 244 patients with preexisting NRTI's and DTG (with a control cohort of PLWH on PI/r and one or two NRTI's with matched genotype susceptibility scores) were followed.  Median observation time was 78 weeks (interquartile range 50–98 weeks) for participants on DTG and 75 weeks (50–101 weeks) for individuals on PI/r. Viral failure was detected in four individuals treated with DTG and three individuals treated with PI/r, resulting in similar success rates of 96.7% and 97.5%, respectively. No new mutations were found among participants with treatment failure. DTG in combination with one to two NRTIs was as efficient as PI/r in individuals with pre-existing NRTI mutations in this setting. (Sorstedt et al. May 2018 IJAA)

In the POWER1 and POWER2 studies, individuals with a history of treatment failure were randomized to varying PI based regimens. Approximately 83% of those with baseline viremia <20,000 suppressed, with overall 45% suppression and 61% with at least one log decline at 48 weeks when given DRV/b (with lower response rates with other PI regimens).  In particular there was a higher rate of achieving undetectable viral load when there was <=1 primary DRV mutation, but 26% also achieved virologic suppression despite >=3 DRV associated mutations. Consequently we prioritized inclusion of DRV in individuals with a history of treatment failure.[23]


References