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Indirect Treatment Comparisons of Lenacapavir Plus Optimized Background Regimen Versus Other Treatments for Multidrug-Resistant Human Immunodeficiency Virus

Open AccessPublished:December 22, 2022DOI:https://doi.org/10.1016/j.jval.2022.12.011

      Highlights

      • Available evidence on the efficacy and effectiveness of different therapies in heavily treatment-experienced people with human immunodeficiency virus (HIV) is sparse.
      • This is the first analysis that provides comparative treatment estimates that can be used alongside other outcomes to support decisions regarding the care of people with multidrug-resistant HIV.
      • We have shown that lenacapavir + optimized background regimen is favored over key comparators in terms of achieving virologic suppression and therefore has potential to reduce the burden associated with virologic failure in people with multidrug-resistant HIV.

      Abstract

      Background/Aims

      Heavily treatment-experienced (HTE) people with human immunodeficiency virus (HIV) (PWH) may not achieve virologic suppression (VS) with combination antiretroviral therapy due to multidrug resistance (MDR), intolerance, and safety concerns. These PWH often receive highly individualized treatment regimens, but these regimens may not enable PWH to achieve VS, thereby halting disease progression. Novel medications are required for treating individuals with MDR HIV. Lenacapavir (LEN), a first-in-class HIV capsid inhibitor, is under investigation for the treatment of HTE individuals with MDR HIV in the phase 2/3 CAPELLA study. This study aimed to compare LEN plus optimized background regimen (OBR) with fostemsavir (FTR) + OBR, ibalizumab (IBA) + OBR, and OBR alone in terms of VS, CD4 cell count change from baseline, immunologic recovery, and discontinuation due to adverse events, using indirect treatment comparisons.

      Methods

      A systematic review identified clinical evidence on HIV-1 treatments in HTE PWH. A feasibility assessment evaluated the identified studies for indirect treatment comparison analyses based on population characteristics, interventions, comparators, and outcomes of interest. Unanchored simulated treatment comparisons of LEN + OBR versus comparators were conducted.

      Results

      LEN + OBR had 6.57 times higher odds of VS at weeks 24 to 28 than FTR + OBR (95% confidence interval [CI] 1.34-32.28), 8.93 times higher odds of VS than IBA + OBR (95% CI 2.07-38.46), and 12.74 times higher odds of VS than OBR alone (95% CI 1.70-95.37). Change from baseline in CD4 cell count was similar across LEN + OBR, FTR + OBR, and IBA + OBR.

      Conclusion

      LEN + OBR has statistically significantly greater odds of VS at weeks 24 to 28 than its comparators and represents a novel treatment for people with MDR HIV.

      Keywords

      Introduction

      Human immunodeficiency virus (HIV) is a retrovirus that specifically targets immune cells (particularly CD4 cells). If untreated or poorly controlled, HIV infection can lead to the depletion of CD4 cells, an impaired immune system, and, ultimately, the development of acquired immunodeficiency syndrome.
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      These markers are also important in assessing the efficacy of antiretroviral (ARV) treatments, which prevent HIV replication and result in virologic suppression (VS), while also restoring CD4 cell count and immune functioning.
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      Heavily treatment-experienced (HTE) individuals make up a very small proportion of people with HIV (PWH) (< 1% estimated in the United States in 2012 through 2017).
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      To maximize the probability of achieving VS in this population, highly individualized treatment regimens, also described as optimized regimens, are constructed using the individuals’ treatment profiles (including present and past resistance test results, ARV tolerability, past adherence, and potential for drug-drug interactions).
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      These regimens may include drugs with either partial activity, poorer tolerability profiles or both. The specific drug combinations used in optimized regimens are complex, and the construction of these regimens and subsequent care of HTE PWH impose a disproportionate healthcare resource use burden compared with the general HIV population.
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      HTE PWH are also at risk of transmitting MDR HIV to others, further exacerbating the associated burden.
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      Lenacapavir (LEN; GS-6207) was recently licensed in this indication in Europe and is under review by the US Food and Drug Administration at the time of the current analysis.
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      , LEN is a first-in-class, long-acting injectable inhibitor of HIV that disrupts the viral capsid, the protein shell that is essential for multiple stages of the viral life cycle.
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      LEN has no cross-resistance to ARVs from other classes and is fully active against MDR HIV due to its novel mechanism of action.
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      The clinical benefit of LEN in HTE PWH is under investigation in the CAPELLA study, a phase 2/3 multicenter trial with a randomized and a nonrandomized cohort. In the CAPELLA study, LEN was administered in combination with an optimized background regimen (OBR), a term used for optimized regimens in clinical trials to differentiate them from the experimental agents used in the trial.
      Study to evaluate the safety and efficacy of lenacapavir in combination with an optimized background regimen in heavily treatment experienced participants living with HIV-1 infection with multidrug resistance (Capella, NCT04150068). ClinicalTrials.gov.
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      There is currently a lack of evidence on the relative benefits of the various treatment options for HTE PWH, partly due to the challenges faced when comparing differently defined HTE populations across studies, the heterogeneity in the treatment landscape and complexity of treatment regimens used by HTE PWH. Comparative estimates for the relative efficacy and safety of different treatments could be used alongside other outcomes such as resistance profiles and health-related quality of life (HRQoL), and factors related to the broader healthcare environment to support treatment decisions in the management of HTE individuals. We conducted indirect treatment comparisons (ITCs) to obtain comparative estimates of LEN + OBR versus FTR + OBR, IBA + OBR, and OBR alone in HTE PWH. The analyses aimed to systematically identify and synthesize all relevant clinical evidence regarding key efficacy and safety measures: VS, change from baseline in CD4 cell count (CFB CD4), immunologic recovery, and discontinuation due to AEs. Comparative estimates were obtained for the outcomes for which analyses were deemed feasible.

      Methods

      Systematic Literature Review

      A de novo systematic literature review (SLR) was conducted in January 2021 and subsequently updated in January 2022 to identify studies assessing ARV treatments in HTE PWH. MEDLINE, Embase, the Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Database of Abstracts of Reviews of Effect were searched on January 12, 2021 (original SLR), and again on January 5, 2022 (SLR update). These searches were complemented by hand-searches of gray literature sources including clinical trial registries, conference proceedings from December 2018 to December 2021, and reference lists of relevant SLRs and meta-analyses.
      Studies were included if they reported on relevant HTE PWH populations, were interventional, had a last data collection date from 2007 onward (aligning with the introduction of integrase strand transfer inhibitors into routine clinical practice),
      • Spivack S.
      • Pagkalinawan S.
      • Samuel R.
      • Koren D.E.
      HIV: how to manage heavily treatment-experienced patients.
      and reported efficacy, safety, and tolerability or HRQoL data in HTE PWH. A protocol amendment was implemented to limit the included studies to those reporting on individuals meeting the high-priority definitions of HTE PWH and studies conducted mostly in high-income or upper middle-income countries,
      High income countries data. The World Bank.
      ,
      Upper middle income countries data. The World Bank.
      ensuring that the included study populations and healthcare systems were relatively similar to each other and the CAPELLA study population, to maximize the homogeneity of the populations for the ITCs. The subsequent SLR update used the amended eligibility criteria from the start (full eligibility criteria are presented in Appendix Table 1 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.12.011 along with the detailed search strategies in Appendix Tables 2-7 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.12.011). Abstracts and full texts were reviewed against the eligibility criteria by 2 independent reviewers, as per Cochrane recommendations (details of included, deprioritized and excluded studies provided in Appendix Tables 8-10 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.12.011).
      • Higgins J.
      • Thomas J.
      • Chandler J.
      • et al.
      Cochrane handbook for systematic reviews of interventions, version 6.3. Cochrane Training.
      Data extraction was performed in line with guidelines from the University of York’s Centre for Reviews and Dissemination.
      Centre for Reviews and Dissemination
      Systematic Reviews: CRD’s Guidance for Undertaking Reviews in Health Care.
      Study quality was assessed using the Cochrane risk of bias tool-2 for randomized controlled trials (Appendix Table 11 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.12.011)
      • Higgins J.P.T.
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      The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.
      and the Cochrane ROBINS-I tool for nonrandomized controlled trial interventional studies (Appendix Table 12 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.12.011).
      • Sterne J.A.
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      Robins-I: a tool for assessing risk of bias in non-randomised studies of interventions.

      Feasibility Assessment

      Studies identified through the SLR were assessed for their suitability for inclusion in comparative analyses based on study design, similarity of participant baseline characteristics to that of the randomized cohort of the CAPELLA study, interventions investigated (FTR + OBR, IBA + OBR, OBR alone), outcomes, and timepoints reported. To assess the key measures of treatment efficacy and safety for people with MDR HIV, the following outcomes were assessed: VS (defined as < 40 or < 50 copies/mL), CFB CD4, immunologic recovery (defined as the proportion of participants whose CD4 cell count increased above a specific threshold, for example, 200 cells/mm3; changes in CD4 cell count within a specified time period; or any other definition of immunologic recovery as specified by the authors), and discontinuation due to AEs, reported at weeks 24 to 28.

      Indirect Treatment Comparisons

      Individual participant data (IPD) from the randomized cohort of the CAPELLA study and aggregated data identified in the SLR were used to conduct ITCs of LEN + OBR versus comparators using unanchored simulated treatment comparison (STC) methodology for population adjustment. Studies were grouped into separate analyses according to their reported treatment arms: FTR + OBR,
      • Kozal M.
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      Fostemsavir in adults with multidrug-resistant HIV-1 infection.
      IBA + OBR,
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      Outcomes of patients not achieving primary endpoint from an ibalizumab phase III trial [Conference abstract].
      ,
      • Towner W.
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      Long-term efficacy, safety, and durability of ibalizumab-based regimens in subgroup of TMB-202 participants.
      and OBR alone
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      • et al.
      Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial.
      ,
      • Anis A.H.
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      • Sun H.
      • et al.
      Quality of life of patients with advanced HIV/AIDS: measuring the impact of both AIDS-defining events and non-AIDS serious adverse events.
      ,
      • Lazzarin A.
      • Campbell T.
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      Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial.
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      Immunological success is predicted by enfuvirtide but not interleukin-2 therapy in immunodepressed patients.
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      Lack of benefit of 3-month intensification with enfuvirtide plus optimized background regimen (OBR) versus OBR alone in patients with multiple therapeutic failures: the INNOVE study.
      Trial of maraviroc (UK-427,857) in combination with optimized background therapy versus optimized background therapy alone for the treatment of HIV-1 infected subjects (MOTIVATE 1) NCT00098306. ClinicalTrials.gov.
      Trial of maraviroc (UK-427,857) in combination with optimized background therapy versus optimized background therapy alone for the treatment of HIV-1 infected subjects (MOTIVATE 2) NCT00098722. ClinicalTrials.gov.
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      A randomized study to evaluate injection site reactions using three different enfuvirtide delivery mechanisms (the OPTIONS study).
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      Vicriviroc in combination therapy with an optimized regimen for treatment-experienced subjects: 48-week results of the VICTOR-E1 phase 2 trial.
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      Safety and efficacy of enfuvirtide in combination with Darunavir-ritonavir and an optimized background regimen in treatment-experienced human immunodeficiency virus-infected patients: the below the level of quantification study.
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      Effect of raltegravir on the total and unintegrated proviral HIV DNA during raltegravir-based HAART.
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      (Table 1
      • DeJesus E.
      • Emu B.
      • Weinheimer S.
      • Cohen Z.
      • Cash B.
      • Lewis S.
      Outcomes of patients not achieving primary endpoint from an ibalizumab phase III trial [Conference abstract].
      ,
      • Kozal M.
      • Aberg J.
      • Pialoux G.
      • et al.
      Fostemsavir in adults with multidrug-resistant HIV-1 infection.
      ,
      • Towner W.
      • DeJesus E.
      • Schrader S.
      • et al.
      Long-term efficacy, safety, and durability of ibalizumab-based regimens in subgroup of TMB-202 participants.
      ,
      • Morand-Joubert L.
      • Ghosn J.
      • Delaugerre C.
      • et al.
      Lack of benefit of 3-month intensification with enfuvirtide plus optimized background regimen (OBR) versus OBR alone in patients with multiple therapeutic failures: the INNOVE study.
      ). For LEN + OBR versus IBA + OBR, 2 comparisons were conducted: given that TMB-301 was the phase 3 study of IBA + OBR in people with MDR HIV used to inform IBA’s US and European licenses, the comparison with TMB-301 was considered the base case analysis and the comparison with the phase 2 TMB-202 study was considered a sensitivity analysis. For studies reporting on OBR, treatment arms consisting of OBR alone were selected for a base case analysis. For all studies in which participants received an investigational agent (darunavir [DRV], dolutegravir, enfuvirtide, maraviroc, raltegravir, ritonavir) in addition to an OBR, only the placebo + OBR arms were used for the OBR alone base case comparisons. Meta-analyses were performed to generate pooled estimates of baseline characteristics and the treatment outcomes analyzed in the ITCs for the studies reporting on OBR alone.
      Table 1Details of pairwise comparisons and the input data for the ITCs.
      Comparator treatmentAim of comparisonBaseline variables adjusted for in the STCsInput data for the ITCs
      Source of input dataVS at week 24-28, % (95% CI)Mean (SD) CFB CD4 at week 24-28, cells/mm3
      FTR + OBRComparative estimate of LEN + OBR vs FTR + OBRViral load, CD4 cell count, number of fully active agents in the OBR, ageBRIGHTE,
      • Kozal M.
      • Aberg J.
      • Pialoux G.
      • et al.
      Fostemsavir in adults with multidrug-resistant HIV-1 infection.
      FTR + OBR, all randomized participants
      57 (NR)90.4 (6.8)
      IBA + OBR (base case)Comparative estimate of LEN + OBR vs IBA + OBR, using results from the licensing trial for IBA + OBRViral load, CD4 cell count, number of previous ARV agents, OSS scoreTMB-301,
      • DeJesus E.
      • Emu B.
      • Weinheimer S.
      • Cohen Z.
      • Cash B.
      • Lewis S.
      Outcomes of patients not achieving primary endpoint from an ibalizumab phase III trial [Conference abstract].
      IBA 800 mg Q2W + OBR
      43 (NR)62.4 (16.7)
      IBA + OBR (sensitivity)Validation of base case results for LEN + OBR vs IBA + OBRViral load, CD4 cell count, years since HIV diagnosis, ageTMB-202,
      • Towner W.
      • DeJesus E.
      • Schrader S.
      • et al.
      Long-term efficacy, safety, and durability of ibalizumab-based regimens in subgroup of TMB-202 participants.
      IBA 800 mg Q2W + OBR
      44 (NR)36.5 (8.2)
      OBR alone (base case)Comparative estimate of LEN + OBR vs OBR alone, using only treatment arms that reported on OBR aloneViral load, CD4 cell count, ageMeta-analysis estimate from base case analysis47.89 (30.15-66.17)67.4 (6.3)
      OBR alone (SA1)Validation of base case results for LEN + OBR vs OBR alone after the inclusion of additional treatment arms with investigational agentsViral load, CD4 cell count, ageMeta-analysis estimate from SA151.66 (41.59-61.60)85.0 (4.9)
      OBR alone (SA2)
      SA2 and 3 aimed to partly address the differences in OBR composition, by excluding studies for which DRV was not permitted in the OBR, given that inclusion of DRV was suspected to lead to better response rates in participants.
      Validation of base case results for LEN + OBR vs OBR alone after the removal of studies in which DRV was not permitted in the OBR (studies enrolling participants before DRV’s approval in 2006 were removed from base case)Viral load, CD4 cell count, ageMeta-analysis estimate from SA257.31 (37.59-74.94)83.5 (9.7)
      OBR alone (SA3)
      SA2 and 3 aimed to partly address the differences in OBR composition, by excluding studies for which DRV was not permitted in the OBR, given that inclusion of DRV was suspected to lead to better response rates in participants.
      Validation of base case results for LEN + OBR vs OBR alone after the inclusion of additional treatment arms with investigational agents and the removal of studies in which DRV was not permitted in the OBR (studies enrolling participants before DRV’s approval in 2006 were removed from SA1)Viral load, CD4 cell count, ageMeta-analysis estimate from SA357.60 (45.01-69.28)87.0 (5.6)
      OBR alone (SA4)
      SA4 was only performed for the CFB CD4 analysis.
      Validation of base case results for LEN + OBR vs OBR alone for CFB CD4, after the removal of the INNOVE study,
      • Morand-Joubert L.
      • Ghosn J.
      • Delaugerre C.
      • et al.
      Lack of benefit of 3-month intensification with enfuvirtide plus optimized background regimen (OBR) versus OBR alone in patients with multiple therapeutic failures: the INNOVE study.
      which reported a considerably higher CFB CD4 than other included studies
      Viral load, CD4 cell count, ageMeta-analysis estimate from SA4NA66.7 (2.6)
      Note. VS and CFB CD4 at weeks 24 to 28 values for FTR + OBR and IBA + OBR comparisons are the absolute values reported by BRIGHTE and TMB-301/202 trials, respectively. For these studies, VS was reported without a 95% CI; the log-odds of VS and their associated standard errors were calculated directly from the reported proportions and used as inputs for the ITCs. For all the OBR alone analyses, VS and CFB CD4 at weeks 24 to 28 values are the pooled estimates obtained from the respective meta-analysis.
      ARV indicates antiretroviral; CFB, change from baseline; CI, confidence interval; DRV, darunavir; FTR, fostemsavir; HIV, human immunodeficiency virus; IBA, ibalizumab; ITC, indirect treatment comparison; LEN, lenacapavir; NA, not applicable; NR, not reported; OBR, optimized background regimen; OSS, overall susceptibility score; Q2W, once every 2 weeks; SA, sensitivity analysis; STC, simulated treatment comparison; VS, virologic suppression.
      SA2 and 3 aimed to partly address the differences in OBR composition, by excluding studies for which DRV was not permitted in the OBR, given that inclusion of DRV was suspected to lead to better response rates in participants.
      SA4 was only performed for the CFB CD4 analysis.
      Sensitivity analyses, chosen based on discussions with HIV clinical experts, were performed to investigate the effect of including treatment arms with additional investigational agents or excluding studies in which DRV was not permitted in participants’ OBR or excluding studies with a low sample size. DRV is currently one of the most fundamental ARV therapies in optimized regimens for HTE PWH.
      • Spagnuolo V.
      • Castagna A.
      • Lazzarin A.
      Darunavir for the treatment of HIV infection.
      ,
      Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV 2021. Clinicalinfo.HIV.gov.
      Some studies enrolled participants before DRV was approved in 2006 and so did not permit DRV in participant’s OBR. In addition, published evidence indicated that participants taking DRV could have better response rates than those who did not have DRV in their OBRs.
      • Madruga J.V.
      • Cahn P.
      • Grinsztejn B.
      • et al.
      Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial.
      ,
      • Lazzarin A.
      • Campbell T.
      • Clotet B.
      • et al.
      Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial.
      ,
      • Steigbigel R.T.
      • Cooper D.A.
      • Kumar P.N.
      • et al.
      Raltegravir with optimized background therapy for resistant HIV-1 infection.
      Therefore, these studies were excluded as part of sensitivity analyses to partly address the bias resulting from differences in OBR composition across the included studies and lesser relevance of studies not permitting DRV. Details of each analysis, including the baseline variables that were adjusted for and the main analysis aims, are summarized in Table 1.
      • DeJesus E.
      • Emu B.
      • Weinheimer S.
      • Cohen Z.
      • Cash B.
      • Lewis S.
      Outcomes of patients not achieving primary endpoint from an ibalizumab phase III trial [Conference abstract].
      ,
      • Kozal M.
      • Aberg J.
      • Pialoux G.
      • et al.
      Fostemsavir in adults with multidrug-resistant HIV-1 infection.
      ,
      • Towner W.
      • DeJesus E.
      • Schrader S.
      • et al.
      Long-term efficacy, safety, and durability of ibalizumab-based regimens in subgroup of TMB-202 participants.
      ,
      • Morand-Joubert L.
      • Ghosn J.
      • Delaugerre C.
      • et al.
      Lack of benefit of 3-month intensification with enfuvirtide plus optimized background regimen (OBR) versus OBR alone in patients with multiple therapeutic failures: the INNOVE study.
      Each comparative analysis was adjusted for up to 4 key baseline characteristics, selected based on clinical judgement and the availability of data from the comparator trials. Four was the maximum number of variables adjusted for because of the small sample size of the randomized cohort of the CAPELLA study (n = 36).
      • Peduzzi P.
      • Concato J.
      • Kemper E.
      • Holford T.R.
      • Feinstein A.R.
      A simulation study of the number of events per variable in logistic regression analysis.
      Years since diagnosis was adjusted for in the IBA + OBR sensitivity analysis, but not in the base case analysis. For the IBA + OBR base case analysis, variables that were deemed more clinically relevant were prioritized and adjusted for (number of previous ARV agents, overall susceptibility score). However, these variables were only reported by TMB-301 and not TMB-202.
      Given that the CAPELLA study and the comparator trials did not have a common comparator at the week 24 to 28 timepoint, unanchored STCs were conducted. IPD from the randomized cohort of the CAPELLA study and aggregate data for FTR + OBR and IBA + OBR from relevant comparator trials were used as inputs for their respective analyses. For the OBR alone analyses, pooled meta-analysis estimates were obtained for VS and CFB CD4 as well as key baseline characteristics (age, viral load, CD4 count). Unadjusted comparisons were also performed to provide a reference versus the population-adjusted STC results, but these were not used as a method of assessing the treatment effect.
      • Phillippo D.M.
      • Dias S.
      • Ades A.E.
      • Welton N.J.
      Assessing the performance of population adjustment methods for anchored indirect comparisons: a simulation study.
      All analyses were conducted following the recommendations of the UK’s National Institute for Health and Care Excellence Decision Support Unit Technical Support Document 18.
      • Phillippo D.M.
      • Ades A.E.
      • Dias S.
      • Palmer S.
      • Abrams K.R.
      • Welton N.J.
      NICE DSU technical support document 18: methods for population-adjusted indirect comparisons in submissions to NICE. NICE Decision Support Unit.
      Additional details on the analysis methods can be found in the Appendix in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.12.011.

      Results

      Study Selection

      The SLR and SLR update identified 129 records reporting on 38 unique studies of HIV-1 treatments in HTE PWH (Fig. 1). Following the SLR, the feasibility assessment concluded that sufficient data were available to perform ITCs for VS and CFB CD4 and that these ITCs could be adjusted for key baseline characteristics. Fifteen studies were included in the VS analyses and 18 studies in the CFB CD4 analyses (Fig. 1). The included studies, along with their respective treatment arms and key baseline characteristics, are detailed in Tables 2
      • DeJesus E.
      • Emu B.
      • Weinheimer S.
      • Cohen Z.
      • Cash B.
      • Lewis S.
      Outcomes of patients not achieving primary endpoint from an ibalizumab phase III trial [Conference abstract].
      ,
      • Kozal M.
      • Aberg J.
      • Pialoux G.
      • et al.
      Fostemsavir in adults with multidrug-resistant HIV-1 infection.
      ,
      Study to evaluate the safety and efficacy of lenacapavir in combination with an optimized background regimen in heavily treatment experienced participants living with HIV-1 infection with multidrug resistance (Capella, NCT04150068). ClinicalTrials.gov.
      ,
      • Segal-Maurer S.
      • DeJesus E.
      • Stellbrink H.J.
      • et al.
      Capsid inhibition with lenacapavir in multidrug-resistant HIV-1 infection.
      ,
      • Towner W.
      • DeJesus E.
      • Schrader S.
      • et al.
      Long-term efficacy, safety, and durability of ibalizumab-based regimens in subgroup of TMB-202 participants.
      and 3.
      • Madruga J.V.
      • Cahn P.
      • Grinsztejn B.
      • et al.
      Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial.
      ,
      • Anis A.H.
      • Nosyk B.
      • Sun H.
      • et al.
      Quality of life of patients with advanced HIV/AIDS: measuring the impact of both AIDS-defining events and non-AIDS serious adverse events.
      ,
      • Lazzarin A.
      • Campbell T.
      • Clotet B.
      • et al.
      Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial.
      • Viard J.P.
      • Fagard C.
      • Chaix M.L.
      • et al.
      Immunological success is predicted by enfuvirtide but not interleukin-2 therapy in immunodepressed patients.
      • Morand-Joubert L.
      • Ghosn J.
      • Delaugerre C.
      • et al.
      Lack of benefit of 3-month intensification with enfuvirtide plus optimized background regimen (OBR) versus OBR alone in patients with multiple therapeutic failures: the INNOVE study.
      Trial of maraviroc (UK-427,857) in combination with optimized background therapy versus optimized background therapy alone for the treatment of HIV-1 infected subjects (MOTIVATE 1) NCT00098306. ClinicalTrials.gov.
      Trial of maraviroc (UK-427,857) in combination with optimized background therapy versus optimized background therapy alone for the treatment of HIV-1 infected subjects (MOTIVATE 2) NCT00098722. ClinicalTrials.gov.
      • Boyd M.A.
      • Truman M.
      • Hales G.
      • Anderson J.
      • Dwyer D.E.
      • Carr A.
      A randomized study to evaluate injection site reactions using three different enfuvirtide delivery mechanisms (the OPTIONS study).
      • Suleiman J.
      • Zingman B.S.
      • Diaz R.S.
      • et al.
      Vicriviroc in combination therapy with an optimized regimen for treatment-experienced subjects: 48-week results of the VICTOR-E1 phase 2 trial.
      • DeJesus E.
      • Gottlieb M.S.
      • Gathe Jr., J.C.
      • Greenberg M.L.
      • Guittari C.J.
      • Zolopa A.R.
      Safety and efficacy of enfuvirtide in combination with Darunavir-ritonavir and an optimized background regimen in treatment-experienced human immunodeficiency virus-infected patients: the below the level of quantification study.
      • Nicastri E.
      • Tommasi C.
      • Abbate I.
      • et al.
      Effect of raltegravir on the total and unintegrated proviral HIV DNA during raltegravir-based HAART.
      • Cahn P.
      • Pozniak A.L.
      • Mingrone H.
      • et al.
      Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study.
      • Eron J.
      • Livrozet J.M.
      • Morlat P.
      • et al.
      Activity of the integrase inhibitor S/GSK1349572 in subjects with HIV exhibiting raltegravir resistance: week 24 results of the VIKING study (ING112961).
      • Castagna A.
      • Maggiolo F.
      • Penco G.
      • et al.
      Dolutegravir in antiretroviral-experienced patients with raltegravir-and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study.
      • Akil B.
      • Blick G.
      • Hagins D.P.
      • et al.
      Dolutegravir versus placebo in subjects harbouring HIV-1 with integrase inhibitor resistance associated substitutions: 48-week results from VIKING-4, a randomized study.
      Figure thumbnail gr1
      Figure 1PRISMA diagram for the SLR and feasibility assessment. SA1 (inclusion of investigational agents), SA2 (non-DRV studies removed from base case), SA3 (non-DRV studies removed from sensitivity analysis 1), SA4 (INNOVE removed from base case analysis, performed for CFB CD4 only).
      CDSR indicates Cochrane Database of Systematic Reviews; CENTRAL, Cochrane Central Register of Controlled Trials; CFB, change from baseline; DARE, Database of Abstracts of Reviews of Effect; DRV, darunavir; FTR, fostemsavir; HTE, heavily treatment-experienced; IBA, ibalizumab; OBR, optimized background regimen; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; SA, sensitivity analysis; SLR, systematic literature review; VS, virologic suppression.
      Table 2Summary of baseline characteristics for the LEN + OBR, FTR + OBR, and IBA + OBR studies included in the analyses.
      StudyRegimenSample sizeAge, yearsViral load, log10 copies/mLCD4 cell count, cells/mm3Years since HIV diagnosisNumber of previous agents, nOSS ≥ 2, n (%)
      CAPELLA,
      Study to evaluate the safety and efficacy of lenacapavir in combination with an optimized background regimen in heavily treatment experienced participants living with HIV-1 infection with multidrug resistance (Capella, NCT04150068). ClinicalTrials.gov.
      ,
      • Segal-Maurer S.
      • DeJesus E.
      • Stellbrink H.J.
      • et al.
      Capsid inhibition with lenacapavir in multidrug-resistant HIV-1 infection.
      randomized cohort
      LEN → LEN 900 mg + OBR24
      CFB CD4 data from 2 participants in this arm were not available at week 26, giving a total sample size of 22 for this arm for the CFB CD4 analysis.
      553.97 (0.92)199 (166)2797 (29)
      Placebo → LEN 900 mg + OBR12544.87 (0.39)85 (63)2693 (25)
      BRIGHTE,
      • Kozal M.
      • Aberg J.
      • Pialoux G.
      • et al.
      Fostemsavir in adults with multidrug-resistant HIV-1 infection.
      all randomized participants
      FTR + OBR272484.7100NRNRNR
      TMB-301
      • DeJesus E.
      • Emu B.
      • Weinheimer S.
      • Cohen Z.
      • Cash B.
      • Lewis S.
      Outcomes of patients not achieving primary endpoint from an ibalizumab phase III trial [Conference abstract].
      IBA 800 mg Q2W + OBR4051 (11)4.5 (0.8)150 (182)20 (8)11 (5)23 (58)
      TMB-202
      • Towner W.
      • DeJesus E.
      • Schrader S.
      • et al.
      Long-term efficacy, safety, and durability of ibalizumab-based regimens in subgroup of TMB-202 participants.
      IBA 800 mg Q2W + OBR59485.1106 (91)17 (4)NRNR
      Note. Results presented as mean (SD) for continuous outcomes and n (%) for categorical outcomes; for studies not reporting the mean values, the median values were used instead; for studies not reporting the SD, this was approximated from the IQR where possible using the formula SD = IQR/1.35.
      CFB indicates change from baseline; FTR, fostemsavir; HIV, human immunodeficiency virus; IBA, ibalizumab; IQR, interquartile range; LEN, lenacapavir; NR, not reported; OBR, optimized background regimen; OSS, overall susceptibility score; Q2W, biweekly.
      CFB CD4 data from 2 participants in this arm were not available at week 26, giving a total sample size of 22 for this arm for the CFB CD4 analysis.
      Table 3Summary of baseline characteristics for the OBR alone studies and the studies included in each analysis.
      StudyRegimenDRV in OBRSample sizeAge, yearsViral load, log10 copies/mLCD4 cell count, cells/mm3BCSA1SA2SA3SA4
      DUET 1
      • Madruga J.V.
      • Cahn P.
      • Grinsztejn B.
      • et al.
      Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial.
      Placebo + DRV/rtv 600/100 mg BID + OBRAll participants308454.9109YYYYY
      DUET 2
      • Lazzarin A.
      • Campbell T.
      • Clotet B.
      • et al.
      Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial.
      Placebo + DRV/rtv 600/100 mg BID + OBRAll participants296454.8108YYYYY
      ETOILE
      Studies were included in the analyses of CFB in CD4 cell count outcome only.
      ,
      • Viard J.P.
      • Fagard C.
      • Chaix M.L.
      • et al.
      Immunological success is predicted by enfuvirtide but not interleukin-2 therapy in immunodepressed patients.
      OBT only, ENF optimizationNR
      Not reported; assumed no DRV in participants’ OBR based on the study start years (OPTIMA 20019; ETOILE 200443) and the DRV launch year (2006).
      1248 (11.11)4.9 (0.44)98.2YYNNY
      OBT only, no ENF optimizationNR
      Not reported; assumed no DRV in participants’ OBR based on the study start years (OPTIMA 20019; ETOILE 200443) and the DRV launch year (2006).
      1648 (11.11)4.9 (0.44)55.4YYNNY
      INNOVE
      • Morand-Joubert L.
      • Ghosn J.
      • Delaugerre C.
      • et al.
      Lack of benefit of 3-month intensification with enfuvirtide plus optimized background regimen (OBR) versus OBR alone in patients with multiple therapeutic failures: the INNOVE study.
      OBR60% of participants15424294YYYYN
      OBR + ENF57% participants14444.3364NYNYN
      MOTIVATE 1
      Trial of maraviroc (UK-427,857) in combination with optimized background therapy versus optimized background therapy alone for the treatment of HIV-1 infected subjects (MOTIVATE 1) NCT00098306. ClinicalTrials.gov.
      Placebo + OBRDRV not permitted in OBR120464.84 (0.56)178.5 (127.09)YYNNY
      MVC 150/300 mg QD + OBRDRV not permitted in OBR241464.85 (0.64)187.5 (149.88)NYNNN
      MVC 150/300 mg BID + OBRDRV not permitted in OBR240464.86 (0.61)176.5 (143.93)NYNNN
      MOTIVATE 2
      Trial of maraviroc (UK-427,857) in combination with optimized background therapy versus optimized background therapy alone for the treatment of HIV-1 infected subjects (MOTIVATE 2) NCT00098722. ClinicalTrials.gov.
      Placebo + OBRDRV not permitted in OBR94454.89 (0.7)198.5 (140.39)YYNNY
      MVC 150/300 mg QD + OBRDRV not permitted in OBR186454.87 (0.66)206.0 (171.99)NYNNN
      MVC 150/300 mg BID + OBRDRV not permitted in OBR194474.84 (0.62)204.9 (149.21)NYNNN
      OPTIMA
      Studies were included in the analyses of CFB in CD4 cell count outcome only.
      ,
      • Anis A.H.
      • Nosyk B.
      • Sun H.
      • et al.
      Quality of life of patients with advanced HIV/AIDS: measuring the impact of both AIDS-defining events and non-AIDS serious adverse events.
      No interruptionNR
      Not reported; assumed no DRV in participants’ OBR based on the study start years (OPTIMA 20019; ETOILE 200443) and the DRV launch year (2006).
      17548.5 (8.47)4.75 (0.66)131 (109)YYNNY
      OPTIONS
      • Boyd M.A.
      • Truman M.
      • Hales G.
      • Anderson J.
      • Dwyer D.E.
      • Carr A.
      A randomized study to evaluate injection site reactions using three different enfuvirtide delivery mechanisms (the OPTIONS study).
      OBR (with NRTIs)56% of participants (total cohort)18146 (8.15)4.2 (0.81)193 (201.48)YYYYY
      OBR (without NRTIs)56% of participants (total cohort)17946 (8.15)4.2 (0.74)212 (180)YYYYY
      VICTOR-E1
      • Suleiman J.
      • Zingman B.S.
      • Diaz R.S.
      • et al.
      Vicriviroc in combination therapy with an optimized regimen for treatment-experienced subjects: 48-week results of the VICTOR-E1 phase 2 trial.
      Placebo + OBR16% of participants3745.5 (8.8)4.62 (0.79)226.1 (196.6)YYYYY
      Vicriviroc 20 mg + OBR23% of participants (total cohort)4044.0 (8.0)4.50 (0.89)202.1 (144.5)NYNYN
      Vicriviroc 30 mg + OBR23% of participants (total cohort)3944.9 (7.3)4.52 (0.88)202.2 (159.2)NYNYN
      BLQ Study
      • DeJesus E.
      • Gottlieb M.S.
      • Gathe Jr., J.C.
      • Greenberg M.L.
      • Guittari C.J.
      • Zolopa A.R.
      Safety and efficacy of enfuvirtide in combination with Darunavir-ritonavir and an optimized background regimen in treatment-experienced human immunodeficiency virus-infected patients: the below the level of quantification study.
      ENF + DRV + OBRAll participants13146.3 (7.8)4.7 (0.8)161.6 (157.3)NYNYN
      Nicastri et al
      Studies were included in the analyses of CFB in CD4 cell count outcome only.
      ,
      • Nicastri E.
      • Tommasi C.
      • Abbate I.
      • et al.
      Effect of raltegravir on the total and unintegrated proviral HIV DNA during raltegravir-based HAART.
      RAL-based HAART77% of participants3147 (9)4.4 (0.82)256 (177)NYNYN
      SAILING
      • Cahn P.
      • Pozniak A.L.
      • Mingrone H.
      • et al.
      Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study.
      DTG 50 mg QD + OBR35% of participants (total cohort)35442 (10.37)4.17 (1.01)204.5 (207.41)NYNYN
      RAL 400 mg BID + OBR35% of participants (total cohort)36143 (9.63)4.21 (1.05)193 (199.26)NYNYN
      VIKING
      • Eron J.
      • Livrozet J.M.
      • Morlat P.
      • et al.
      Activity of the integrase inhibitor S/GSK1349572 in subjects with HIV exhibiting raltegravir resistance: week 24 results of the VIKING study (ING112961).
      DTG 50 mg QD (cohort 2) + OBR15% of participants24474.3202NYNYN
      DTG 50 mg BID (cohort 1) + OBR46% of participants27484.5114NYNYN
      VIKING-3
      • Castagna A.
      • Maggiolo F.
      • Penco G.
      • et al.
      Dolutegravir in antiretroviral-experienced patients with raltegravir-and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study.
      DTG 50 mg BID + OBR65% of participants18348 (6.67)4.26 (0.93)140 (214.81)NYNYN
      VIKING-4
      • Akil B.
      • Blick G.
      • Hagins D.P.
      • et al.
      Dolutegravir versus placebo in subjects harbouring HIV-1 with integrase inhibitor resistance associated substitutions: 48-week results from VIKING-4, a randomized study.
      Placebo/DTG 50 mg BID + OBR77% of participants (total cohort)1648.6 (8.85)4.52 (0.76)91 (164.44)NYNYN
      DTG/DTG 50 mg BID + OBR77% of participants (total cohort)1447.5 (11.56)4.38 (0.94)164 (88.89)NYNYN
      Note. SA1 included treatment arms from the OBR alone BC analysis and treatment arms containing investigational agents. SA2 and SA3 excluded studies where DRV was not permitted in the participants’ OBR, but otherwise matched the criteria of OBR BC and SA1, respectively. SA4 (performed for CFB in CD4 cell count outcome only) excluded the INNOVE study from the BC. Included studies in each analysis are denoted by “Y” and excluded studies by “N”. Results for baseline characteristics presented as mean (SD); for studies not reporting the mean values, the median values were used instead; for studies not reporting the SD, this was approximated from IQR where possible using the formula SD = IQR/1.35. Values are reported to 2 decimal places or to the number of decimal places reported in the publication, if this was < 2.
      BC indicates base case; BID, twice daily; CFB, change from baseline; DRV, darunavir; DTG, dolutegravir; ENF, enfuvirtide; HAART, highly active antiretroviral therapy; IQR, interquartile range; MVC, maraviroc; NR, not reported; NRTI, nucleos(t)ide reverse transcriptase inhibitor; OBR, optimized background regimen; OBT, optimized background therapy; QD, once daily; RAL, raltegravir; rtv, ritonavir; SA, sensitivity analysis.
      Not reported; assumed no DRV in participants’ OBR based on the study start years (OPTIMA 2001
      • Anis A.H.
      • Nosyk B.
      • Sun H.
      • et al.
      Quality of life of patients with advanced HIV/AIDS: measuring the impact of both AIDS-defining events and non-AIDS serious adverse events.
      ; ETOILE 2004
      • Viard J.P.
      • Fagard C.
      • Chaix M.L.
      • et al.
      Immunological success is predicted by enfuvirtide but not interleukin-2 therapy in immunodepressed patients.
      ) and the DRV launch year (2006).
      Studies were included in the analyses of CFB in CD4 cell count outcome only.
      STC analyses for immunologic recovery and discontinuation due to AEs were not deemed feasible given that no studies of the key comparators, FTR + OBR and IBA + OBR, reported immunologic recovery at weeks 24 to 28 and no participants discontinued due to AEs at week 26 in the randomized cohort of the CAPELLA study.

      Study Characteristics

      The demographic and baseline clinical characteristics of participants in the FTR + OBR (BRIGHTE) and IBA + OBR (TMB-301 and TMB-202) studies were broadly similar to that of the randomized cohort of the CAPELLA study (Table 2
      • DeJesus E.
      • Emu B.
      • Weinheimer S.
      • Cohen Z.
      • Cash B.
      • Lewis S.
      Outcomes of patients not achieving primary endpoint from an ibalizumab phase III trial [Conference abstract].
      ,
      • Kozal M.
      • Aberg J.
      • Pialoux G.
      • et al.
      Fostemsavir in adults with multidrug-resistant HIV-1 infection.
      ,
      Study to evaluate the safety and efficacy of lenacapavir in combination with an optimized background regimen in heavily treatment experienced participants living with HIV-1 infection with multidrug resistance (Capella, NCT04150068). ClinicalTrials.gov.
      ,
      • Segal-Maurer S.
      • DeJesus E.
      • Stellbrink H.J.
      • et al.
      Capsid inhibition with lenacapavir in multidrug-resistant HIV-1 infection.
      ,
      • Towner W.
      • DeJesus E.
      • Schrader S.
      • et al.
      Long-term efficacy, safety, and durability of ibalizumab-based regimens in subgroup of TMB-202 participants.
      ). Nevertheless, the mean number of years since HIV diagnosis was lower in the IBA + OBR trials than the CAPELLA study.
      In the studies presenting data for OBR alone, study start dates varied from 2001 to 2012 and studies showed a high degree of heterogeneity in OBR composition. Mean age was similar across studies included in the OBR alone analyses, but slightly lower than the CAPELLA study, whereas time since HIV diagnosis, viral load, and CD4 count at baseline were broadly similar across the OBR studies and generally comparable with the randomized cohort of the CAPELLA study.

      Meta-Analyses

      The pooled meta-analysis estimates for VS (defined as <50 copies/mL for CAPELLA, TMB-301, and pooled OBR estimates; < 40 copies/mL for BRIGHTE and TMB-202), CFB CD4 and key baseline characteristics (age, viral load, and CD4 count at baseline) across the studies included in the OBR alone analyses are presented in Table 1
      • DeJesus E.
      • Emu B.
      • Weinheimer S.
      • Cohen Z.
      • Cash B.
      • Lewis S.
      Outcomes of patients not achieving primary endpoint from an ibalizumab phase III trial [Conference abstract].
      ,
      • Kozal M.
      • Aberg J.
      • Pialoux G.
      • et al.
      Fostemsavir in adults with multidrug-resistant HIV-1 infection.
      ,
      • Towner W.
      • DeJesus E.
      • Schrader S.
      • et al.
      Long-term efficacy, safety, and durability of ibalizumab-based regimens in subgroup of TMB-202 participants.
      ,
      • Morand-Joubert L.
      • Ghosn J.
      • Delaugerre C.
      • et al.
      Lack of benefit of 3-month intensification with enfuvirtide plus optimized background regimen (OBR) versus OBR alone in patients with multiple therapeutic failures: the INNOVE study.
      and Appendix Table 8 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.12.011, respectively. The corresponding forest plots for the base case and sensitivity meta-analyses are also presented in the Appendix in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.12.011 (Appendix Figs. 1 and 2 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.12.011).

      VS Analyses

      In the randomized cohort of the CAPELLA study, 81% of participants (29 of 36) achieved VS at week 26.
      • Segal-Maurer S.
      • DeJesus E.
      • Stellbrink H.J.
      • et al.
      Capsid inhibition with lenacapavir in multidrug-resistant HIV-1 infection.
      In the base case STC analyses, LEN + OBR had 6.57 times higher odds of VS at week 24 to 28 than FTR + OBR (95% confidence interval [CI] 1.34-32.28), 8.93 times higher odds of VS than IBA + OBR (95% CI 2.07-38.46), and 12.74 times higher odds of VS than OBR alone (95% CI 1.70-95.37). These results were statistically significant; however, the wide 95% CIs indicate a high level of uncertainty in these estimates (Fig. 2).
      Figure thumbnail gr2
      Figure 2Forest plot of STC and unadjusted estimates of the OR for VS of LEN + OBR versus comparator treatments at weeks 24 to 28. The x-axis has a logarithmic scale. Results with “∗” were statistically significant; dashed line indicates an OR equal to 1 (no difference between comparator and LEN); ORs > 1 favor LEN over comparator treatments; CIs that include 1 (cross the dashed line) indicate a result that is not statistically significant. Blue boxes have been used to highlight the BC analyses and gray boxes to highlight the sensitivity analyses. SA1 included treatment arms from the OBR BC analysis and treatment arms containing investigational agents. SA2 and SA3 excluded studies where DRV was not permitted in the participants’ OBR, but otherwise matched the criteria of BC and SA1, respectively. ∗∗Baseline variables adjusted for in each of the STCs are specified in .
      • DeJesus E.
      • Emu B.
      • Weinheimer S.
      • Cohen Z.
      • Cash B.
      • Lewis S.
      Outcomes of patients not achieving primary endpoint from an ibalizumab phase III trial [Conference abstract].
      ,
      • Kozal M.
      • Aberg J.
      • Pialoux G.
      • et al.
      Fostemsavir in adults with multidrug-resistant HIV-1 infection.
      ,
      • Towner W.
      • DeJesus E.
      • Schrader S.
      • et al.
      Long-term efficacy, safety, and durability of ibalizumab-based regimens in subgroup of TMB-202 participants.
      ,
      • Morand-Joubert L.
      • Ghosn J.
      • Delaugerre C.
      • et al.
      Lack of benefit of 3-month intensification with enfuvirtide plus optimized background regimen (OBR) versus OBR alone in patients with multiple therapeutic failures: the INNOVE study.
      BC indicates base case; CI, confidence interval; DRV, darunavir; FTR, fostemsavir; IBA, ibalizumab; Invest., investigational; LEN, lenacapavir; OBR, optimized background regimen; OR, odds ratio; SA, sensitivity analysis; STC, simulated treatment comparison; VS, virologic suppression.
      Sensitivity analyses were performed for IBA + OBR and for OBR alone. In the IBA + OBR sensitivity analysis, LEN + OBR had 5.36 times higher odds of VS than IBA + OBR (95% CI 0.97-29.57). This result was not statistically significant with wide 95% CIs, which could be due to an imbalance in baseline characteristics of the participants in each trial. In particular, mean number of years since diagnosis was lower in TMB-202 (17 years) than in the CAPELLA study randomized cohort (26 years). Nevertheless, years since diagnosis was adjusted for in the analyses.
      In all sensitivity analyses for OBR alone, LEN + OBR had statistically significantly higher odds of VS than OBR alone: 10.91 (95% CI 1.63-73.13) times higher odds than OBR in sensitivity analysis 1, 8.31 (95% CI 1.15-59.87) times higher odds than OBR in sensitivity analysis 2, and 8.04 (95% CI 1.26-51.17) times higher odds than OBR in sensitivity analysis 3. Although all OBR comparisons were statistically significantly favored LEN + OBR over OBR alone, the odds ratio (OR) for VS was higher in the base case analysis than sensitivity analysis 2, which removed 2 studies that did not allow DRV in the OBR (12.74 for base case vs 8.31 for sensitivity analysis 2). This difference in OR between the base case and sensitivity analysis 2 was expected, given that the 2 trials excluded in sensitivity analysis 2 (sample sizes of 120 and 94) had a low proportion of participants with VS, and given the limited number of studies in the base case analysis, they had a considerable effect on the meta-analysis estimates for VS. The unadjusted comparisons were consistent with the STCs (Fig. 2), with statistically significant ORs in favor of LEN + OBR for all comparisons aside from sensitivity analysis 2 (OR 3.09, 95% CI 0.98-9.75).

      CFB CD4 Analyses

      At week 26, the least-squares mean increase in the CD4 count was 75 cells/mm3 in the randomized cohort of the CAPELLA study.
      • Segal-Maurer S.
      • DeJesus E.
      • Stellbrink H.J.
      • et al.
      Capsid inhibition with lenacapavir in multidrug-resistant HIV-1 infection.
      In the base case STC analyses, LEN + OBR was favored numerically in all STC comparisons at weeks 24 to 28; mean CFB CD4 for LEN + OBR was 18 cells/mm3 greater than FTR + OBR (95% CI −22.0 to 58.2), 21 cells/mm3 greater than IBA + OBR (95% CI −32.5 to 74.2), and 41 cells/mm3 greater than OBR alone (95% CI 1.7-80.3) (Fig. 3). The base case analyses were not statistically significant except for the comparison between LEN + OBR and OBR alone, in which LEN + OBR was favored. All base case STC results were associated with wide 95% CIs, indicating a high level of uncertainty. There was a trend favoring LEN + OBR over IBA + OBR and OBR alone in all CFB CD4 sensitivity analyses (Fig. 3). Nevertheless, only the IBA sensitivity analysis and OBR sensitivity analysis 4 were statistically significant. Similar to the base case analyses, all sensitivity analyses were associated with wide 95% CIs and a high level of uncertainty.
      Figure thumbnail gr3
      Figure 3Forest plot of STC and unadjusted estimates of between-treatment difference in mean CFB CD4 (cells/mm3) of LEN + OBR versus comparator treatments at weeks 24 to 28. Results with “∗” were statistically significant; dashed line indicates difference in mean CFB CD4 between LEN and comparator equal to 0 (no difference between comparator and LEN); Differences > 0 favor LEN over comparator treatments; CIs that include 0 (cross the dashed line) indicate a result that is not statistically significant; SA1 included treatment arms from the OBR BC analysis and treatment arms containing investigational agents. SA2 and SA3 excluded studies where DRV was not permitted in the participants’ OBR, but otherwise matched the criteria of BC and SA1, respectively. SA4 (performed for CFB in CD4 cell count outcome only) excluded the INNOVE study from the BC. ∗∗Baseline variables adjusted for in each of the STCs are specified in .
      • DeJesus E.
      • Emu B.
      • Weinheimer S.
      • Cohen Z.
      • Cash B.
      • Lewis S.
      Outcomes of patients not achieving primary endpoint from an ibalizumab phase III trial [Conference abstract].
      ,
      • Kozal M.
      • Aberg J.
      • Pialoux G.
      • et al.
      Fostemsavir in adults with multidrug-resistant HIV-1 infection.
      ,
      • Towner W.
      • DeJesus E.
      • Schrader S.
      • et al.
      Long-term efficacy, safety, and durability of ibalizumab-based regimens in subgroup of TMB-202 participants.
      ,
      • Morand-Joubert L.
      • Ghosn J.
      • Delaugerre C.
      • et al.
      Lack of benefit of 3-month intensification with enfuvirtide plus optimized background regimen (OBR) versus OBR alone in patients with multiple therapeutic failures: the INNOVE study.
      BC indicates base case; CFB, change from baseline; CI, confidence interval; DRV, darunavir; FTR, fostemsavir; IBA, ibalizumab; Invest., investigational; LEN, lenacapavir; OBR, optimized background regimen; SA, sensitivity analysis; STC, simulated treatment comparison.
      In the unadjusted CFB CD4 comparisons, there were smaller differences between LEN + OBR and the comparators than in the STC analyses (Fig. 3), and no comparisons were statistically significant. In 4 cases, the direction of the unadjusted comparison point estimates differed from the STCs (Fig. 3), suggesting that the imbalances in baseline characteristics between the CAPELLA study and comparator studies may have biased the unadjusted CFB CD4 analyses.

      Discussion

      Data on the efficacy and effectiveness of different therapies in the HTE population are generally lacking, both in clinical trial and real-world settings, partly due to the small proportion of PWH who are considered to be HTE, the heterogenous nature of this population, and the lack of a standard treatment regimen. Here we present the first comparative estimates for LEN + OBR versus key comparators (FTR + OBR, IBA + OBR, and OBR alone) in individuals with MDR HIV. These analyses may be used to support decision making in high-/upper middle-income settings regarding treatment choices in this difficult-to-treat population, alongside data on other outcomes such as resistance, HRQoL, and safety, and considering factors related to the broader healthcare environment.
      The analyses were based on a comprehensive evidence base for the current standard of care in HIV management, obtained through an SLR. The SLR adopted a broad approach to identify HTE PWH populations by allowing a range of different population definitions to be included. This enabled a substantial volume of evidence to be considered for inclusion in the ITCs. Nevertheless, it is possible that some potentially relevant studies were missed due to differences in HTE definitions and terminology and due to our focus on studies published in English and mostly conducted in higher-/upper middle-income countries. Given that the evidence base for ARV treatments in HTE PWH is constantly evolving, additional data may also have become available since the SLR update.
      Comparisons of the safety and efficacy of different ARV regimens have been previously conducted in HIV in treatment-naïve
      • Patel D.A.
      • Snedecor S.J.
      • Tang W.Y.
      • et al.
      48-week efficacy and safety of dolutegravir relative to commonly used third agents in treatment-naive HIV-1-infected patients: a systematic review and network meta-analysis.
      • Snedecor S.J.
      • Radford M.
      • Kratochvil D.
      • Grove R.
      • Punekar Y.S.
      Comparative efficacy and safety of dolutegravir relative to common core agents in treatment-naïve patients infected with HIV-1: a systematic review and network meta-analysis.
      • Nickel K.
      • Halfpenny N.J.A.
      • Snedecor S.J.
      • Punekar Y.S.
      Comparative efficacy, safety and durability of dolutegravir relative to common core agents in treatment-naïve patients infected with HIV-1: an update on a systematic review and network meta-analysis.
      and treatment-experienced populations.
      • Pichenot M.
      • Deuffic-Burban S.
      • Cuzin L.
      • Yazdanpanah Y.
      Efficacy of new antiretroviral drugs in treatment-experienced HIV-infected patients: a systematic review and meta-analysis of recent randomized controlled trials.
      ,
      • Kanters S.
      • Socias M.E.
      • Paton N.I.
      • et al.
      Comparative efficacy and safety of second-line antiretroviral therapy for treatment of HIV/AIDS: a systematic review and network meta-analysis.
      • Ewald H.
      • Santini-Oliveira M.
      • Bühler J.E.
      • et al.
      Comparative effectiveness of tenofovir in HIV-infected treatment-experienced patients: systematic review and meta-analysis.
      • Huang Y.
      • Huang X.
      • Luo Y.
      • et al.
      Assessing the efficacy of lopinavir/ritonavir-based preferred and alternative second-line regimens in HIV-infected patients: a meta-analysis of key evidence to support WHO recommendations.
      However, most of these analyses did not use population adjustment methods to account for differences in clinically important participant characteristics across studies and were not conducted in HTE individuals specifically. The availability of IPD from the CAPELLA study allowed for population adjustment to be conducted in this analysis, to account for differences in several aspects of the disease profile of participants, including baseline disease severity and ARV resistance profile. Population adjustment was particularly important for these analyses given that they involved unanchored ITCs, which require the adjustment of all effect-modifying and prognostic variables to avoid systematic bias.
      • Phillippo D.M.
      • Dias S.
      • Ades A.E.
      • Welton N.J.
      Assessing the performance of population adjustment methods for anchored indirect comparisons: a simulation study.
      ,
      • Phillippo D.M.
      • Ades A.E.
      • Dias S.
      • Palmer S.
      • Abrams K.R.
      • Welton N.J.
      NICE DSU technical support document 18: methods for population-adjusted indirect comparisons in submissions to NICE. NICE Decision Support Unit.
      STCs were the preferred population adjustment approach over matching-adjusted indirect comparisons, based on findings from a simulation study
      • Phillippo D.M.
      • Dias S.
      • Ades A.E.
      • Welton N.J.
      Assessing the performance of population adjustment methods for anchored indirect comparisons: a simulation study.
      and recommendations by an evidence synthesis report update by the UK’s National Institute for Health and Care Excellence Decision Support Unit (April 2020).
      • Welton N.
      • Phillippo D.
      • Owen R.
      NICE Decision Support Unit: CHTE2020 sources and synthesis of evidence: update to evidence synthesis methods.
      Moreover, given the small sample size of the randomized cohort of the CAPELLA study, STCs were appropriate given that their resulting estimates are less sensitive to small sample sizes.
      LEN + OBR was associated with statistically significantly higher odds of VS at weeks 24 to 28 than FTR + OBR, IBA + OBR, and OBR alone, and these results were consistent across the STCs and unadjusted comparisons performed. For the comparisons with IBA + OBR and OBR alone, sensitivity analyses were also conducted to validate the base case and address the potential bias introduced by certain treatment arms into the meta-analysis results, in the case of the OBR alone sensitivity analyses. Nevertheless, given the rapidly evolving treatment landscape and features of the included studies, it was not possible to account for all step changes in HIV treatment in the present study. Overall, the comparisons performed indicate that LEN has the potential to help individuals with MDR HIV achieve VS, which may decrease morbidity and mortality and reduce the economic and healthcare resource use burden associated with MDR HIV.
      Gilead data on file
      Lenacapavir (LEN) Marketing Authorization Application (MAA).
      ,
      • Deeks S.G.
      • Overbaugh J.
      • Phillips A.
      • Buchbinder S.
      HIV infection.
      Compared with OBR alone for CFB CD4, LEN + OBR was statistically significantly favored in the base case analysis and 1 of the 4 sensitivity analyses. There was no statistically significant difference between LEN + OBR and FTR + OBR or between LEN + OBR and IBA + OBR for CFB CD4. All CFB CD4 analyses were associated with wide 95% CIs. Such uncertainty might be expected given that many factors beyond current treatment can affect participants’ CD4 cell count recovery, such as age, baseline CD4 cell count, previous treatments, and genetic factors,
      • Stirrup O.T.
      • Copas A.J.
      • Phillips A.N.
      • et al.
      Predictors of CD4 cell recovery following initiation of antiretroviral therapy among HIV-1 positive patients with well-estimated dates of seroconversion.
      ,
      • Montarroyos U.R.
      • Miranda-Filho D.B.
      • Cesar C.C.
      • et al.
      Factors related to changes in CD4+ T-cell counts over time in patients living with HIV/AIDS: a multilevel analysis.
      which may not be reported in detail by studies. Given the small sample sizes and the heterogeneity in participant characteristics across the included studies, between-treatment differences in CFB CD4 were difficult to detect with certainty. In addition, no studies were found to report immunologic recovery at weeks 24 to 28 for the key comparators; therefore, no analyses could be performed.
      It is worth noting that outcomes such as HRQoL and factors related to the broader healthcare environment such as drug acquisition, administration, monitoring, costs, and societal preferences are also important for decision making but were beyond the scope of this study. In addition, resistance would be an interesting factor to analyze; however, there is substantial heterogeneity in its reporting in trial publications, and therefore, despite its importance in clinical decision making, a robust analysis of resistance was not feasible.
      Participants from both the randomized (cohort 1) and the nonrandomized (cohort 2) cohorts of the CAPELLA study were included in a secondary analysis of LEN + OBR versus OBR alone, to increase the number of LEN-treated participants included in this comparison (n = 71 for the VS comparison and n = 67 for the CFB CD4 comparison). These analyses showed statistically significant differences in favor of LEN + OBR over OBR alone in terms of both VS and CFB CD4 (results not shown) and validated the conclusions from the primary analyses. The results from the secondary analyses also had reduced uncertainty (narrower 95% CIs) than those from the primary analysis, potentially due to the larger sample size.
      STCs for discontinuation due to AEs in participants treated with LEN + OBR versus comparators were not performed, given that no participants discontinued due to AEs in the CAPELLA study at week 26. Nevertheless, a descriptive comparison showed a similar rate of discontinuation due to AEs between the CAPELLA study (LEN + OBR, n = 36, 0% discontinuations due to AEs) and the BRIGHTE study (FTR + OBR, n = 272, 4% discontinuations due to AEs), which appeared lower than in the TMB-301 study (IBA + OBR, n = 40, 13% discontinuations due to AEs). Notably, safety data for week 52 of the CAPELLA study have been published that are consistent with the low rate of discontinuation due to AEs at week 26: by week 52 only 1 participant had discontinued due to a grade 1 AE of injection site nodule.
      • Segal-Maurer S.
      • Castagna A.
      • Berhe M.
      • Richmond G.
      • Ruane J.P.
      • GI S.
      These analyses were limited by the fact that all ITCs were unanchored, given that the CAPELLA study and the comparator trials for FTR + OBR and IBA + OBR (BRIGHTE, TMB-301 and TMB-202) did not include a common comparator arm at the weeks 24 to 28 timepoint. This potentially introduced systematic bias into the resulting estimates, providing less precision than an anchored approach. To avoid this bias, unanchored comparisons require all treatment effect-modifying and prognostic variables to be adjusted for in the STC
      • Phillippo D.M.
      • Dias S.
      • Ades A.E.
      • Welton N.J.
      Assessing the performance of population adjustment methods for anchored indirect comparisons: a simulation study.
      ,
      • Phillippo D.M.
      • Ades A.E.
      • Dias S.
      • Palmer S.
      • Abrams K.R.
      • Welton N.J.
      NICE DSU technical support document 18: methods for population-adjusted indirect comparisons in submissions to NICE. NICE Decision Support Unit.
      ; however, not all differences in baseline characteristics between the CAPELLA study and comparator trials could be adjusted for due to the medical complexity of HTE individuals and the small sample size of the CAPELLA study and some of the comparator trials. Additionally, different treatment effects due to effect modification (eg, subgroup effects) could not be captured due to limited data availability. The distribution of the effect-modifying and prognostic variables could vary according to the source of IPD used for the analyses, further limiting the generalizability of these results. Due to the bias resulting from these unaccounted factors, further analyses should be conducted using IPD from future clinical trials when available, to validate the conclusions and assess reproducibility of this study. Finally, further limitations could include standard modelling assumptions, such as linearity between predictors and CFB CD4 or log odds of VS.
      A further limitation was that the 95% CIs for the STC results were relatively wide. The uncertainty in the STCs of LEN + OBR versus OBR alone could have been introduced by the heterogeneity across studies included in the OBR alone analyses. For the meta-analysis inputs used in the OBR alone analyses (Appendix Table 13 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.12.011), a random effects model was chosen given that the I2 values were > 50% and were considered indicative of substantial heterogeneity.
      Cochrane handbook for systematic reviews of interventions. Imputing standard deviations. The Cochrane Collaboration.
      Sixteen individuals from cohort 1 of the CAPELLA study received either FTR or IBA as part of their OBR. Nevertheless, given that the ITCs were conducted between LEN + OBR versus FTR/IBA + OBR, the treatment effect obtained can still be attributed to LEN.

      Conclusion

      This is the first analysis that provides comparative estimates of the efficacy of different treatment options for HTE PWH. The results suggest that LEN + OBR is favored over FTR + OBR, IBA + OBR, and OBR alone in terms of VS, offering statistically significantly higher odds of VS at weeks 24 to 28. Overall, the analyses indicate that by improving odds of VS, LEN has an improved potential to optimize treatment outcomes in HTE individuals with MDR HIV compared with other available treatment options.

      Article and Author Information

      Author Contributions: Concept and design: Chatzidaki, Curteis, Luedke, Mezzio, McArthur, Eddowes
      Acquisition of data: Rhee, McArthur, Luedke
      Analysis and interpretation of the data: Chatzidaki, Curteis, Luedke, Mezzio, McArthur, Rhee, Eddowes
      Drafting the article or revising it critically for important intellectual content: Chatzidaki, Curteis, Luedke, Mezzio, Rhee, McArthur, Eddowes
      Final approval of the version of the article to be published: Chatzidaki, Curteis, Luedke, Mezzio, Rhee, McArthur, Eddowes
      Obtaining funding: Mezzio
      Administrative, technical, or logistic support and supervision: Mezzio, Eddowes
      Conflict of Interest Disclosures: Messrs Chatzidak and Curteis, Mss Luedke and McArthur, and Dr Eddowes are employees of Costello Medical, which was funded by Gilead to conduct the study. Drs Mezzio and Rhee are employees and stock owners of Gilead Sciences. Some of the findings from this study were also presented at the Academy of Managed Care Pharmacy Meeting held in Chicago, IL, March 29 to April 1, 2022. No other disclosures were reported.
      Funding/Support: This study was funded by Gilead Sciences. Support for third-party writing assistance for this article, provided by Costello Medical, UK, was funded by Gilead Sciences in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).
      Role of the Funder/Sponsor: Dylan and Martin are employees of the study sponsor (Gilead) and did contribute to the design and conduct, analysis, interpretation, preparation, review and approval of the manuscript, and decision to submit it.

      Acknowledgment

      The authors acknowledge Hui Wang, PhD, and Hadas Dvory-Sobol, PhD, (Gilead Sciences, USA) for providing the individual participant data from CAPELLA; Denise Globe, PhD, Yumi Asukai, MSc, Lauren Temme, PharmD, MBA, Joel Gallant, MD, MPH, and David Piontkowsky, JD, MD (Gilead Sciences, USA) for their review of the study concept and the manuscript; Ania Bobrowska, PhD, Alice Reading, BSc, Audrey Artignan, MPhil, Seth Francis-Graham, PhD, Miyana Yoshino, MSc, and Sophie Messiha, MSc (Costello Medical, UK) for support with the systematic literature review; Benjamin G. Farrar, PhD, Vaishali Yadav, PhD, and Elliot Dryer-Beers, MSc (Costello Medical, UK) for support with the analysis; and Vaishali Yadav, PhD (Costello Medical, UK) for medical writing and editorial assistance based on the authors’ input and direction.
      Ethical Approval: The CAPELLA trial was approved by the institutional review board or ethics committee at each site and was conducted in compliance with international laws and guidelines. All patients provided a written informed consent. No further ethical clearance was required for conducting these statistical analyses.

      Supplementary Material

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