An indirect comparison of 144-week efficacy, safety, and tolerability of dolutegravir plus lamivudine and second-generation integrase inhibitor-based, 3-drug, single-tablet regimens in therapy-naive people with HIV-1.

BACKGROUND: The long-term efficacy and safety of the 2-drug regimen dolutegravir (DTG) + lamivudine (3TC) and 3-drug single-tablet regimens recommended for antiretroviral therapy (ART)-naive people with HIV-1 (PWH) have yet to be compared directly in clinical trials. This indirect treatment comparison (ITC) was conducted to compare the durability of efficacy and long-term safety of DTG + 3TC vs second-generation, integrase strand transfer inhibitor (INSTI)-based, 3-drug, single-tablet regimens bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) and DTG/abacavir/3TC (DTG/ABC/3TC) at Week 144 after treatment initiation. METHODS: A systematic literature review identified 4 trials evaluating the treatment regimens of interest in ART-naive PWH (GEMINI-1, GEMINI-2, GS-US-380-1489, and GS-US-380-1490). Safety, efficacy, and tolerability results were compared using fixed-effects Bucher ITC methodology to calculate relative outcomes. RESULTS: Rates of virologic suppression (HIV-1 RNA < 50 copies/mL, US Food and Drug Administration Snapshot analysis) and virologic failure (HIV-1 RNA ≥ 50 copies/mL) as well as mean change in CD4 + cell count were similar with DTG + 3TC, BIC/FTC/TAF, and DTG/ABC/3TC at Week 144. Serious adverse events occurred less frequently with DTG + 3TC compared with both BIC/FTC/TAF (odds ratio [OR], 0.51; 95% CI 0.29-0.87; P = 0.014) and DTG/ABC/3TC (OR, 0.38; 95% CI 0.19-0.75; P = 0.006). Discontinuations and overall adverse events were similar across all 3 regimens. CONCLUSIONS: These results suggest that the 2-drug regimen DTG + 3TC offers comparable and durable efficacy with fewer serious adverse events vs BIC/FTC/TAF and DTG/ABC/3TC through 144 weeks of treatment in ART-naive PWH. These long-term comparative data support the therapeutic value of DTG + 3TC for PWH.

Indirect comparison of 48-week efficacy and safety of long-acting cabotegravir and rilpivirine maintenance every 8 weeks with daily oral standard of care antiretroviral therapy in participants with virologically suppressed HIV-1-infection.

BACKGROUND: Efficacy and safety of long-acting cabotegravir (CAB) + rilpivirine (RPV) every 8 weeks (Q8W) versus daily oral standard of care (SoC) maintenance in treatment-experienced individuals with virologically suppressed human immunodeficiency virus type 1 (HIV-1) has not been directly compared in randomized clinical trials. This analysis aimed to indirectly compare these regimens. METHODS: An adjusted indirect treatment comparison of CAB + RPV Q8W with daily oral SoC was performed, using Phase 3 data from studies of CAB + RPV every 4 weeks (Q4W) vs SoC (ATLAS/FLAIR, n = 591 per group) and a Phase 3b trial of CAB + RPV Q8W vs Q4W (ATLAS-2M [excluding participants with prior CAB + RPV exposure]; n = 327 per group). Eligible participants were virologically suppressed (viral load < 50 HIV-1 ribonucleic acid (RNA) copies/mL), treatment-experienced individuals with HIV-1-infection. Treatment efficacy and safety assessments at Week 48 included virologic suppression and lack of virologic suppression (proportion of participants with plasma HIV-1 RNA < 50 copies/mL or ≥ 50 copies/mL, respectively; both as per FDA snapshot algorithm), CD4-cell count change from baseline, no virologic data, discontinuations due to adverse events (AEs), and overall AEs, serious AEs and Grade 3-5 AEs excluding injection-site reactions. A subgroup analysis stratified by baseline third active drug class was performed. RESULTS: Baseline characteristics between the Q4W arms of ATLAS/FLAIR and ATLAS-2M showed no significant differences or differences were not judged to be clinically relevant, apart from participants switching from a baseline third active drug class; more participants switched from integrase strand inhibitors in ATLAS/FLAIR, and from non-nucleoside reverse transcriptase inhibitors in ATLAS-2M. Injections of CAB + RPV Q8W showed no significant differences across efficacy and safety outcomes versus daily oral SoC. Univariate subgroup analysis found there were no significant differences on virologic suppression or lack of virologic suppression for any baseline third active drug class subgroup. These results suggest that CAB + RPV Q8W is non-inferior to daily oral SoC. CONCLUSIONS: This analysis supports the therapeutic potential of CAB + RPV Q8W for virologically suppressed people living with HIV-1 infection seeking an alternative maintenance treatment option to daily oral SoC. TRIAL REGISTRATION: NCT02938520, NCT02951052, NCT03299049.

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.

BACKGROUND: The objective of this study was to assess the durability of response of dolutegravir (DTG) as an antiretroviral core agent by comparing its efficacy and safety with other recommended or commonly used core agents up to 96-weeks (W96). METHODS: A previously published systematic review was updated to identify phase 3/4 randomised controlled trials (RCTs) of core agents in treatment-naïve HIV-1 patients. Efficacy [virologic suppression (VS), CD4+ cell change from baseline] and safety [adverse events [AEs], discontinuations, drug-related AEs [DRAEs]] were analysed at W96 using Bayesian network meta-analysis (NMA) adjusting for nucleoside/nucleotide reverse transcriptase inhibitors' (NRTIs') backbone. Subgroups of patients with VL > 100,000 copies/mL or CD4+ ≤ 200 cells/µL at baseline were analysed separately. RESULTS: The NMA included 20 studies reporting data at W96. A higher proportion of patients receiving DTG achieved VS compared to those on protease inhibitors [PI:Range:8.7%(CrI:3.1,16.0)-19.9%(10.8,30.5)], efavirenz [EFV:6.9%(1.3,10.8)] and cobicistat-boosted elvitegravir [EVG/c:8.2%(0.2,17.4)], and similar but numerically higher compared to rilpivirine [RPV:5.0%(- 2.8,12.5)], raltegravir [RAL:2.9%(- 1.6,7.7)] and bictegravir [BIC:2.7%(- 2.7,10.6)]. The probability that more patients on DTG would achieve VS at W96 compared to any other core agent was greater than 80%. A higher proportion of patients on DTG achieved VS compared to PI/rs [Range:33.1%(13.6,50.4)-45.3%(24.1,61.6)] and RAL [16.7%(3.3,31.2)] in patients with VL > 100,000 copies/mL at baseline, and similar VS was achieved in patients with CD4+ ≤ 200 cells/µL at baseline. DTG also achieved greater increase in CD4+ cells from baseline compared to EFV [32.6(10.7,54.7)], ritonavir-boosted darunavir [DRV/r:25.7(3.6,48.1)] and BIC [24.7(1.5,47.7)]. Patients receiving DTG had lower odds of discontinuing therapy by W96 compared to PI/rs, EFV, RAL and EVG/c. Patients on DTG had lower odds of experiencing an adverse event (AE) compared to patients on EFV [odds ratio:0.6(0.3,0.9)], ATV/r [0.4(0.3,0.6)] and LPV/r [0.3(0.2,0.5)]. For patients on DTG, the odds of experiencing a drug-related AE were lower than the odds for patients on EFV [0.3(0.2,0.4)], comparable to patients on RAL [1.1(0.8,1.4)] and higher than those on BIC [1.5(1.1,2.0)]. CONCLUSION: Un-boosted integrase inhibitors had better efficacy and similar safety compared to PI/rs at W96 in treatment-naïve patients with HIV-1, with DTG being among the most efficacious core agent, particularly in patients with baseline VL > 100,000 copies/mL or ≤ 200 CD4+ cells/µL, who can be difficult to treat.

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.

BACKGROUND: Network meta-analyses (NMAs) provide comparative treatment effects estimates in the absence of head-to-head randomized controlled trials (RCTs). This NMA compared the efficacy and safety of dolutegravir (DTG) with other recommended or commonly used core antiretroviral agents. METHODS: A systematic review identified phase 3/4 RCTs in treatment-naïve patients with HIV-1 receiving core agents: ritonavir-boosted protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), or integrase strand inhibitors (INSTIs). Efficacy (virologic suppression [VS], CD4+ cell count change from baseline) and safety (adverse events [AEs], discontinuations, discontinuation due to AEs, lipid changes) were analyzed at Week 48 using Bayesian NMA methodology, which allowed calculation of probabilistic results. Subgroup analyses were conducted for VS (baseline viral load [VL] ≤/> 100,000copies/mL, ≤/> 500,000copies/mL; baseline CD4+ ≤/>200cells/µL). Results were adjusted for the nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) combined with the core agent (except subgroup analyses). RESULTS: The NMA included 36 studies; 2 additional studies were included in subgroup analyses only. Odds of achieving VS with DTG were statistically superior to PIs (odds ratios [ORs] 1.78-2.59) and NNRTIs (ORs 1.51-1.86), and similar but numerically higher than other INSTIs. CD4+ count increase was significantly greater with DTG than PIs (difference: 23.63-31.47 cells/µL) and efavirenz (difference: 34.54 cells/µL), and similar to other core agents. INSTIs were more likely to result in patients achieving VS versus PIs (probability: 76-100%) and NNRTIs (probability: 50-100%), and a greater CD4+ count increase versus PIs (probability: 72-100%) and NNRTIs (probability: 60-100%). DTG was more likely to result in patients achieving VS (probability: 94-100%), and a greater CD4+ count increase (probability: 53-100%) versus other core agents, including INSTIs (probability: 94-97% and 53-93%, respectively). Safety outcomes with DTG were generally similar to other core agents. In patients with baseline VL > 100,000copies/mL or ≤ 200 CD4+cells/µL (18 studies), odds of achieving VS with DTG were superior or similar to other core agents. CONCLUSION: INSTI core agents had superior efficacy and similar safety to PIs and NNRTIs at Week 48 in treatment-naïve patients with HIV-1, with DTG being among the most efficacious, including in patients with baseline VL > 100,000copies/mL or ≤ 200 CD4+cells/µL, who can be difficult to treat.

Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis.

'Double-hit lymphomas' (DHL), defined by concurrent MYC and BCL2 (or, alternatively, BCL6) rearrangements, have a very poor outcome compared to standard-risk, diffuse large B-cell lymphomas (DLBCL). Consequently, dose-intensive (DI) therapies and/or consolidation with high-dose therapy and transplant have been explored in DHL, although benefit has been debated. This meta-analysis compared survival outcomes in DHL patients receiving dose-escalated regimens [DI: R-Hyper-CVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) or R-CODOX-M/IVAC (rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high dose cytarabine); or intermediate-dose: R-EPOCH (rituximab, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone)] versus standard-dose regimens (R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in the first-line setting. Data were synthesized to estimate hazard ratios of dose-escalated treatments versus R-CHOP using a Weibull proportional hazards model within a Bayesian meta-analysis framework. Eleven studies examining 394 patients were included. Patients were treated with either front-line R-CHOP (n = 180), R-EPOCH (n = 91), or R-Hyper-CVAD/rituximab, methotrexate, cytarabine (R-M/C), R-CODOX-M/R-IVAC (DI) (n = 123). Our meta-analysis revealed that median progression-free survival (n = 350) for the R-CHOP, R-EPOCH and DI groups was 12·1, 22·2, and 18·9 months, respectively. First-line treatment with R-EPOCH significantly reduced the risk of a progression compared with R-CHOP (relative risk reduction of 34%; P = 0·032); however, overall survival (n = 374) was not significantly different across treatment approaches. A subset of patients might benefit from intensive induction with/without transplant. Further investigation into the role of transplant and novel therapy combinations is necessary.

Systematic review and meta-analysis of pharmacological therapies for painful diabetic peripheral neuropathy.

BACKGROUND: Painful diabetic peripheral neuropathy (pDPN) is prevalent among persons with diabetes and increases over time. Published guidelines recommend a number of medications to treat this condition providing clinicians with a variety of treatment options. This study provides a comprehensive systematic review and meta-analysis of published pharmacologic therapies for pDPN. METHODS: The published literature was systematically searched to identify randomized, controlled trials of all available pharmacologic treatments for pDPN (recommended or nonrecommended) reporting predefined efficacy and safety outcomes. Bayesian fixed-effect mixed treatment comparison methods were used to assess relative therapeutic efficacy and harms. RESULTS: Data from 58 studies including 29 interventions and 11,883 patients were analyzed. Pain reduction over that of placebo on the 11-point numeric rating scale ranged from -3.29 for sodium valproate (95% credible interval [CrI] = [-4.21, -2.36]) to 1.67 for Sativex (-0.47, 0.60). Estimates for most treatments were clustered between 0 and -1.5 and were associated with more study data and smaller CrIs. Pregabalin (≥ 300 mg/day) was the most effective on the 100-point visual analog scale (-21.88; [-27.06, -16.68]); topiramate was the least (-3.09; [-3.99, -2.18]). Relative risks (RRs) of 30% pain reduction ranged from 0.78 (Sativex) to 1.84 (lidocaine 5% plaster). Analysis of the RR ratio of these 2 treatments reveals marginal significance for Sativex (3.27; [1.07, 9.81]), indicating the best treatment is only slightly better than the worst. Relative risks of 50% pain reduction ranged from 0.98 (0.56, 1.52) (amitriptyline) to 2.25 (1.51, 3.00) (alpha-lipoic acid). RR ratio for these treatments was not statistically different (3.39; [0.88, 3.34]). Fluoxetine had the lowest risk of adverse events (0.94; [0.62, 1.23]); oxycodone had the highest (1.55; [1.45, 1.64]). Discontinuation RRs were clustered around 0.8 to 1.5, with those on the extreme having greater uncertainty. CONCLUSIONS: Selecting an appropriate pDPN therapy is key given the large number of available treatments. Comparative results revealed relative equivalence among many of the studied interventions having the largest overall sample sizes and highlight the importance of standardization of methods to effectively assess pain.

Potential public health impact of a Neisseria meningitidis A, B, C, W, and Y pentavalent vaccine in the United States.

OBJECTIVE: Globally, 5 serogroups (A, B, C, W, and Y) cause the majority of invasive meningococcal disease (IMD). Vaccines targeting these serogroups are currently part of the US adolescent immunization platform, which includes 1 + 1 dosing of a MenACWY vaccine routinely at ages 11 and 16 years and 2 doses of a MenB vaccine at age 16-23 years under shared clinical decision-making between the patient and healthcare provider. In 2018, MenACWY vaccination coverage was 86.6% for ≥1 dose and 50.8% for ≥2 doses, whereas MenB vaccination coverage was 17.2% for ≥1 dose and <50% for completion of the multidose series. A pentavalent MenABCWY vaccine could simplify immunization schedules and improve vaccination coverage. We estimated the public health impact of a pentavalent MenABCWY vaccine using a model that considers meningococcal carriage and vaccination coverage. METHODS: A population-based dynamic model estimated the 10-year reduction in IMD from implementing a MenABCWY vaccine within the existing US meningococcal immunization platform. Five vaccination schedules (4 new, 1 existing) were examined to estimate the impact of different recommendations on the overall reduction in the number of IMD cases. Sensitivity analyses were performed by varying vaccination coverage at age 16 years. RESULTS: The existing schedule and coverage of MenACWY and MenB vaccines (total 4 doses) could potentially avert 165 IMD cases over 10 years versus no vaccination. Assuming similar MenABCWY and MenACWY vaccination coverage rates at age 16 years, replacing 1 or more MenACWY and/or MenB doses with MenABCWY could avert more cases, ranging from 189 to 256. The most beneficial MenABCWY vaccine schedule was 2 doses at age 11 years and 1 dose at age 16 years. CONCLUSIONS: Replacing one or more MenACWY/MenB vaccine doses with MenABCWY could reduce IMD caused by all 5 meningococcal serogroups among the US adolescent population, while also reducing the number of injections required.

Real-World Effectiveness of Belimumab in Systemic Lupus Erythematosus: A Systematic Literature Review.

INTRODUCTION: Belimumab is a recombinant human monoclonal antibody that binds to soluble B-lymphocyte stimulator and inhibits its biological activity. Since receiving approvals for the treatment of systemic lupus erythematosus (SLE), several observational studies have investigated the effectiveness of belimumab in the real-world setting. This study reports a systematic review and meta-analysis of the literature to evaluate the real-world effectiveness of belimumab for the treatment of SLE. METHODS: A literature search following PRISMA Guidelines and limited to studies in English was performed (2014-2020) to identify relevant studies reporting effectiveness outcomes of belimumab in patients with SLE. A modified version of the Newcastle-Ottawa Scale was used to assess study quality. Outcomes, including SLE Disease Activity Index (SLEDAI) score, prednisone-equivalent use, and SLE flare were pooled and analyzed using statistical aggregation methods. RESULTS: The literature search identified 514 articles for initial review. Of these, 17 articles were suitable for data extraction and summary. Baseline characteristics of patients in real-world studies were generally similar to those of relevant clinical trials, including age, sex, disease duration, SLEDAI score, and prednisone-equivalent use. Real-world use of belimumab was associated with reductions in SLEDAI score (mean baseline score to month 6: 10.1-4.4; 57% reduction), prednisone-equivalent dosing (mean baseline dose to month 6: 12.1 mg/day to 6.9 mg/day; 43% reduction), and flare frequency (12 months prior to belimumab to 12 months after belimumab: 1.15-0.39 mean flares per patient per year; 66% reduction). Long-term data (up to 2 years post-treatment initiation) for SLEDAI score and prednisone-equivalent dose indicated that improvements in both outcomes continue over time among patients remaining on therapy. CONCLUSIONS: In the real-world setting, observed outcomes with belimumab for the treatment of SLE are consistent with those reported from randomized clinical trials. Improvements persist long-term for SLEDAI activity and prednisone-equivalent use with belimumab.

Effects of Levodopa-Carbidopa Intestinal Gel on Dyskinesia and Non-Motor Symptoms Including Sleep: Results from a Meta-Analysis with 24-Month Follow-Up.

BACKGROUND: In advanced Parkinson's disease (PD), dyskinesias and non-motor symptoms such as sleep dysfunction can significantly impair quality of life, and high-quality management is an unmet need. OBJECTIVE: To analyze changes in dyskinesia and non-motor symptoms (including sleep) among studies with levodopa-carbidopa intestinal gel (LCIG) in patients with advanced PD. METHODS: A comprehensive literature review identified relevant studies examining LCIG efficacy. Outcomes of interest were dyskinesia (UDysRS, UPDRS IV item 32), overall non-motor symptoms (NMSS), mentation/behavior/mood (UPDRS I), and sleep/daytime sleepiness (PDSS-2, ESS). The pooled mean (95% confidence interval) change from baseline per outcome was estimated for each 3-month interval with sufficient data (i.e., reported by≥3 studies) up to 24 months using a random-effects model. RESULTS: Seventeen open-label studies evaluating 1243 patients with advanced PD were included. All outcomes of interest with sufficient data for meta-analysis showed statistically significant improvement within 6 months of starting LCIG. There were statistically significant improvements in dyskinesia duration as measured by UPDRS IV item 32 at 6 months (-1.10 [-1.69, -0.51] h/day) and 12 months (-1.35 [-2.07, -0.62] h/day). There were statistically and clinically significant improvements in non-motor symptoms as measured by NMSS scores at 3 months (-28.71 [-40.26, -17.15] points). Significant reduction of NMSS burden was maintained through 24 months (-17.61 [-21.52, -13.70] points). UPDRS I scores significantly improved at 3 months (-0.39 [-0.55, -0.22] points). Clinically significant improvements in PDSS-2 and ESS scores were observed at 6 and 12 months in individual studies. CONCLUSION: Patients with advanced PD receiving LCIG showed significant sustained improvements in the burden of dyskinesia and non-motor symptoms up to 24 months after initiation.

Short Communication: Prevalence of Transmitted Resistance to Non-Nucleoside Reverse Transcriptase Inhibitors in European and North American Countries Over 20 Years: An Updated Meta-Analysis.

The prevalence of transmitted non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance around the world has been estimated up to 2010. Treatment recommendations have since evolved from NNRTIs to integrase strand inhibitors (INSTIs). This analysis estimates more recent trends in transmitted NNRTI resistance given emerging INSTI use. Studies reporting prevalence of transmitted NNRTI resistance in Europe, the United States, and Canada were meta-analyzed to generate yearly estimates in four regions. Overall prevalence of transmitted resistance continued to rise in the United States to >10% in 2015. Prevalence in European countries with larger surveillance networks was consistent at ∼4% from 2000 through 2012, increasing to 7% in 2016. Prevalence in European countries with fewer available data was generally <5%. Two publications with Canadian data were identified, reporting 0%-3% resistance. This analysis showed increasing prevalence of transmitted NNRTI resistance up to 2016, despite the availability of newer classes of treatments.

Cost-effectiveness of intravenous vedolizumab vs subcutaneous adalimumab for moderately to severely active ulcerative colitis.

BACKGROUND: The efficacy of intravenous (IV) vedolizumab vs subcutaneous (SC) adalimumab for the treatment of moderately to severely active ulcerative colitis (UC) was assessed in the VARSITY clinical trial, which demonstrated for the first time in a head-to-head clinical trial setting the superiority of IV vedolizumab with respect to clinical remission and endoscopic improvement. Both therapies offer better clinical outcomes compared with immunomodulators and corticosteroids but are often more expensive than other pharmacologic treatment options. Thus, payers and decision makers face the task of leveraging finite resources for optimal health benefits, which can be aided by the use of cost-effectiveness models. OBJECTIVE: To assess the cost-effectiveness of IV vedolizumab vs SC adalimumab from a US payer perspective using head-to-head data from the VARSITY trial. METHODS: A cohort decision tree was developed to estimate the costs and clinical outcomes associated with IV vedolizumab vs SC adalimumab to treat adults with moderately to severely active UC. Simulated cohorts began the model at treatment induction and continued to maintenance treatment with vedolizumab or adalimumab unless experiencing nonresponse or serious adverse drug reaction (ADR), in which case those patients transitioned to second-line treatment with tofacitinib, infliximab, or golimumab, where they could achieve response and/or remission or not. Those who still did not achieve response or remission or who had a serious ADR transitioned to a state of nonresponse for the remainder of the model or received surgery. The process was modeled for patients who were treatment naive and treatment experienced at baseline separately. Efficacy and safety inputs for vedolizumab and adalimumab were taken from the VARSITY trial, and corresponding inputs for other biologics were derived from a network meta-analysis. All clinical inputs were extrapolated over 2 years. Direct medical costs (expressed in 2019 US dollars) included those related to drug acquisition and administration, ADRs, routine monitoring, and additional treatment procedures. Outcomes were not discounted given the short time horizon. Univariate sensitivity and scenario analysis were applied to evaluate the robustness of the model to underlying parameter and structural uncertainty. RESULTS: Initial treatment with vedolizumab was associated with a higher remission rate at 2 years (73.5% vs 71.5%) and higher persistence (22.0% vs 14.4%) compared with adalimumab. Total direct medical costs were lower for the vedolizumab cohort ($100,022 vs $151,133), primarily driven by the lower annual drug acquisition cost of vedolizumab ($85,953 vs $137,492). When endoscopic improvement was used as the outcome measure, IV vedolizumab was also associated with higher endoscopic remission and lower overall costs. CONCLUSIONS: With better clinical outcomes and lower direct medical costs over a 2-year model horizon, vedolizumab IV was the dominant treatment strategy vs adalimumab SC in adults with moderately to severely active UC. Outcomes were driven primarily by the probability of major ADRs and induction response. DISCLOSURES: This study was supported by Takeda Pharmaceuticals U.S.A., Inc. (Lexington, MA). Schultz and Turpin are employees of Takeda Pharmaceuticals U.S.A., Inc. Turpin has stock or stock options in Takeda Pharmaceuticals. Diakite, Carter, and Snedecor are employees of OPEN Health (Bethesda, MD), which received payment from Takeda for the design and execution of this study. This study was presented at the European Crohn's and Colitis Organisation (ECCO) 2020 Congress and Digestive Disease Week (DDW), 2020 Virtual Congress.

Impact of carbidopa-levodopa enteral suspension on quality of life and activities of daily living in patients with advanced Parkinson's disease: Results from a pooled meta-analysis.

INTRODUCTION: To estimate the impact of carbidopa/levodopa enteral suspension (CLES) on key patient-centered outcomes in patients with advanced Parkinson's disease (PD). METHODS: A comprehensive literature review identified relevant studies, from which data were meta-analyzed over 3-month intervals up to 24 months. Patient-centered outcomes of interest included mean (95% CI) changes from baseline (Δ) in quality of life (QoL), measured using PD-specific (PDQ-8, PDQ-39) and generic (EQ-5D) instruments; activities of daily living (ADL), measured in On and Off states using UPDRS Part II; and motor symptoms (i.e., Off time/day and motor examination [measured in On and Off states using UPDRS Part III]). RESULTS: The pooled meta-analysis included data from 26 studies evaluating 1556 patients on CLES. At 3 months, all outcomes showed significant improvement: QoL (ΔPDQ-39 = -10.26 [-11.54, -8.97], ΔEQ-5DVAS = 15.42 [12.58, 18.26]); ADL (ΔUPDRS IION = -4.32 [-5.63, -3.01]); motor symptoms (ΔOff time hours/day = -3.48 [-4.15, -2.82], ΔUPDRS IIION = -6.20 [-9.88, -2.51]). At 24 months, there were statistically significant mean improvements in QoL (ΔPDQ-39 = -7.74 [-12.40, -3.07], ΔEQ-5DVAS = 11.18 [6.90, 15.45]) and ADL (ΔUPDRS IIOFF = -3.88 [-5.34, -2.42]), and Off time (-4.21 [-5.16, -3.26] hours/day). CONCLUSIONS: Impact of CLES on significantly reducing Off time/day was observed to be rapid and durable (i.e., remained consistent across 24 months). Most QoL and ADL measures showed a consistent pattern of improvement with initiation of treatment and remained significantly improved from baseline at 24 months.

Corrigendum: Economic Value of Lost Productivity Attributable to Human Papillomavirus Cancer Mortality in the United States.

[This corrects the article DOI: 10.3389/fpubh.2020.624092.].

Economic outcomes of eszopiclone treatment in insomnia and comorbid major depressive disorder.

BACKGROUND: Eszopiclone is effective for the treatment of insomnia in patients with insomnia and comorbid major depressive disorder (MDD). Both conditions impose significant economic burden, with the US societal cost of depression estimated at USD 50 billion annually. AIMS OF THE STUDY: The purpose of this analysis was to examine the costs and benefits of eszopiclone co-administered with fluoxetine (ESZ+FLX) compared to placebo co-administered with fluoxetine (PBO+FLX) in adults meeting the DSM-IV criteria for insomnia and MDD. METHODS: Data from 434 patients enrolled in an 8-week clinical trial who met the economic-subanalysis criteria were examined. The costs of medical care (in 2007 USUSD ) and lost work time were estimated from the Hamilton Depression Scale (HAM-D17) scores using published algorithms. Cost of lost productivity while at work was based on responses to the Work Limitations Questionnaire. The impact of therapy on quality-adjusted life years (QALYs) was estimated by transforming HAM-D17 (base case analysis) or Short Form Health Survey (SF-12) (scenario analyses) responses into health utility scores using published algorithms. Drug costs were estimated based on average wholesale price. RESULTS: The mean 8-week increases in QALYs from baseline were 0.0392 and 0.0334 for the ESZ+FLX and PBO+FLX groups, respectively. Mean per-patient costs were USD 1,279 and USD 1,198 for the respective groups. Thus, co-treatment resulted in net increases of 0.0058 QALYs and USD 81, leading to an incremental cost per QALY gained of approximately USD 14,000. DISCUSSION AND LIMITATIONS: Co-administration of eszopiclone and fluoxetine improved patients' insomnia symptoms and appeared to be a cost-effective treatment strategy for patients with insomnia and comorbid MDD. One limitation of this study is that optimal utility estimation techniques were not available. Utilities were instead derived indirectly using the HAM-D17 (disease-specific, not generic) or SF-12 (generic, but potentially insensitive to important changes in some conditions) instruments. IMPLICATIONS FOR HEALTH CARE PROVISION: Sleep disturbance is predictive of depression relapse, and is the most common residual symptom in patients who have been successfully treated with fluoxetine for depression. Thus, identifying cost-effective strategies for the treatment of insomnia symptoms is important for this patient population. IMPLICATIONS FOR HEALTH POLICIES: Treatment guidelines and drug coverage decisions should be based on clinical evidence, effectiveness, and economic criteria (i.e., whether an effective drug therapy produces sufficient benefits given its costs). This information about the overall value of eszopiclone can be measured as the cost per QALY gained with the use of ESZ+FLX compared with FLX alone. In order to make decisions based on value, payers and policy makers must have access to reliable cost-effectiveness information. IMPLICATIONS FOR FURTHER RESEARCH: The residual efficacy observed in the clinical trial following the discontinuation of co-therapy should be explored further to determine whether intermittent treatment with ESZ+FLX is a cost-effective strategy.

Cost-effectiveness of alternative strategies for vaccination of adolescents against serogroup B IMD with the MenB-FHbp vaccine in Canada.

OBJECTIVE: Serogroup B meningococci (MnB) are now the largest cause of invasive meningococcal disease (IMD) in Canada. We assessed the clinical and economic impact of 3 adolescent MenB-FHbp immunization strategies. METHODS: A population-based dynamic transmission model was developed to simulate the transmission of MnB among the entire Canadian population over a 30-year time horizon. Age group-based IMD incidence, bacterial carriage and transmission, disease outcomes, costs, and impact on quality of life were obtained from Canadian surveillance data and published literature. The vaccine was assumed to provide 85% protection against IMD and 26.6% against carriage acquisition. The model estimated the impact of routine vaccination with MenB-FHbp in 3 strategies: (1) age 14, along with existing school-based programs, with 75% uptake; (2) age 17 with 75% uptake, assuming school vaccination; and (3) age 17 with 30% uptake, assuming vaccination outside of school. Costs were calculated from the Canadian societal perspective. RESULTS: With no vaccination, an estimated 3974 MnB cases would be expected over 30 years. Vaccination with strategies 1-3 were estimated to avert 688, 1033, and 575 cases, respectively. These outcomes were associated with incremental costs per quality-adjusted life-year of $976,000, $685,000, and $490,000. CONCLUSIONS: Our model indicated that if the vaccine reduces risk of carriage acquisition, vaccination of older adolescents, even at lower uptake, could have a significant public health impact. Due to low disease incidence, MnB vaccination is unlikely to meet widely accepted cost-effectiveness thresholds, but evaluations of new programs should consider the overall benefits of the vaccination.

Economic Value of Lost Productivity Attributable to Human Papillomavirus Cancer Mortality in the United States.

Objectives: To estimate years of potential life lost (YPLL) and present value of future lost productivity (PVFLP) associated with premature mortality due to HPV-attributable cancers, specifically those targeted by nonavalent HPV (9vHPV) vaccination, in the United States (US) before vaccine use. Methods: YPLL was estimated from the reported number of deaths in 2017 due to HPV-related cancers, the proportion attributable to 9vHPV-targeted types, and age- and sex-specific US life expectancy. PVFLP was estimated as the product of YPLL by age- and sex-specific probability of labor force participation, annual wage, value of non-market labor, and fringe benefits markup factor. Results: An estimated 7,085 HPV-attributable cancer deaths occurred in 2017 accounting for 154,954 YPLL, with 5,450 deaths (77%) and 121,226 YPLL (78%) attributable to 9vHPV-targeted types. The estimated PVFLP was $3.3 billion for cancer deaths attributable to 9vHPV-targeted types (86% from women). The highest productivity burden was associated with cervical cancer in women and anal and oropharyngeal cancers in men. Conclusions: HPV-attributable cancer deaths are associated with a substantial economic burden in the US, much of which could be vaccine preventable.

Cost-effectiveness of eszopiclone for the treatment of adults with primary chronic insomnia.

STUDY OBJECTIVE: To assess the cost-effectiveness of treatment with eszopiclone for chronic primary insomnia in adults. METHODS: A model using patient-level data from a 6-month, double-blind, placebo-controlled, clinical trial (n = 824), combined with data from a claims database and published literature, was used to assess the quality-adjusted life years (QALYs) gained and costs associated with eszopiclone versus placebo in adults with primary insomnia. Quality of life data were collected during the trial via the SF-36, from which preference-based utility scores were derived using published algorithms. Medical and absenteeism costs, estimated via a retrospective analysis of a claims and absenteeism database, were assigned to patients based on the degree of severity of their insomnia, assessed via the Insomnia Severity Index collected in the clinical trial. Presenteeism costs (lost productivity while at work) were estimated from responses to the Work Limitation Questionnaire collected during the trial. Six-month gains in QALYs and costs for each treatment group were calculated to derive cost-effectiveness ratios. Uncertainty was addressed via univariate and multivariate sensitivity analyses. RESULTS: Over the 6-month period, eszopiclone use resulted in a net gain of 0.0137 QALYs over placebo at an additional cost of $67, resulting in an incremental cost per QALY gained of slightly less than $5,000. When absenteeism and presenteeism costs were excluded, the cost-effectiveness ratio increased to approximately $33,000 per QALY gained, which is below the commonly used threshold of $50,000 used to define cost-effectiveness. Extensive sensitivity analyses indicate the results are generally robust. CONCLUSION: Our model, based on efficacy data from a clinical trial, demonstrated eszopiclone was cost-effective for the treatment of primary insomnia in adults, especially when lost productivity costs were included.

Review of Economic Value Drivers of the Treatment of Overactive Bladder.

Overactive bladder (OAB) is a symptom-driven condition with economic burden estimated to be on the order of several hundred dollars or euros per patient in some North American and European countries. This work reviews recently published economic models to evaluate how health states are defined, what cost components are considered, and what utility values are used to estimate the cost effectiveness of OAB pharmacotherapies, botulinum toxin, or sacral neuromodulation. It was found that no clear standard exists for determining OAB health states, although most were defined by some measure of incontinence frequency. Costs of physician visits and incontinence pads were included in nearly all models; however, OAB-associated depression and nursing home costs were rarely included, despite being large cost drivers of global economic burden studies. Utility values used in the models ranged from 0.544 to 0.933, highlighting the uncertainty associated with how OAB patients value health-related quality of life. More research is warranted so that health states providing delineations among OAB symptom severity and quality of life are clinically and economically meaningful as well as meaningful to affected patients.

Clinical and economic analysis of outcomes of dose tapering or withdrawal of tumor necrosis factor-α inhibitors upon achieving stable disease activity in rheumatoid arthritis patients.

OBJECTIVE: To compare the real-world, 5-year clinical and cost impact of maintaining treatment with the tumor necrosis factor-α inhibitors (anti-TNFs) adalimumab, etanercept, or infliximab vs dose tapering or withdrawal in rheumatoid arthritis (RA) patients who have achieved remission (defined as a 28-joint count Disease Activity Score [DAS28] < 2.6) or low disease activity (LDA; DAS28 < 3.2). METHODS: Using a 5-year Markov model with 1-month cycle length, we examined the clinical and cost impact of three treatment strategies: withdrawal, tapering, or maintenance of anti-TNFs among RA patients in remission or who have achieved LDA. This model assessed the time to loss of disease control, time to regaining control after treatment reinitiation, and associated medical and anti-TNF costs. To determine the risk of losing disease control, 14 studies (2309 patients) were meta-analyzed, adjusted for treatment strategy, anti-TNF, RA patient type (early or established RA), and model entry criterion (remission or LDA). RESULTS: Anti-TNF withdrawal and tapering incurred comparable 5-year total costs (€37,900-€59,700 vs €47,500-€59,200), which were lower than those incurred by anti-TNF maintenance (€67,100-€72,100). Established RA patients had higher total costs than early RA patients (€45,900-€72,100 vs €37,900-€71,700). Maintenance was associated with the longest time to loss of disease control (range, 27.3-47.1 months), while withdrawal had the shortest (range, 6.9-30.5 months). CONCLUSION: Dose tapering or withdrawal of anti-TNFs results in similar reduction of health care costs but less time in sustained disease control compared to maintaining therapy. Future research is needed to understand the long-term clinical consequences of these strategies and patient preferences for treatment withdrawal.