Cost-effectiveness and budget impact of dolutegravir/lamivudine for treatment of human immunodeficiency virus (HIV-1) infection in the United States.

BACKGROUND: Dolutegravir(DTG)/lamivudine(3TC) is the first 2-drug regimen recommended as an initial treatment for people living with HIV (PLHIV). OBJECTIVE: To assess the cost-effectiveness and potential budget impact of DTG/3TC in the US healthcare setting. METHODS: A previously published hybrid decision-tree and Markov cohort state transition model was adapted to estimate the incremental costs and health outcome benefits over a patients' lifetime. DTG/3TC was compared with current standard of care in treatment naive and treatment experienced virologically suppressed PLHIV. Health states included in the model were based upon virologic response and CD4 cell count, with death as an absorbing state. Clinical data was informed by the Phase III GEMINI 1 and 2 clinical trials, a published network meta-analysis (NMA) in treatment-naive patients and the Phase III TANGO clinical trial in treatment experienced patients. Costs and utilities were informed by published data and discounted annually at a rate of 3%. A separate 5-year budget impact analysis was conducted assuming 5%-15% uptake in eligible treatment naive and 10%-30% uptake in eligible treatment experienced patients. RESULTS: In the treatment naive analyses based on GEMINI 1 and 2, DTG/3TC dominated, i.e., was less costly and more effective, than all comparators. DTG/3TC resulted in 0.083 incremental quality-adjusted life-years (QALYs) at a cost saving of $199,166 compared with the DTG + tenofovir disoproxil(TDF)/emtricitabine(FTC) comparator arm. The incremental QALY and cost savings for DTG/3TC compared with DTG/abacavir(ABC)/3TC, cobicistat-boosted darunavir(DRV/c)/tenofovir alafenamide(TAF)/FTC, and bictegravir (BIC)/TAF/FTC, based on NMA results were 0.465, 0.142, and 0.698, and $42,948, $122,846, and $44,962, respectively. In the analyses of treatment-experienced virologically suppressed patients based on TANGO, DTG/3TC offered slightly lower QALYs (-0.037) with an estimated savings of $78,730 when compared with continuation of TAF-based regimen (TBR). Sensitivity analyses demonstrated that these conclusions were relatively insensitive to alternative parameter estimates. The budget impact analysis estimated that by 5th year a total of 70,240 treatment naive patients and 1,340,480 treatment experienced patients could be eligible to be prescribed DTG/3TC. The estimated budget savings over 5 years ranged from $1.12b to $3.35b (corresponding to 27,512 to 82,536 on DTG/3TC by year 5) in the lowest and highest uptake scenarios, respectively. CONCLUSION: In conclusion, DTG/3TC with its comparable efficacy and lower drug acquisition costs, has the potential to offer significant cost savings to US healthcare payers for the initial treatment of treatment naive patients and as a treatment switching option for virologically suppressed patients. DISCLOSURES: This study was funded in full by ViiV healthcare, Brentford, UK. Medical writing to support this study was also funded in full by ViiV Healthcare, Brentford, UK. Butler, Hayward, and Jacob are employees of HEOR Ltd, the company performing this study funded by ViiV Healthcare. Anderson is an employee of GlaxoSmithKline and owns shares in the company. Punekar, Evitt, and Oglesby are employees of ViiV Healthcare and own stocks in GlaxoSmithKline.

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.

Prevalence, determinants, and impact of suboptimal adherence to HIV medication in 25 countries.

Modern antiretroviral therapy (ART) has improved the lives of people living with HIV (PLHIV) but currently requires daily adherence. We assessed prevalence and correlates of suboptimal adherence, and measured associations with self-reported health outcomes. Data were from web-based surveys of confirmed HIV+ adults on antiretroviral treatment within 25 countries during 2019 (n = 2389). Suboptimal adherence was a report of ≥1 reason for missing ART ≥5 times within the past month. Multivariable logistic regression examined associations between suboptimal adherence and self-reported overall health and virologic suppression. Overall, 24.1% (575/2389) reported suboptimal adherence, from 10.0% (5/50) in Austria, to 62.0% (31/50) in China. The most common reasons for missing ART ≥5 times in the overall population were feeling depressed/overwhelmed (7.4%, 176/2389), trying to forget about HIV (7.0%, 168/2389), and work (6.1%, 145/2389). Correlates of suboptimal adherence included being heterosexual, <50 years old, ≤high school, having gastrointestinal treatment side effects, and privacy concerns. Odds of suboptimal overall health were 1.41 (95%CI, 1.11-1.80), 2.10 (95%CI, 1.65-2.68), and 2.55 (95%CI, 2.00-3.25) among those who reported the maximum number of times missed ART for any reason within the past month as 1, 2-4, or ≥5 times respectively, vs not missing at all. Odds of virologic nonsuppression were 1.80 (95%CI, 1.33-2.45), and 2.24 (95%CI, 1.66-3.02) for 2-4, or ≥5 times of missed ART respectively, vs not missing at all; missing for only 1 time was not significantly associated with virologic nonsuppression. Novel ART strategies designed to improve adherence along with interventions to empower PLHIV and support self-medication may improve health outcomes and quality of life.

"It made me more confident that I have it under control": Patient and provider perspectives on moving to a two-drug ART regimen in the United States and Spain.

BACKGROUND: Two-drug regimens (2DR) to treat HIV infection have the potential to reduce long-term toxicity and increase therapeutic options for people living with HIV (PLHIV). Prior phase III trials, SWORD-1 and SWORD-2, as well as GEMINI-1 and GEMINI-2, have demonstrated that a dolutegravir-based 2DR is as effective as three- or four-drug regimens among virologically suppressed patients. Limited information exists, however, on patient and provider experiences with 2DR to inform roll-out and integration into routine clinical care. METHODS: We conducted 39 in-depth interviews with PLHIV currently on 2DR in the context of routine care and 8 of their clinical care providers in the United States (U.S.) and Spain. Participants included 33 male and 6 female PLHIV and 8 providers. Interview topics explored perceptions of and experiences with 2DR compared to prior anti-retroviral regimens (ARVs), side effects, patient satisfaction, and clinical performance. Interviews were audio-recorded, transcribed and analyzed using thematic content analysis. RESULTS: Participants viewed 2DR as a significant and positive advance, in terms of its ability to effectively treat HIV with reduced toxicity and essentially no reported side effects. Patients noted the central role providers played in the decision to switch to a 2DR regimen and, among U.S. participants, the importance of insurance coverage making this preferred option feasible. Patients and providers agreed that a 2DR regimen would be appropriate for any PLHIV regardless of whether they were treatment naïve or had significant experience with ARVs. CONCLUSIONS: Participants' experiences with a 2DR regimen were positive with no participants, reporting side effects and all reporting continued viral suppression. Providers valued the reduced toxicity offered by 2DR and served as the primary gateway to a transition to 2DR for patients in both settings. This study provides a foundation for further research on the transition to 2DR regimens in other populations and contexts including low- and middle-income settings.

Estimating HIV Management and Comorbidity Costs Among Aging HIV Patients in the United States: A Systematic Review.

BACKGROUND: As life expectancy of patients infected with human immunodeficiency virus (HIV) approaches that of the general population, the composition of HIV management costs is likely to change. OBJECTIVES: To (a) review treatment and disease management costs in HIV, including costs of adverse events (AEs) related to antiretroviral therapy (ART) and long-term toxicities, and (b) explore the evolving cost drivers. METHODS: A targeted literature review between January 2012 and November 2017 was conducted using PubMed and major conferences. Articles reporting U.S. costs of HIV management, acquired immunodeficiency syndrome (AIDS)-defining events, end of life care, and ART-associated comorbidities such as cardiovascular disease (CVD), chronic kidney disease (CKD), and osteoporosis were included. All costs were inflated to 2017 U.S. dollars. A Markov model-based analysis was conducted to estimate the effect of increased life expectancy on costs associated with HIV treatment and management. RESULTS: 22 studies describing HIV costs in the United States were identified, comprising 16 cost-effectiveness analysis studies, 5 retrospective analyses of health care utilization, and 1 cost analysis in a resource-limited setting. Management costs per patient per month, including routine care costs (on/off ART), non-HIV medication, opportunistic infection prophylaxis, inpatient utilization, outpatient utilization, and emergency department utilization were reported as CD4+ cell-based health state costs ranging from $1,192 for patients with CD4 > 500 cells/mm3 to $2,873 for patients with CD4 < 50 cells/mm3. Event costs for AEs ranged from $0 for headache, pain, vomiting, and lipodystrophy to $31,545 for myocardial infarction. The mean monthly per-patient costs for CVD management, CKD management, and osteoporosis were $5,898, $6,108, and $4,365, respectively. Improvements in life expectancy, approaching that of the general population in 2018, are projected to increase ART-related and AE costs by 35.4% and comorbidity costs by 175.8% compared with estimated costs with HIV life expectancy observed in 1996. CONCLUSIONS: This study identified and summarized holistic cost estimates appropriate for use within U.S. HIV cost-effectiveness analyses and demonstrates an increasing contribution of comorbidity outcomes, primarily associated with aging in addition to long-term treatment with ART, not typically evaluated in contemporary HIV cost-effectiveness analyses. DISCLOSURES: This analysis was sponsored by ViiV Healthcare, which had no role in the analyses and interpretation of study results. Ward, Sugrue, Hayward, and McEwan are employees of HEOR Ltd, which received funding from ViiV Healthcare to conduct this study. Anderson is an employee of GlaxoSmithKline and holds shares in the company. Punekar and Oglesby are employees of ViiV Healthcare and hold shares in GlaxoSmithKline. Lopes was employed by ViiV Healthcare at the time of the study and holds shares in GlaxoSmithKline.

Comedication prescription patterns and potential for drug-drug interactions with antiretroviral therapy in people living with human immunodeficiency virus type 1 infection in Germany.

PURPOSE: Various first-line recommended antiretroviral therapy (ART) regimens have different drug-drug interaction (DDI)/contraindication profiles. The aim of this study was to estimate the rate of potential DDIs/contraindications of real-world prescribed non-ART comedication with first-line recommended ART in people living with HIV (PLHIV) in Germany. METHODS: A retrospective, cross-sectional cohort design was used to collect non-ART comedication prescription data from a representative sample of a German health insurance claims database. PLHIV who were prescribed ART during 2016 were included in the analysis. Patients were stratified by sex, age, comorbidities, and time on ART. Prescribed comedications were used to estimate potential DDIs/contraindications for each recommended first-line ART per patient based on criteria from www.hiv-druginteractions.org. RESULTS: Records from 2680 PLHIV were analyzed. Prescriptions for non-ART comedications were common (mean of seven per patient in the overall population, 10.2 in PLHIV aged 50 years and older). Antiretroviral regimens with the lowest proportion of patients with at least 1 potential DDI/contraindication were unboosted integrase inhibitor, non-tenofovir disoproxil fumarate-based regimens that included raltegravir + emtricitabine/tenofovir alafenamide fumarate (13%), dolutegravir + lamivudine (14%), dolutegravir/abacavir/lamivudine (14%), dolutegravir/emtricitabine/tenofovir alafenamide fumarate (15%), and bictegravir/emtricitabine/tenofovir alafenamide fumarate (19%). Boosted regimens and efavirenz-based regimens presented the highest potential for DDIs/contraindications. CONCLUSIONS: Comedication with potential DDIs/contraindications with ART is frequently prescribed among PLHIV in Germany. Potential risks for DDIs/contraindications vary by ART, with the lowest potential seen in unboosted integrase strand transfer inhibitor-based regimens, including raltegravir + emtricitabine/tenofovir alafenamide fumarate, followed by three dolutegravir-based regimens.

Improving access to antiretrovirals in China: economic analyses of dolutegravir in HIV-1 patients.

BACKGROUND: The World Health Organisation recommended dolutegravir (DTG)-based antiretroviral therapy (ART) regimens are available but not reimbursed through the public reimbursement system in China. The objective of this analysis was to evaluate the cost-effectiveness of DTG (DTG + TDF/3TC) compared to efavirenz (EFV + TDF/3TC) in treatment-naive and ritonavir-boosted lopinavir (LPV/r + TDF/3TC) in first-line ART failure HIV-1-infected patients in China. METHODS: A dynamic Markov model comprising of 5 response states and 6 CD4+ count-based health states was used. Efficacy, estimated as probability of virologic suppression (HIV RNA < 50 copies/mL) at 48 weeks, was obtained from a published network meta-analysis for ART-naive patients and from the DAWNING study for patients failing first-line ART. Baseline cohort characteristics were informed using DTG phase 3 studies and the DAWNING study data, respectively. Health state utilities were derived from DTG phase 3 studies. A 5-year cost-effectiveness analyses was conducted using the societal perspective. Outcomes were quality-adjusted-life-years (QALYs), life-years (LYs), incremental cost per QALYs (ICER). RESULTS: The viral suppression rates for DTG + TDF/3TC were higher than EFV + TDF/3TC (75.3% vs 64.0%) in treatment-naive and LPV/r + TDF/3TC (74.8% vs 58.4%) in first-line ART failure patients. This resulted in higher QALYs for DTG + TDF/3TC in treatment-naive (4.232 vs 4.227) and first-line failure settings (4.224 vs 4.221). Total discounted cost for DTG + TDF/3TC patients (RMB 219.259 in treatment-naive and RMB 238,746 in first-line failures) were lower than comparators (EFV + TDF/3TC:RMB 221,605; LPV/r + TDF/3TC:RMB 244,364), thereby DTG dominated in both settings. Probabilistic sensitivity analyses indicated the probability of DTG + TDF/3TC being cost effective was 98.2% in treatment-naive setting and 100% in first-line failure setting at a willingness to pay threshold of RMB 100,000/QALY. CONCLUSIONS: With lower costs, higher response rates and higher QALYs, DTG + TDF/3TC can be considered as a cost-effective alternative for treatment naive and first-line failure patients in China.

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.

Comparative efficacy and safety and dolutegravir and lamivudine in treatment naive HIV patients.

OBJECTIVE: Compare the efficacy and safety of the 2-drug antiretroviral therapy regimen dolutegravir + lamivudine (DTG + 3TC) with traditional 3-drug regimens in treatment-naive patients with HIV-1. DESIGN: Data from double-blind, randomized controlled trials of at least 48 weeks' duration in treatment-naive patients with HIV-1 identified by systematic review were evaluated using a Bayesian network meta-analysis methodology. METHODS: The primary outcome was virologic suppression at Week 48 for 3-drug regimens versus DTG + 3TC (also analyzed in patient subgroup with baseline viral load >100 000 RNA copies/ml). Secondary outcomes included CD4 cell count change from baseline and safety (adverse events, serious adverse events, and drug-related adverse events) at Week 48. RESULTS: The network contains 14 unique regimens from 14 randomized controlled trials based on data from 10 043 patients. The proportional difference for viral suppression at 48 weeks for DTG + 3TC versus the other 13 regimens included in the network ranged from -2.7% (-11.0, 5.6%) versus DTG + tenofovir alafenamide/emtricitabine (FTC) to 7.3% (0.6, 13.8%) versus efavirenz + tenofovir disoproxil fumarate/FTC. DTG + 3TC was found to be significantly better than efavirenz + tenofovir disoproxil fumarate/FTC and similar to all other regimens analysed in terms of viral suppression at 48 weeks. With regard to other outcomes (CD4, adverse event, serious adverse event, drug-related adverse events) at 48 weeks, DTG+3TC was broadly similar to all regimens analysed. CONCLUSION: This network meta-analysis demonstrates similar efficacy and safety outcomes over 48 weeks with DTG + 3TC compared with traditional 3-drug antiretroviral therapy regimens.

Dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with HIV-1 infection in whom first-line therapy has failed (DAWNING): an open-label, non-inferiority, phase 3b trial.

BACKGROUND: Doubts exist regarding optimal second-line treatment options for HIV-1-infected patients in resource-limited settings. We assessed safety and efficacy of dolutegravir compared with ritonavir-boosted lopinavir, plus two nucleoside reverse transcriptase inhibitors (NRTIs) in adults in whom previous first-line antiretroviral therapy with a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two NRTIs has failed. METHODS: DAWNING is a phase 3b, open-label, parallel-group, non-inferiority, active-controlled trial done at 58 sites in 13 countries. Eligible adults were aged at least 18 years and, during at least 6 months of treatment with a first-line treatment containing an NNRTI and two NRTIs, had virological failure (confirmed HIV-1 RNA ≥400 copies per mL). Participants were randomly assigned by a central randomisation system to receive oral dolutegravir (50 mg once daily) or ritonavir-boosted lopinavir (800 mg lopinavir plus 200 mg ritonavir once daily or 400 mg plus 100 mg twice daily), plus two investigator-selected NRTIs (at least one fully active based on resistance testing at screening). The primary outcome was the proportion of participants achieving viral suppression (defined as plasma HIV-1 RNA <50 copies per mL) at week 48 using the snapshot algorithm and a non-inferiority margin of -12%. The primary analysis was done in an intention-to-treat-exposed (ITT-E) population of participants who received at least one dose of study medication, according to original group assignment. Safety was analysed in all participants who received at least one dose of study drug, according to which drug was received. The study was registered at ClinicalTrials.gov, number NCT02227238, and viiv-studyregister.com, number 200304. FINDINGS: Between Dec 11, 2014, and June 27, 2016, 968 adults were screened and 627 were randomly assigned to the dolutegravir group (n=312) or the ritonavir-boosted lopinavir group (n=315). Three patients in the ritonavir-boosted lopinavir group did not receive study medication and so 624 were included in the ITT-E population. At week 48, 261 (84%) of 312 participants in the dolutegravir group achieved viral suppression compared with 219 (70%) of 312 in the ritonavir-boosted lopinavir group (adjusted difference 13·8%; 95% CI 7·3-20·3). Non-inferiority was achieved on the basis of the 95% CI of the adjusted treatment difference having a lower bound greater than -12% (prespecified non-inferiority margin). Because the lower bound of the 95% CI is greater than zero (7·3%), superiority of dolutegravir was also concluded (p<0·0001). The safety profile for dolutegravir was favourable compared with that of ritonavir-boosted lopinavir. More grade 2-4 drug-related adverse events occurred with ritonavir-boosted lopinavir than dolutegravir (44 [14%] of 310 with ritonavir-boosted lopinavir vs 11 [4%] of 314 with dolutegravir), mainly driven by gastrointestinal disorders. INTERPRETATION: When administered with two NRTIs, dolutegravir was superior to ritonavir-boosted lopinavir at 48 weeks and can be considered a suitable option for second-line treatment. FUNDING: ViiV Healthcare.

COPD treatment pathways in France: a retrospective analysis of electronic medical record data from general practitioners.

BACKGROUND: Increasing availability of therapeutic options for COPD may drive new treatment pathways. This study describes COPD treatment in France, focusing on identifying initial treatment modifications in patients with COPD who either initiated long-acting bronchodilator (LABD)-based therapy or escalated to triple therapy (long-acting muscarinic antagonist [LAMA] + long-acting ß2-agonist [LABA] + inhaled corticosteroid [ICS]). METHODS: This retrospective analysis of patients with COPD in a large general practitioner database (IQVIA Longitudinal Patient Database) in France included two cohorts: Cohort 1 - new initiators of LABD-based therapy (LAMA, LABA, LAMA + LABA, LAMA + ICS, LABA + ICS or LAMA + LABA + ICS); Cohort 2 - patients escalating to triple therapy from mono- or dual-bronchodilator-based maintenance treatment. Both cohorts were indexed on the date of initiation/escalation (January 2008-December 2013), and the first treatment modification (at class level) within the 18-month post-index observational period was described. Five mutually exclusive outcomes were defined: continuous use (no modification), discontinuation (permanent [≥91 days with no restart] or temporary [≥91 days with subsequent restart]), switch, and augmentation (Cohort 1 only). Exploratory analysis of Cohort 1 explored potential drivers of treatment initiation. RESULTS: Overall, 5,065 patients initiated LABD-based therapy (Cohort 1), and 501 escalated to triple therapy (Cohort 2). In Cohort 1, 7.0% of patients were continuous users, 46.5% discontinued permanently, 28.5% discontinued temporarily, 2.8% augmented (added LAMA and/or LABA and/or ICS), and 15.2% switched therapy. In Cohort 2, 18.2% of patients were continuous users, 7.2% discontinued permanently, 27.9% discontinued temporarily, and 46.7% switched therapy. Exploratory analyses showed that time since COPD diagnosis was first recorded, pre-index exacerbation events, and concomitant medical conditions were potential drivers of initial maintenance treatment choices. CONCLUSION: Discontinuation among new initiators of LABD-based therapy was high in France, whereas few switched or augmented treatment. In comparison, permanent discontinuation within 18 months was low in patients escalating to triple therapy.

Cost-Effectiveness of Dolutegravir as a First-Line Treatment Option in the HIV-1-Infected Treatment-Naive Patients in Russia.

OBJECTIVES: To evaluate the cost effectiveness of dolutegravir + abacavir/lamivudine (DTG + ABC/3TC) compared with raltegravir + abacavir/lamivudine (RAL + ABC/3TC) and ritonavir-boosted darunavir + abacavir/lamivudine (DRV/r + ABC/3TC) in HIV-1-infected treatment-naive patients in Russia. METHODS: A dynamic Markov model was developed with five response states and six CD4+-based health states. Efficacy estimated as probability of viral suppression (HIV RNA <50 copies/ml) at 48 weeks was obtained from a published network meta-analysis. Baseline cohort characteristics and health state utilities were informed using DTG phase 3 clinical trials. Health care resource use was obtained from literature and costed using published unit costs. Costs (presented in Russian rubles) included antiretroviral drug costs; HIV management costs such as routine care; costs of treating cardiovascular conditions, opportunistic infections, and drug-related adverse effects; and mortality costs. A patient lifetime analysis was conducted using the societal perspective. Outcomes were quality-adjusted life-years (QALYs), life-years, incremental cost per QALY ratio, and incremental cost per responder. RESULTS: The viral suppression rate among patients receiving DTG + ABC/3TC was 71.7% compared with 65.2% for RAL + ABC/3TC and 59.6% for DRV/r + ABC/3TC. The mean duration of response per patient was 116.6 months for DTG + ABC/3TC, 108.6 months for RAL + ABC/3TC, and 98.9 months for DRV/r + ABC/3TC. Total discounted costs for treatment over patient lifetime were RUB 2.89, 5.32, and 4.38 million for DTG + ABC/3TC, RAL + ABC/3TC, and DRV/r + ABC/3TC, respectively. Lifetime discounted QALYs were 12.73 for patients on DTG + ABC/3TC and 12.72 each for patients on RAL + ABC/3TC and DRV/r + ABC/3TC. DTG + ABC/3TC thus dominated the other two alternatives. CONCLUSIONS: With lower costs, higher response rates, and comparable QALYs, DTG + ABC/3TC can be considered as a cost-effective alternative.

A Review of Long-Term Toxicity of Antiretroviral Treatment Regimens and Implications for an Aging Population.

Human immunodeficiency virus (HIV) is a chronic infectious disease currently requiring lifelong antiretroviral therapy (ART). People living with HIV (PLWH) face an increased risk of comorbidities associated with aging, chronic HIV, and the toxicity arising from long-term ART. A literature review was conducted to identify the most recent evidence documenting toxicities associated with long-term ART, particularly among aging PLWH. In general, PLWH are at a greater risk of developing fractures, osteoporosis, renal and metabolic disorders, central nervous system disorders, cardiovascular disease, and liver disease. There remains limited evidence describing the economic burden of long-term ART. Overall, an aging HIV population treated with long-term ART presents a scenario in which the clinical, humanistic, and economic burden for healthcare systems will demand thoughtful policy solutions that preserve access to treatment. Newer treatment regimens with fewer drugs may mitigate some of the cumulative toxicity burden of long-term ART.Funding: ViiV Healthcare.

Systematic review of the association between exercise tests and patient-reported outcomes in patients with chronic obstructive pulmonary disease.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is an increasingly common cause of death worldwide. Its cardinal symptoms include breathlessness and severely reduced exercise capacity. Several patient-reported outcome (PRO) measures are used to assess health-related quality of life (HRQoL), functional performance, and breathlessness in patients with COPD. Exercise testing is employed to measure functional performance objectively, which is generally believed to impact on overall HRQoL. However, the extent to which commonly used laboratory- and field-based exercise test results correlate with PROs has not been systematically assessed. MATERIALS AND METHODS: A search of Embase, MedLine, and the Cochrane Library identified primary publications in English that reported data on the correlations (Pearson's r or Spearman's ρ) between the outcomes of exercise tests and HRQoL and breathlessness PROs. Studies reporting on the following tests were included: 6-minute walk test (6MWT), 12MWT, incremental and endurance shuttle walk tests, incremental and endurance cycle ergometer tests, and treadmill tests. RESULTS: Of 3,205 articles screened, 28 were deemed eligible for inclusion. The most commonly reported HRQoL PRO measure was the St George's Respiratory Questionnaire (13 studies), and the most commonly reported breathlessness PRO measure was the Baseline Dyspnea Index (six studies). The St George's Respiratory Questionnaire appears to correlate very weakly to moderately with the 6MWT, and breathlessness PROs appear to be moderately to strongly associated with 6MWT outcomes. Across all studies, the 6MWT was the most commonly reported exercise test. Very few publications reporting associations between other exercise tests and PRO measures were found. CONCLUSION: This review found evidence to support the association of 6MWT outcomes with HRQoL and breathlessness PROs. There were limited data showing correlations with the outcomes of other exercise tests. Further work is required to examine the associations between these PROs and exercise test outcomes.

Rescue medication use as a patient-reported outcome in COPD: a systematic review and regression analysis.

BACKGROUND: Reducing rescue medication use is a guideline-defined goal of asthma treatment, however, little is known about the validity of rescue medicine use as a marker of symptoms in chronic obstructive pulmonary disease (COPD). To improve patient outcomes, greater insight is needed into the relationship between rescue medication use and alternative COPD outcomes. METHODS: A systematic search of electronic databases (Embase®, MEDLINE® and Cochrane CENTRAL) was conducted from database start to 26 May, 2015. Studies of bronchodilator therapy with a duration of ≥24 weeks were included if they reported either mean change from baseline (CFB) in rescue medication use in puffs/day or % rescue-free days (%RFD), and at least one other COPD endpoint. Correlation and meta-regression analyses were undertaken to test the association between rescue medication use and other COPD outcomes using weighted means (weights proportional to the sample size of the treatment group) and unweighted means (equal weight for each treatment group). Each association was assessed at 6 months and study end. RESULTS: Forty-six studies involving 46,531 patients provided mean data from 145 treatment groups for evaluation. Changes in both measures of rescue medication use were correlated with changes in trough forced expiratory volume in one second ([FEV1]; Pearson correlation coefficients |r| ≥ 0.63; p < 0.0001) and with St George's Respiratory Questionnaire (SGRQ) score (|r| ≥ 0.70; p < 0.0001) at study end. Change in rescue medication use in puffs/day during the study correlated with annualized rates of moderate/severe exacerbations at 6 months and study end (both r = 0.66; p ≤ 0.0028). CFB in puffs/day was not well correlated with Transition Dyspnoea Index (TDI), but %RFD did correlate with TDI score at 6 months and study end (both r = 0.69; p < 0.0001). The values for CFB in puffs/day corresponding to the proposed minimal clinically important differences for trough FEV1 and SGRQ score were -1.3 and -0.6 puffs/day, respectively. A -1.0 puffs/day CFB in rescue use corresponded to a change of 0.26 events/patient-year in moderate/severe exacerbations. CONCLUSION: This analysis provides clear evidence of associations at a patient group level between rescue medication use and other clinically important COPD outcomes.

A Network Meta-Analysis of Long-Acting Muscarinic Antagonist (LAMA) and Long-Acting ß2-Agonist (LABA) Combinations in COPD.

INTRODUCTION: Comparative data on the efficacies of long-acting muscarinic antagonist (LAMA) and long-acting ß2-agonist (LABA) combinations for the treatment of moderate-to-very-severe chronic obstructive pulmonary disease (COPD) are limited. The aim of this Bayesian network meta-analysis (NMA) is to assess the relative efficacies of available open combinations (delivered via separate inhalers) and fixed-dose combinations (FDCs, delivered via a single inhaler). METHODS: We conducted a systematic literature review with the aim of identifying randomized controlled trials (RCTs) of ≥8-week duration in adults aged ≥40 years with COPD that compared LAMA + LABA combinations with each other, with tiotropium (TIO), or with placebo. Data on changes from baseline in trough forced expiratory volume in 1 s (FEV1) and on St George's Respiratory Questionnaire (SGRQ) total score, the Transition Dyspnea Index (TDI) focal score, and rescue medication use at 12 and 24 weeks were extracted from these RCTs and analyzed using a NMA in a Bayesian framework. RESULTS: Data from 44 RCTs were included in the NMA. All FDCs showed improvements relative to placebo in terms of trough FEV1, SGRQ total score, and TDI focal score above clinically relevant thresholds, with the exception of TIO/olodaterol and aclidinium/formoterol, both of which failed to show clinically relevant improvements in SGRQ score at 24 weeks. All FDCs demonstrated reduced rescue medication use versus placebo. Open combinations demonstrated improved efficacy in all outcomes versus placebo, but these improvements did not consistently exceed clinically relevant thresholds for SGRQ and TDI scores. All once-daily FDCs showed improved efficacy versus TIO, but improvements were less consistently observed versus TIO with open dual combinations and combinations containing formoterol or salmeterol administered twice daily. Relative probabilities of improvement between FDCs highlighted potential between-class differences for trough FEV1 but suggested little potential for differences in patient-reported outcomes. CONCLUSION: LAMA + LABA combinations generally showed improved outcomes versus placebo and TIO. FDCs appeared to perform better than open dual combinations. A potential effectiveness gradient was observed between FDCs for objectively assessed functional outcomes, although further prospective trials are required to confirm these findings. FUNDING: GSK.

Non-persistence and non-adherence to long-acting COPD medication therapy: A retrospective cohort study based on a large German claims dataset.

OBJECTIVES: The main objectives of this study, based on a large cohort of German COPD patients, were to assess the level of non-persistence (NP) and non-adherence (NA) with long-acting COPD inhaler treatment and to describe factors that may be associated with NP and NA. METHODS: This was a retrospective cohort analysis based on claims data provided by a German statutory health insurance fund (years 2010-2012). NP was analyzed for treatment-naïve patients only; it was defined as a gap of >90 days in medication availability. With regard to NA, first the overall yearly medication possession ratio (MPR) was analyzed, NA was defined as MPR<80%. Secondly, adherence was explored only for the period in which a patient continued therapy with a long-acting COPD agent (no gap>90 days). RESULTS: 45,937 COPD patients who received at least one prescription of any long-acting COPD agent were identified (mean age 71.4 years; 45.2% female). Among these, 22,276 (42.4%) were classified as newly treated. The percentage of NP patients after 12 months was 65.3% on an overall patient level. Agent-specific NP rates were: 58.5% for LABA, 47.9% for LAMA, 78.0% for ICS, and 69.4% for single-device LABA/ICS combination treatment. The overall 12-month MPR across all agent classes on a patient level was 57.9% (70.0% of patients classified as non-adherent). During periods of general treatment continuation, the mean MPR/NA rates were 85.0%/30.1% (patient level across all agents), 89.3%/28.2% (LABA), 92.1%/16.2% (LAMA), 84.2%/43.8% (ICS) and 84.1%/42.8% (LABA/ICS combination). In the Cox regression analyses, several factors like female gender, higher CCI or lower number of specialist' visits were associated with earlier discontinuation of therapy. In comparison to LABA therapy, LAMA therapy was less likely to be associated with early NP, whereas patients who initiated ICS therapy or a single-device LABA/ICS combination therapy faced a higher NP risk. CONCLUSIONS: In German COPD patients, persistence and adherence with respect to long-acting bronchodilator therapy is poor. Approximately two thirds of patients fail to continue treatment after 12 months. In addition, about one third implement their treatment poorly during periods of general therapy continuation.

Bronchodilator reliever use and its association with the economic and humanistic burden of COPD: a propensity-matched study.

BACKGROUND AND AIMS: Short-acting bronchodilators are normally used as supplemental relief medication for breakthrough symptoms in COPD patients. The objective of this cross-sectional study was to assess if more frequent vs infrequent use of relief medication in maintenance-treated COPD patients, split by the severity dyspnea, was associated with an increase in the overall disease burden. METHODS: A population-based cross-sectional survey (Adelphi DSP) was conducted among patients with COPD in five European countries. Information was collected on demographic and clinical characteristics, reliever inhaler use, dyspnea (mMRC), health status (CAT, EQ-5D), sleep quality (JSEQ) and healthcare resource use including moderate-severe COPD exacerbations, physician visits, COPD medications and other COPD related resources. The humanistic and economic burden was compared between patients with infrequent reliever use (<1 occasion/week) and more frequent use (≥ 1 occasion/week). The association between increased reliever use and economic burden was also examined after matching patients based on propensity-scores balancing demographic and disease burden characteristics. RESULTS: Among the 1373 COPD patients prescribed a reliever inhaler, 29% reported using reliever medication ≥1 occasion/week. In the unmatched cohort, more frequent reliever use (n = 377) compared to infrequent use (n = 996) was linked to poorer health status (CAT: 25.7 vs 20.0; p < .0001; EQ-5D-3L: 0.63 vs 0.82; p < .0001) and poorer sleep quality (JSEQ: 8.6 vs 4.6 units; p < .0001). More frequent reliever use was also associated with higher annual rates of moderate/severe exacerbations (1.6 vs 1.0 events/year; p < .0001) and respiratory specialist visits (2.8 vs 2.2 events/year; p = .0001). In the propensity-score matched population, more frequent reliever use was also associated with significantly higher annual costs for COPD management (€5,034 vs €3,705, p = .0327) compared to patients with infrequent reliever use. CONCLUSION: In moderate-to-severe COPD, more frequent reliever use is associated with increased exacerbation risk and increased management costs.

Can Assessment of Disease Burden Prior to Changes in Initial COPD Maintenance Treatment Provide Insight into Remaining Unmet Needs? A Retrospective Database Study in UK Primary Care.

This retrospective cohort study aimed to assess treatment patterns over 24 months amongst patients with chronic obstructive pulmonary disease (COPD), initiating a new COPD maintenance treatment, and to understand clinical indicators of treatment change. Patients included in the study initiated a long-acting ß2-agonist (LABA), a long-acting muscarinic antagonist (LAMA), or a combination of LABA and an inhaled corticosteroid (ICS/LABA) between January 1, 2009, and November 30, 2013, as recorded in the United Kingdom Clinical Practice Research Datalink (UK CPRD). Treatment modifications (switching or adding maintenance treatments) over 24 months were assessed, and patient characteristics, disease burden, medication and healthcare resource use during the 30 days before treatment modification were evaluated. The cohort comprised 17,258 patients [LABA (8%), LAMA (39%) and ICS/LABA (54%)] with similar age, body mass index and dyspnoea distribution. LABA users were more likely than LAMA users to add a maintenance therapy. Distinct patterns of treatment augmentations were noted, whereby LABA users typically received dual therapy before moving to triple therapy, while LAMA users moved to triple therapy by directly adding an ICS/LABA. Exacerbation events immediately prior to treatment change were not frequently recorded; however, the need for rescue short-acting medication and assessment of dyspnoea in the 30 days prior to the treatment change suggest that dyspnoea is a remaining unmet need driving therapy change.