The Cost-Effectiveness of Directly Observed Highly-Active Antiretroviral Therapy in the Third Trimester in HIV-Infected Pregnant Women

Background: In HIV-infected pregnant women, viral suppression prevents mother-to-child HIV transmission. Directly observed highly-active antiretroviral therapy (HAART) enhances virological suppression, and could prevent transmission. Our objective was to project the effectiveness and cost-effectiveness of directly observed administration of antiretroviral drugs in pregnancy. Methods and Findings: A mathematical model was created to simulate cohorts of one million asymptomatic HIV-infected pregnant women on HAART, with women randomly assigned self-administered or directly observed antiretroviral therapy (DOT), or no HAART, in a series of Monte Carlo simulations. Our primary outcome was the quality-adjusted life expectancy in years (QALY) of infants born to HIV-infected women, with the rates of Caesarean section and HIV-transmission after DOT use as intermediate outcomes. Both self-administered HAART and DOT were associated with decreased costs and increased life-expectancy relative to no HAART. The use of DOT was associated with a relative risk of HIV transmission of 0.39 relative to conventional HAART; was highly cost-effective in the cohort as a whole (cost-utility ratio $14,233 per QALY); and was cost-saving in women whose viral loads on self-administered HAART would have exceeded 1000 copies/ml. Results were stable in wide-ranging sensitivity analyses, with directly observed therapy cost-saving or highly cost-effective in almost all cases. Conclusions: Based on the best available data, programs that optimize adherence to HAART through direct observation in pregnancy have the potential to diminish mother-to-child HIV transmission in a highly cost-effective manner. Targeted use of DOT in pregnant women with high viral loads, who could otherwise receive self-administered HAART would be a cost-saving intervention. These projections should be tested with randomized clinical trials

ECOSTRESS: NASA's next generation mission to measure evapotranspiration from the International Space Station

The ECOsystem Spaceborne Thermal Radiometer Experiment on Space Station ECOSTRESS) was launched to the International Space Station on June 29, 2018. The primary science focus of ECOSTRESS is centered on evapotranspiration (ET), which is produced as level‐3 (L3) latent heat flux (LE) data products. These data are generated from the level‐2 land surface temperature and emissivity product (L2_LSTE), in conjunction with ancillary surface and atmospheric data. Here, we provide the first validation (Stage 1, preliminary) of the global ECOSTRESS clear‐sky ET product (L3_ET_PT‐JPL, version 6.0) against LE measurements at 82 eddy covariance sites around the world. Overall, the ECOSTRESS ET product performs well against the site measurements (clear‐sky instantaneous/time of overpass: r2 = 0.88; overall bias = 8%; normalized RMSE = 6%). ET uncertainty was generally consistent across climate zones, biome types, and times of day (ECOSTRESS samples the diurnal cycle), though temperate sites are over‐represented. The 70 m high spatial resolution of ECOSTRESS improved correlations by 85%, and RMSE by 62%, relative to 1 km pixels. This paper serves as a reference for the ECOSTRESS L3 ET accuracy and Stage 1 validation status for subsequent science that follows using these data

Aging, working memory capacity and the proactive control of recollection:An event-related potential study

The present study investigated the role of working memory capacity (WMC) in the control of recollection in young and older adults. We used electroencephalographic event-related potentials (ERPs) to examine the effects of age and of individual differences in WMC on the ability to prioritize recollection according to current goals. Targets in a recognition exclusion task were words encoded using two alternative decisions. The left parietal ERP old/new effect was used as an electrophysiological index of recollection, and the selectivity of recollection measured in terms of the difference in its magnitude according to whether recognized items were targets or non-targets. Young adults with higher WMC showed greater recollection selectivity than those with lower WMC, while older adults showed nonselective recollection which did not vary with WMC. The data suggest that aging impairs the ability to engage cognitive control effectively to prioritize what will be recollected

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

The Cost-Effectiveness of Directly Observed Highly- Active Antiretroviral Therapy in the Third Trimester in HIV-Infected Pregnant Women

Background: In HIV-infected pregnant women, viral suppression prevents mother-to-child HIV transmission. Directly observed highly-active antiretroviral therapy (HAART) enhances virological suppression, and could prevent transmission. Our objective was to project the effectiveness and cost-effectiveness of directly observed administration of antiretroviral drugs in pregnancy. Methods and Findings: A mathematical model was created to simulate cohorts of one million asymptomatic HIV-infected pregnant women on HAART, with women randomly assigned self-administered or directly observed antiretroviral therapy (DOT), or no HAART, in a series of Monte Carlo simulations. Our primary outcome was the quality-adjusted life expectancy in years (QALY) of infants born to HIV-infected women, with the rates of Caesarean section and HIV-transmission after DOT use as intermediate outcomes. Both self-administered HAART and DOT were associated with decreased costs and increased lifeexpectancy relative to no HAART. The use of DOT was associated with a relative risk of HIV transmission of 0.39 relative to conventional HAART; was highly cost-effective in the cohort as a whole (cost-utility ratio $14,233 per QALY); and was costsaving in women whose viral loads on self-administered HAART would have exceeded 1000 copies/ml. Results were stable in wide-ranging sensitivity analyses, with directly observed therapy cost-saving or highly cost-effective in almost all cases. Conclusions: Based on the best available data, programs that optimize adherence to HAART through direct observation i

Selected Model Variables.

<p><b>NOTE:</b> HAART, highly-active antiretroviral therapy; DOT, directly observed therapy; QALE, quality-adjusted life expectancy.</p><p>* Complete response considered to be a sustained reduction in viral load of 2.0 log₁₀ copies/ml; partial response considered to be a sustained reduction of 0.75 log₁₀ copies/ml; non-response associated with a reduction of 0.25 log₁₀ copies/ml <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-DeHovitz1" target="_blank">[32]</a>.</p><p>† Non-elective Caesarean at term and Caesarean section with premature delivery were not associated with reduced risk of mother-to-child HIV transmission <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-The4" target="_blank">[59]</a>.</p><p>‡ Base-case probability of prematurity approximates that seen in a cohort of HIV-infected New York Medicaid recipients; upper bound based on rates of premature delivery seen in a subgroup of women receiving methadone maintenance therapy <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-Turner2" target="_blank">[58]</a>.</p><p>§ In base case, risk of antiretroviral toxicity in infants was assumed to be negligible, consistent with available data <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-Perinatal1" target="_blank">[6]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-Lipshultz1" target="_blank">[62]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-The5" target="_blank">[65]</a>. Risk of severe toxicity used in sensitivity analysis based on upper bound confidence limit for mitochondrial toxicity in a French cohort study <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-Blanche1" target="_blank">[63]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-Barret1" target="_blank">[64]</a>. Risk of moderate toxicity based on best estimate of plausible upper bound.</p><p>∥ Base-case estimates and ranges for viral loads greater than 1000 copies/ml derived based on outcomes among individuals receiving peripartum zidovudine in a prospective multi-centre study of HIV in pregnancy <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-Garcia1" target="_blank">[5]</a>.</p><p>¶ QALY and lifetime cost estimates presented in table based on the use of a 3% discount rate. Base-case quality-adjustment for HIV-uninfected individuals 45 years of age and older performed using community-derived utility estimates, as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-Fryback1" target="_blank">[78]</a>, while upper bound estimates are not quality-adjusted.</p><p>** Quality-adjusted survival in HIV-infected infants was estimated based on the assumption that 2/3 of person-time with HIV infection would be symptom-free, while 1/3 of person-time with HIV would include HIV-attributable symptoms. Acquired immune deficiency syndrome was assumed to be present in the last two years of life. Death due to HIV in infected children has declined markedly in both the U.S. and Europe with the advent of HAART, making estimation of survival in HIV-infected children difficult due to small numbers of events <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-Sanchez1" target="_blank">[35]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-Selik1" target="_blank">[37]</a>. Survival in HIV-infected children was assumed to approximate that seen in the youngest adults treated with HAART <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-Egger1" target="_blank">[36]</a>. Lower bound survival estimates for HIV were generated using community-derived utility weights for life with HIV infection <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-Schackman1" target="_blank">[34]</a>, while upper bound estimates were generated using more favorable survival estimates, and without quality-adjustment <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-The7" target="_blank">[79]</a>.</p><p>†† Based on in-hospital mortality in 15% of premature infants (including third-trimester still-births), with a risk of moderate to severe cognitive impairment in 10–30% <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-deKleine1" target="_blank">[68]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-International1" target="_blank">[70]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-Vollmer1" target="_blank">[76]</a>. Reduction in quality-adjusted survival estimated based on health utility weight of 0.67 predicted for an individual with moderate cognitive and sensory impairment and impaired self-care ability using the Health Utilities Index Mark II <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-Torrance1" target="_blank">[69]</a>.</p><p>‡‡ Based on intravenous zidovudine during 12 hour labor, and average dose of 1 ml zidovudine syrup (10 mg/ml) administered to neonate qid for 6 weeks postpartum <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-Perinatal1" target="_blank">[6]</a>.</p><p>§§ Estimated based on weighted average healthcare costs associated with prematurity in infants born from 28 to 36 weeks of gestation in the state of California <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-Gilbert1" target="_blank">[75]</a>, with future costs occurring due to developmental delay in 15–30% of surviving infants <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-deKleine1" target="_blank">[68]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-Zupancic1" target="_blank">[74]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-Vollmer1" target="_blank">[76]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-Waitzman1" target="_blank">[80]</a>.</p

Sensitivity Analysis of Increasing Baseline Effectiveness of Self-Administered Antiretroviral Therapy.

<p>The proportion of women with a full response to self-administered antiretroviral therapy (i.e., 2.0 log₁₀ reduction in viral load) is presented on the X-axis. The left-sided Y-axis indicates the proportion of 200-person clinical trials that find directly observed therapy to be cost-effective for various willingness-to-pay thresholds (thick black curve, WTP = $0; medium black curve, WTP =$50,000; thin black curve, WTP = $150,000). Average incremental cost-effectiveness ratios for directly observed therapy, relative to self-administered antiretroviral therapy (dark dashed curve) are presented on the right-sided Y-axis; values below$0 indicate that directly observed therapy is a cost-saving health intervention. As the proportion of women who have a full response to self-administered HAART increases, there is a decrease in the proportion of women for whom DOT is cost-effective. An increase in the willingness-to-pay threshold leads to an increase in the proportion of women who find this intervention cost effective. Arrows indicate base-case values.</p

Simplified Depiction of Model Tree Structure.

<p>Pregnant women with HIV infection enter the third trimester of pregnancy already on highly-active antiretroviral therapy, with or without direct observation. Round “nodes” represent chance events, while squares represent clinical decisions. Women either experience preterm or term delivery, with a viral load (VL, in copies/ml) that is a function of baseline viral load, effectiveness of antiretroviral drugs, and the availability of directly observed therapy. For both detectable and undetectable viral load responses, a proportion of women receive emergency Caesarean sections. Delivery may otherwise be by elective Caesarean section, or by vaginal delivery. Vaginal delivery is an option only in women with low viral loads on antiretroviral therapy. Health outcomes in the infant are predicted by prematurity (not shown) and the occurrence of mother-to-child transmission.</p

Selected Univariate Sensitivity Analyses of Directly Observed HAART Relative to Self-Administered HAART.

<p><b>NOTE:</b> HAART, highly-active antiretroviral therapy; QALY, quality-adjusted life years. Each estimate based on 10 simulated randomized trials with 1000 women per trial.</p><p>* Simulated through 0.75 log₁₀ reduction in viral load in 65% of women, with 0.25 log₁₀ response in the remainder.</p><p>† Highest probability of vertical transmission incorporated upper-bound transmission probability for each maternal viral load, and lower-bound estimate for effectiveness of Caesarean section, while lowest probability incorporated lower-bound transmission probabilities and upper-bound estimate for effectiveness of Caesarean section.</p><p>‡ A health care intervention is “dominated” if it costs more, but provides less health benefit, than a competing intervention. A dominated health intervention is never preferred <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-Laupacis1" target="_blank">[50]</a>. A health care intervention is considered to be “cost-saving” when it costs less a competing intervention; “highly cost-effective” when it costs less than the GDP per capita; and “cost-effective” when it is between one and three times a country's GDP per capita, given that the intervention provides more health benefit than a competing intervention <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-World1" target="_blank">[49]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010154#pone.0010154-Laupacis1" target="_blank">[50]</a>.</p><p>§ Discounted to present value at 3% per annum.</p><p>¶ Incorporated upper- and lower-bound estimates for costs of highly-active antiretroviral therapy (HAART), peripartum zidovudine therapy, and delivery of directly observed HAART.</p><p>∥ Incorporated upper- and lower-bound estimates for costs of vaginal delivery and Caesarean section.</p