Clinician- and Patient-Directed Communication Strategies for Patients With Cancer at High Mortality Risk: A Cluster Randomized Trial.

Importance: Serious illness conversations (SICs) that elicit patients' values, goals, and care preferences reduce anxiety and depression and improve quality of life, but occur infrequently for patients with cancer. Behavioral economic implementation strategies (nudges) directed at clinicians and/or patients may increase SIC completion. Objective: To test the independent and combined effects of clinician and patient nudges on SIC completion. Design, Setting, and Participants: A 2 × 2 factorial, cluster randomized trial was conducted from September 7, 2021, to March 11, 2022, at oncology clinics across 4 hospitals and 6 community sites within a large academic health system in Pennsylvania and New Jersey among 163 medical and gynecologic oncology clinicians and 4450 patients with cancer at high risk of mortality (≥10% risk of 180-day mortality). Interventions: Clinician clusters and patients were independently randomized to receive usual care vs nudges, resulting in 4 arms: (1) active control, operating for 2 years prior to trial start, consisting of clinician text message reminders to complete SICs for patients at high mortality risk; (2) clinician nudge only, consisting of active control plus weekly peer comparisons of clinician-level SIC completion rates; (3) patient nudge only, consisting of active control plus a preclinic electronic communication designed to prime patients for SICs; and (4) combined clinician and patient nudges. Main Outcomes and Measures: The primary outcome was a documented SIC in the electronic health record within 6 months of a participant's first clinic visit after randomization. Analysis was performed on an intent-to-treat basis at the patient level. Results: The study accrued 4450 patients (median age, 67 years [IQR, 59-75 years]; 2352 women [52.9%]) seen by 163 clinicians, randomized to active control (n = 1004), clinician nudge (n = 1179), patient nudge (n = 997), or combined nudges (n = 1270). Overall patient-level rates of 6-month SIC completion were 11.2% for the active control arm (112 of 1004), 11.5% for the clinician nudge arm (136 of 1179), 11.5% for the patient nudge arm (115 of 997), and 14.1% for the combined nudge arm (179 of 1270). Compared with active control, the combined nudges were associated with an increase in SIC rates (ratio of hazard ratios [rHR], 1.55 [95% CI, 1.00-2.40]; P = .049), whereas the clinician nudge (HR, 0.95 [95% CI, 0.64-1.41; P = .79) and patient nudge (HR, 0.99 [95% CI, 0.73-1.33]; P = .93) were not. Conclusions and Relevance: In this cluster randomized trial, nudges combining clinician peer comparisons with patient priming questionnaires were associated with a marginal increase in documented SICs compared with an active control. Combining clinician- and patient-directed nudges may help to promote SICs in routine cancer care. Trial Registration: ClinicalTrials.gov Identifier: NCT04867850.

Cluster Randomized Pragmatic Clinical Trial Testing Behavioral Economic Implementation Strategies to Improve Tobacco Treatment for Patients With Cancer Who Smoke.

PURPOSE: Few cancer centers systematically engage patients with evidence-based tobacco treatment despite its positive effect on quality of life and survival. Implementation strategies directed at patients, clinicians, or both may increase tobacco use treatment (TUT) within oncology. METHODS: We conducted a four-arm cluster-randomized pragmatic trial across 11 clinical sites comparing the effect of strategies informed by behavioral economics on TUT engagement during oncology encounters with cancer patients. We delivered electronic health record (EHR)-based nudges promoting TUT across four nudge conditions: patient only, clinician only, patient and clinician, or usual care. Nudges were designed to counteract cognitive biases that reduce TUT engagement. The primary outcome was TUT penetration, defined as the proportion of patients with documented TUT referral or a medication prescription in the EHR. Generalized estimating equations were used to estimate the parameters of a linear model. RESULTS: From June 2021 to July 2022, we randomly assigned 246 clinicians in 95 clusters, and collected TUT penetration data from their encounters with 2,146 eligible patients who smoke receiving oncologic care. Intent-to-treat (ITT) analysis showed that the clinician nudge led to a significant increase in TUT penetration versus usual care (35.6% v 13.5%; OR = 3.64; 95% CI, 2.52 to 5.24; P < .0001). Completer-only analysis (N = 1,795) showed similar impact (37.7% clinician nudge v 13.5% usual care; OR = 3.77; 95% CI, 2.73 to 5.19; P < .0001). Clinician type affected TUT penetration, with physicians less likely to provide TUT than advanced practice providers (ITT OR = 0.67; 95% CI, 0.51 to 0.88; P = .004). CONCLUSION: EHR nudges, informed by behavioral economics and aimed at oncology clinicians, appear to substantially increase TUT penetration. Adding patient nudges to the implementation strategy did not affect TUT penetration rates.

Behavioral economic implementation strategies to improve serious illness communication between clinicians and high-risk patients with cancer: protocol for a cluster randomized pragmatic trial.

BACKGROUND: Serious illness conversations (SICs) are an evidence-based approach to eliciting patients' values, goals, and care preferences that improve patient outcomes. However, most patients with cancer die without a documented SIC. Clinician-directed implementation strategies informed by behavioral economics ("nudges") that identify high-risk patients have shown promise in increasing SIC documentation among clinicians. It is unknown whether patient-directed nudges that normalize and prime patients towards SIC completion-either alone or in combination with clinician nudges that additionally compare performance relative to peers-may improve on this approach. Our objective is to test the effect of clinician- and patient-directed nudges as implementation strategies for increasing SIC completion among patients with cancer. METHODS: We will conduct a 2 × 2 factorial, cluster randomized pragmatic trial to test the effect of nudges to clinicians, patients, or both, compared to usual care, on SIC completion. Participants will include 166 medical and gynecologic oncology clinicians practicing at ten sites within a large academic health system and their approximately 5500 patients at high risk of predicted 6-month mortality based on a validated machine-learning prognostic algorithm. Data will be obtained via the electronic medical record, clinician survey, and semi-structured interviews with clinicians and patients. The primary outcome will be time to SIC documentation among high-risk patients. Secondary outcomes will include time to SIC documentation among all patients (assessing spillover effects), palliative care referral among high-risk patients, and aggressive end-of-life care utilization (composite of chemotherapy within 14 days before death, hospitalization within 30 days before death, or admission to hospice within 3 days before death) among high-risk decedents. We will assess moderators of the effect of implementation strategies and conduct semi-structured interviews with a subset of clinicians and patients to assess contextual factors that shape the effectiveness of nudges with an eye towards health equity. DISCUSSION: This will be the first pragmatic trial to evaluate clinician- and patient-directed nudges to promote SIC completion for patients with cancer. We expect the study to yield insights into the effectiveness of clinician and patient nudges as implementation strategies to improve SIC rates, and to uncover multilevel contextual factors that drive response to these strategies. TRIAL REGISTRATION: ClinicalTrials.gov , NCT04867850 . Registered on April 30, 2021. FUNDING: National Cancer Institute P50CA244690.

Rationale and protocol for a cluster randomized pragmatic clinical trial testing behavioral economic implementation strategies to improve tobacco treatment rates for cancer patients who smoke.

BACKGROUND: Routine evidence-based tobacco use treatment minimizes cancer-specific and all-cause mortality, reduces treatment-related toxicity, and improves quality of life among patients receiving cancer care. Few cancer centers employ mechanisms to systematically refer patients to evidence-based tobacco cessation services. Implementation strategies informed by behavioral economics can increase tobacco use treatment engagement within oncology care. METHODS: A four-arm cluster-randomized pragmatic trial will be conducted across nine clinical sites within the Implementation Science Center in Cancer Control Implementation Lab to compare the effect of behavioral economic implementation strategies delivered through embedded messages (or "nudges") promoting patient engagement with the Tobacco Use Treatment Service (TUTS). Nudges are electronic medical record (EMR)-based messages delivered to patients, clinicians, or both, designed to counteract known patient and clinician biases that reduce treatment engagement. We used rapid cycle approaches (RCA) informed by relevant stakeholder experiences to refine and optimize our implementation strategies and methods prior to trial initiation. Data will be obtained via the EMR, clinician survey, and semi-structured interviews with a subset of clinicians and patients. The primary measure of implementation is penetration, defined as the TUTS referral rate. Secondary outcome measures of implementation include patient treatment engagement (defined as the number of patients who receive FDA-approved medication or behavioral counseling), quit attempts, and abstinence rates. The semi-structured interviews, guided by the Consolidated Framework for Implementation Research, will assess contextual factors and patient and clinician experiences with the nudges. DISCUSSION: This study will be the first in the oncology setting to compare the effectiveness of nudges to clinicians and patients, both head-to-head and in combination, as implementation strategies to improve TUTS referral and engagement. We expect the study to (1) yield insights into the effectiveness of nudges as an implementation strategy to improve uptake of evidence-based tobacco use treatment within cancer care, and (2) advance our understanding of the multilevel contextual factors that drive response to these strategies. These results will lay the foundation for how patients with cancer who smoke are best engaged in tobacco use treatment and may lead to future research focused on scaling this approach across diverse centers. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04737031 . Registered 3 February 2021.

Correction to: Mass testing and treatment for malaria followed by weekly fever screening, testing and treatment in Northern Senegal: feasibility, cost and impact.

An amendment to this paper has been published and can be accessed via the original article.

Cost-Effectiveness of Focal Mass Drug Administration and Mass Drug Administration with Dihydroartemisinin-Piperaquine for Malaria Prevention in Southern Province, Zambia: Results of a Community-Randomized Controlled Trial.

Community-wide administration of antimalarial drugs in therapeutic doses is a potential tool to prevent malaria infection and reduce the malaria parasite reservoir. To measure the effectiveness and cost of using the antimalarial drug combination dihydroartemisinin-piperaquine (DHAp) through different community-wide distribution strategies, Zambia's National Malaria Control Centre conducted a three-armed community-randomized controlled trial. The trial arms were as follows: 1) standard of care (SoC) malaria interventions, 2) SoC plus focal mass drug administration (fMDA), and 3) SoC plus MDA. Mass drug administration consisted of offering all eligible individuals DHAP, irrespective of a rapid diagnostic test (RDT) result. Focal mass drug administration consisted of offering DHAP to all eligible individuals who resided in a household where anyone tested positive by RDT. Results indicate that the costs of fMDA and MDA per person targeted and reached are similar (US$9.01 versus US$8.49 per person, respectively, P = 0.87), but that MDA was superior in all cost-effectiveness measures, including cost per infection averted, cost per case averted, cost per death averted, and cost per disability-adjusted life year averted. Subsequent costing of the MDA intervention in a non-trial, operational setting yielded significantly lower costs per person reached (US$2.90). Mass drug administration with DHAp also met the WHO thresholds for "cost-effective interventions" in the Zambian setting in 90% of simulations conducted using a probabilistic sensitivity analysis based on trial costs, whereas fMDA met these criteria in approximately 50% of simulations. A sensitivity analysis using costs from operational deployment and trial effectiveness yielded improved cost-effectiveness estimates. Mass drug administration may be a cost-effective intervention in the Zambian context and can help reduce the parasite reservoir substantially. Mass drug administration was more cost-effective in relatively higher transmission settings. In all scenarios examined, the cost-effectiveness of MDA was superior to that of fMDA.

Malaria case investigation with reactive focal testing and treatment: operational feasibility and lessons learned from low and moderate transmission areas in Amhara Region, Ethiopia.

BACKGROUND: When malaria transmission is very low, investigation of passively detected malaria cases and reactive focal testing and treatment (FTAT) in the case and neighbouring households can identify and contain the source and spread of infections. METHODS: Case investigation with reactive FTAT for malaria was implemented in 10 villages in Amhara Region, Ethiopia during the 2014/2015 malaria transmission season. Intervention villages were purposively selected based on the incidence of passively detected Plasmodium falciparum and mixed infections (P. falciparum and Plasmodium vivax) during the 2013 transmission season. A passively detected P. falciparum or mixed index case triggered an investigation that targeted the index case household and the closest 10 neighbouring households in a 100-m radius. All consenting household members received a rapid diagnostic test (RDT) and RDT-positive individuals received artemether-lumefantrine (P. falciparum, mixed) or chloroquine (P. vivax). RESULTS: From October 2014 to February 2015, 407 P. falciparum or mixed index cases (approximately 6.5 per 1000 population) were passively detected. Of these, 220 (54.1%) were investigated, of which 87.3% were male, 61.8% were age 20-39 years [median age: 27 years (range 1-90)], and 58.6% spent ≥ 1 night away from home in the past month (ranging from 0.0 to 94.1% by village). Among the 4077 residents in the 914 households investigated, 3243 (79.5%) received an RDT and 127 (3.9%) were RDT-positive (2.2% P. falciparum, 0.5% P. vivax, 1.2% mixed). Three epidemiological patterns were found. In six villages, there were almost no cases, with less than 10 index and secondary cases. In three villages, most index cases had a history of travel (> 62%), but there were a small number of secondary cases (< 10). Lastly, in one village none of the index cases had a history of recent travel and there was a large number of secondary cases (n = 105). CONCLUSIONS: Three types of malaria transmission patterns were observed: (1) low importation and low local transmission; (2) high importation and low local transmission; and, (3) low importation and high local transmission. To achieve malaria elimination in Amhara Region, intervention strategies targeting these different patterns of transmission and population movement are required.

A framework for evaluating the costs of malaria elimination interventions: an application to reactive case detection in Southern Province of Zambia, 2014.

BACKGROUND: This paper summarizes a framework for evaluating the costs of malaria elimination interventions and applies this approach to one key component of the elimination strategy-reactive case detection (RCD)-implemented through 173 health facilities across 10 districts in Southern Province of Zambia during 2014. METHODS: The primary unit of analysis is the health facility catchment area (HFCA). A five-step approach was followed to estimate implementation costs: organize preliminary information; estimate basic unit costs; estimate activity unit costs; estimate and organize final unit cost database; and create the final costing database (one row of data per HFCA). By working through a specific application, the overall logic of the analysis and details of each step are presented. An electronic annex also provides all details of the analysis. Because population varies substantially across HFCAs, all results are reported per 1000 population in HFCAs. RESULTS: During 2014, 38.9 households per HFCA were visited for RCD services; 166.8 individuals were tested and 32.3 tested positive and were treated. The mean annual cost per HFCA was $1177 (median = $923, IQR $651-$1417). Variation in costs was driven by the number of CHWs and passive cases detected. CHW-related costs and data review meetings accounted for the largest share of costs. Rapid diagnostic tests and drugs accounted for less than 10 % of total costs. CONCLUSIONS: The framework presented here follows standard methods in applied costing of public health interventions (combining ingredients- and activity-based costing approaches into one final cost analysis). Through an application to a specific programme implemented in Zambia in 2014, the details of how to apply such methods to an actual programme are presented. Such details are not typically presented in existing costing analyses but are required for applied analysts working with national malaria control programmes and other organizations to complete such analyses as part of routine programme implementation. Obtaining data and information for implementing the approach remains complicated, in part because analysts from one organization may not have easy access to information from another organization. This basic approach is transparent and easily applied to other malaria elimination interventions being implemented in sub-Saharan Africa and elsewhere.

Mass testing and treatment for malaria in low transmission areas in Amhara Region, Ethiopia.

BACKGROUND: In areas with ongoing malaria transmission, strategies to clear parasites from populations can reduce infection and transmission. The objective of this paper was to describe a malaria mass testing and treatment (MTAT) intervention implemented in six kebeles (villages) in Amhara Region, Ethiopia, at the beginning of the 2014 transmission season. METHODS: Intervention kebeles were selected based on incidence of passively detected Plasmodium falciparum and mixed (P. falciparum and P. vivax) malaria cases during the 2013 malaria transmission season. All households in intervention kebeles were targeted; consenting residents received a rapid diagnostic test (RDT) and RDT-positive individuals received artemether-lumefantrine for P. falciparum/mixed infections or chloroquine for P. vivax. Data were collected on MTAT participation, sociodemographic characteristics, malaria risk factors, and RDT positivity. RESULTS: Of 9162 households targeted, 7974 (87.0 %) participated in the MTAT. Among the 35,389 residents of these households, 30,712 (86.8 %) received an RDT. RDT-positivity was 1.4 % (0.3 % P. vivax, 0.7 % P. falciparum, 0.3 % mixed), ranging from 0.3 to 5.1 % by kebele; 39.4 % of RDT-positive individuals were febrile, 28.5 % resided in the same household with another RDT-positive individual, 23.0 % were not protected by vector control interventions [mosquito net or indoor residual spray (IRS)], and 7.1 % had travel history. For individuals under 10 years of age, the odds of being RDT-positive was significantly higher for those with fever, recent use of anti-malarial drugs or residing in the same household with another RDT-positive individual; 59.0 % of RDT-positive individuals had at least one of these risk factors. For individuals 10 years of age and older, the odds of being RDT positive was significantly higher for those with reported travel, fever, recent use of anti-malarial drugs, no use of vector control, and those residing in the same household as another RDT-positive individual; 71.2 % of RDT-positive individuals had at least one of these risk factors. CONCLUSIONS: In the Ethiopia setting, an MTAT intervention is operationally feasible and can be conducted with high coverage. RDT-positivity is low and varies widely by kebele. While several risk factors are significantly associated with RDT-positivity, there are still many RDT-positive individuals who do not have any of these risk factors. Strategies that target populations for testing and treatment based on these risk factors alone are likely to leave many infections undetected.

The impact of the 2013 WHO antiretroviral therapy guidelines on the feasibility of HIV population prevention trials.

BACKGROUND: Several cluster-randomized HIV prevention trials aim to demonstrate the population-level preventive impact of antiretroviral therapy (ART). 2013 World Health Organization (WHO) guidelines raising the ART initiation threshold to CD4 <500/µL could attenuate these trials' effect size by increasing ART usage in control clusters. METHODS: We used a computational model to simulate strategies from a hypothetical cluster-randomized HIV prevention trial. The primary model outcome was the relative reduction in 24-month HIV incidence between control (ART offered with CD4 below threshold) and intervention (ART offered to all) strategies. We assessed this incidence reduction using the revised (CD4 <500/µL) and prior (CD4 <350/µL) control ART initiation thresholds. Additionally, we evaluated changes to trial characteristics that could bolster the incidence reduction. RESULTS: With a control ART initiation threshold of CD4 <350/µL, 24-month HIV incidence under control and intervention strategies was 2.46/100 person-years (PY) and 1.96/100 PY, a 21% reduction. Raising the threshold to CD4 <500/µL decreased the incidence reduction by more than one-third, to 12%. Using this higher threshold, moving to a 36-month horizon (vs 24-month), yearly control-strategy HIV screening (vs bian-nual), and intervention-strategy screening every 2 months (vs biannual), resulted in a 31% incidence reduction that was similar to effect size projections for ongoing trials. Alternate assumptions regarding cross-cluster contamination had the greatest influence on the incidence reduction. CONCLUSIONS: Implementing the 2013 WHO HIV treatment threshold could substantially diminish the incidence reduction in HIV population prevention trials. Alternative HIV testing frequencies and trial horizons can bolster this incidence reduction, but they could be logistically and ethically challenging. The feasibility of HIV population prevention trials should be reassessed as the implementation of treatment guidelines evolves.

Resource Utilization and Costs of Care prior to ART Initiation for Pediatric Patients in Zambia.

Objective. We estimated time to initiation, outpatient resource use, and costs of outpatient care during the 6 months prior to ART initiation for HIV-infected pediatric patients in Zambia. Methods. We enrolled 1,102 children who initiated ART at <15 years of age between 2006 and 2011 at 5 study sites. Of these, 832 initiated ART ≤6 months after first presenting to care at the study sites. Data on time in care and resources utilized during the 6 months prior to ART initiation were extracted from patient medical records. Costs were estimated from the provider's perspective and are reported in 2011 USD. Results. For the patients who initiated ART ≤6 months after presenting to care, median age at presentation to care was 3.9 years; median CD4 percentage was 13%. Median time to ART initiation was 26 days. Patients made, on average, 2.38 clinic visits prior to ART initiation and received 0.81 CD4 tests, 0.74 full blood count tests, and 0.49 blood chemistry tests. The mean cost of pre-ART care was $20 per patient. Conclusions. Zambian pediatric patients initiating ART ≤6 months after presenting to care do so quickly, utilize fewer resources than mandated by national guidelines, and accrue low costs.

Retention in care, resource utilization, and costs for adults receiving antiretroviral therapy in Zambia: a retrospective cohort study.

BACKGROUND: Of the estimated 800,000 adults living with HIV in Zambia in 2011, roughly half were receiving antiretroviral therapy (ART). As treatment scale up continues, information on the care provided to patients after initiating ART can help guide decision-making. We estimated retention in care, the quantity of resources utilized, and costs for a retrospective cohort of adults initiating ART under routine clinical conditions in Zambia. METHODS: Data on resource utilization (antiretroviral [ARV] and non-ARV drugs, laboratory tests, outpatient clinic visits, and fixed resources) and retention in care were extracted from medical records for 846 patients who initiated ART at ≥15 years of age at six treatment sites between July 2007 and October 2008. Unit costs were estimated from the provider's perspective using site- and country-level data and are reported in 2011 USD. RESULTS: Patients initiated ART at a median CD4 cell count of 145 cells/µL. Fifty-nine percent of patients initiated on a tenofovir-containing regimen, ranging from 15% to 86% depending on site. One year after ART initiation, 75% of patients were retained in care. The average cost per patient retained in care one year after ART initiation was $243 (95% CI, $194-$293), ranging from $184 (95% CI, $172-$195) to $304 (95% CI, $290-$319) depending on site. Patients retained in care one year after ART initiation received, on average, 11.4 months' worth of ARV drugs, 1.5 CD4 tests, 1.3 blood chemistry tests, 1.4 full blood count tests, and 6.5 clinic visits with a doctor or clinical officer. At all sites, ARV drugs were the largest cost component, ranging from 38% to 84% of total costs, depending on site. CONCLUSIONS: Patients initiate ART late in the course of disease progression and a large proportion drop out of care after initiation. The quantity of resources utilized and costs vary widely by site, and patients utilize a different mix of resources under routine clinical conditions than if they were receiving fully guideline-concordant care. Improving retention in care and guideline concordance, including increasing the use of tenofovir in first-line ART regimens, may lead to increases in overall treatment costs.

Uptake, outcomes, and costs of antenatal, well-baby, and prevention of mother-to-child transmission of HIV services under routine care conditions in Zambia.

BACKGROUND: Zambia adopted Option A for prevention of mother-to-child transmission of HIV (PMTCT) in 2010 and announced a move to Option B+ in 2013. We evaluated the uptake, outcomes, and costs of antenatal, well-baby, and PMTCT services under routine care conditions in Zambia after the adoption of Option A. METHODS: We enrolled 99 HIV-infected/HIV-exposed (index) mother/baby pairs with a first antenatal visit in April-September 2011 at four study sites and 99 HIV-uninfected/HIV-unexposed (comparison) mother/baby pairs matched on site, gestational age, and calendar month at first visit. Data on patient outcomes and resources utilized from the first antenatal visit through six months postpartum were extracted from site registers. Costs in 2011 USD were estimated from the provider's perspective. RESULTS: Index mothers presented for antenatal care at a mean 23.6 weeks gestation; 55% were considered to have initiated triple-drug antiretroviral therapy (ART) based on information recorded in site registers. Six months postpartum, 62% of index and 30% of comparison mother/baby pairs were retained in care; 67% of index babies retained had an unknown HIV status. Comparison and index mother/baby pairs utilized fewer resources than under fully guideline-concordant care; index babies utilized more well-baby resources than comparison babies. The average cost per comparison pair retained in care six months postpartum was $52 for antenatal and well-baby services. The average cost per index pair retained was $88 for antenatal, well-baby, and PMTCT services and increased to $185 when costs of triple-drug ART services were included. CONCLUSIONS: HIV-infected mothers present to care late in pregnancy and many are lost to follow up by six months postpartum. HIV-exposed babies are more likely to remain in care and receive non-HIV, well-baby care than HIV-unexposed babies. Improving retention in care, guideline concordance, and moving to Option B+ will result in increased service delivery costs in the short term.

Retention in care and outpatient costs for children receiving antiretroviral therapy in Zambia: a retrospective cohort analysis.

BACKGROUND: There are few published estimates of the cost of pediatric antiretroviral therapy (ART) in Africa. Our objective was to estimate the outpatient cost of providing ART to children remaining in care at six public sector clinics in Zambia during the first three years after ART initiation, stratified by service delivery site and time on treatment. METHODS: Data on resource utilization (drugs, diagnostics, outpatient visits, fixed costs) and treatment outcomes (in care, died, lost to follow up) were extracted from medical records for 1,334 children at six sites who initiated ART at <15 years of age between 2006 and 2011. Fixed and variable unit costs (reported in 2011 USD) were estimated from the provider's perspective using site level data. RESULTS: Median age at ART initiation was 4.0 years; median CD4 percentage was 14%. One year after ART initiation, 73% of patients remained in care, ranging from 60% to 91% depending on site. The average annual outpatient cost per patient remaining in care was $209 (95% CI, $199-$219), ranging from $116 (95% CI, $107-$126) to $516 (95% CI, $499-$533) depending on site. Average annual costs decreased as time on treatment increased. Antiretroviral drugs were the largest component of all outpatient costs (>50%) at four sites. At the two remaining sites, outpatient visits and fixed costs together accounted for >50% of outpatient costs. The distribution of costs is slightly skewed, with median costs 3% to 13% lower than average costs during the first year after ART initiation depending on site. CONCLUSIONS: Outpatient costs for children initiating ART in Zambia are low and comparable to reported outpatient costs for adults. Outpatient costs and retention in care vary widely by site, suggesting opportunities for efficiency gains. Taking advantage of such opportunities will help ensure that targets for pediatric treatment coverage can be met.

The cost-effectiveness of rapid HIV testing in substance abuse treatment: results of a randomized trial.

BACKGROUND: The President's National HIV/AIDS Strategy calls for coupling HIV screening and prevention services with substance abuse treatment programs. Fewer than half of US community-based substance abuse treatment programs make HIV testing available on-site or through referral. METHODS: We measured the cost-effectiveness of three HIV testing strategies evaluated in a randomized trial conducted in 12 community-based substance abuse treatment programs in 2009: off-site testing referral, on-site rapid testing with information only, on-site rapid testing with risk-reduction counseling. Data from the trial included patient demographics, prior testing history, test acceptance and receipt of results, undiagnosed HIV prevalence (0.4%) and program costs. The Cost-Effectiveness of Preventing AIDS Complications (CEPAC) computer simulation model was used to project life expectancy, lifetime costs, and quality-adjusted life years (QALYs) for HIV-infected individuals. Incremental cost-effectiveness ratios (2009 US $/QALY) were calculated after adding costs of testing HIV-uninfected individuals; costs and QALYs were discounted at 3% annually. RESULTS: Referral for off-site testing is less efficient (dominated) compared to offering on-site testing with information only. The cost-effectiveness ratio for on-site testing with information is $60,300/QALY in the base case, or $76,300/QALY with 0.1% undiagnosed HIV prevalence. HIV risk-reduction counseling costs $36 per person more without additional benefit. CONCLUSIONS: A strategy of on-site rapid HIV testing offer with information only in substance abuse treatment programs increases life expectancy at a cost-effectiveness ratio <$100,000/QALY. Policymakers and substance abuse treatment leaders should seek funding to implement on-site rapid HIV testing in substance abuse treatment programs for those not recently tested.

Could early antiretroviral therapy entail more risks than benefits in sub-Saharan African HIV-infected adults? A model-based analysis.

BACKGROUND: Initiation of antiretroviral therapy (ART) in all HIV-infected adults, regardless of CD4⁺ T-cell count, is a proposed strategy for reducing HIV transmission. We investigated the conditions under which starting ART early could entail more risks than benefits for patients with high CD4⁺ T-cell counts. METHODS: We used a simulation model to compare ART initiation upon entry to care ('immediate ART') to initiation at CD4⁺ T-cell count ≤ 350 cells/µl ('WHO 2010 ART') in African adults with CD4⁺ T-cell counts >500 cells/µl. We varied inputs to determine the combination of parameters (population characteristics, conditions of care, treatment outcomes) that would result in higher 15-year mortality with immediate ART. RESULTS: The 15-year mortality was 56.7% for WHO 2010 ART and 51.8% for immediate ART. In one-way sensitivity analysis, lower 15-year mortality was consistently achieved with immediate ART unless the rate of fatal ART toxicity was >1.0/100 person-years, the rate of withdrawal from care was >1.2-fold higher or the rate of ART failure due to poor adherence was >4.3-fold higher on immediate than on WHO 2010 ART. In multi-way sensitivity analysis, immediate ART led to higher mortality when moderate rates of fatal ART toxicity (0.25/100 person-years) were combined with rates of withdrawal from care >1.1-fold higher and rates of treatment failure >2.1-fold higher on immediate than on WHO 2010 ART. CONCLUSIONS: In sub-Saharan Africa, ART initiation at entry into care would improve long-term survival of patients with high CD4⁺ T-cell counts, unless it is associated with increased withdrawal from care and decreased adherence. In early ART trials, a focus on retention and adherence will be crucial.

The clinical and economic impact of genotype testing at first-line antiretroviral therapy failure for HIV-infected patients in South Africa.

BACKGROUND: In resource-limited settings, genotype testing at virologic failure on first-line antiretroviral therapy (ART) may identify patients with wild-type (WT) virus. After adherence counseling, these patients may safely and effectively continue first-line ART, thereby delaying more expensive second-line ART. METHODS: We used the Cost-Effectiveness of Preventing AIDS Complications International model of human immunodeficiency virus (HIV) disease to simulate a South African cohort of HIV-infected adults at first-line ART failure. Two strategies were examined: no genotype vs genotype, assuming availability of protease inhibitor-based second-line ART. Model inputs at first-line ART failure were mean age 38 years, mean CD4 173/µL, and WT virus prevalence 20%; genotype cost was $300 per test and delay to results, 3 months. Outcomes included life expectancy, per-person costs (2010 US dollars), and incremental cost-effectiveness ratios (dollars per years of life saved [YLS]). RESULTS: No genotype had a projected life expectancy of 106.1 months, which with genotype increased to 108.3 months. Per-person discounted lifetime costs were $16 360 and $16 540, respectively. Compared to no genotype, genotype was very cost-effective, by international guidance, at $900/YLS. The cost-effectiveness of genotype was sensitive to prevalence of WT virus (very cost-effective when prevalence ≥ 12%), CD4 at first-line ART failure, and ART efficacy. Genotype-associated delays in care ≥ 5 months decreased survival and made no genotype the preferred strategy. When the test cost was <$100, genotype became cost-saving. CONCLUSIONS: Genotype resistance testing at first-line ART failure is very cost-effective in South Africa. The cost-effectiveness of this strategy will depend on prevalence of WT virus and timely response to genotype results.

The cost-effectiveness of tuberculosis preventive therapy for HIV-infected individuals in southern India: a trial-based analysis.

BACKGROUND: Regimens for isoniazid-based preventive therapy (IPT) for tuberculosis (TB) in HIV-infected individuals have not been widely adopted given concerns regarding efficacy, adherence and drug resistance. Further, the cost-effectiveness of IPT has not been studied in India. METHODS: We used an HIV/TB model to project TB incidence, life expectancy, cost and incremental cost-effectiveness of six months of isoniazid plus ethambutol (6EH), thirty-six months of isoniazid (36H) and no IPT for HIV-infected patients in India. Model input parameters included a median CD4 count of 324 cells/mm(3), and a rate ratio of developing TB of 0.35 for 6EH and 0.22 for 36H at three years as compared to no IPT. Results of 6EH and 36H were also compared to six months of isoniazid (6H), three months of isoniazid plus rifampin (3RH) and three months of isoniazid plus rifapentine (3RPTH). RESULTS: Projected TB incidence decreased in the 6EH and 36H regimens by 51% and 62% respectively at three-year follow-up compared to no IPT. Without IPT, projected life expectancy was 136.1 months at a lifetime per person cost of $5,630. 6EH increased life expectancy by 0.8 months at an additional per person cost of $100 (incremental cost-effectiveness ratio (ICER) of $1,490/year of life saved (YLS)). 36H further increased life expectancy by 0.2 months with an additional per person cost of $55 (ICER of $3,120/YLS). The projected clinical impact of 6EH was comparable to 6H and 3RH; however when compared to these other options, 6EH was no longer cost-effective given the high cost of ethambutol. Results were sensitive to baseline CD4 count and adherence. CONCLUSIONS: Three, six and thirty-six-month regimens of isoniazid-based therapy are effective in preventing TB. Three months of isoniazid plus rifampin and six-months of isoniazid are similarly cost-effective in India, and should be considered part of HIV care.

The cost-effectiveness of pre-exposure prophylaxis for HIV infection in South African women.

BACKGROUND: Recent trials report the short-term efficacy of tenofovir-based pre-exposure prophylaxis (PrEP) for prevention of human immunodeficiency virus (HIV) infection. PrEP's long-term impact on patient outcomes, population-level transmission, and cost-effectiveness remains unknown. METHODS: We linked data from recent trials to a computer model of HIV acquisition, screening, and care to project lifetime HIV risk, life expectancy (LE), costs, and cost-effectiveness, using 2 PrEP-related strategies among heterosexual South African women: (1) women receiving no PrEP and (2) women not receiving PrEP (a tenofovir-based vaginal microbicide). We used a South African clinical cohort and published data to estimate population demographic characteristics, age-adjusted incidence of HIV infection, and HIV natural history and treatment parameters. Baseline PrEP efficacy (percentage reduction in HIV transmission) was 39% at a monthly cost of $5 per woman. Alternative parameter values were examined in sensitivity analyses. RESULTS: Among South African women, PrEP reduced mean lifetime HIV risk from 40% to 27% and increased population discounted (undiscounted) LE from 22.51 (41.66) to 23.48 (44.48) years. Lifetime costs of care increased from $7280 to $9890 per woman, resulting in an incremental cost-effectiveness ratio of $2700/year of life saved, and may, under optimistic assumptions, achieve cost savings. Under baseline HIV infection incidence assumptions, PrEP was not cost saving, even assuming an efficacy >60% and a cost <$1. At an HIV infection incidence of 9.1%/year, PrEP achieved cost savings at efficacies ≥50%. CONCLUSIONS: PrEP in South African women is very cost-effective by South African standards, conferring excellent value under virtually all plausible data scenarios. Although optimistic assumptions would be required to achieve cost savings, these represent important benchmarks for future PrEP study design.

Cost-effectiveness of adding an agent that improves immune responses to initial antiretroviral therapy (ART) in HIV-infected patients: guidance for drug development.

PURPOSE: Adding an immune-enhancing agent to initial antiretroviral therapy (ART) for HIV is a potential strategy to ensure that patients achieve optimal immune response. METHOD: Using a mathematical model of HIV disease and treatment, we evaluated the treatment benefits and cost-effectiveness of adding a hypothetical immune-enhancing agent to the initial 6 months of ART. We assumed that the additional agent would result in a higher CD4 increase that would provide clinical benefit. The additional cost ($1,900/month) was based on the cost of a drug currently under investigation for immune enhancement. Outcomes included projected life expectancy and cost-effectiveness in 2009 US dollars/quality-adjusted life year (QALY) with costs and QALYs discounted at 3% annually. RESULTS: Compared to standard ART, immune-enhanced ART resulting in an additional 40 CD4 cell/µL increase at 6 months yields a 2.4 month projected undiscounted life expectancy increase with a cost-effectiveness ratio of $107,600/QALY. Achieving a cost-effectiveness ratio <$100,000/QALY requires a >43 CD4 cell/µL improvement, or >19 cells/µL if immune-enhancing agent costs are halved. CONCLUSIONS: In addition to showing clinical efficacy, investigational immune enhancement agents need to increase CD4 counts more than has been previously observed or have a lower cost to be considered cost-effective in the United States.