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.

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.

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.

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.

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.

Test and treat DC: forecasting the impact of a comprehensive HIV strategy in Washington DC.

BACKGROUND: The United States and international agencies have signaled their commitment to containing the human immunodeficiency virus (HIV) epidemic via early case identification and linkage to antiretroviral therapy (ART) immediately at diagnosis. We forecast outcomes of this approach if implemented in Washington DC. METHODS: Using a mathematical model of HIV case detection and treatment, we evaluated combinations of HIV screening and ART initiation strategies. We define current practice as no regular screening program and ART at CD4 counts < or = 350 cells/microL, and we define test and treat as annual screening and administration of ART at diagnosis. Outcomes include life expectancy of HIV-infected persons and changes in the population time with transmissible HIV RNA levels. Data, largely from Washington DC, include undiagnosed HIV prevalence of 0.6%, annual incidence of 0.13%, 31% rate of test offer, 60% rate of acceptance, and 50% linkage to care. Input parameters, including optimized ART efficacy, are varied in sensitivity analyses. RESULTS: Projected life expectancies, from an initial mean age of 41 years, are 23.9, 25.0, and 25.6 years for current practice, test and treat, and test and treat with optimized ART, respectively. Compared with current practice, test and treat leads to a 14.7% reduction in time spent with transmissible HIV RNA level in the next 5 years; test and treat with optimized ART results in a 27.3% reduction. CONCLUSIONS: An expanded HIV test and treat program in Washington DC will increase life expectancy of HIV-infected patients but will have a modest impact on HIV transmission over the next 5 years and is unlikely to halt the HIV epidemic.

The "ART" of linkage: pre-treatment loss to care after HIV diagnosis at two PEPFAR sites in Durban, South Africa.

BACKGROUND: Although loss to follow-up after antiretroviral therapy (ART) initiation is increasingly recognized, little is known about pre-treatment losses to care (PTLC) after an initial positive HIV test. Our objective was to determine PTLC in newly identified HIV-infected individuals in South Africa. METHODOLOGY/PRINCIPAL FINDINGS: We assembled the South African Test, Identify and Link (STIAL) Cohort of persons presenting for HIV testing at two sites offering HIV and CD4 count testing and HIV care in Durban, South Africa. We defined PTLC as failure to have a CD4 count within 8 weeks of HIV diagnosis. We performed multivariate analysis to identify factors associated with PTLC. From November 2006 to May 2007, of 712 persons who underwent HIV testing and received their test result, 454 (64%) were HIV-positive. Of those, 206 (45%) had PTLC. Infected patients were significantly more likely to have PTLC if they lived > or = 10 kilometers from the testing center (RR = 1.37; 95% CI: 1.11-1.71), had a history of tuberculosis treatment (RR = 1.26; 95% CI: 1.00-1.58), or were referred for testing by a health care provider rather than self-referred (RR = 1.61; 95% CI: 1.22-2.13). Patients with one, two or three of these risks for PTLC were 1.88, 2.50 and 3.84 times more likely to have PTLC compared to those with no risk factors. CONCLUSIONS/SIGNIFICANCE: Nearly half of HIV-infected persons at two high prevalence sites in Durban, South Africa, failed to have CD4 counts following HIV diagnosis. These high rates of pre-treatment loss to care highlight the urgent need to improve rates of linkage to HIV care after an initial positive HIV test.

Cost-effectiveness of tenofovir as first-line antiretroviral therapy in India.

BACKGROUND: World Health Organization guidelines for antiretroviral treatment (ART) in resource-limited settings recommend either stavudine or tenofovir as part of initial therapy. We evaluated the clinical outcomes and cost-effectiveness of first-line ART using tenofovir in India, compared with current practice using stavudine or zidovudine. METHODS: We used a state-transition model of human immunodeficiency virus (HIV) disease to examine strategies using different nucleoside reverse-transcriptase inhibitors, combined with lamivudine and nevirapine, compared with no ART: (1) stavudine, (2) stavudine with substitution by zidovudine after 6 months, (3) zidovudine, and (4) tenofovir. Data were from the Y. R. Gaitonde Centre for AIDS Research and Education in Chennai, India, and published studies. Results. Discounted mean per person survival was 36.9 months (40.2 months undiscounted) with no ART, 115.5 months (145.3) with stavudine-containing ART, 115.7 months (145.6) with stavudine and 6-month zidovudine substitution, 115.8 months (145.6) with zidovudine-containing ART, and 125.8 months (162.0) with initial tenofovir. Discounted lifetime medical costs were $610 with no ART and ranged from $5580 with stavudine-containing ART to $5720 with zidovudine-containing ART. Initial tenofovir had an incremental cost-effectiveness ratio of $670 per year of life saved, compared with no ART, and was more economically efficient than the other regimens. RESULTS: were most sensitive to variations in the costs of first-line tenofovir, access to additional ART after treatment failure, and quality of life adjustment. CONCLUSIONS: Using tenofovir as part of first-line ART in India will improve survival, is cost-effective by international standards, and should be considered for initial therapy for HIV-infected patients in India.

HIV preexposure prophylaxis in the United States: impact on lifetime infection risk, clinical outcomes, and cost-effectiveness.

BACKGROUND: The combination of tenofovir and emtricitabine shows promise as HIV preexposure prophylaxis (PrEP). We sought to forecast clinical, epidemiologic, and economic outcomes of PrEP, taking into account uncertainties regarding efficacy, the risks of developing drug resistance and toxicity, behavioral disinhibition, and drug costs. METHODS: We adapted a computer simulation of HIV acquisition, detection, and care to model PrEP among men who have sex with men and are at high risk of HIV infection (i.e., 1.6% mean annual incidence of HIV infection) in the United States. Base-case assumptions included 50% PrEP efficacy and monthly tenofovir-emtricitabine costs of $753. We used sensitivity analyses to examine the stability of results and to identify critical input parameters. RESULTS: In a cohort with a mean age of 34 years, PrEP reduced lifetime HIV infection risk from 44% to 25% and increased mean life expectancy from 39.9 to 40.7 years (21.7 to 22.2 discounted quality-adjusted life-years). Discounted mean lifetime treatment costs increased from $81,100 to $232,700 per person, indicating an incremental cost-effectiveness ratio of $298,000 per quality-adjusted life-year gained. Markedly larger reductions in lifetime infection risk (from 44% to 6%) were observed with the assumption of greater (90%) PrEP efficacy. More-favorable incremental cost-effectiveness ratios were obtained by targeting younger populations with a higher incidence of infection and by improvements in the efficacy and cost of PrEP. CONCLUSIONS: PrEP could substantially reduce the incidence of HIV transmission in populations at high risk of HIV infection in the United States. Although it is unlikely to confer sufficient benefits to justify the current costs of tenofovir-emtricitabine, price reductions and/or increases in efficacy could make PrEP a cost-effective option in younger populations or populations at higher risk of infection. Given recent disappointments in HIV infection prevention and vaccine development, additional study of PrEP-based HIV prevention is warranted.

The cost-effectiveness of HLA-B*5701 genetic screening to guide initial antiretroviral therapy for HIV.

OBJECTIVE: To evaluate the clinical impact and cost-effectiveness of HLA-B*5701 testing to guide selection of first-line HIV regimens in the United States. DESIGN: Cost-effectiveness analysis using a simulation model of HIV disease. The prevalence of HLA-B*5701 and the probabilities of confirmed and unconfirmed severe systemic hypersensitivity reaction among patients taking abacavir testing HLA-B*5701 positive and negative were from the Prospective Randomized Evaluation of DNA Screening in a Clinical Trial study. The monthly costs of abacavir-based and tenofovir-based regimens were $1135 and $1139, respectively; similar virologic efficacy was assumed and this assumption was varied in sensitivity analysis. PATIENTS: Simulated cohort of patients initiating HIV therapy. INTERVENTIONS: The interventions are first-line abacavir, lamivudine, and efavirenz without pretreatment HLA-B*5701 testing; the same regimen with HLA-B*5701 testing; and first-line tenofovir, emtricitabine, and efavirenz. MAIN OUTCOME MEASURES: Quality-adjusted life years and lifetime medical costs discounted at 3% per annum, cost-effectiveness ratios ($/QALY). RESULTS: Abacavir-based treatment without HLA-B*5701 testing resulted in a projected 30.93 years life expectancy, 16.23 discounted quality-adjusted life years, and $472,200 discounted lifetime cost per person. HLA-B*5701 testing added 0.04 quality-adjusted months at an incremental cost of $110, resulting in a cost-effectiveness ratio of $36,700/QALY compared with no testing. Initiating treatment with a tenofovir-based regimen increased costs without improving quality-adjusted life expectancy. HLA-B*5701 testing remained the preferred strategy only if abacavir-based treatment had equal efficacy and cost less per month than tenofovir-based treatment. Results were also sensitive to the cost of HLA-B*5701 testing and the prevalence of HLA-B*5701. CONCLUSION: Pharmacogenetic testing for HLA-B*5701 is cost-effective only if abacavir-based treatment is as effective and costs less than tenofovir-based treatment.