Overview
Within an on-going prospective research study that was providing safer conception to HIV-discordant couples in Chitungwiza, Zimbabwe (SAFER (www.clinicaltrials.gov NCT#03049176)), we measured the total cost per couple for individual and combination strategies using micro-costing, including time & motion data. We then modeled cost for a range of implementation scenarios, representing differences from the trial in input prices, intervention intensity, and increments from current HIV prevention and treatment guidelines and practices.
Study setting
The SAFER Study was a prospective non-randomized open-label clinical trial evaluating the uptake, adherence to, impact, and cost-effectiveness of safer reproduction strategies to prevent HIV transmission in HIV-discordant couples who have expressed a desire to conceive a child. SAFER was implemented in the University of Zimbabwe College of Health Sciences Clinical Trials Research Centre (UZCHS-CTRC) Zengeza 3 Clinical Research Site in Chitungwiza from March 2017 to July 2019. It was approved by the Medical Research Council of Zimbabwe and University of California, San Francisco ethical review boards. SAFER enrolled HIV-discordant couples (n = 23) who expressed a desire to conceive a child, were willing to use at least one safer strategy, and were able to provide informed consent. All counseling and services in the study were delivered per protocol, and couples received appropriate medical care and lab tests per local and global guidelines [8–12].
Interventions
In SAFER, all couples received comprehensive HIV counselling and testing and pre-conception counseling. Each couple was offered a choice of up to three safer conception options (depending on the sex of the index partner), including 1) ART for the HIV-positive partner with monthly viral load testing (ART-VL) until achieving undetectable viral load, and quarterly viral load testing thereafter; 2) daily oral pre-exposure prophylaxis (PrEP, [TRUVADA®, tenofovir / emtricitabine]) for the HIV-negative partner with 6-monthly creatinine testing; 3) semen-washing with intrauterine insemination for couples with an HIV-positive male partner; and 4) instruction and supplies to perform manual self-insemination at home for couples with an HIV-positive female partner. Couples selected the strategy or combination of strategies that best suited their needs and preferences. All HIV-negative partners received monthly HIV testing, and all female partners received folic acid supplementation and monthly urine pregnancy testing.
Micro-costing of services in clinical trial
We used empirical micro-costing methods to estimate all costs associated with delivering the safer conception strategies during the trial, including personnel, consumable supplies, facilities, capital equipment, training, and promotion and outreach to patients [13]. We collected data on resource use and prices from SAFER Study administrative records, the UZCHS-CTRC, clinical study site, and affiliated laboratories. We tabulated total costs per strategy or combination of strategies per couple. Shared costs, such as for administration and facilities, were divided equally across couples. Because ART for HIV treatment is provided by the Ministry of Health (and not by the clinical research site), costs for ART (including personnel time, provision of ART medications, and non-safer specific tests) were estimated using published literature for Zimbabwe and the region [14, 15]. We used an estimated average time from strategy initiation to conception of 6 months based on estimates in literature [16, 17]. We did not include costs for maternity care. We computed the cost per couple by adding the costs for inputs and services per couple – including clinic personnel time; lab tests; facility-related and infrastructure costs; and other costs, such as office and clinic supplies that are not specific to an individual strategy or related to lab tests (e.g., patient charts, cleaning solution, ovulation tracking tools) – for each individual strategy over a 6-month period, plus a 2-month “run-in” period for initial screening and enrollment.
For strategy combinations, we similarly added the costs for inputs and services noted above for the 2-month run-in period and estimated 6 months of strategy use. The cost of strategy combinations was less than additive due to efficiencies in the delivery of multiple strategies. For example, costs associated with general HIV-prevention counseling (including prevention of mother-to-child transmission), counseling on ovulation tracking, pelvic exams, HIV testing for the seronegative partner, and outreach are the same regardless of the number of strategies selected in this model. Therefore, we estimated the total costs per couple for each strategy individually and for the most commonly selected combinations.
Personnel
We estimated personnel costs based on salary records for the types of personnel involved in delivering the safer conception strategies. SAFER Study staff are employed in the private sector; Ministry of Health salaries are used in the implementation scenarios below [18].
To quantify personnel effort to deliver each strategy, we conducted a time & motion study. Clinic staff involved in the delivery of patient services participated, including the receptionist/clerk, HIV counsellor, nurses, physicians, pharmacy staff, and onsite laboratory staff. We developed single-page forms based on previously used tools [19], with task codes specific for SAFER. We piloted the forms with staff to ensure codes were aligned with and captured all tasks. Using data collected over a typical week, we calculated the proportion of staff time spent per day for each safer conception strategy. We conducted a separate time & motion study to evaluate time spent performing offsite laboratory tests. We omitted time spent on research tasks; we allocated shared time (e.g., meetings and breaks) proportionally to each strategy.
Medications
Medication prices were estimated for first-line ART (TENOLAM-E, tenofovir / lamivudine / efavirenz) and oral PrEP (TRUVADA®, tenofovir / emtricitabine) from records obtained through the Zimbabwe Ministry of Health and Child Care (MOHCC). We also obtained prices from Clinton Health Access Initiative (CHAI) [20, 21] and from the UZCHS-CTRC medication price lists to gather the highest and lowest potential monthly prices for ART and PrEP. The total cost of ART and PrEP included an additional 22 percent overhead to drug price (per MOHCC correspondence) to capture administrative and distribution costs specific to the dispensing of ART and PrEP.
Laboratory monitoring
We estimated laboratory test frequencies (e.g. creatinine clearance, CD4 count, HIV viral load, Hepatitis B virus) based on the SAFER protocol and guidelines [8–12]. Test costs were obtained through on- and off-site lab records for reagents and test kit prices (prorated based on the number of tests per kit or per reagent unit). Lab facility costs, lab-specific recurrent goods, and capital equipment (including overhead and operating costs based on annual costs, prorated for the number of tests run per year for each type of test) were obtained from clinic and off-site laboratory records. Lab staff costs were captured in this category and obtained through a review of lab records; interviews with lab staff, and a time & motion study.
Other costs
Facility and infrastructure costs including rent, utilities, phone service, and water were collected from administrative records and prorated for the fraction of space within the Zengeza 3 clinical research site where the safer conception services were delivered and the number of couples enrolled in the SAFER study. Costs for non-medication recurrent goods, such as office supplies, exam gloves, cotton swabs, and cleaning supplies were estimated per couple for each type of clinic visit provided, accounting for wastage (based on clinic staff interviews).
Capital items purchased specifically for SAFER were amortized based on estimated longevity and allocated based on estimated number of couples that could be served per year in this setting. We allocated costs associated with staff training and patient outreach based on the number of couples in the trial.
Semen-washing is not widely available in Zimbabwe; as such, we estimated startup and capital costs associated with adding semen-washing as a service within the clinical setting, amortized over a 5-year period.
Modeling of implementation scenarios
We estimated the cost of providing safer conception services in the SAFER study as well as three real-world (non-study) implementation scenarios (Table 1). The first scenario, “High Intensity + Real-world Prices”, applies usual public sector prices to the same resource use observed in the trial. MOHCC clinics pay lower wages and have access to lower-cost reagents for viral load testing (e.g. $46.79 vs $9.40 per person for reagents) [22, 23]. These lower prices are used in all three implementation scenarios. The other two scenarios also consider service intensity. The second scenario, “Target Intensity, Incremental Cost Added to Current Practice”, estimates the extra costs to deliver safer conception strategies at the target service intensity (lower than in the trial; discussed below) over and above the current standard of care in the community (e.g., ART delivery). The third scenario, “Target Intensity, Incremental Cost Added to Standard of Care”, estimates the extra costs to deliver safer conception strategies at the target service intensity that are over and above the standard of care recommended by the MOHCC, which is more intensive than current practice. Each scenario was costed by varying price and/or resource use assumptions in the micro-costing. These scenario estimation methods were based on prior cost modeling in HIV and other infectious disease programs [19, 24].
We modeled costs for up to 1 year of conception attempts, with a run-in time of up to 2 months for screening and eligibility, plus an estimated average time to conception of 6 months based on literature [16, 17].
Table 1: Safer conception cost analysis scenarios
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Scenario
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Description
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Components and context
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0) SAFER Study
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Total cost as observed in the clinical trial, including high intensity of resource use and above-market prices. Incremental to current practice as observed in trial.
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・High private sector prices
・Monthly visits and monitoring until pregnancy confirmed
・Up to 12 months of conception attempts
・100% of trial participants used MoHCC delivered ART, therefore no ART cost included in this scenario
・Full costs for delivery of VL testing, PrEP, AVI, and SW
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1) High Intensity + Real-world Prices
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Same resource intensity as above, but using prices normally paid by the Zimbabwe MoHCC.
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・Public sector prices
・Monthly visits and monitoring until pregnancy confirmed
・Up to 12 months of conception attempts
・Full costs for delivery of VL testing, PrEP, AVI, and SW
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2) Target Intensity, Incremental Cost Added to Current Practice
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Target resource intensity*, incremental to current population service coverage for HIV treatment and prevention.
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・Public sector prices
・After strategy initiation, visits and monitoring q3-6 months until pregnancy confirmed
・Up to 12 months of conception attempts
・With 72% ART coverage in community, includes costs to provide ART for 28% of HIV+, ART-naive individuals
・Includes costs for needed VL tests beyond those recommended in MoHCC guidelines
・Full costs for delivery of PrEP, AVI, SW, safer conception counselling
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3) Target Intensity, Incremental Cost Added to Standard of Care
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Same as above, except incremental to current MoHCC-specified standard of care.
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・Public sector prices
・After strategy initiation, visits and monitoring q3-6 months until pregnancy confirmed
・Up to 12 months of conception attempts
・No costs for ART and PrEP, which are in MoHCC guidelines
as standard of care
・Includes costs for needed VL tests beyond those recommended in MoHCC guidelines
・Includes full costs for delivering AVI, SW, safer conception counselling
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* For a summary of target resource intensity, see Figure 1; for a full description and definition of target resource intensity, see Supplement A.
ART=Antiretroviral therapy. ART-VL=Antiretroviral therapy with frequent viral load testing. AVI=Artificial vaginal insemination, at home. MoHCC=Ministry of Health and Child Care. PrEP=Pre-exposure prophylaxis. SOC=Standard of Care. SW=Semen-washing.
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The target resource intensity for the latter two scenarios specifies the number of clinic visits, lab tests, and other resources required for the implementation of safer conception strategies in a non-research setting (Fig. 1). We interviewed local clinicians with expertise in reproductive health regarding the potential implementation of safer conception strategies in the public sector to establish a reasonable, less-intensive real-world target. The target intensity reduces costs by lowering service utilization per patient, using non-physician clinicians (such as nurses and HIV counsellors) to deliver care, and allocating fixed resources across more patients.
We based the “current practice” and “standard of care” scenarios on a review of local guidelines that govern the delivery of PrEP, ART, and other HIV prevention services and other literature regarding the delivery of HIV-related treatment and prevention in Zimbabwe [8–12]. We interviewed local experts in HIV treatment and prevention (including co-authors) to understand current standards of care and level of coverage.
Sensitivity analyses
We also performed one-way sensitivity analyses on input variables that we observed were associated with substantial uncertainty and were not represented in the scenarios, including the price of PrEP and scale-up of the semen-washing process (i.e., increased utilization of capital equipment).