Under each analytical framework, we considered six different strategies for the screening and treatment of cervical pre-cancerous lesions in HIV positive women, guided by the policy options under consideration by decision makers in 2017.
2.1 Comparison strategies
Strategy 1 was VIA with cryotherapy treatment for screen-positive women, or LEEP if a woman was not eligible for cryotherapy, in 1 visit; Strategy 2 was 2-visit VIA with cryotherapy (or LEEP if ineligible); Strategy 3 was 3-visit cytology, followed by diagnostic testing with colposcopy and biopsy for screen-positive women, and treatment with cryotherapy (or LEEP if ineligible); Strategy 4 was 3-visit cytology, followed by colposcopy and biopsy for screen-positive women, and treatment restricted to LEEP; Strategy 5 was 2-visit HPV DNA testing followed by treatment with cryotherapy-+y (or LEEP if ineligible); Strategy 6 was HPV DNA testing followed by treatment with LEEP only (Table 1). For strategies involving cryotherapy, we assumed that 83% of women were eligible for cryotherapy (i.e., had lesions that did not extend to the endocervix and covered less than 75% of the cervix) (18); women ineligible for cryotherapy received LEEP.
Table 1: Cervical cancer screening and treatment strategies compared in the three evaluations
Screening
|
Additional diagnostic test
|
Treatment
|
Total visits to facility for screen-positive women
|
VIA (1 visit)
|
None
|
Cryotherapy or LEEP
|
1
|
VIA (2 visits)
|
None
|
Cryotherapy or LEEP
|
2
|
Cytology (Pap smear)
|
Colposcopic biopsy
|
Cryotherapy or LEEP
|
3
|
Cytology (Pap smear)
|
Colposcopic biopsy
|
LEEP only
|
3
|
HPV DNA testing
|
None
|
Cryotherapy or LEEP
|
2
|
HPV DNA testing
|
None
|
LEEP only
|
2
|
2.2 Data sources
Data on the success rates of screening and treatment interventions were collected in two clinical trials conducted in Johannesburg, South Africa (19,20). Both trials enrolled HIV-positive women only. The screening trial compared the effectiveness (i.e., proportion of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) detected) of VIA, cytology, and HPV DNA testing. Effectiveness was measured as the proportion of cases of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) detected. The treatment trial compared cryotherapy versus LEEP for treatment of cervical dysplasia. Treatment success, or cure, was defined as the absence of lesions at 12 months (19,20).
We obtained provider cost and health care utilization data for these strategies from published cost-effectiveness studies conducted at the same sites and in parallel with the clinical trials mentioned above (21,22). Personnel, consumables, equipment and laboratory costs were included, but building costs were excluded.
Table 2: Screening and treatment parameters used in the three evaluations
Screening
|
Start age
|
25 years old
|
[19]
|
Interval
|
Every 3 years
|
[19]
|
|
|
|
Test performance
|
Sensitivity for CIN2+/ Specificity for <CIN2
|
Source
|
VIA
|
0.76/0.68
|
[20]
|
Cytology*
|
0.95/0.36
|
[20]
|
Colposcopic biopsy**
|
1/1
|
[20]
|
HPV DNA
|
0.93/0.51
|
[20]
|
|
Treatment
|
Effectiveness against CIN2+ at 12 months
|
Source
|
Cryotherapy
|
70%
|
[21]
|
LEEP
|
86%
|
[21]
|
|
Visits
|
Lost to follow up per clinical encounter
|
Source
|
Visits
|
15%
|
[19]
|
We obtained costs incurred by patients for screening and pre-cancer treatment as well as cervical cancer treatment from a separate cost-effectiveness study comparing cervical cancer screening and treatment for HIV-positive women in South Africa (18). Patient costs include both direct costs, such as travel costs, as well as the opportunity cost of lost time, valued as the median income of the sample.
Table 3: Cost parameters used in the three evaluations
Cost type
|
Cost (2017 USD)
|
Source
|
Health provider costs*
|
|
|
VIA
|
3.24
|
[22]
|
Cytology
|
16.81
|
[22]
|
HPV DNA testing
|
45.35
|
[22]
|
Colposcopy
|
54.25
|
[22]
|
Cryotherapy
|
3.70
|
[18]
|
LEEP
|
56.38
|
[18]
|
Cost of cancer treatment – Local cancer
|
2 552
|
[19]
|
Cost of cancer treatment – Regional cancer
|
8 768
|
[19]
|
Cost of cancer treatment – Distant cancer
|
8 805
|
[19]
|
Patient opportunity costs
|
Screening facility wait time
|
2.57
|
[19]
|
Referral facility wait time
|
0.64
|
[19]
|
Screening facility transport time
|
0.97
|
[19]
|
Patient direct costs
|
Transport to screening facility (round trip)
|
0
|
[19]
|
Transport to referral facility (round trip)
|
2.22
|
[19]
|
Patient costs during cancer treatment
|
Local cancer
|
243
|
[19]
|
Regional cancer
|
555
|
[19]
|
Distant cancer
|
545
|
[19]
|
2.3 Economic evaluation
For the CEA, we used a Monte Carlo simulation model previously developed to fit the natural history of HPV infection and cervical cancer among HIV-infected women in South Africa (18). Girls entered the model at 9 years of age, were assumed to be infected with HIV at 20 years and diagnosed at age 25 years. HPV incidence was based on age, and probabilities of HPV genotype-specific acquisition were calibrated to age-specific HPV prevalence data among HIV-infected women in South Africa. Transition probabilities between HPV-related health states, including HPV clearance, progression to precancer (i.e., CIN2, CIN3), and progression to invasive cervical cancer were stratified by HPV genotype and duration of HPV infection. Costs were evaluated from the provider as well as patient perspective and calculated in 2017 USD. ICERs were calculated by dividing the incremental cost by the incremental effectiveness of each strategy relative to the next most costly strategy after eliminating strategies that were dominated (i.e. more costly and less effective, or have a higher ICER than a more effective strategy). Based on these ICERs, we determined the value of the interventions by considering a) a commonly used threshold of 1-3 times of per capita GDP, and b) a threshold based on supply side opportunity cost. Under the first threshold, strategies are considered very cost-effective if they fall below per capita GDP, which in 2017 was $6,180 in South Africa. The opportunity cost threshold for South Africa has been estimated at between $1,175 and $4,714 (23).
Next, we calculated the budget impact of each strategy over five years starting in 2017 at full implementation scale. We used the same cost and effectiveness data as for the CEA, but applied these data to the estimated population of HIV-positive women in South Africa. Age-stratified transition probabilities between states in the BIA were based on literature (19,24–26). The BIA compared strategies to the baseline equivalent of the current budget, whereas the CEA uses a baseline of no screening and treatment of pre-cancer. The “current budget” reflects expected costs if screening and treatment remain consistent with the old policy and documented coverage.
Finally, we conducted a multi-criteria decision analysis (MCDA), using a questionnaire with select criteria from the EVIDEM framework (10). Criteria for inclusion were determined through analysis of literature and past policy decisions as well as current decision-making processes and included domains such as disease impact, intervention effectiveness and budget impact (Table 4). We used criteria weights established for an EVIDEM MCDA focused on health care interventions to be offered in the private sector in South Africa (27); this study assembled a panel of experts including doctors, pharmacists and nurses with at least one year’s experience in health policy decision-making for a health plan.
To implement the survey and obtain scores relevant for our strategies, we selected potential participants purposively based on their expertise or their recent experience in drafting the updated cervical cancer policy, including experts from the South African National Department of Health and National Treasury, clinicians, and health economists with experience in cervical cancer care in South Africa. Participants were emailed the questionnaire and relevant information to assist with scoring (based on data in Tables 2, 3, 5-9). All five self-administered the survey between November 2018 and April 2019. Scores were entered per criterion and multiplied by the criterion-specific weights in order to arrive at a total, weighted score. The survey is included as Appendix A.
Table 4: Criteria and weights against which the strategies were scored in the multi-criteria decision analysis
Quality of Evidence – the current quantity and standard of evidence available for the strategies/options, referring to completeness and consensus of information.
|
Weight
|
Q1
|
Adherence to requirements of National Department of Health
|
0.063
|
Q2
|
Completeness and consistency of reporting evidence
|
0.073
|
Q3
|
Relevance and validity of evidence
|
0.070
|
Disease impact – the severity of the health condition with respect to morbidity, mortality and impact on quality of life as well as the size of the affected population.
|
|
D1
|
Disease severity
|
0.065
|
D2
|
Size of population affected by disease
|
0.066
|
Intervention – the capacity of the strategies/options to prevent, or produce a beneficial change in the targeted condition.
|
|
I1
|
Agreement with expert consensus/ current clinical guidelines
|
0.064
|
I2
|
Current strategy's limitations
|
0.066
|
I3
|
Improvement of efficacy/ effectiveness
|
0.070
|
I4
|
Improvement of safety and tolerability
|
0.061
|
I5
|
Improvement in patient reported outcomes, convenience & adherence
|
0.066
|
I6
|
Public health interest
|
0.059
|
I7
|
Type of medical service
|
0.066
|
Economics – the cost and budget implications of the strategies/options.
|
|
E1
|
Impact on public health budget
|
0.074
|
E2
|
Cost-effectiveness of intervention
|
0.074
|
E3
|
Impact on other spending – Other medical costs
|
0.064
|