ESTIMATING RESOURCES AND COSTS

As established thus far, the economic cost of vaccination services delivered at school, as part of a school-based SRH platform, was estimated from the provider’s perspective using an ingredients- based costing approach in the South African public sector.

Cost inputs regarding the HIV intervention included HIV testing, pre-and post-test counselling, the cost of the actual vaccine dose, vaccine delivery and the human resources required to deliver such services. Overhead costs were omitted in the school-based programmes. Participants found to be HIV-positive were worked up for and initiated on ART by the school nurse if indicated. Those ineligible for ART received the standard of care prescribed by the 2013 South African HIV Treatment Guideline (247). Besides the actual ART drugs, the costing included adherence counselling and the laboratory monitoring specified by the national HIV treatment guideline at each appointment (247). Those found to be HIV-negative would receive the applicable risk- reduction counselling. In the absence of the HIV vaccine, all procedures mentioned above would be adhered to without the vaccine intervention itself.

The 2001 National Guideline for Cervical Cancer Screening Programme was introduced under Chapter 4 (Section 2.3 Comparator and Intervention). As mentioned previously, the deleterious impact of HIV on cervical disease has necessitated more aggressive cervical screening practices with annual Pap smears being the current recommendation proposed by the HIV treatment guidelines (247, 463). Unlike the HIV vaccine, there would be no prior screening of adolescent girls prior to the administration of the HPV vaccine. Screening young, sexually naïve girls by Pap smear is generally not recommended as cervical cancer is extremely rare under the age of 21 years; most abnormal lesions in this age group spontaneously regress and interventions targeting abnormal cervical cytology can result in undue anxiety and potential pregnancy complications in the future (634). HPV DNA blood testing would prove financially prohibitive in a potential national roll-out of this programme (635, 636). However, the fact that young South African girls have a concerning incidence of non-consensual sexual encounters at an early age brings into

115 question the HPV vaccines overall efficacy that is diminished in light of previous exposure to HPV types/strains (252, 254). The HPV vaccine programme would include pre-counselling and vaccine administration. Costs relating to vaccine delivery (e.g. syringes, needles, human resources) were considered. Several of these accounts overlap with the HIV vaccine service and these were accounted for in the model (e.g. one unit of pre-counselling would occur prior to both vaccines for efficiency).

While the model assumed full adherence to medication and visiting schedules when representing costs, the sensitivity analyses conducted on the cost assumptions may realistically reflect potential lower uptake of these health services as is sometimes the expected behaviour in a non-clinical trial environment (623). The development of the school-based health service was initially outlined in the ISHP in 2012 (153). It is unclear what progress or coverage the programme has achieved to date. Suffice to say, the start-up costs for a school-based programme would be considerable when considering provider education and recruitment of personnel. These costs were not considered in the cost-effectiveness models but should rather be the subject of budget impact studies (623). Key study input values are discussed below.

4.1.1 Epidemiology

HIV: The South African HIV epidemic remains the largest in the world with a national prevalence

of 12% and approximately 396 000 new cases occurring in 2012 (300). A 75% increase in ART uptake was reported between 2009 and 2011 with a resultant 2 002 000 people on ART in 2012 (97, 299). Despite this, there remains a 58% shortfall in treatment access (300). HIV-related mortality remained high, with approximately 35% of deaths attributable to the disease in 2012 (637).

HPV: While the numbers affected by HPV disease appears deceptively small, the synergistic

relationship between HIV and HPV should not be underestimated. South African cervical cancer incidence and mortality rates are higher than global average estimates and the disease is the highest cause of cancer-related mortality among women aged 15-44 years in South Africa (92). Approximately 64% of cervical cancer cases in South Africa are HPV 16, 18 positive (92). Table 12 described the epidemiological parameters considered.

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Table 12. Relevant South African epidemiology

The table describes the relevant general, HIV-related and HPV-related parameters sourced from the literature as indicated. These 2012 estimates were drawn from the South African literature.

Total Male Female Reference

General Population 52 274 945 100% 25 453 074 48.7% 26 821 871 51.3% (97) Life expectancy 67.4 - 64.1 - 70.6 - (637) Mortality 1.48% - 1.56% - 1.42% - (637) HIV-related disease Incidence 396 000 1.72% 145 000 1.21% 251 000 2.28% (97) Prevalence 6 422 000 12.20% 2 531 000 9.90% 3 873 000 14.40% (97) On ART 2 002 000 29.00% 651 000 25.70% 1 344 000 34.70% (97) Life expectancy 59.3 - 57.3 - 61.3 - (637) Mortality 1.69% - 1.75% - 1.63% - (637) Related mortality 203 293 35.30% - - - - (637)

HPV-related disease (Cervical cancer statistics)

Women at risk of cervical cancer (≥ 15 years) 19.43 million (92)

Crude incidence 30.2 / 100 000 (92)

Annual cases 7 735 (92)

Crude mortality 16.6 / 100 000 (92)

Annual deaths 4 248 (92)

Prevalence (%) of HPV 16 and/or 18 with cervical cancer 63.90% (92)

*generic population epidemiological estimates are given here. Age-specific estimates were used in the calculations.

4.1.2 Economic considerations

An ingredients based costing approach was employed for most parameters while some estimates were obtained from the literature as referenced. To ensure meaningful and consistent monetary quantities, local costs were adjusted to 2012 using South African inflation indices. Costs and outcomes were adjusted at 3% p.a. (range: 0-6%) respectively in keeping the WHO-CHOICE recommendations (537). The vaccine delivery cost, including pharmaceutical, human resources and laboratory costs, was calculated at US$ 17 (the micro-costing elements of this total appears in Appendix A). Further, the base HIV vaccine cost was estimated at US$ 12 (the range of costs

117 assessed in this evaluation [US$ 2 – 24] is shown in Annexure A). Table 13 describes the costs and economic considerations included in the evaluation.

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Table 13. Parameter costs and economic considerations used in this analysis

The values in Table 13 were drawn from the South African literature for 2012.

Economics Value Range Reference

Cost 3.0% (0 – 6%) (537)

Outcome 3.0% (0 – 6%) (537)

International comparison (ZAR: 1US$) ZAR 8.21 (591)

HIV disease related costs Distribution Value Reference

HIV prevention programme

HIV vaccine* - 12 (164)

Vaccine delivery per dose* Gamma 17 (638-642)

Existing prevention programme (incl. HR) Gamma 65 (639-643)

HIV counselling and testing (HCT) (per test) Gamma 23 (639, 640)

Cost of HIV rapid testing Gamma 1 (639, 640)

Current HIV programme (annual costs)

Asymptomatic treatment (not on ARV) Gamma 131 (247, 643)

Symptomatic treatment (not on ARV) Gamma 137 (247, 643)

AIDS treatment (not on ARV) Gamma 182 (247, 643)

Patient on ARV (average) Gamma 424 (247, 644)

ART cost (annual)

First-line regimen Gamma 10 (644)

Second-line regimen Gamma 27 (644)

Third-line regimen Gamma 173 (644)

Laboratory costs (annual)

First-line regimen (first year) Gamma 17 (247, 643)

First-line regimen (subsequent years) Gamma 46 (247, 643)

Second-line regimen Gamma 46 (247, 643)

Third-line regimen Gamma 92 (247, 643)

Not on ARV Gamma 65 (643)

HPV-related disease Distribution Value Reference

HPV prevention programme

Cervical screening Gamma 82 (640, 643)

HPV vaccine - 17 (645)

Vaccine delivery per dose* Gamma 17 (638, 640)

Treatment costs

HSIL Gamma 942 (130)

Cervical cancer Gamma 7329 (130)

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4.1.3 Health care

HIV: The study assumed global uptake of voluntary HCT services offered in the school

programme. The uptake of ART was considered 29% (300). The programme was delivered as an out-patient service with the number of annual visits directed by the extent of disease (646).

HPV: At 13%, the uptake of cervical screening services has been poor and significantly lower

than the anticipated screening target of 70% (92, 246). A sensitivity analyses was conducted at various coverage rates of vaccination achieved. Most lesions spontaneously regress, but in some, the HPV disease has a protracted latent phase (10-20 years) and disease manifestation commonly occurs several years after initial infection (647, 648). As the study adopted a lifetime horizon, the treatment costs of clinical disease were calculated with and without the HPV vaccination.

The parameters are shown in Table 14.

Table 14. Health care parameters used in the modelling process

Underlying principles adopted into the economic evaluation. The same set of parameters was applied to all models. The values in Table 14 were drawn from the South African literature for 2012.

Parameters Value Reference

Health care

Cervical screening 13.60% (92)

ARV uptake 29.00% (300)

HPV treatment 35.30% (250)

Reduction in disease progression with ART 46.00% (649)

4.1.4 Vaccine characteristics

HIV: The HIV vaccine described is hypothetical. The vaccine that was assessed represents the

target product profile of the P5 and embodies the minimum characteristics that would recognise the vaccine as a potential candidate for licensure. An annual booster was included in the analyses given the documented waning of vaccine protective effect documented in the RV144/Thai trial 12 months following vaccine administration (339). While it is anticipated that the booster vaccination

120 would afford duration of protection exceeding a year, the annual booster (for the purposes of this study) represents merely an overestimation of costs than if the booster were administered less frequently.

HPV: The bivalent HPV vaccine has been used in this analysis, despite the availability of a

quadrivalent vaccine (in South Africa) and the American Food and Drug Administration (FDA) approval of the use of the nonavalent (nine valent) vaccine – both of which covers additional serotypes. The bivalent vaccine has already been introduced as part of the national government programme to deliver HPV vaccines to school-going adolescents and these analyses would project the potential health outcomes of this programme (650). Further, the majority of the South African cervical cancer disease burden (64%) can be attributed to the HPV 16, 18 serotypes contained in the bivalent vaccine, thus justifying the its use (92). The analysis was intended to assess the health impacts of an extended coverage of the existing programme. The cost-effectiveness of the HPV vaccine is without question, but this cost-effectiveness has been widely limited to use in adolescent females only; and not in their male counterparts (281, 282, 284). The parameters are shown in Table 15.

Table 15. Vaccine characteristics used in the modelling process

Underlying principles adopted into the economic evaluation. The same set of parameters was applied to all models. The estimates were obtained from relevant South African literature for the year 2012.

Parameters Value (Range) Reference

Vaccine characteristics

Coverage 60% (30 – 70) assumption

HPV vaccine efficacy 70% (45 – 99) (274)

HIV vaccine efficacy 50% (30 – 70) assumption

4.1.5 Disease transitions

The HIV and HPV disease transitions had to be considered independently and in combination because of the well documented relationship existing between HIV and HPV (459, 463, 651, 652). The acquisition of each disease is enhanced in the presence of the other but also progresses more rapidly and aggressively (653-655). Primary data obtained from a cohort of HIV-infected adults

121 from Soweto was analysed to quantify the degree of disease acquisition and progression when HIV-positive cohort attending a wellness clinic were routinely screened for cervical disease (51, 268). The HIV stages used in this model were guided by the WHO staging criteria and were documented as asymptomatic, symptomatic and AIDS defining (310). Every stage could potentially access ART and the treatment pool was sub-categorized into Regimens one, two and three. The transition probabilities among the HIV states and subsequently among the treatment regimens were obtained from the literature. Similarly, the HPV-related cervical disease was staged using the Bethesda Classification and annotated as normal, low-grade intraepithelial lesions (LSIL), high-grade intraepithelial lesions (HSIL) and cervical cancer (270, 656). Recurrences in HPV disease among HIV-positive individuals were known to occur and were accounted for in the modelling process. The parameters are shown in Table 16.