Vickerman, Peter DPhil*; Devine, Angela MSc*; Foss, Anna M. MMath, PhD*; Delany-Moretlwe, Sinead MBBCh, PhD†; Mayaud, Philippe MD, MSc*; Meyer-Rath, Gesine MD*†
Health care interventions for HIV-positive individuals who are not eligible for antiretroviral therapy (ART) in sub-Saharan Africa are limited. Many patients are lost after diagnosis because clinics have little to offer them.1
Several recent trials have demonstrated that herpes simplex virus-type 2 (HSV-2) suppressive therapy, with daily aciclovir or valaciclovir, can decrease HIV-1 plasma viral load in HIV-1 and HSV-2 coinfected individuals by 0.25 to 0.53 log10copies/mL.2–7 This effect suggested that HSV-2 suppressive therapy could decrease HIV-1 transmission8–11 and slow the impairment of immune function.8–10,12
These hypothesized HIV-related effects of HSV-2 suppressive therapy were tested by the recent “Partners in Prevention HSV/HIV transmission trial” (Partners HSV/HIV Transmission Study). With a comparable decrease in HIV-1 plasma viral load,7 the trial showed no decrease in HIV-1 incidence amongst HIV-serodiscordant couples, but a 16% (95% confidence intervals [CI]: 2%–29%) reduction in a composite measure of HIV-1 disease progression.7,13 The trial's effect on HIV disease progression raises the question of whether daily medication with aciclovir, provided from the time of HIV diagnosis until an individual's CD4 cell count reaches the ART initiation threshold could be used to delay the time until ART need. To determine if this could be a worthwhile strategy, this analysis uses data from the Johannesburg HSV-2 suppressive therapy trial involving 300 HSV-2/HIV-1 infected women,2 and effectiveness estimates from the Partners HSV/HIV Transmission Study,7,13 to explore the cost-effectiveness of providing HSV-2 suppressive therapy to HIV-1-infected women not yet eligible for ART in a South African primary health care (PHC) HIV clinic.
Summary of Analysis
The purpose of the analysis was to establish the incremental economic cost-effectiveness of providing HSV-2 suppressive therapy to HIV-1-infected women not yet qualifying for ART in a PHC HIV clinic in Johannesburg, South Africa. HSV-2 suppressive therapy was given to all HIV-1 infected women, irrespective of their HSV-2 status, because of the high prevalence of HSV-2 in African women infected with HIV-1. A cost analysis was conducted from a health service provider's perspective, and a Markov model projected the HIV-related impact and recurrent costs of providing women with HSV-2 suppressive therapy.
Details of Intervention
We considered the addition of HSV-2 suppressive therapy to standard care for all HIV-1-infected women not yet eligible for ART in Johannesburg. All HIV-1 seropositive women with CD4 counts >200 cells/μL were placed on suppressive therapy and were assumed to require an initial meeting, monthly visits for the first 3 months and 6-monthly visits thereafter. Following discussions with trial staff, it was thought that at their initial meeting, women would receive 20 minutes of counseling (auxiliary nurse at salary US $9574 per year) and 30 minutes with a senior nurse (salary of US $18,330 per year) on the use of aciclovir suppressive therapy, whereas at follow-up meetings half of this would be required. At each 6 monthly meeting, it was assumed that a CD4 cell count testing would be undertaken to determine if a woman was eligible for ART. Because this is part of the standard care provided for HIV-infected individuals, only the costs of additional testing due to a lengthened duration before ART eligibility was modeled.
In line with national guidelines, we assumed that women with genital ulcer disease at any visit underwent a pelvic examination, that active herpes infection would be treated with aciclovir 400 mg 3 times daily for 5 days14 and that other sexually transmitted infection (STI) syndromes would also be treated.
Retention in care remains a challenge for patients not yet on ART, so the staff costs for 1 defaulter tracer was added.15 This role, default16 and return rates were modeled on experiences of ART clinics in Johannesburg15 and Durban.17 No defaulter tracer was included in the standard care comparison, and all defaulting women were assumed not to return.
Cost data were collected through interviews with trial staff and from expenditure records at the Johannesburg trial site. Resources required by the trial for standard care of HIV-infected women, rather than the intervention, were excluded. Costs were divided into capital and recurrent costs,18 and capital costs were annualized and discounted at 3% (0%–6%) per year.19 Cost data from previous years were adjusted for inflation to 2008 constant costs20 and converted to US dollars (US $1.00 = ZAR7.64).21
Drug costs included the costs of aciclovir (400 mg twice-daily) and syndromic management of other STIs. The baseline aciclovir cost was the government's procurement cost in 2008 (US $0.14 per day22,23), with the cheapest internationally available aciclovir also being considered (US $0.026 per day22). South African syndromic management guidelines, STI prevalence data from the Johannesburg trial, and the lowest drug costs22 were used to determine other STI treatment costs (Table 1). Since a significant reduction in GUD was observed under HSV-2 suppressive therapy in the Johannesburg trial (Table 1),2 cost savings through GUD cases averted by HSV-2 suppressive therapy were included. Other recurrent cost items included the quantities of additional consumables required for the intervention based on opinion of trial managers.
Capital costs included equipment needed for the intervention that would not typically be found in a PHC clinic (Table 1) and the cost of training the defaulter tracer and 2 nurses to provide clinical examination and management for HSV-2 and other STIs.
Modeling the Costs and Impact of HSV-2 Suppressive Therapy
A dynamic Markov health-state transition model simulated a cohort of 300 HIV-1-infected female patients to calculate the duration of HSV-2 suppressive therapy for each patient. Transitions away from HSV-2 suppressive therapy due to defaulting were calculated for each 6-month cycle, and transitions back into therapy from this state was also included. Model exit points were either becoming eligible for ART or HIV-related death. Trial outcomes and published data were used to determine the model transition rates (Table 1).
The rate at which women become eligible for ART was estimated by modeling the decline in CD4 count of the Johannesburg trial cohort. Trial data were used for the baseline and 3-month follow-up CD4 counts.2 Thereafter, CD4 counts were modeled using the estimated decline for 3 CD4 count strata (>500 cells/μL, 351–500 cells/μL, 201–350 cells/μL) from a cohort study in Cape Town.24 Death rates were also stratified by CD4 count using data from the same cohort,25 and the proportion of women in each stratum was used to produce an average death rate for each cycle of the Markov model.
The Markov model was used to estimate the impact of HSV-2 suppressive therapy. Women in the model cohort were stratified by HSV-2 serostatus, and suppressive therapy was assumed to reduce the rate at which HSV-2 infected women became eligible for ART and their rate of HIV-related death.7 Impact was estimated in terms of the total life-years gained (LYG) by the women before they left the cohort, due to death or becoming eligible for ART. Additionally, when a woman left the cohort because her CD4 cell count dropped below the ART threshold level, those women still on suppressive therapy were assumed to go on ART. Using relevant data from South Africa1,26,27 and elsewhere,28,29 additional life years and associated costs were added depending on whether the women went on ART or not (Table 1). As with costs, all LYGs were discounted at 3% (0%–6%) per year.19 The model is described in detail in the Technical Appendix (online only, Supplementary Digital Content, available at: http://links.lww.com/OLQ/A11).
The model used the cost- and intervention-specific data described above (Table 1) to estimate the cost-effectiveness of providing HSV-2 suppressive therapy in Johannesburg, compared to no therapy, for aciclovir costing $0.14 or $0.026 per day. Uncertainty in the parameter estimates were incorporated by running the Markov model 10,000 times while randomly sampling from parameter uncertainty ranges using Latin hypercube sampling (LHS30). When available, a parameter's uncertainty range was its 95% confidence interval, whereas otherwise it was generally the point estimate ±50%.
The cost-effectiveness projections assumed that HSV-2 suppressive therapy reduced both, the rate of becoming eligible for ART and HIV-related death. Scenario 1 assumed an ART eligibility criteria of CD4 count <200 cells/μL (current threshold for ART eligibility in South Africa except for pregnant women and active tuberculosis cases) and scenario 2 considered the WHO recommended criteria of CD4 count <350 cells/μL. The Partners HSV/HIV Transmission Study effectiveness estimates (Table 1) were used in all scenarios. The uncertainty analysis for each scenario was used to produce confidence intervals for the impact/cost-effectiveness of the intervention, to explore how the projections were dependent on parameter uncertainty (just scenario 1), and to determine the likelihood of the intervention being cost-effective when compared to a low estimate for the cost-effectiveness of ART provision in South Africa (∼US $1200 per LYG based on a range of treatment sites26,27,31). This stringent cost-effectiveness threshold was used because HSV-2 suppressive therapy is unlikely to be accepted as a viable intervention if it is less cost-effective than ART.
A multivariate sensitivity analysis was undertaken to explore how randomly changing all important model parameters by ±50% of their midpoint baseline values (Table 1) affected the model's projected cost-effectiveness for the mean effectiveness estimates from the Partners HSV/HIV Transmission Study, an ART eligibility criteria of CD4 count <200 cells/μL, and the lowest daily aciclovir cost. The sensitivity analysis also considered the implications of using HSV-2 antibody testing to determine which women initiate HSV-2 suppressive therapy. The analysis assumed the use of the Focus Herpes Select test, at a cost quoted by the South African National Health Laboratory Service (US $11.6 per test), with sensitivity (97%) and specificity (80%) as estimated amongst HIV-infected women in Johannesburg.32 In this scenario, only women positive with the test initiated HSV-2 suppressive therapy, but all women still in contact with the clinic started ART when they became eligible. Latin hypercube sampling produced 10,000 model simulations and a multilinear regression analysis determined the amount each parameter altered the projected cost-effectiveness. The sensitivity analysis only considered the costs/LYGs directly associated with HSV-2 suppressive therapy.
Cost Projections for Johannesburg
The model estimated that if aciclovir costs US $0.14 per day, and the CD4 count eligibility threshold for ART was 200 cells/μL (scenario 1 in Table 2), then providing HSV-2 suppressive therapy to 300 HIV-1-infected women would cost US $224,260 (95% CI: 147,616–342,121) for their full period of therapy, or US $94 (95% CI: 63–137) per patient-year. The model projected that the average duration on treatment was 7.8 (95% CI: 6.7–9.6) years, while the longest treatment duration was 25 years (95% CI: 20–31).
Drugs and staff comprised 44% (95% CI: 37–55) and 49% (95% CI: 37–58) of total costs, respectively, capital costs 6%. Intervention costs decrease by 40% to US $61 (95% CI: 37–95) per patient-year if aciclovir costs US $0.026 per day, but change little (US $99 [95% CI: 70–138] per patient-year) if the CD4 count eligibility threshold for ART was 350 cells/μL (scenario 2 in Table 2).
In addition, because HSV-2 suppressive therapy decreases HIV-related death and loss to follow-up before ART, projections suggest the intervention will result in 80 (95% CI: 31–159) additional women initiating ART if the eligibility criteria is CD4 count <200 cells/μL, or 67 (95% CI: 24–124) if it is <350 cells/μL. This equates to an 230% (95% CI: 50%–720%) increase compared to not undertaking HSV-2 suppressive therapy at the lower CD4 count threshold and a 90% (95% CI: 20%–210%) increase at the higher threshold. This dramatically increases the incremental cost and impact of the intervention (Table 2).
Cost-Effectiveness Projections for Johannesburg
Table 2 shows that if the ART eligibility criteria is CD4 count <200 cells/μL, HSV-2 suppressive therapy amongst this cohort of women (scenario 1) results in 142 (95% CI: 46–302) LYG, with 16 (95% CI: 9–46) person-years of treatment required for each LYG and 0.47 (95% CI: 0.15–1.01) LYG per woman initiating therapy. In this scenario, there is a moderate likelihood (67%) that the cost per LYG will be <US $1200 at the cheapest aciclovir cost (US $0.026 per day), but will be 50% more costly if aciclovir costs US $0.14 per day.
In contrast, if the CD4 count eligibility criteria for ART was 350 cells/μL (scenario 2), then the LYGs decrease by 20% to 25% because fewer women are initially eligible for HSV-2 therapy and remain eligible for a shorter period, but the likelihood of the intervention costing <US $1200 per LYG increases to 86% if daily aciclovir costs $0.026. This improvement in the cost-effectiveness occurs because on average the cohort of woman on suppressive therapy now has a greater rate of decline in CD4 cell count due to their higher average CD4 cell count (Table 1). Suppressive therapy results in the same relative decrease in this progression rate, which results in a greater absolute decrease due to their higher progression rates, and so more LYGs per dose of aciclovir.
Lastly, if the incremental costs and impact of ART are also included into the projections for scenario 1 or 2, then the intervention results in greater impact (98% chance that LYGs increase >2-fold), at a cost per LYG that is elevated 1 to 2-fold due to the higher cost of ART.
When the effect of ART is not included in the model's projections, most of the variability in the cost-effectiveness projections is due to uncertainty in the efficacy of HSV-2 suppressive therapy for reducing either the rate of becoming eligible for ART or the rate of HIV-related death. For the lower aciclovir cost scenario, Figure 1 shows that small changes in either efficacy estimate results in major changes in the likelihood of the intervention costing <US $1200 per LYG, and so the cost-effectiveness of the intervention. Conversely, for the higher aciclovir cost scenario, the intervention is only cost-effective if both efficacy estimates are towards the upper bounds of their ranges (i.e., towards lower bounds of hazard ratios in Fig. 1) from the Partners HSV/HIV Transmission Study.
When the effect of ART is included in the model's projections, most of the variability in the projected additional impact of the intervention (due to more women initiating ART) is due to uncertainty in the degree to which HSV-2 suppressive therapy reduces the women's default rate before initiating ART, and the amount by which the default tracer returns these women to the intervention (Appendix Fig. 2, online only).
For the cheaper aciclovir price, Figure 2 suggests the cost-effectiveness of the intervention (not including the incremental costs/impact of ART) is highly sensitive to the proportion of HIV-1-infected women who are HSV-2 infected, the initial number of patients receiving HSV-2 suppressive therapy and the salary of the defaulter tracer. The first 2 factors affect the intervention's impact; whereas, changes in the salary of the defaulter tracer has a major effect because it accounts for 87% of all salary costs. Changes in other costs, such as the cost of aciclovir or salary costs for the auxiliary and senior nurses have a smaller effect because they contribute less to the total costs.
The results are also sensitive to the HIV-related death rate, because although increasing the HIV-related death rate over this range does not notably change the number of LYGs, the intervention costs reduce and so cost-effectiveness improves.
Lastly, decreasing the discount rate by 50% improves the cost-effectiveness of the intervention because a large portion of the LYGs due to HSV-2 suppressive therapy occur late on when few women remain in the “no HSV-2 therapy” comparator cohort but greater numbers exist in the treatment cohort due to their reduced HIV-1 disease progression rate. All other parameters, including the use of HSV-2 diagnostic testing to determine who initiates HSV-2 suppressive therapy, have a small effect (less than 3%).
This is the first analysis to assess the cost-effectiveness of providing HSV-2 suppressive therapy to HIV-1-infected women in sub-Saharan Africa to prevent HIV disease progression. Using effectiveness estimates from the Partners HSV/HIV Transmission Study,7 the analysis shows the intervention could result in a large number of LYG through slowing the pace at which women become eligible for ART or experience HIV-related death. Projections suggest that each woman starting treatment will achieve ∼0.47 LYG on average with 11 to 16 years of treatment being required for each LYG. The resulting cost per LYG in South Africa is likely to be less than ART (∼US $1200 per LYG26,27,31) if the cheapest available aciclovir is used, whereas this is unlikely for the current aciclovir cost in South Africa. Alternative criteria proposed by the Commission on Macroeconomics and Health33 suggest HSV-2 suppressive therapy could be highly cost-effective at either aciclovir cost. This is because suppressive therapy costs much less per LYG than the per capita gross national income for South Africa (US $9780 in international dollars for 200834)—their threshold for “very cost-effective” interventions.
These results suggest that HSV-2 suppressive therapy could be a viable intervention for slowing HIV disease progression and death among individuals not yet eligible for ART, but highlights the importance of cheaply available aciclovir in South Africa and other African settings.23 In addition, HSV-2 suppressive therapy could help as a much needed strategy to retain patients in the health care system so improving loss to follow-up before initiating ART. This would also provide opportunities for risk reduction counseling, prophylaxis and treatment against opportunistic coinfections, and opportunities to address other reproductive health needs including contraception and screening for cervical cancer. Importantly, through reducing loss to follow-up, HSV-2 suppressive therapy could substantially increase the impact of ART (>2-fold in our projections) irrespective of whether the ART eligibility criteria is CD4 count <200 or 350 cells/μL. However, it is possible that initiating ART at higher CD4 cell counts could be more cost-effective than HSV-2 suppressive therapy. Data on this is currently lacking though, and so the use of aciclovir should be encouraged at CD4 cell counts above these thresholds because of its ease of use compared to ART, i.e., few side effects and requirement for biologic monitoring.
While the findings of this study have relevance for other countries, the results could vary due to differences in the target populations or health systems. Because all HIV-infected women are put on to suppressive therapy, a lower HSV-2 prevalence in a country's HIV-positive population would decrease the intervention's cost-effectiveness. However, considering the HSV-2 prevalence amongst HIV-infected women is generally high (>80%) in most African settings35 this should be a minor issue. Similarly, HIV-related death rates vary in different African settings7,36 and so the intervention's cost-effectiveness could be reduced in settings with lower HIV-related death rates, and vice versa in settings with higher death rates. Lastly, differently organized health systems might require more or less staff time, training, or equipment, which could dramatically affect the intervention's overall cost.
This analysis has a number of limitations. These include the usual uncertainty in model parameters, such as the effectiveness of HSV-2 suppressive therapy, the HIV-related death rate and CD4 count decline rates. The uncertainty ranges for these model parameters were incorporated in the analysis. In addition, a composite effectiveness measure for the combined effect of HSV-2 suppressive therapy on HIV-1 disease progression and HIV-related death was used. It is possible that the effectiveness for each outcome may be different, although this cannot be determined without further trials. Although suggested by previous trials,2–7 no effect of HSV-2 suppressive therapy on HIV transmission was modeled because of the lack of any observed effect in the Partners HSV/HIV Transmission Study. As with other cost-effectiveness analyses, this analysis assumed a yearly discount rate on costs and impact projections. Because much of the benefit of suppressive therapy occurs late in the intervention, this may have resulted in the model producing conservative projections. The costs of managing possibly emerging aciclovir-resistant HSV-2 strains were not included in this analysis because no aciclovir resistance occurred in recent trials.37 The small possibility of resistant strains emerging through widespread use in HIV-positive populations38 should be monitored. Lastly, intervention effectiveness may decrease if treatment adherence becomes lower than the high adherence (95%) observed during the trial.2
Despite some data limitations, this analysis produces evidence that HSV-2 suppressive therapy could be a cost-effective intervention for increasing the survival of HIV-1-infected individuals before ART. The attractiveness of the intervention is dependent on aciclovir becoming widely available at a much cheaper cost than current procurement prices, and HSV-2 suppressive therapy being an effective strategy for improving pre-ART loss to follow-up.
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