Cost Effectiveness of HIV Prevention Interventions in the U.S.

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1 Cost Effectiveness of HIV Prevention Interventions in the U.S. Feng Lin, PhD, Paul G. Farnham, PhD, Ram K. Shrestha, PhD, Jonathan Mermin, MD, Stephanie L. Sansom, PhD Introduction: The purpose of this study was to assess and compare the cost effectiveness of current HIV prevention interventions in the U.S. using a consistent, standardized methodology. Methods: The cost effectiveness of common and emerging HIV biomedical and behavioral prevention interventions as delivered to men who have sex with men, injection drug users, and sexually active heterosexuals was estimated. Data on program costs, intervention efficacy, risk behaviors, and per contact transmission probabilities were collected from peer-reviewed papers and health department reports. These data were combined with 2010 national HIV incidence and prevalence surveillance data in a Bernoulli process model to estimate the reduced annual risk of HIV transmission or acquisition associated with these interventions. The cost per prevented case of HIV and the cost per saved qualityadjusted life year were then calculated. Analyses were conducted between 2014 and Results: Interventions to diagnose HIV and provide ongoing care and treatment had the lowest cost per prevented case. Among interventions targeted at specific risk groups, interventions for men who have sex with men were the most cost effective. The least cost-effective interventions typically addressed people at risk of acquiring HIV rather than those at risk of transmitting the disease. Conclusions: HIV prevention interventions targeted at high-risk populations, those associated with the care continuum, and those that reduce the transmission risk of HIV-infected people are typically the most cost effective. Decision makers can consider these results in planning an efficient allocation of HIV prevention resources. (Am J Prev Med 2016;50(6): ) Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine Introduction Although HIV incidence has decreased substantially over the past two decades, 1,2 more than 1.2 million people are living with HIV in the U.S., and approximately 50,000 people become infected annually. 3,4 As people with HIV are living longer, and budgets for prevention initiatives are constrained, using the most cost-effective means for preventing new infections becomes more important. This emphasis on prevention is reflected in the first major goal of the 2010 National HIV/AIDS Strategy for the U.S. 5 : reducing the annual number of new infections and the HIV transmission rate and increasing the percentage of people living with HIV who know their status. From the Division of HIV/AIDS Prevention, National Center for HIV/ AIDS, Viral Hepatitis, STD, and TB Prevention, CDC, Atlanta, Georgia Address correspondence to: Ram K. Shrestha, PhD, Division of HIV/ AIDS Prevention, CDC, 1600 Clifton Road, MS E-48, Atlanta GA biu0@cdc.gov /$ Interventions for HIV prevention include biomedical and behavioral approaches. HIV antiretroviral therapy (ART) is a biomedical intervention that reduces or suppresses HIV RNA viral load to r200 copies/ml, so that each contact between an infected and an uninfected person is less likely to result in transmission. 6 Several related interventions promote viral load suppression, including diagnosis, linkage to care, retention in care, prescription of ART, and adherence to ART. 7-9 Behavioral interventions are designed to reduce behaviors associated with HIV transmission or acquisition, such as sex unprotected by condoms. 10,11 Pre-exposure prophylaxis (PrEP) and male circumcision are biomedical interventions that reduce the risk of infection among those who are uninfected. 12,13 Numerous studies have evaluated the cost effectiveness of various interventions. 7,8,14-24 However, these analyses vary in their methodologies, outcome measures, and the conditions under which their conclusions hold, making comparisons across interventions difficult. This study combined data from the National HIV Surveillance Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine Am J Prev Med 2016;50(6):

2 700 System, estimates of the efficacy of behavioral and biomedical interventions, and data on the costs of implementing interventions to develop a standardized method of estimating the incremental cost effectiveness of a wide range of HIV prevention interventions. A societal perspective that comprehensively measured the additional costs and effects of the interventions compared with the standard of care was used. Methods Intervention Selection The interventions assessed in this study included HIV testing in clinical and non-clinical settings and through partner services for those with newly diagnosed HIV; care- and treatment-related interventions, such as those promoting linkage to care, retention in care, and adherence to ART, for those diagnosed with HIV; behavioral interventions for those aware of their infections as well as for those not infected; and PrEP for uninfected people in all risk groups and adult circumcision for heterosexual men not infected with HIV (Appendix Table 1, available online). Intervention efficacy was derived from U.S. settings where available or from international clinical trials. HIV interventions for which the intervention s direct effect on HIV transmission or acquisition was difficult to observe or quantify, including structural interventions, such as condom distribution and media campaigns, were excluded. Targeted interventions were defined as those delivered to a particular transmission risk group: men who have sex with men (MSM), injection drug users (IDUs), or all sexually active heterosexuals. Targeted interventions included testing in non-clinical settings, partner services, behavioral interventions, PrEP, and adult circumcision for heterosexual men. Non-targeted interventions, including HIV testing in clinical settings, linkage to care, retention in care, and adherence to ART, were delivered to all patients regardless of their HIV transmission risk group. This classification resulted in 20 combinations of interventions and populations. Interventions targeting heterosexuals at higher risk of transmitting or acquiring HIV owing to increased sexual risk taking were also evaluated with their results reported separately. Lin et al / Am J Prev Med 2016;50(6): or acquisition (for those who were HIV negative) resulting from the client s exposure to the intervention compared with the standard of care that would have occurred without the intervention. To obtain the intervention effect, the program effect was multiplied by the transmission effect, which was multiplied by the expected duration of the effect in years to obtain the number of HIV cases prevented by the intervention. Direct benefits to the program client, including increased length and quality of life, were excluded, given the focus in this paper on the benefits of these interventions in reducing transmission rates and new infections. The incremental cost per prevented case of HIV was defined as the additional unit cost of the intervention per person divided by the intervention effect (Figure 1, Appendix Equation 3, available online). 28 The cost per saved quality-adjusted life year (QALY) was defined as the cost per prevented HIV case minus the lifetime HIV treatment cost of $418,000 saved per prevented infection, all divided by an estimated 4.45 saved QALYs associated with each prevented HIV case (Appendix Equation 4, available online). 29,30 Interventions in which the cost per prevented case was less than the lifetime treatment cost were considered to be cost saving. All costs were measured in 2012 U.S. dollars. For all interventions, each incremental cost per prevented case or cost per saved QALY was estimated comparing the program s effect with the standard of care. Additional Analyses Threshold analysis on all intervention population combinations that were not cost saving in the base case analysis were conducted. Estimating Cost Effectiveness Several steps were used to consistently estimate the incremental cost effectiveness of each intervention population combination compared with the standard of care (Figure 1 and details in the Appendix, available online). This study first derived the unit cost of each intervention or the additional cost incurred to provide an intervention to one client (Appendix Tables 1 and 2, available online). The per-person program effect of each intervention measured by program providers or documented in controlled trials was then determined. HIV prevalence and incidence data collected in 2010 were obtained from the HIV surveillance reports, 3,4 and other parameter values were obtained from the literature. Analyses were conducted between 2014 and A Bernoulli process model was used to estimate the transmission effect associated with the per-person program effect The transmission effect indicated the percentage reduction in the annual risk of HIV transmission (for those who were HIV positive) Figure 1. Calculating the cost per case of HIV prevented. a For interventions associated with the test and treat continuum, marginal treatment costs were added to unit costs. See Appendix (available online) for a more complete discussion. b A is the number of cases of HIV prevented.

3 Table 1. Incremental Cost per Case of HIV Prevented and per QALY Saved for HIV Prevention Interventions Intervention Cost per case of HIV prevented Cost per QALY saved a MSM Testing, non-clinical: MSM 115,918 Partner services: MSM 116,118 Behavioral: HIVþ MSM 151,413 Behavioral: HIV MSM 327,128 Pre-exposure prophylaxis: MSM 679,878 58,849 Heterosexuals IDUs Partner services: heterosexuals 349,397 Partner services: high-risk heterosexuals 110,050 Behavioral: HIVþ heterosexuals 420, Behavioral: HIVþ high-risk heterosexuals 132,589 Testing, non-clinical: heterosexuals 692,013 61,576 Testing, non-clinical: high-risk heterosexuals 217,984 Circumcision: heterosexual men 7,299,488 1,546,402 Circumcision: high-risk heterosexual men 827,127 91,941 Behavioral: HIV heterosexuals 117,459,567 26,301,476 Behavioral: HIV high-risk heterosexuals 14,062,455 3,066,170 Pre-exposure prophylaxis: heterosexuals 170,766,231 38,280,501 Pre-exposure prophylaxis: high-risk heterosexuals 20,636,101 4,543,393 Partner services: IDUs 263,308 Testing, non-clinical: IDUs 315,832 Behavioral: HIVþ IDUs 487,004 15,507 Behavioral: HIV IDUs 965, ,009 Pre-exposure prophylaxis: IDUs 1,020, ,422 Non-targeted interventions Lin et al / Am J Prev Med 2016;50(6): Testing, clinical 165,424 Linkage to care 270,075 Adherence to ART 338,842 Retention in care 477,897 13,460 Note: Costs are in 2012 U.S. dollars. a Dashes indicate negative cost per QALY ratios, which represent cost savings. The magnitude of cost savings are typically not reported in the literature. ART, antiretroviral therapy; IDU, injection drug user; MSM, men who have sex with men; QALY, quality-adjusted life-year. The authors determined how much unit costs would have to be reduced, or program effects increased, for the combinations not found to be cost saving/effective in the base case analysis to become cost saving/effective. A cost-effectiveness threshold of $100,000 per saved QALY was used. 31 Key results in order of the cost per prevented HIV case and the cost per saved QALY for each targeted population and for the non-targeted interventions are presented. The results for the analysis of the subset of interventions targeted at high-risk heterosexuals are also discussed. Univariate sensitivity analysis was conducted on the 20 intervention population combinations to explore the effect of using minimum and maximum values for program effect size, effect duration, and unit cost on the cost per prevented case. Sensitivity analyses were also conducted using the assumption of a 1-year June 2016

4 702 duration for all interventions and exploring behavior change for IDUs. Findings were calibrated by comparing the number of infections generated by each risk group and across all risk groups with the mean annual number of new cases reported by HIV surveillance data from 2007 to 2010 (Appendix, available online). Results All of the interventions for MSM were cost saving except for PrEP, which was cost effective (Table 1). Testing in non-clinical settings, partner services, and behavioral interventions for HIV-infected MSM were the most cost effective of all of the intervention population combinations examined in this analysis. For heterosexuals, testing in non-clinical settings, partner services, and behavioral interventions for infected individuals were either cost saving or cost effective. Three intervention population combinations aimed at all sexually active heterosexuals adult circumcision, behavioral interventions for the uninfected, and PrEP fell far outside the cost-effectiveness Lin et al / Am J Prev Med 2016;50(6): threshold with costs per saved QALY of $1.5 million and higher (Appendix Table 3, available online). For IDUs, testing in non-clinical settings, partner services, and behavioral interventions for HIV-infected people were cost saving or cost effective, whereas behavioral interventions for uninfected individuals and PrEP would not be considered cost effective with a $100,000/QALY threshold. Three of the non-targeted continuum interventions (testing, linkage, and adherence to ART) were cost saving, while the fourth (retention in care) was cost effective. Evaluating interventions for heterosexuals at higher risk of HIV resulted in lower costs per prevented HIV case for all interventions. Two of the interventions, testing in non-clinical settings and behavior change for infected individuals, became cost saving (Table 1). Among interventions for uninfected heterosexuals, adult male circumcision became cost effective. Behavior change and PrEP remained not cost effective. Threshold analysis indicated that by reducing costs or increasing program benefits, many of the combinations Table 2. Threshold Analysis of the Incremental Cost per Case of HIV Prevented for HIV Prevention Interventions Base case values Cost-saving threshold a Cost-effective threshold b Intervention (base case costeffectiveness designation) Unit cost ($ c ) Program effects (%) Unit cost ($ c ) Program effects (%) Unit cost ($ c ) Program effects (%) MSM Pre-exposure prophylaxis: MSM 10, , Heterosexuals Testing, non-clinical: heterosexuals Behavioral: HIVþ heterosexuals 1, , Behavioral: HIV heterosexuals Infeasible 6 Infeasible Circumcision: heterosexual men 2, Infeasible 247 Infeasible Pre-exposure prophylaxis: heterosexuals 10, Infeasible 52 Infeasible IDUs Behavioral HIVþ IDUs 1, , Behavioral: HIV IDUs Pre-exposure prophylaxis: IDUs 10, ,234 Infeasible 8, Non-targeted interventions Retention in care a Cost-saving threshold where the cost per case of HIV prevented is less than or equal to lifetime treatment costs of HIV, $418,000 in 2012 U.S. dollars, i.e., C / A r TorC/Ar $418,000. b Cost-effectiveness threshold is defined as follows: (C AT) / AQ ¼ [(C / A) T] / Q, [(C / A) T] / Q r $100,000, (C / A) r $100,000 (Q) þ T, (C / A) r ($100,000) (4.45) þ $418,000, (C / A) r $863,000, where C is unit cost; A is intervention effect or number of cases of HIV prevented; T is lifetime treatment cost saved per HIV infection prevented ¼ $418,000, and Q is quality-adjusted life years saved per HIV infection prevented ¼ c Costs are in 2012 U.S. dollars. IDU, injection drug user; MSM, men who have sex with men.

5 Lin et al / Am J Prev Med 2016;50(6): Table 3. One-Way Sensitivity Analysis on Incremental Cost Per Case of HIV Prevented by Program Effect Size, Intervention Duration, and Unit Cost Inputs Cost per case prevented a Variable Base case Lower bound Upper bound Base case ($ b ) Lower bound (%) Upper bound (%) MSM Testing, non-clinical: MSM Effect , Duration Cost c Partner services: MSM Effect , Duration Cost c , Behavioral: HIVþ MSM Effect , Cost c 1, , Behavioral: HIV MSM Effect c , Cost , Pre-exposure prophylaxis: MSM Effect c , Cost 10,338 7,753 12, Heterosexuals Partner services: heterosexuals Effect , Duration Cost c , Behavioral: HIVþ heterosexuals Effect , Cost c 1, , Testing, non-clinical: heterosexuals Effect , Duration Cost c (continued on next page) June 2016

6 704 Lin et al / Am J Prev Med 2016;50(6): Table 3. One-Way Sensitivity Analysis on Incremental Cost Per Case of HIV Prevented by Program Effect Size, Intervention Duration, and Unit Cost (continued) Inputs Cost per case prevented a Variable Base case Lower bound Upper bound Base case ($ b ) Lower bound (%) Upper bound (%) Circumcision: heterosexual men Effect ,299, Duration c Cost 2,110 1,055 3, Behavioral: HIV heterosexuals Effect c ,459, Cost , Pre-exposure prophylaxis: heterosexuals Effect c ,766, Cost 10,338 7,753 12, IDUs Partner services: IDUs Effect , Duration Cost c , Testing, non-clinical: IDUs Effect , Duration Cost c Behavioral: HIVþ IDUs Effect , Cost c 1, , Behavioral: HIV IDUs Effect c , Cost , Pre-exposure prophylaxis: IDUs Effect c ,020, Cost 10,338 7,753 12, Non-targeted interventions Testing, clinical Effect , (continued on next page)

7 Lin et al / Am J Prev Med 2016;50(6): Table 3. One-Way Sensitivity Analysis on Incremental Cost Per Case of HIV Prevented by Program Effect Size, Intervention Duration, and Unit Cost (continued) Inputs Cost per case prevented a Variable Base case Lower bound Upper bound Base case ($ b ) Lower bound (%) Upper bound (%) Duration c Cost Linkage to care Effect c , Cost , Adherence to ART Effect , Duration Cost c , Retention in care Effect c , Duration Cost , a Variation in cost per case prevented is reported as percent difference from the base case. b Costs are in 2012 U.S. dollars. c Indicates the variable that produced the largest percentage change from the base case in cost per prevented case for each intervention. Duration was not relevant in linkage to care and pre-exposure prophylaxis interventions. ART, antiretroviral therapy; IDU, injection drug users; MSM, men who have sex with men. that were cost effective in the base case analysis could become cost saving (Table 2). A possible exception was PrEP for IDUs, the cost of which would have to decrease by nearly half at the same level of efficacy. In the case of combinations that were not cost effective in the base case, the analysis indicated that changes sufficient to achieve cost effectiveness were unlikely for either unit costs or program effects for interventions aimed at preventing infections among all sexually active heterosexuals. In the univariate sensitivity analysis, variations in cost generated the largest changes in outcomes for ten of the 20 intervention population combinations, effectiveness for eight, and duration for two (Table 3). Intervention population combinations where the cost per prevented case was most affected by changes in the unit cost were testing in non-clinical settings and through partner services, behavioral interventions for the infected, and adherence to ART. Combinations where the cost per prevented case was most affected by changes in the program effect were behavioral interventions for the uninfected, linkage to and retention in care, and PrEP for all three risk groups. Combinations where the cost per prevented case was most affected by changes in the duration of program effect were testing in clinical settings and adult circumcision for all sexually active heterosexual men. Table 3 indicates which variables were associated with the largest percentage change from the base case in cost per prevented case for each intervention. Further sensitivity analysis assuming that all interventions had a 1-year duration (Appendix Table 4, available online) showed that interventions for MSM remained cost saving, and interventions for IDUs and the nontargeted interventions changed from cost saving to cost effective. Non-clinical testing and partner services for heterosexuals remained cost effective, while circumcision for heterosexual men remained not cost effective. In the sensitivity analysis of needle sharing (Appendix Table 5, available online), varying the base case value (26.5%) used for reduction in the number of needles shared among IDUs who became aware of their HIV infection from 0% to 50% had little impact on the cost effectiveness of non-clinical testing and partner services for IDUs. Both interventions remained cost saving. Discussion Using consistent, standardized methods to assess the costs and benefits of established and emerging HIV June 2016

8 706 prevention strategies, this analysis demonstrates some of the most and least efficient ways to prevent HIV among key populations. Interventions to diagnose HIV and provide ongoing care and treatment had the lowest cost per prevented HIV case. The costliest interventions were those that focused on reducing the risk of sexually active heterosexuals acquiring HIV. Among interventions targeted to groups at specific risk for HIV, the cost effectiveness varied broadly according to the target group, with interventions for MSM being most cost effective. This result occurred largely because the types of sex practiced by different groups are associated with different per-act transmission risks, and IDUs had the added risk of shared needles. Programmatic data for testing interventions also indicated variations by risk group in the proportion of all tests that resulted in new HIV diagnoses. Interventions that were least cost effective typically addressed people at risk of acquiring HIV rather than those at risk of transmitting the disease. The risk of the former is, on average, much lower than that of the latter. 32 For interventions delivered to heterosexuals at highest risk of HIV transmission or acquisition, testing this population, including in non-clinical settings and through partner services, was cost saving, as were behavior change interventions for the infected. For uninfected, high-risk heterosexuals, adult male circumcision was cost effective. Thus, targeting prevention interventions to the highest-risk heterosexuals may be cost effective for some interventions. These findings present the relative cost effectiveness of key HIV prevention interventions in the U.S. based on national-level data. They could be used as inputs to resource allocation models, particularly when considering the other factors involved in optimal allocation: the prevention budget, the number of people who can be served by an intervention as a fraction of all those who would benefit from it and, for targeted interventions, the size of populations by risk group. 33 The cost-effectiveness results in this analysis are consistent with the findings from a published resource allocation model for HIV prevention funding with its emphasis on testing and behavioral interventions for those who are infected, and less emphasis on interventions targeting a general population. 34 A recent paper on optimal resource allocation in New York City, in contrast to the present findings, indicates a high cost per case of HIV prevented through testing. 35 The authors indicate that testing rates in New York City are high already, and the marginal benefits of expanded testing are low. Using a similar methodology for most interventions, Cohen et al. 36 estimated the cost effectiveness of a set of Lin et al / Am J Prev Med 2016;50(6): interventions relevant in Their model did not include interventions related to moving HIV-infected people along the continuum of care to achieve viral load suppression. Although Cohen and colleagues estimated only the cost per prevented case as their outcome, many of their interventions would be considered cost saving when comparing their estimates of cost per prevented case with the lifetime cost of treating a case of HIV. Although these results were similar to this study, Cohen et al. examined a range of interventions that necessitated the use of multiple analytic methods for estimating cost effectiveness, thus reducing the comparability of their results among interventions. This analysis differs from systematic reviews of published cost-effectiveness studies of HIV prevention, 37 because those papers included cost-effectiveness findings based on a variety of approaches to assessing costs and effectiveness that are not easily compared, even for a given category of intervention such as HIV screening. This study derived independent estimates for costs and efficacy and used standardized methods to summarize cost effectiveness across all included interventions. 38 The static model in this analysis required assumptions about program effectiveness and behavior over time that might not be necessary in more complex disease progression and dynamic compartmental models, which could incorporate these changes directly. The approach in this paper could potentially overstate the impact of prevented infections on treatment costs and QALYs saved. However, this type of model was useful in making standardized comparisons across interventions. The cost effectiveness of the interventions from the test-and-treat continuum in this model reflects the efficacy of ART in reducing HIV transmission, estimated at 96% in a trial conducted among heterosexuals. 6 Although the 96% reduction in transmission was observed among all those receiving ART, the reduction was applied in this analysis only to those who achieved viral load suppression. This may be a conservative approach. On the other hand, trial participants received additional prevention and adherence counseling, which could have increased efficacy compared with what might be observed outside of a trial. Treatment also provides substantial benefits to the infected person. Although these benefits to the infected person were not considered in the present analysis of these HIV prevention interventions, they would make treatment-related interventions more cost effective. 39 This study assumed an efficacy of PrEP in reducing infection that corresponded to average adherence in trial data. Higher efficacy associated with better adherence would make PrEP more cost effective. The benefits of testing in this analysis also resulted from the association

9 of learning one s infection status with ongoing reductions in unprotected sex with partners who are uninfected or whose HIV serostatus is unknown. 9 Benefits associated with receiving a repeat diagnosis were not included. However, for people who previously tested positive but did not enter care, a repeat diagnosis may provide another opportunity to enter treatment and receive additional services to prevent transmission. Benefits from the interventions related to testing, care, and treatment, as constructed in this analysis, are dependent on the underlying proportion of HIVinfected people who advance from one step of the continuum to another. These underlying proportions themselves rely on previous investments in the continuum of care interventions, and influence the marginal costs and benefits of these interventions. This study analyzed all continuum-related interventions separately, given the lack of data on programs that combine interventions from diagnosis to adherence and assess their joint effect on viral load suppression. Improvements in care and treatment interventions may serve to improve the effectiveness of the interventions that precede them. For instance, improved retention in care and adherence to ART make testing and linkage to care more likely to result in viral load suppression, reducing transmission risk. Juusola and Brandeau 40 developed a resource allocation model with and without a function that estimated overlap among prevention programs. They noted that overlap might be ignored if program implementation levels were relatively low and that inclusion of overlap did not change the optimal solution in their model. The interventions included in this analysis varied in the strength of the scientific evidence supporting their estimated efficacy. Differences in the strength of scientific data were not explicitly incorporated into the analysis, but careful consideration of the strength of the evidence is another factor that could be considered in decision making. 41 Conclusions This study, which used consistent methods of analysis, offers information on the relative cost effectiveness of varying approaches to HIV prevention in the U.S. The cost effectiveness of targeted interventions varies substantially by the target population, with interventions for MSM being cost saving or highly cost effective. Many HIV prevention interventions, particularly those associated with the care continuum or otherwise directed toward helping people living with HIV reduce their transmission risk, are likely to be cost effective or even cost saving. Interventions focusing on reducing the risk of acquiring Lin et al / Am J Prev Med 2016;50(6): HIV, particularly among heterosexuals, are unlikely to result in efficient use of society s resources. The authors gratefully acknowledge the contributions of Drs. Emine Yaylali and Arielle Lasry for advice on the model structure, Drs. Gabriela Paz-Bailey and Eli Rosenberg for review of and suggestions for behavioral inputs, and Dr. Tim Green and Ms. Abby Viall for comments on the manuscript. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of CDC. No financial disclosures were reported by the authors of this paper. References 1. Holtgrave D, Hall HI, Rhodes PH, Wolitski R. Updated annual HIV transmission rates in the United States, J Acquir Immune Defic Syndr. 2009;50(2): e be. 2. Holtgrave DR. Estimation of annual HIV transmission rates in the United States, J Acquir Immune Defic Syndr. 2004;35 (1): CDC. 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