Among South African women, vaginal PrEP would be a highly cost-effective intervention. At $2700/YLS, PrEP remained below the WHO-suggested very cost-effective threshold in South Africa, under a range of model parameter values chosen to capture the performance of both vaginal and oral alternatives. Cost savings could only be achieved under optimistic assumptions, in which PrEP was targeted to populations in which the incidence of HIV infection is high (≥5%/year), with high efficacy (≥50%) and at lower PrEP drug costs (<$40/year). The cost-effectiveness results compare very favorably with those that have been published for ART and CD4 cell count laboratory monitoring for HIV in South Africa [12
Improvements in adherence—whether through easier regimens, such as a vaginal ring, targeting populations likely to be most receptive, or training providers to encourage compliance—are crucial to maximizing the effectiveness of a PrEP program. The results from FEM-PrEP and the early termination of the TDF-only arm in VOICE might suggest that efficacy of oral chemoprophylaxis is exquisitely sensitive to suboptimal adherence, because vaginal levels are marginal for protection even with the best adherence [5
]. The more recent termination of the vaginal gel arm of VOICE, with no statistical benefit over placebo, results in more confusion in light of the earlier CAPRISA findings [9
]. It is still not known whether daily gel administration, as in VOICE, may provide inferior protection than the before and after pericoital regimen studied in CAPRISA 004 [1
Although they have not emerged as significant issues in clinical trials, PrEP-induced toxicity, resistance, and risk compensation remain an implementation concern. We found that the clinical benefits of PrEP at the population level overwhelmingly offset any plausible level of adverse reactions, resistant breakthrough infections, or behavioral disinhibition [11
]. Of note, risk-reduction effects have been demonstrated in microbicide, pre- and postexposure prophylaxis, and vaccine studies [1
]. The challenge will be to sustain these effects if PrEP becomes a public health program with less frequent clinical monitoring.
Despite its excellent value, PrEP implementation will not pay for itself. This analysis suggests that the per-woman investment would be $1075/person, or $6.0 billion, for 50% coverage of all eligible women in South Africa over the next 5 years. This investment will pay substantial dividends both in HIV cases averted and in the associated care costs prevented. However, if a one-size-fits-all prevention approach proves to be infeasible, targeting PrEP to women at highest risk and/or those most likely to adhere will pay the highest returns on investment and may even prove to be cost saving.
Although our findings offer very strong evidence of the cost-effectiveness of PrEP, they are more tempered than those that have been previously reported [60
]. We believe that the following modeling choices explain and justify our more conservative conclusions: first, we accounted explicitly for the indirect costs of providing PrEP (including regular HIV testing and chemistry panels); second, we captured the possibility (and the expected costs) of adverse outcomes, including PrEP-related toxicity and the potential for antiretroviral resistance attributable to prophylaxis failure; third, we recognized the time value of cost-effectiveness outcomes and that the costs of PrEP are incurred long before its prevention benefits are realized; fourth, in the absence of data demonstrating capacity to accurately target PrEP to those at the highest risk, we model it as a lifelong (or until infected) intervention.
This analysis has several limitations. We applied efficacies from short-term trials conducted in groups at high risk of HIV infection (heterosexual women, men, and men who have sex with men) at high risk to different populations and projected these results over longer periods [5
]. Until trials can confirm the durable efficacy of a tenofovir vaginal gel, the efficacy and optimal dosing of PrEP remain uncertain. Recognizing this uncertainty, we considered a wide range of efficacies and dosing strategies. Second, we considered only the first generation of HIV infections prevented, conservatively ignoring the additional benefit of later HIV infections averted. Last, we estimated and considered a wide range of PrEP program costs, because costs for a vaginal gel and for PrEP implementation are not yet available.
This analysis suggests that PrEP, when applied to South African women, will substantially reduce the lifetime risk of HIV infection and be very cost-effective. Given the long-awaited proof-of-concept of PrEP as an effective female-initiated prevention option, its implementation holds substantial potential for reducing the incidence of HIV infection in South Africa, where PrEP will provide excellent value for money.