In July 2012, the US Food and Drug Administration (FDA) approved tenofovir/emtricitabine for use as oral pre-exposure prophylaxis (PrEP) [
1]. Estimates of PrEP efficacy in preventing HIV infection range from 39% to 86% in randomized controlled trials [
2‐
6]. PrEP consumer demand has accelerated since mid-2013 [
7]. PrEP coverage among men who have sex with men (MSM) in San Francisco was estimated at 9.6% in 2014 [
8]. In May 2016, more than 6000 MSM in San Francisco were reported to receive PrEP [
9], suggesting a coverage of approximately 12% given that the HIV-negative MSM population is estimated at 50,000 [
7,
10,
11]. In 2010, prior to this increased PrEP uptake, San Francisco was one of the first cities to institute guidelines to initiate antiretroviral therapy (ART) as early as possible post-infection rather than waiting for signs of disease progression, such as clinical symptoms or low CD4+ cell counts [
12], given findings that early ART initiation improves survival while reducing the risks of transmission to others [
13]. However, it has been hypothesized that early ART initiation might provide more time for the evolution of drug resistance and that subsequent transmission of drug-resistant HIV might reduce PrEP effectiveness [
14‐
16].
Herein, we address the long-term population-level costs and health benefits of expanding PrEP coverage in combination with increasingly early ART initiation among the MSM population in San Francisco. We assess the effectiveness and cost-effectiveness of expanding PrEP coverage, with and without earlier ART guidelines, using an infection–age-structured model [
17,
18]. The model tracks the transmission rate and life expectancy of individuals at each infection age, while accounting for ART-mediated drug resistance and the costs of treatment failure and second-line regimens. We fit this model to epidemiological data on the annual incidence of newly diagnosed AIDS cases and deaths amongst MSM in San Francisco (simultaneously matching prevalence, resistance, and demographic data [
18]) and estimate the impact of various intervention scenarios over the next 20 years.
Several modeling studies have addressed the impact of PrEP in San Francisco, including estimates of coverage required to curtail transmission [
7], an assessment of whether PrEP might increase the drug-resistant transmission [
14], and a cost-effectiveness analysis of PrEP in combination with a partially effective HIV vaccine [
19]. Our study differs from these prior analyses and others of PrEP cost-effectiveness [
20‐
26] in the United States in several aspects. First, we analyze the expansion in PrEP coverage in conjunction with changing ART guidelines, rather than comparing initiation of PrEP to no PrEP [
7,
14,
19‐
24,
27,
28]. Second, we model the acquisition and transmission of ART-mediated resistance and the indirect population-level effects of PrEP (i.e., by reducing the number of infected individuals, PrEP indirectly benefits other individuals in the population who could have otherwise been infected by individuals on PrEP), which have not been addressed in previous studies [
7,
19‐
25]. While two prior analyses of PrEP [
16,
26] considered ART-mediated resistance and subsequent treatment failure, one [
16] did not address the impact of earlier ART initiation on PrEP cost-effectiveness, and the other [
26] did not account for increased costs and effectiveness of second-line drugs. Third, we consider increasingly earlier initiation of ART and the consequent increases in survival. In contrast, many prior studies modeled early ART by assuming individuals initiate ART whilst their CD4+ T cell counts remain above 350 cells/mm
3 [
29], by assuming ART eligibility occurs once their CD4+ T cell count drops below 500 cells/mm
3 [
30,
31], or by assuming ART initiation occurs within 2 years of infection [
32]. Two studies that modeled ART initiation at 1 year post-infection [
33,
34] did not incorporate the increased survival times, which may cause underestimation of intervention cost-effectiveness.