Early antiretroviral therapy and potent second-line drugs could decrease HIV incidence of drug resistance

Abstract

Early initiation of antiretroviral therapy (ART) reduces the risk of drug-sensitive HIV transmission but may increase the transmission of drug-resistant HIV. We used a mathematical model to estimate the long-term population-level benefits of ART and determine the scenarios under which earlier ART (treatment at 1 year post-infection, on average) could decrease simultaneously both total and drug-resistant HIV incidence (new infections). We constructed an infection-age-structured mathematical model that tracked the transmission rates over the course of infection and modelled the patients' life expectancy as a function of ART initiation timing. We fitted this model to the annual AIDS incidence and death data directly, and to resistance data and demographic data indirectly among men who have sex with men (MSM) in San Francisco. Using counterfactual scenarios, we assessed the impact on total and drug-resistant HIV incidence of ART initiation timing, frequency of acquired drug resistance, and second-line drug effectiveness (defined as the combination of resistance monitoring, biomedical drug efficacy and adherence). Earlier ART initiation could decrease the number of both total and drug-resistant HIV incidence when second-line drug effectiveness is sufficiently high (greater than 80%), but increase the proportion of new infections that are drug resistant. Thus, resistance may paradoxically appear to be increasing while actually decreasing.

Keywords: acquired drugresistance; early antiretroviral therapy initiation; mathematical model; second-line drug effectiveness; transmission of drug-resistant HIV.

Figure 1.

(a) Model fit (lines) to the incidence of AIDS diagnoses (magenta circles) and AIDS deaths (blue squares) from 1980 to 2014 among MSM population in San Francisco. Dashed vertical black line denotes the divide between the pre-treatment and post-treatment phases of our model, roughly approximating the increase in ART availability post-1995 in San Francisco. (b) Observed HIV prevalence data among the sampling MSM populations (black square and 95% CI if available) from previous different studies [–52] and model fit with and without (w/o) considering the effect of treatment post-1995. (c) Observed proportion of new infections that are drug resistant (black dots, with 95% CI if available, denote genotypic resistance and red dots denote phenotypic resistance) among previous cohorts [–32] and model fit (blue line). Previous comparison between model and empirical data for trends of percentage of new drug-resistant infections in San Francisco (1996–2005) can be found in [37]. ART, antiretroviral therapy; MSM, men who have sex with men. (Online version in colour.)

Figure 2.

(a,b) The cumulative total incidence (new infections) and drug-resistant incidence over time from 2018 to 2038 for early ART (assumed ART initiation timing of 1 year, dashed lines) and late ART (estimated ART initiation timing of 1.6 years, solid lines), respectively. (c,d) One-way sensitivity analysis about the ratios of cumulative total incidence over 20 years (early versus late ART, denoted as C^e_total and C^l_total) and drug-resistant incidence (early versus late ART, denoted as C^e_r and C^l_r), respectively. The horizonal bars represent the range of the ratios (C^e_total/C^l_total and C^e_r/C^l_r) as each variable (second-line drug effectiveness, the fraction of acquired drug resistance and the shortened lifespan for treated drug-resistant individuals compared with treated drug-sensitive individuals) is varied across its plausible range listed. The black solid vertical lines indicate the base case ratios (C^e_total/C^l_total = 0.74 and C^e_r/C^l_r = 0.94). The red dashed vertical line represents the threshold whether early ART would increase incidence. (e) Area plots of the ratios of cumulative incidence. In the red area, it shows that early ART can increase both the total incidence and drug-resistant incidence. In the blue area, it shows that early ART can decrease total incidence, but increase drug-resistant incidence. In the green area, early ART can decrease both the total incidence and drug-resistant incidence. The black star denotes the base case (second-line drug effectiveness is 80%, and 25% of treated cases have acquired drug resistance and all of them switch to second-line drugs timely). All the other parameters are fixed as shown in electronic supplementary material, table S1. ART, antiretroviral therapy. (Online version in colour.)

Figure 3.

Results of Latin hypercube uncertainty analysis, with scatterplots showing the effect of second-line drug effectiveness (a), the fraction of acquired drug resistance (b) and the shortened lifespan for treated drug-resistant individuals compared with treated drug-sensitive individuals (c) on the ratios of cumulative incidence between treatment scenarios (early versus late ART for total incidence, C^e_total/C^l_total, in blue; early versus late ART for drug-resistant incidence, denoted as C^e_r/C^l_r, in red), where C^e_total, C^l_total and C^e_r, C^l_r are the same as shown in figure 2. Each point represents a single simulation from a sample 1000 Latin hypercube parameter samples. All the other parameters are fixed as shown in electronic supplementary material, table S1. ART, antiretroviral therapy. (Online version in colour.)