Impact of isoniazid preventive therapy for HIV-infected adults in Rio de Janeiro, Brazil: an epidemiological model

Abstract

Background: The potential epidemiological impact of isoniazid preventive therapy (IPT), delivered at levels that could be feasibly scaled up among people living with HIV (PLHIV) in modern, moderate-burden settings, remains uncertain.

Methods: We used routine surveillance and implementation data from a cluster-randomized trial of IPT among HIV-infected clinic patients with good access to antiretroviral therapy in Rio de Janeiro, Brazil, to populate a parsimonious transmission model of tuberculosis (TB)/HIV. We modeled IPT delivery as a constant process capturing a proportion of the eligible population every year. We projected feasible reductions in TB incidence and mortality in the general population and among PLHIV specifically at the end of 5 years after implementing an IPT program.

Results: Data on time to IPT fit an exponential curve well, suggesting that IPT was delivered at a rate covering 20% (95% confidence interval: 16% to 24%) of the 2500 eligible individuals each year. By the end of year 5 after modeled program rollout, IPT had reduced TB incidence by 3.0% [95% uncertainty range (UR): 1.6% to 7.2%] in the general population and by 15.6% (95% UR: 15.5% to 36.5%) among PLHIV. Corresponding reductions in TB mortality were 4.0% (95% UR: 2.2% to 10.3%) and 14.3% (14.6% to 33.7%). Results were robust to wide variations in parameter values on sensitivity analysis.

Conclusions: TB screening and IPT delivery can substantially reduce TB incidence and mortality among PLHIV in urban, moderate-burden settings. In such settings, IPT can be an important component of a multi-faceted strategy to feasibly reduce the burden of TB in PLHIV.

Figure 1. Structure of Compartmental Transmission Model

Rates of flow between each compartment are governed by differential equations, as described in the Appendix. Each compartment is further sub-divided by HIV status and drug-resistance status (multidrug-resistant or not multidrug-resistant). IPT (dotted line) is modeled as a one-time intervention, delivered only to people living with HIV, providing immediate partial protection (among those who will complete therapy) against reactivation TB, no protection against reinfection, and no benefit for those infected with multidrug-resistant TB. After completing IPT, individuals remain in the post-IPT state for the remainder of the analysis. Per contemporary Brazilian policy, ART was assumed to be available only to those with CD4 counts ≤350, and to provide immediate benefit (equivalent to having a CD4 count >350) upon initiation.

Figure 2. Estimated Rate of Isoniazid Preventive Therapy (IPT) Delivery in the THRio Trial

The green line shows the Kaplan-Meier survival function of time from clinic randomization date to receipt of IPT in the THRio study, among all HIV-infected individuals without a history of TB treatment or IPT and having a positive tuberculin skin test (TST). This analysis assumes that the probability of a positive TST was the same in those who were never screened as in those who were. The orange line shows the predicted function after fitting these data to an exponential decay curve.

Figure 3. Five-Year Impact of Isoniazid Preventive Therapy on HIV-Associated TB in Rio de Janeiro, Brazil

Blue lines show the baseline (steady-state) scenario, while red lines show the projected TB incidence and mortality as a function of time after rolling out a program for isoniazid preventive therapy (IPT) capable of providing IPT to 20% of the eligible HIV-infected population per year. The upper set of lines and leftward axis display TB incidence, whereas the lower set of lines and the rightward axis display TB mortality.

Figure 4. Sensitivity Analysis: Five-Year Impact of IPT on TB Incidence

Each model parameter was varied across a range (shown in Table 1) capable of changing the corresponding epidemiological data point (e.g., TB incidence) by 25% over 5 years; only those parameters that changed the projected impact of IPT on HIV-associated TB incidence at 5 years by 10% or more (i.e., outside the range of 14.1%–17.1% reduction) are shown. Red bars indicate a reduction in the specified parameter; blue bars indicate an increase. All parameter values were simultaneously varied (including those not shown here) across beta distributions in probabilistic uncertainty analysis. * = projected impact of IPT reached a maximum at a rate of 0.14/year; increases or decreases in parameter value from this estimate lowered the projected impact of IPT, with the minimum value shown.