Dissertations and Theses

Date of Degree

6-1-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Epidemiology and Biostatistics

Advisor(s)

Denis Nash

Committee Members

Annette H. Sohn

Jessie K. Edwards

Elizabeth A. Kelvin

Katarzyna Wyka

Subject Categories

Infectious Disease | Public Health

Keywords

Implementation science, HIV, AIDS, antiretroviral therapy, dolutegravir, integrase strand transfer inhibitors

Abstract

Background
Dolutegravir, an integrase strand transfer inhibitor, is now recommended by international guidelines as part of preferred antiretroviral therapy (ART) regimens for people living with HIV. In low- and middle-income countries (LMICs), HIV treatment programs are transitioning from non-nucleoside reverse transcriptase inhibitors (NNRTIs) to dolutegravir because of its superior efficacy and tolerability, and high genetic barrier to HIV drug resistance. Along with the optimism surrounding widespread dolutegravir use, key questions regarding its implementation have emerged. In this dissertation, I sought to achieve the following specific aims: Aim 1: Characterize dolutegravir uptake in LMICs and identify potential disparities related to sex and age through the trajectory of a safety signal potentially implicating dolutegravir with infant neural tube defects; Aim 2: Assess whether having viral load testing and suppression before switching to a dolutegravir-containing regimen impacts HIV treatment outcomes; Aim 3: Examine the effect of dolutegravir-containing ART on HIV treatment outcomes among patients with tuberculosis co-infection.

Methods
This dissertation research was conducted using observational data from the International epidemiology Databases to Evaluate AIDS (IeDEA) research consortium. For aim 1, I computed the cumulative incidence of dolutegravir uptake (i.e., newly initiating ART with dolutegravir or switching to dolutegravir from another regimen) stratified by age and sex. The cohort consisted of 134,672 patients aged 16 years or older who received HIV care from January 2017 through March 2020 in 11 LMICs in sub-Saharan Africa, Asia, and the Americas. For aim 2, I compared HIV treatment outcomes after switching to dolutegravir by most recent viral load test before switching, specifically examining patients with no viral load test, those with a viral load ≥1000 copies/mL, and those with a viral load 200-999 copies/mL vs. patients with a viral load /mL. The cohort consisted of 36,393 patients established on ART who switched from an NNRTI-containing regimen to dolutegravir in 5 countries in sub-Saharan Africa. For aim 3, I conducted a cross-sectional site survey assessing practices related to prescribing concomitant dolutegravir and rifampicin at clinical sites in sub-Saharan Africa. I also compared virologic outcomes among patients with HIV and tuberculosis co-infection receiving ART with either dolutegravir or efavirenz using a controlled before-and-after study. The cohort for this aim consisted of 3563 patients in 11 countries in sub-Saharan Africa.

Results
Differences in dolutegravir uptake among females of reproductive age (16 to 49 years) emerged after the safety signal and by the end of follow-up of the cohort, 6-8 months after the World Health Organization recommended dolutegravir for all people living with HIV, the cumulative incidence of dolutegravir uptake among females 16 to 49 years old was 29.4% (95% CI: 29.0-29.7) compared with 57.7% (95% CI: 57.2-58.3) among males 16 to 49 years old. The sex and age disparities in dolutegravir uptake were greater in countries that began implementing dolutegravir before the safety signal and initially had highly restrictive policies versus countries with a later rollout. Dolutegravir uptake was similar among females and males aged 50 years or older.

Among patients established on NNRTI-containing ART who switched to dolutegravir, 4% did not have a recent viral load test and 1% had a viral load ≥1000 copies/mL. When compared with patients who switched with a viral load/mL, both these patient groups had significantly increased hazards of an incident viral load ≥1000 copies/mL without evidence of resuppression, new or recurrent pulmonary tuberculosis or a WHO Clinical Stage 4 event, switch back to an NNRTI-containing regimen, and death or loss to program. Additionally, patients with a pre-switch viral load ≥1000 copies/mL had significantly increased hazards of subsequently switching to a second-line protease inhibitor-based regimen.

In the survey, 96% (86/90) of HIV clinics in 15 countries reported prescribing dolutegravir to patients who were receiving rifampicin-containing tuberculosis treatment, with 78 (91%) reporting that they use twice-daily dosing of dolutegravir for at least some patients. In the cohort study, among those receiving ART with dolutegravir, the crude cumulative incidence of viral suppression by 12 months (among those with ≥1 viral load measurement) was 90.7% (95% CI: 86.8%-93.5%) vs. 80.3% (95% CI: 78.1%-82.3%) among patients receiving efavirenz with a tuberculosis diagnosis before the introduction of dolutegravir.

Discussion
Substantial disparities in dolutegravir uptake affecting females of reproductive age through early 2020 were documented in my aim 1 research. Although this disparity was anticipated because of country-level restrictions on access, the results highlight its extent and initial persistence. To mitigate the anticipated negative downstream effects of lower dolutegravir uptake among females of reproductive age, HIV treatment programs and policymakers at community, national, and international levels should reaffirm the safety of dolutegravir and educate women, clinicians, and other stakeholders about the current evidence.

HIV treatment programs are transitioning from NNRTIs to dolutegravir, including switching ART experienced patients. My aim 2 research showed that assessing viral load has an important role in helping to identify patients who may benefit from additional clinical monitoring and/or adherence support after switching to dolutegravir to preserve it as a long-term option. At a population level, further surveillance of patients who switched to dolutegravir with an unknown or unsuppressed viral load is needed, as these patients were at highest risk for adverse HIV treatment outcomes while on dolutegravir.

The recommendation for dolutegravir-containing ART is inclusive of patients with active tuberculosis; however, use of dolutegravir is complicated by a drug-drug interaction with rifampicin. The site survey found that facilities had varying approaches to managing the drug-drug interaction between dolutegravir and rifampicin, but most routinely used twice daily dosing of dolutegravir to overcome the interaction. In the patient-level analysis, dolutegravir was associated with a better virologic outcome compared with efavirenz among patients with tuberculosis co-infection. Clinical trial data evaluating dolutegravir for people with HIV and tuberculosis co-infection are very limited, so these results provide real-world evidence that further supports the use of dolutegravir for this group.

Available for download on Thursday, August 17, 2023

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