Abstract
Background:
The transition to dolutegravir-containing antiretroviral therapy (ART) in low- and middle-income countries (LMICs) was complicated by an initial safety signal in May 2018 suggesting that exposure to dolutegravir at conception was possibly associated with infant neural tube defects. On the basis of additional evidence, in July 2019, the World Health Organization recommended dolutegravir for all adults and adolescents living with HIV.
Objective:
To describe dolutegravir uptake and disparities by sex and age group in LMICs.
Design:
Observational cohort study.
Setting:
87 sites that began using dolutegravir in 11 LMICs in the Asia-Pacific; Caribbean, Central and South America network for HIV epidemiology (CCASAnet); and sub-Saharan African regions of the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium.
Patients:
134 672 patients aged 16 years or older who received HIV care from January 2017 through March 2020.
Measurements:
Sex, age group, and dolutegravir uptake (that is, newly initiating ART with dolutegravir or switching to dolutegravir from another regimen).
Results:
Differences in dolutegravir uptake among females of reproductive age (16 to 49 years) emerged after the safety signal. By the end of follow-up, the cumulative incidence of dolutegravir uptake among females 16 to 49 years old was 29.4% (95% CI, 29.0% to 29.7%) compared with 57.7% (CI, 57.2% to 58.3%) among males 16 to 49 years old. This disparity was 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.
Limitation:
Follow-up was limited to 6 to 8 months after international guidelines recommended expanding access to dolutegravir.
Conclusion:
Substantial disparities in dolutegravir uptake affecting females of reproductive age through early 2020 are documented. Although this disparity was anticipated because of country-level restrictions on access, the results highlight its extent and initial persistence.
Primary Funding Source:
National Institutes of Health.
Introduction
Dolutegravir, an integrase strand transfer inhibitor, was first recommended in the World Health Organization (WHO) antiretroviral therapy (ART) guidelines in 2016, and in 2018, it was conditionally recommended as part of the preferred first- and second-line regimens for adults and adolescents living with HIV (1, 2). The ongoing transition to dolutegravir in low- and middle-income countries (LMICs) represents a landmark shift in the public health approach to global HIV treatment. For the past 2 decades, a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen containing either nevirapine or efavirenz was the recommended first-line treatment and has been used for millions of people living with HIV (3, 4). The reach of dolutegravir-containing ART is anticipated to be extensive and it is projected to be the most commonly used regimen among people living with HIV in LMICs by 2025 (4). Robust evidence indicates that dolutegravir-containing ART is associated with improved viral suppression, less drug resistance, and fewer discontinuations compared with the previous preferred first-line regimen of efavirenz-containing ART (5).
Despite the promise of dolutegravir, its widespread use has not been without controversy. In May 2018, an interim analysis of the Tsepamo cohort in Botswana found a possible association between dolutegravir exposure at conception and infant neural tube defects (NTDs) (6). The WHO subsequently cautioned against dolutegravir use among females of reproductive age for whom consistent contraception could not be assured and emphasized the importance of ongoing surveillance (7). Many countries and organizations issued their own policies about dolutegravir use, largely restricting access for most females of reproductive age (8–12). This development especially affected the dolutegravir transition in sub-Saharan Africa where females of reproductive age are the population most affected by HIV (13) and more broadly in LMICs where there are limited options for antiretroviral drugs (4).
In July 2019, the WHO fully recommended dolutegravir-containing ART for all adults and adolescents living with HIV, including females of reproductive age regardless of contraception (14). This was informed by a weaker association of NTDs in expanded data through March 2019 from the Tsepamo cohort (15) and a more holistic understanding of the risks versus benefits. Modeling studies supported the use of dolutegravir because its benefits (for example, fewer deaths and HIV transmissions) outweighed even a potentially higher risk for NTDs (16, 17). Many countries, such as Kenya, which initially restricted dolutegravir use for females of reproductive age, revised their policies to recommend its use in accordance with the WHO recommendation (9, 18). Other countries that began implementing dolutegravir more recently have had a less restrictive trajectory of dolutegravir use (19–24).
Because of the known benefits of dolutegravir, a disparity in uptake for females of reproductive age, particularly a sustained one, could result in excess HIV-related morbidity and mortality. Therefore, we sought to describe dolutegravir uptake and disparities by sex and age group in LMICs in the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium.
Methods
Data Sources
The IeDEA is an international research consortium of HIV care sites that collects and harmonizes clinical data across 7 geographic regions (www.iedea.org). This analysis used data from the Asia-Pacific; Caribbean, Central and South America network for HIV epidemiology (CCASAnet); and Central, East, and Southern Africa regions. During clinical encounters at the sites, patient data are collected either on paper forms, which are later extracted into local databases, or directly into the local electronic medical record. Data are deidentified before transmission to a regional data management center. Site-level data are collected through surveys completed by local staff. Institutional review boards or research ethics committees at each site and regional data management center provided ethical oversight and approved the use of deidentified data for this analysis. Informed consent requirements were deferred to the local approving bodies.
Sites
We included sites in LMICs in the participating regions that had begun to prescribe dolutegravir. We excluded sites with a database closure date before January 2020. We further restricted the analysis to sites with 50 or more patients in care and 1% or more with documented dolutegravir use since the earliest date of dolutegravir use at the site.
Patients
We included patients who were 16 years or older at the time of enrollment into HIV care, had at least 1 visit on or after the date that their site began to use dolutegravir, and were newly initiating or already receiving ART. The age minimum of 16 years was chosen because globally this is the most common legal age to consent to medical treatment (25). On the basis of WHO guidelines, ART was defined as receiving a regimen containing an NNRTI, integrase strand transfer inhibitor, or protease inhibitor (1, 2, 14). We excluded persons who had missing data for sex, were unknown to be ART naive or experienced at the start of follow-up, or had incomplete information for an ART regimen (Appendix Figure).
Measures
Our main outcome was dolutegravir uptake, which we defined as newly initiating ART with a dolutegravir-containing regimen or switching to dolutegravir from another regimen. Start dates for medications were based on clinician documentation of a new prescription or pharmacy dispensing records, depending on the site. Our main exposures were sex and age group. Age group was based on age at start of follow-up and was categorized into 2 groups based on the reproductive age for females (that is, 15 to 49 years [7]): 16 to 49 years and 50 years or older. We also examined subgroups within each age category.
Other variables of interest were ART experience at the start of follow-up; year of ART initiation among ART-experienced patients; ART regimen base (that is, dolutegravir, efavirenz, nevirapine, protease inhibitor, other integrase strand transfer inhibitor or other NNRTI); pregnancy status, which was only available for this analysis from sites in Kenya, Tanzania, and Uganda and was defined as presenting pregnant at a visit; site urbanicity; site level of care; and country start of dolutegravir implementation, either before or after the safety signal in May 2018, based on each country’s earliest date of dolutegravir use in our cohort (Appendix Table 1).
Statistical Analysis
The observation period of the study was from January 2017 through March 2020. Follow-up for individual patients began on the date at which their site began to use dolutegravir or when they started ART, whichever occurred later. Follow-up ended on the date of dolutegravir uptake or, for those not initiating dolutegravir treatment, it ended on the date after the last recorded contact among those who were lost to follow-up (that is, no recorded contacts for ≥7 months immediately preceding the date of site database closure) or known to have left care, date of death among those known to have died, or date of site database closure among those who remained alive and in care.
We computed descriptive statistics for sample characteristics and ART regimen information, including dolutegravir use among ART-naive and ART-experienced patients. Among females aged 16 to 49 years, we computed the proportion who newly initiated ART on a visit with a documented pregnancy and ART regimens among this group. We also computed the proportion who were receiving dolutegravir before their earliest visit with a pregnancy and the proportion who started dolutegravir treatment on a visit with a documented pregnancy.
We used the Aalen–Johansen estimator (26) to compute cumulative incidence function estimates for dolutegravir uptake, considering any reason for dropout to be a competing event. We first computed and graphed cumulative incidence proportions at the end of each month during the observation period of the study, overall and stratified by sex and age group. We then computed cumulative incidence proportions with 95% CIs overall and by sex and age group at 3 time points: before the safety signal (until 18 May 2018), after the safety signal (until 22 July 2019), and after the WHO recommended dolutegravir for all (until 31 March 2020). We further stratified sex- and age-group specific estimates by ART experience, year of starting ART (among ART-experienced patients), and country start of dolutegravir implementation. Because more than half of our data were from Kenya, we did a sensitivity analysis excluding patients in Kenya to see how our results changed.
To gain a preliminary understanding of how disparities in dolutegravir uptake changed before and after WHO recommended dolutegravir for all in July 2019, we computed and graphed ratios of cumulative incidence proportions for the 2 periods (that is, until 22 July 2019 and until 31 March 2020) to compare females with males by age strata. At database closure, we computed descriptive statistics for latest ART regimen among all patients alive and engaged in care, including among patients who left the cohort after initiating dolutegravir treatment. All analyses were done using SAS, version 9.4 (SAS Institute).
Role of the Funding Source
The funder was not involved in the design of the study; the collection, analysis, and interpretation of the data; or the decision to approve publication of the finished manuscript.
Results
Sample Disposition and Characteristics
We included 134 672 persons at 87 facilities in 11 countries, from the earliest site use of dolutegravir in January 2017 to site database closure from January through March 2020 (Appendix Table 1). Overall, 138 198 patients were assessed for eligibility, and 3% were excluded (Appendix Figure). By the end of follow-up, 14% of patients had prematurely left the cohort because of death, loss to follow-up, or a known reason for leaving care. Median follow-up was 14 months (interquartile range, 7 to 23 months). Overall, 52% of patients were females aged 16 to 49 years, 25% were males aged 16 to 49 years, 13% were females aged 50 years or older, and 10% were males aged 50 years or older (Table 1). About half (52%) of patients accessed care at rural sites, 42% at sites with a primary level of care, 58% at sites in Kenya, and 76% were in countries that began implementing dolutegravir before the safety signal.
Table 1.
Sample Characteristics of Patients Receiving Care at Sites That Began Using Dolutegravir, Overall and Stratified by Sex and Age Group
| Characteristic | All Patients | Females Aged 16–49 y | Males Aged 16–49 y | Females Aged ≥50 y | Males Aged ≥50 y |
|---|---|---|---|---|---|
| Total, n (%) | 134 672 (100) | 69 578 (51.7) | 33 620 (25.0) | 18 073 (13.4) | 13 401 (10.0) |
| Mean age (SD), y | 41 (12) | 36 (8) | 38 (7) | 57 (6) | 58 (6) |
| Experience with ART at start of follow-up, n (%) | |||||
| Naive | 22 100 (16.4) | 11 818 (17.0) | 7507 (22.3) | 1417 (7.8) | 1358 (10.1) |
| Experienced | 112 572 (83.6) | 57 760 (83.0) | 26 113 (77.7) | 16 656 (92.2) | 12 043 (89.9) |
| Year of starting ART (among ART-experienced patients), n (%) | |||||
| 2010 or prior | 38 214 (34.0) | 17 649 (30.6) | 6398 (24.5) | 8117 (48.7) | 6050 (50.2) |
| 2011–2015 | 47 522 (42.2) | 25 365 (43.9) | 11 641 (44.6) | 6120 (36.7) | 4396 (36.5) |
| 2016 or later | 26 836 (23.8) | 14 746 (25.5) | 8074 (30.9) | 2419 (14.5) | 1597 (13.3) |
| Site urbanicity, n (%) * | |||||
| Rural | 69 264 (52.3) | 36 359 (53.1) | 16 629 (50.2) | 9631 (54.7) | 6645 (50.6) |
| Urban | 63 060 (47.7) | 32 056 (46.9) | 16 527 (49.9) | 7981 (45.3) | 6496 (49.4) |
| Site level of care, n (%) * | |||||
| Primary | 54 889 (41.5) | 28 175 (41.2) | 13 398 (40.4) | 7859 (44.6) | 5457 (41.5) |
| Secondary | 45 420 (34.3) | 24 032 (35.1) | 10 588 (31.9) | 6432 (36.5) | 4368 (33.2) |
| Tertiary | 32 015 (24.2) | 16 208 (23.7) | 9170 (27.7) | 3321 (18.9) | 3316 (25.2) |
| Country, n (%) | |||||
| Brazil | 1991 (1.5) | 337 (0.5) | 1394 (4.2) | 74 (0.4) | 186 (1.4) |
| Cambodia | 323 (0.2) | 114 (0.2) | 182 (0.5) | 7 (0.04) | 20 (0.2) |
| Democratic Republic of the Congo | 440 (0.3) | 288 (0.4) | 49 (0.2) | 61 (0.3) | 42 (0.3) |
| Haiti | 682 (0.5) | 331 (0.5) | 239 (0.7) | 56 (0.3) | 56 (0.4) |
| Kenya | 77 546 (57.6) | 40 382 (58.0) | 17 882 (53.2) | 11 110 (61.5) | 8172 (61.0) |
| Lesotho | 6305 (4.7) | 3053 (4.4) | 1262 (3.8) | 1242 (6.9) | 748 (5.6) |
| Mozambique | 7847 (5.8) | 4736 (6.8) | 2066 (6.2) | 652 (3.6) | 393 (2.9) |
| Rwanda | 9313 (6.9) | 4244 (6.1) | 2947 (8.8) | 1081 (6.0) | 1041 (7.8) |
| Tanzania | 2221 (1.7) | 1218 (1.8) | 662 (2.0) | 192 (1.1) | 149 (1.1) |
| Uganda | 13 324 (9.9) | 7474 (10.7) | 3819 (11.4) | 1012 (5.6) | 1019 (7.6) |
| Zimbabwe | 14 680 (10.9) | 7401 (10.6) | 3118 (9.3) | 2586 (14.3) | 1575 (11.8) |
| Time country started implementing dolutegravir regimen, n (%) | |||||
| Before the May 2018 safety signal† | 102 497 (76.1) | 52 551 (75.5) | 26 224 (78.0) | 13 284 (73.5) | 10 438 (77.9) |
| After the May 2018 safety signal‡ | 32 175 (23.9) | 17 027 (24.5) | 7396 (22.0) | 4789 (26.5) | 2963 (22.1) |
ART = antiretroviral therapy.
Missing data for 2348 patients.
Brazil, Cambodia, Kenya, Rwanda, and Uganda.
Democratic Republic of the Congo, Haiti, Lesotho, Mozambique, Tanzania, and Zimbabwe.
Dolutegravir Use by ART Experience and Among Pregnant Women
Overall, 22 100 (16%) patients newly initiated ART, and among these patients, 8160 (37%) started a dolutegravir-containing regimen (Table 2). Initiating ART with dolutegravir occurred among 20% of females aged 16 to 49 years, 57% of males aged 16 to 49 years, 55% of females aged 50 years or older, and 55% of males aged 50 years or older. Among the 13 940 patients who newly initiated ART with a non–dolutegravir-containing regimen, 3108 (22%) eventually switched to dolutegravir. Later switching to dolutegravir occurred among 12% of females aged 16 to 49 years, 40% of males aged 16 to 49 years, 51% of females aged 50 years or older, and 50% of males aged 50 years or older.
Table 2.
Antiretroviral Therapy Regimens and Dolutegravir Use, Overall and Stratified by Sex and Age Group
| Variable | All Patients | Females Aged 16–49 y | Males Aged 16–49 y | Females Aged ≥50 y | Males Aged ≥50 y |
|---|---|---|---|---|---|
| Regimen bases among patients newly initiating ART, n/N (%) | |||||
| Dolutegravir | 8160/22 100 (36.9) | 2377/11 818 (20.1) | 4262/7507 (56.8) | 773/1417 (54.6) | 748/1358 (55.1) |
| Efavirenz | 13 424/22 100 (60.7) | 9168/11 818 (77.6) | 3088/7507 (41.1) | 602/1417 (42.5) | 566/1358 (41.7) |
| Nevirapine | 278/22 100 (1.3) | 158/11 818 (1.3) | 71/7507 (1.0) | 26/1417 (1.8) | 23/1358 (1.7) |
| Protease inhibitor | 190/22 100 (0.9) | 101/11 818 (0.9) | 61/7507 (0.8) | 15/1417 (1.1) | 13/1358 (1.0) |
| Other | 48/22 100 (0.2) | 14/11 818 (0.1) | 25/7507 (0.3) | 1/1417 (0.1) | 8/1358 (0.6) |
| Initially ART-naive patients who later switched to dolutegravir, n/N (%) | 3108/13 940 (22.3) | 1161/9441 (12.3) | 1311/3245 (40.4) | 328/644 (50.9) | 308/610 (50.5) |
| ART-experienced patients who switched to dolutegravir, n/N (%) | 46 231/112 572 (41.1) | 15 311/57 760 (26.5) | 13 464/26 113 (51.6) | 9996/16 656 (60.0) | 7460/12 043 (61.9) |
| All patients who switched to dolutegravir from another regimen, n/N (%) | 49 339/126 512 (39.0) | 16 472/67 201 (24.5) | 14 775/29 358 (50.3) | 10 324/17 300 (59.7) | 7768/12 653 (61.4) |
| Previous regimen bases among all patients who switched to dolutegravir, n/N (%) | |||||
| Efavirenz | 29 748/49 339 (60.3) | 9649/16 472 (58.6) | 10 210/14 775 (69.1) | 5640/10 324 (54.6) | 4249/7768 (54.7) |
| Nevirapine | 18 482/49 339 (37.5) | 6352/16 472 (38.6) | 4237/14 775 (28.7) | 4533/10 324 (43.9) | 3360/7768 (43.3) |
| Protease inhibitor | 1010/49 339 (2.1) | 442/16 472 (2.7) | 283/14 775 (1.9) | 144/10 324 (1.4) | 141/7768 (1.8) |
| Other | 99/49 339 (0.2) | 29/16 472 (0.2) | 45/14 775 (0.3) | 7/10 324 (0.1) | 18/7768 (0.2) |
| Latest regimen bases among all patients alive and engaged in care at database closure, n/N (%) | |||||
| Dolutegravir | 50 308/112 426 (44.8) | 15 956/57 877 (27.6) | 16 718/26 919 (62.1) | 10 019/16 108 (62.2) | 7615/11 522 (66.1) |
| Efavirenz | 48 680/112 426 (43.3) | 34 786/57 877 (60.1) | 7370/26 919 (27.4) | 4103/16 108 (25.5) | 2421/11 522 (21.0) |
| Nevirapine | 3432/112 426 (3.1) | 1894/57 877 (3.3) | 544/26 919 (2.0) | 625/16 108 (3.9) | 369/11 522 (3.2) |
| Protease inhibitor | 9971/112 426 (8.9) | 5225/57 877 (9.0) | 2275/26 919 (8.5) | 1357/16 108 (8.4) | 1114/11 522 (9.7) |
| Other | 35/112 426 (0.03) | 16/57 877 (0.03) | 12/26 919 (0.04) | 4/16 108 (0.02) | 3/11 522 (0.03) |
ART = antiretroviral therapy.
Overall, 112 572 (84%) patients were already receiving ART when their site began to use dolutegravir, and 76% of these patients started ART before 2016 (Table 1). Among ART-experienced patients, 46 231 (41%) switched to a dolutegravir-containing regimen. Switching to dolutegravir among the ART-experienced patients occurred among 27% of females aged 16 to 49 years, 52% of males aged 16 to 49 years, 60% of females aged 50 years or older, and 62% of males aged 50 years or older (Table 2). When considering all patients who switched to dolutegravir regardless of ART experience at the start of follow-up (n = 49 339), 60% did so from an efavirenz-containing regimen and 38% from a nevirapine-containing regimen.
Among 49 074 females aged 16 to 49 years in Kenya, Tanzania, and Uganda, 4873 (10%) were pregnant at some time during follow-up, among whom 619 (13%) newly initiated ART on a visit with a documented pregnancy (data not shown in the tables). Of those initiating ART, 568 (92%) started an efavirenz-containing regimen, 45 (7%) started a dolutegravir-containing regimen, and 6 (1%) started another regimen. Among the 4254 patients already on ART, 268 (6%) were already receiving dolutegravir before their first visit with a pregnancy. Overall, 143/4873 (3%) started a dolutegravir-containing regimen on a visit with a pregnancy.
Cumulative Incidence of Dolutegravir Uptake and Differences by Sex and Age Group
By the time of the safety signal, 3.2% (95% CI, 3.1% to 3.3%) of patients had initiated dolutegravir treatment (Table 3), and differences by sex and age group emerged thereafter (Figure 1). By the time the WHO recommended dolutegravir for all, the cumulative incidence of dolutegravir uptake was 16.2% (CI, 15.9% to 16.5%) among females aged 16 to 49 years and 40.4% (CI, 39.8% to 40.9%) among males aged 16 to 49 years. By the end of follow-up, cumulative incidence was 29.4% (CI, 29.0% to 29.7%) among females aged 16 to 49 years and 57.7% (CI, 57.2% to 58.3%) among males aged 16 to 49 years (Table 3). Disparities in overall cumulative incidence were greatest when comparing females aged 16 to 29 years (14.2% [CI, 13.6% to 14.8%]) with males aged 16 to 29 years (54.1% [CI, 52.7% to 55.6%]) and females aged 30 to 39 years (21.3% [CI, 20.8% to 21.9%]) with males aged 30 to 39 years (56.8% [CI, 55.9% to 57.6%]). Cumulative incidence was similar among females aged 50 years or older and males aged 50 years or older.
Table 3.
Cumulative Incidence of Dolutegravir Uptake, by Sex and Age Group
| Variable | Summary of Outcomes | Dolutegravir Uptake, Cumulative Incidence Proportion (95% CI) | |||||
|---|---|---|---|---|---|---|---|
| Total Patients, n | Patients Initiating Dolutegravir, n | Patients Who Dropped Out, n | Patients Censored, n | Before the Safety Signal (Until 18 May 2018) | After the Safety Signal (Until 22 July 2019) | After the WHO Recommended Dolutegravir for All (Until 31 March 2020) | |
| Entire sample | 134 672 | 57 499 | 18 736 | 58 437 | 3.2 (3.1–3.3) | 29.6 (29.3–29.8) | 44.6 (44.3–44.9) |
| Sex and age group | |||||||
| Females aged 16–49 y | 69 578 | 18 849 | 10 695 | 40 034 | 2.8 (2.7–3.0) | 16.2 (15.9–16.5) | 29.4 (29.0–29.7) |
| Males aged 16–49 y | 33 620 | 19 037 | 5144 | 9439 | 2.9 (2.7–3.0) | 40.4 (39.8–40.9) | 57.7 (57.2–58.3) |
| Females aged ≥50 y | 18 073 | 11 097 | 1510 | 5466 | 4.3 (4.0–4.6) | 46.4 (45.6–47.1) | 62.6 (61.8–63.3) |
| Males aged ≥50 y | 13 401 | 8516 | 1387 | 3498 | 4.3 (3.9–4.6) | 49.4 (48.5–50.2) | 64.7 (63.8–65.5) |
| Sex and age subgroup | |||||||
| Females aged 16–29 y | 16 056 | 2002 | 3727 | 10 327 | 0.9 (0.8–1.1) | 3.3 (3.0–3.6) | 14.2 (13.6–14.8) |
| Males aged 16–29 y | 4881 | 2583 | 899 | 1399 | 4.2 (3.7–4.8) | 33.8 (32.5–35.1) | 54.1 (52.7–55.6) |
| Females aged 30–39 y | 28 110 | 5315 | 4452 | 18 343 | 2.4 (2.3–2.6) | 9.1 (8.8–9.5) | 21.3 (20.8–21.9) |
| Males aged 30–39 y | 13 142 | 7325 | 2066 | 3751 | 2.1 (1.9–2.4) | 39.2 (38.3–40.0) | 56.8 (55.9–57.6) |
| Females aged 40–49 y | 25 412 | 11 532 | 2516 | 11 364 | 4.5 (4.2–4.8) | 32.1 (31.5–32.7) | 47.6 (47.0–48.3) |
| Males aged 40–49 y | 15 597 | 9129 | 2179 | 4289 | 3.1 (2.8–3.3) | 43.4 (42.6–44.2) | 59.7 (58.9–60.5) |
| Females aged 50–59 y | 12 991 | 8165 | 1053 | 3773 | 4.5 (4.1–4.9) | 48.7 (47.9–49.6) | 64.0 (63.1–64.8) |
| Males aged 50–59 y | 9216 | 5912 | 978 | 2326 | 4.3 (3.9–4.8) | 50.8 (49.8–51.8) | 65.3 (64.2–66.3) |
| Females aged ≥60 y | 5082 | 2932 | 457 | 1693 | 4.0 (3.4–4.5) | 40.4 (39.0–41.7) | 58.8 (57.4–60.2) |
| Males aged ≥60 y | 4185 | 2604 | 409 | 1172 | 4.1 (3.5–4.7) | 46.2 (44.7–47.7) | 63.3 (61.8–64.8) |
WHO = World Health Organization.
Figure 1. Cumulative incidence of dolutegravir uptake, overall and by sex and age group, January 2017 through March 2020.
The graph shows the cumulative incidence of dolutegravir uptake at the end of the calendar month in the observation period. Each tick on the x-axis corresponds to dates of the events described in the graph. NTD = neural tube defect; WHO = World Health Organization.
Disparities in uptake among females aged 16 to 49 years compared with males aged 16 to 49 years were present when stratifying by ART experience and year of starting ART (Table 4). In countries that began implementing dolutegravir treatment before the safety signal, the cumulative incidence of dolutegravir uptake among females and males aged 16 to 49 years was 31.1% (CI, 30.6% to 31.6%) and 65.8% (CI, 65.2% to 66.4%), respectively. In countries that began implementing dolutegravir treatment after the safety signal, the cumulative incidence of dolutegravir uptake among females and males aged 16 to 49 years was 20.3% (CI, 19.7% to 20.9%) and 27.9% (CI, 26.9% to 28.9%), respectively. In our sensitivity analysis excluding patients in Kenya, cumulative incidence proportions were lower in magnitude, but there were similar disparities affecting females aged 16 to 49 years (Appendix Table 2).
Table 4.
Age- and Sex-Group Specific Cumulative Incidence of Dolutegravir Uptake, by Antiretroviral Therapy Experience, Year of Starting Antiretroviral Therapy, and Country Timing of Dolutegravir Implementation
| Variable | Summary of Outcomes | Dolutegravir Uptake, Cumulative Incidence Proportion (95% CI) | |||||
|---|---|---|---|---|---|---|---|
| Total Patients, n | Patients Initiating Dolutegravir, n | Patients Who Dropped Out, n | Patients Censored, n | Before the Safety Signal (Until 18 May 2018) | After the Safety Signal (Until 22 July 2019) | After the WHO Recommended Dolutegravir for All (Until 31 March 2020) | |
| Experience with ART at start of follow-up | |||||||
| Naive | |||||||
| Females aged 16–49 y | 11 818 | 3538 | 2865 | 5415 | 1.6 (1.4–1.9) | 11.7 (11.1–12.2) | 36.3 (35.1–37.5) |
| Males aged 16–49 y | 7507 | 5573 | 1157 | 777 | 4.1 (3.6–4.5) | 43.6 (42.5–44.7) | 75.7 (74.7–76.7) |
| Females aged ≥50 y | 1417 | 1101 | 174 | 142 | 1.8 (1.2–2.6) | 46.4 (43.8–48.9) | 78.6 (76.3–80.7) |
| Males aged ≥50 y | 1358 | 1056 | 193 | 109 | 3.0 (2.1–4.0) | 49.7 (47.0–52.3) | 78.7 (76.4–80.8) |
| Experienced | |||||||
| Females aged 16–49 y | 57 760 | 15 311 | 7830 | 34 619 | 3.1 (3.0–3.2) | 17.1 (16.8–17.4) | 28.4 (28.0–28.8) |
| Males aged 16–49 y | 26 113 | 13 464 | 3987 | 8662 | 2.5 (2.3–2.7) | 39.4 (38.8–40.0) | 52.5 (51.9–53.1) |
| Females aged ≥50 y | 16 656 | 9996 | 1336 | 5324 | 4.6 (4.2–4.9) | 46.4 (45.6–47.1) | 61.2 (60.4–62.0) |
| Males aged ≥50 y | 12 043 | 7460 | 1194 | 3389 | 4.4 (4.0–4.8) | 49.3 (48.4–50.2) | 63.1 (62.2–64.0) |
| Year of starting ART (among ART-experienced patients) | |||||||
| 2010 or prior | |||||||
| Females aged 16–49 y | 17 649 | 7044 | 1900 | 8705 | 5.6 (5.2–5.9) | 31.3 (30.6–32.0) | 43.3 (42.4–44.2) |
| Males aged 16–49 y | 6398 | 3882 | 866 | 1650 | 3.9 (3.4–4.4) | 51.5 (50.3–52.7) | 62.3 (61.0–63.6) |
| Females aged ≥50 y | 8117 | 5261 | 636 | 2220 | 5.7 (5.2–6.2) | 53.3 (52.2–54.4) | 66.5 (65.4–67.6) |
| Males aged ≥50 y | 6050 | 4036 | 590 | 1424 | 5.1 (4.5–5.6) | 56.6 (55.4–57.9) | 68.2 (66.9–69.4) |
| 2011–2015 | |||||||
| Females aged 16–49 y | 25 365 | 6038 | 3282 | 16 045 | 2.8 (2.6–3.0) | 13.7 (13.3–14.1) | 26.1 (25.5–26.7) |
| Males aged 16–49 y | 11 641 | 6365 | 1668 | 3608 | 2.8 (2.5–3.1) | 41.2 (40.3–42.1) | 56.0 (55.1–57.0) |
| Females aged ≥50 y | 6120 | 3704 | 452 | 1964 | 4.4 (3.9–4.9) | 43.9 (42.7–45.1) | 61.7 (60.4–62.9) |
| Males aged ≥50 y | 4396 | 2659 | 408 | 1329 | 4.3 (3.8–5.0) | 45.5 (44.0–47.0) | 61.6 (60.1–63.0) |
| 2016 or later | |||||||
| Females aged 16–49 y | 14 746 | 2229 | 2648 | 9869 | 0.7 (0.5–0.8) | 6.0 (5.6–6.4) | 16.0 (15.4–16.7) |
| Males aged 16–49 y | 8074 | 3217 | 1453 | 3404 | 1.0 (0.8–1.3) | 27.3 (26.3–28.2) | 40.3 (39.2–41.4) |
| Females aged ≥50 y | 2419 | 1031 | 248 | 1140 | 1.2 (0.8–1.7) | 29.2 (27.4–31.1) | 43.0 (41.0–45.0) |
| Males aged ≥50 y | 1597 | 765 | 196 | 636 | 2.0 (1.4–2.8) | 32.3 (30.0–34.6) | 48.3 (45.8–50.8) |
| Time country started implementing dolutegravir regimen | |||||||
| Before the May 2018 safety signal* | |||||||
| Females aged 16–49 y | 52 551 | 15 394 | 9767 | 27 390 | 3.8 (3.6–3.9) | 20.9 (20.5–21.2) | 31.1 (30.6–31.6) |
| Males aged 16–49 y | 26 224 | 16 976 | 4735 | 4513 | 3.7 (3.4–3.9) | 51.0 (50.4–51.6) | 65.8 (65.2–66.4) |
| Females aged ≥50 y | 13 284 | 9680 | 1361 | 2243 | 5.9 (5.5–6.3) | 62.6 (61.8–63.4) | 73.4 (72.6–74.2) |
| Males aged ≥50 y | 10 438 | 7586 | 1278 | 1574 | 5.5 (5.0–5.9) | 62.9 (61.9–63.8) | 73.3 (72.4–74.2) |
| After the May 2018 safety signal† | |||||||
| Females aged 16–49 y | 17 027 | 3455 | 928 | 12 644 | NA | 1.7 (1.5–1.9) | 20.3 (19.7–20.9) |
| Males aged 16–49 y | 7396 | 2061 | 409 | 4926 | NA | 2.6 (2.3–3.0) | 27.9 (26.9–28.9) |
| Females aged ≥50 y | 4789 | 1417 | 149 | 3223 | NA | 1.3 (1.0–1.7) | 29.6 (28.3–30.9) |
| Males aged ≥50 y | 2963 | 930 | 109 | 1924 | NA | 1.9 (1.5–2.4) | 31.4 (29.8–33.1) |
ART = antiretroviral therapy; NA = not applicable.
Brazil, Cambodia, Kenya, Rwanda, and Uganda.
Democratic Republic of the Congo, Haiti, Lesotho, Mozambique, Tanzania, and Zimbabwe.
The disparity in dolutegravir uptake affecting females aged 16 to 49 years began to attenuate after the July 2019 WHO recommendation of dolutegravir for all (Figure 2). The ratio of cumulative incidence proportions (females aged 16 to 49 years to males aged 16 to 49 years) before the recommendation was 0.40, and this increased to 0.51 after the recommendation. The largest changes were among ART-naive patients (0.27 before, 0.48 after) and ART-experienced patients starting ART in 2016 or later (0.22 before, 0.40 after). Ratios for females aged 50 years or older and males aged 50 years or older were close to 1 before and after the recommendation, which is consistent with a lack of disparity.
Figure 2. Ratios of cumulative incidence proportions before and after WHO recommended dolutegravir for all, overall and stratified by other variables.
The graphs show ratios of cumulative incidence proportions from Table 3 comparing females with males in age strata. Year of starting ART is among ART-experienced patients. ART = antiretroviral therapy; WHO = World Health Organization. Left (A). Females aged 16–49 y to males aged 16–49 y. Right (B). Females aged ≥50 y to males aged ≥50 y.
Antiretroviral Therapy Regimens at Database Closure
From January through March 2020, 45% of patients alive and engaged in care were receiving dolutegravir, 43% were receiving efavirenz, and 9% were receiving a protease inhibitor (Table 2). Efavirenz-containing regimens were most common among females aged 16 to 49 years (60%), whereas dolutegravir-containing regimens were most common for males aged 16 to 49 years (62%), females aged 50 years or older (62%), and males aged 50 years or older (66%).
Discussion
This study describes the initial rollout of dolutegravir in 11 LMICs in the IeDEA consortium through the trajectory of a safety signal. Dolutegravir uptake was lowest for females of reproductive age, among whom use of efavirenz prevailed. This disparity was anticipated because of country-level restrictions on access; however, our study highlights the extent and initial persistence of disparities despite recommendations to expand access to dolutegravir. If sustained, this disparity could have implications for HIV treatment outcomes because of the superior efficacy and tolerability of dolutegravir (5) and its anticipated population health benefits (16, 17, 27, 28).
The implications of dolutegravir use at scale are not known, and future research should examine the effect of disparities in dolutegravir uptake on clinical outcomes, considering the real-world context and potential risks. Although the superior efficacy of dolutegravir can be inferred from the breadth of the evidence, some clinical trials in resource-constrained settings have reported similar long-term viral suppression compared with efavirenz (29, 30). Drug resistance mutations in reverse transcriptase are widespread (31) and may have a role in treatment failure associated with first-line dolutegravir-containing ART (32). Dolutegravir has also been associated with greater excess weight gain than efavirenz, especially among women (29, 30, 33), the consequences of which are not yet fully understood when dolutegravir is used at scale.
Although dolutegravir was recommended by the WHO for all adults and adolescents living with HIV in July 2019 (14), additional evidence has emerged since the completion of follow-up in our study in early 2020 that further supports that all women living with HIV should have unrestricted access to dolutegravir. Data from the Tsepamo cohort through April 2020 indicated no statistically significant association between dolutegravir exposure at conception and NTDs (34), and this finding has been corroborated by studies in other settings (35–38). Randomized trials of dolutegravir treatment started during pregnancy have demonstrated its superior virologic efficacy compared with efavirenz, showing the potential to reduce vertical transmission (39, 40). In our study, few patients initiating ART during pregnancy started dolutegravir treatment. These women were likely initiating ART after neural tube closure, so 1 possible explanation for this low use of dolutegravir could be that health care providers were not fully aware of the time window of risk for NTDs. With the recent data, however, we would anticipate that dolutegravir-containing ART becomes a standard of care for pregnant women living with HIV.
The differential effect of sex and age group on dolutegravir uptake by country start of implementation suggests that initial policies and communications about the safety of dolutegravir may have an enduring effect on uptake among females of reproductive age. Countries that began implementing dolutegravir before the safety signal had more restrictive initial policies about the provision of dolutegravir to females of reproductive age, either largely or entirely excluding them (8–12). In contrast, countries with a later rollout after the safety signal had more inclusive, mostly choice-based policies (19–24), which may be a reflection of implementing dolutegravir at a time when more global experience had been gained and more data were available about the risks versus benefits.
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 actively educate women, health care providers, and other stakeholders about the current evidence. In addition, education for providers about shared decision making and integration of contraception and pregnancy planning into HIV care is needed to ensure that patients can make informed decisions about their ART (41). Women living with HIV must be engaged to understand their beliefs, opinions, and needs about the policies and practices that govern the provision of dolutegravir or any other antiretroviral drug to them. Data in the context of the dolutegravir rollout have highlighted how women have felt the acute need for their voices to be heard before policy decisions are made at national and international levels (42, 43).
There are some parallels between the situation of dolutegravir and that of efavirenz more than a decade earlier. After case reports of NTDs among infants exposed to efavirenz at conception (44, 45), the WHO in guidelines in 2006 recommended against the use of efavirenz in females of reproductive age without contraception (46). It was not until several years later that sufficient evidence could be accumulated to show that the risk for fetal harm was limited and the benefits of efavirenz outweighed any potential harms (47). On the basis of the updated data, efavirenz was recommended for all adults and adolescents in the 2013 WHO guidelines (48). During the many years it took to resolve safety concerns, women were undoubtedly denied access to efavirenz-containing regimens, which were more effective and safer than the alternative, nevirapine-containing first-line regimen at the time. Although the initial safety signal with dolutegravir was resolved faster than that of efavirenz, the emergence of safety signals with both drugs highlight the need for a rapid and comprehensive response to simultaneously protect and promote public health (49). A critical component of such a response is robust pharmacovigilance systems, which remain limited in LMICs (50).
Our results should be interpreted in the context of some limitations. Sites and patients within the IeDEA consortium may not be fully representative of a country or region. However, patients included in this analysis received care from public HIV programs that follow local guidelines, so our findings are likely reflective of these programs in general. The data used in this study were originally collected for clinical purposes rather than research and are thus subject to limitations related to data entry error and missingness. However, data in IeDEA conform to a rigorous data exchange standard (51), and for this analysis, few patients were excluded because of missing or erroneous data. We examined females of reproductive age without information on their fertility potential or intent. Although this precluded examining the effect of contraceptive use on dolutegravir uptake, data from an HIV treatment program in Kenya that contributed data to this study found that noncondom contraceptive use was uncommon among women initiating dolutegravir treatment (43). Follow-up of our cohort was limited through early 2020 and therefore, changes in guidance to expand access to dolutegravir may not be fully reflected at the patient level. Even after changes in clinical guidance, additional time must be anticipated for increased procurement and distribution (52). Because antiretroviral drugs are ordered in large quantities and are not wasted, increasing dolutegravir uptake among women of reproductive age may be partly dependent on supply chain factors, such as existing stock of efavirenz. Germane to the discussion of timing of follow-up is that our study largely predates the COVID-19 pandemic, which has negatively affected the delivery of HIV care (53). We can only hypothesize that the COVID-19 public health crisis has further negatively affected the rollout of dolutegravir and expansion of its access to all adults and adolescents.
In conclusion, our study found that profound disparities in the uptake of dolutegravir-containing ART affecting females of reproductive age emerged after the initial safety signal and persisted through early 2020, despite recommendations to expand its use to all adults and adolescents living with HIV. Policymakers need to carefully consider the risks versus benefits of restricting access to an antiretroviral drug, even in the context of a possible safety issue, and should include the population affected in formulating relevant policies and recommendations—in this case women living with HIV. Further monitoring of the global dolutegravir rollout is needed as it relates to use among females of reproductive age. Equitable access to the most effective ART through alignment of clinical practice with evidence is an essential component to ending the HIV epidemic as a public health threat.
Acknowledgment
We thank Dr. Annette Sohn (TREAT Asia/amfAR) for her valuable insights and commentary on this work.
Financial Support:
Research reported in this publication was supported by the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (NIAID), the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA), the National Heart, Lung, and Blood Institute (NHLBI), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the Fogarty International Center (FIC), the National Library of Medicine (NLM), and the Office of the Director (OD) under Award Numbers U01AI069907 (Asia-Pacific), U01AI069923 (CCASAnet), U01AI096299 (Central Africa), U01AI069911 (East Africa), and U01AI069924 (Southern Africa). Informatics resources are supported by the Harmonist project, R24AI124872. Dr. Rena C. Patel’s effort was supported by NIAID (K23AI120855). Dr. John M. Humphrey’s effort was supported by NICHD (K23HD105495).
Appendix
Appendix Table 1.
Number of Sites, Dates of Follow-up, and Initial Policies About Dolutegravir Use for Females of Reproductive Age, by Country
| Country | Sites, n | Earliest Date of Dolutegravir Use in Our Sample | Database Closure Date | Initial Policy About Dolutegravir Use for Females of Reproductive Age After Safety Signal* |
|---|---|---|---|---|
| Start of country dolutegravir implementation before the May 2018 safety signal | ||||
| Brazil | 1 | January 2017† | January 2020 | Women who intend to become pregnant or who are pregnant should not receive dolutegravir. Women of reproductive age must use a contraceptive method preferably not dependent on adherence, e.g., implant or intrauterine device, to access dolutegravir (8). |
| Kenya | 23 | July 2017 | January 2020–February 2020 | Dolutegravir is not recommended for women of childbearing age (15–49 y) and those already receiving it should transition to efavirenz. Pregnant and breastfeeding women who are currently receiving dolutegravir should continue their current regimen until complete cessation of breastfeeding (9). |
| Cambodia | 1 | January 2018 | March 2020 | Adolescent girls and women of childbearing potential who do not currently want to become pregnant can receive dolutegravir together with consistent and reliable contraception. An efavirenz-based regimen is recommended for women desiring pregnancy or women with childbearing potential who do not wish to take contraception (10). |
| Rwanda | 10 | February 2018 | March 2020 | Dolutegravir is contraindicated for all females <50 y (11). |
| Uganda | 1 | February 2018 | March 2020 | Women of reproductive age (15–49 y) are only eligible for dolutegravir if they have long-term contraception (i.e., tubal ligation, implant, intrauterine device). Dolutegravir is recommended for pregnant women starting ART (12). |
| Start of country dolutegravir implementation after the May 2018 safety signal | ||||
| Haiti | 1 | October 2018 | March 2020 | The transition to dolutegravir is inclusive of all women. Programme National de Lutte contre le Sida issued a memo in April 2019 stating that women of reproductive age may choose dolutegravir even in the absence of contraception after counseling on risks and benefits and with informed consent (19). |
| Zimbabwe | 33 | February 2019 | March 2020 | Adolescent girls and women of childbearing potential should be given adequate information to make informed choices about their treatment options. A dolutegravir-containing regimen is recommended if the person has effective contraception (intrauterine device, intrauterine system, implant, injection); otherwise, efavirenz-containing ART is recommended. Women who are pregnant and receiving ART should switch to dolutegravir after their first trimester and continue it while breastfeeding with provision of effective contraception (20). |
| Democratic Republic of the Congo | 1 | February 2019 | March 2020 | The transition to dolutegravir will include women of childbearing potential (21). |
| Mozambique | 8 | May 2019 | March 2020 | Dolutegravir recommended for all adults living with HIV. Efavirenz should be offered to women of reproductive potential age who are planning a pregnancy at the time of starting ART. Women of reproductive age should be offered long-term contraceptive methods (e.g., implant, injection, intrauterine device) (22). Note, earlier in 2019, dolutegravir was only recommended for specific populations (e.g., tuberculosis coinfection) as part of “phase I” of the rollout. |
| Tanzania | 1 | June 2019 | March 2020 | Dolutegravir recommended for all adults and adolescents with HIV, but efavirenz is available for women who choose not to use dolutegravir. A women-centered approach is adopted and women of childbearing potential, including those who are using long-term effective contraception, will be given adequate information to enable them to make informed decision and informed choice consent to using dolutegravir (23). |
| Lesotho | 7 | June 2019 | March 2020 | All women and adolescent girls of childbearing potential should be counseled on the risks and benefits of dolutegravir versus efavirenz and allowed to decide which regimen best suits her needs. Women who do not wish to become pregnant should be offered and encouraged to use consistent and reliable contraception (24). |
ART = antiretroviral therapy.
Earliest policies after the safety signal (May 2018) that pertained to dolutegravir use among females of reproductive age were identified. The terminology used reflects that of the source.
Twenty patients started a dolutegravir-containing regimen in 2016; however, the earliest use date was revised to January 2017 to reflect when dolutegravir was initially recommended as the first-line regimen in national guidelines.
Appendix Table 2.
Sensitivity Analysis Excluding Patients in Kenya: Cumulative Incidence of Dolutegravir Uptake by Sex and Age Group, Overall and by Antiretroviral Therapy Experience, Year of Starting Antiretroviral Therapy, and Country Timing of Dolutegravir Implementation
| Variable | Summary of Outcomes | Dolutegravir Uptake, Cumulative Incidence Proportion (95% CI) | |||||
|---|---|---|---|---|---|---|---|
| Total Patients, n | Patients Initiating Dolutegravir, n | Patients Who Dropped Out, n | Patients Censored, n | Before the Safety Signal (Until 18 May 2018) | After the Safety Signal (Until 22 July 2019) | After the WHO Recommended Dolutegravir for All (Until 31 March 2020) | |
| Entire sample | 57 126 | 16 751 | 6310 | 34 065 | 0.7 (0.6–0.7) | 10.8 (10.5–11.0) | 30.1 (29.7–30.5) |
| Sex and age group | |||||||
| Females aged 16–49 y | 29 196 | 5545 | 3110 | 20 541 | 0.2 (0.1–0.2) | 3.8 (3.6–4.0) | 19.8 (19.3–20.3) |
| Males aged 16–49 y | 15 738 | 6408 | 2188 | 7142 | 1.8 (1.6–2.0) | 20.2 (19.6–20.8) | 41.6 (40.1–42.3) |
| Females aged ≥50 y | 6963 | 2584 | 482 | 3897 | 0.2 (0.1–0.3) | 12.7 (12.0–13.5) | 37.5 (36.4–38.7) |
| Males aged ≥50 y | 5229 | 2214 | 530 | 2485 | 0.8 (0.6–1.1) | 18.7 (17.7–19.8) | 42.9 (41.6–44.3) |
| Experience with ART at start of follow-up | |||||||
| Naive | |||||||
| Females aged 16–49 y | 3537 | 1317 | 487 | 1733 | 0.7 (0.5–1.0) | 9.2 (8.3–10.2) | 39.4 (37.7–41.1) |
| Males aged 16–49 y | 2655 | 1877 | 235 | 543 | 7.8 (6.9–8.9) | 33.8 (32.0–35.6) | 71.9 (70.1–73.6) |
| Females aged ≥50 y | 312 | 201 | 12 | 99 | 1.3 (0.4–3.1) | 23.1 (18.6–27.9) | 65.1 (59.4–70.2) |
| Males aged ≥50 y | 337 | 231 | 31 | 75 | 4.8 (2.8–7.4) | 33.8 (28.8–38.9) | 69.6 (64.2–74.3) |
| Experienced | |||||||
| Females aged 16–49 y | 25 659 | 4228 | 2623 | 18 808 | 0.1 (0.05–0.1) | 3.0 (2.8–3.2) | 17.2 (16.7–17.6) |
| Males aged 16–49 y | 13 083 | 4531 | 1953 | 6599 | 0.6 (0.4–0.7) | 17.4 (16.8–18.1) | 35.3 (34.5–36.2) |
| Females aged ≥50 y | 6651 | 2383 | 470 | 3798 | 0.1 (0.06–0.2) | 12.3 (11.5–13.1) | 36.2 (35.1–37.4) |
| Males aged ≥50 y | 4892 | 1983 | 499 | 2410 | 0.5 (0.3–0.7) | 17.7 (16.7–18.8) | 41.1 (39.7–42.5) |
| Year of starting ART (among ART-experienced patients) | |||||||
| 2010 or prior | |||||||
| Females aged 16–49 y | 4414 | 1181 | 530 | 2703 | 0.1 (0.04–0.3) | 7.6 (6.8–8.4) | 27.8 (26.4–29.2) |
| Males aged 16–49 y | 2127 | 877 | 454 | 796 | 0.5 (0.2–0.8) | 22.8 (21.0–24.6) | 42.0 (39.9–44.1) |
| Females aged ≥50 y | 2643 | 1131 | 243 | 1269 | 0.1 (0.03–0.3) | 17.7 (16.3–19.2) | 43.3 (41.4–45.2) |
| Males aged ≥50 y | 1959 | 915 | 264 | 780 | 0.6 (0.3–1.0) | 24.9 (23.0–26.9) | 47.4 (45.1–49.6) |
| 2011–2015 | |||||||
| Females aged 16–49 y | 12 263 | 2001 | 1104 | 9158 | 0.1 (0.1–0.2) | 2.8 (2.5–3.1) | 17.4 (16.7–18.1) |
| Males aged 16–49 y | 5910 | 2322 | 825 | 2763 | 0.8 (0.6–1.0) | 20.9 (19.8–21.9) | 40.6 (39.3–41.9) |
| Females aged ≥50 y | 2622 | 968 | 141 | 1513 | 0.2 (0.1–0.4) | 10.8 (9.7–12.1) | 37.5 (35.6–39.3) |
| Males aged ≥50 y | 2000 | 800 | 150 | 1050 | 0.5 (0.3–0.9) | 14.8 (13.3–16.4) | 40.7 (38.5–42.8) |
| 2016 or later | |||||||
| Females aged 16–49 y | 8982 | 1046 | 989 | 6947 | 0.02 (0.01–0.1) | 1.1 (0.9–1.3) | 11.9 (11.2–12.6) |
| Males aged 16–49 y | 5046 | 1332 | 674 | 3040 | 0.3 (0.2–0.5) | 11.1 (10.3–12.0) | 26.7 (25.5–27.9) |
| Females aged ≥50 y | 1386 | 284 | 86 | 1016 | 0.1 (0.1–0.4) | 4.6 (3.5–5.7) | 20.6 (18.5–22.8) |
| Males aged ≥50 y | 933 | 268 | 85 | 580 | 0.4 (0.1–1.1) | 8.8 (7.1–10.7) | 29.0 (26.1–31.9) |
| Time country started implementing dolutegravir regimen | |||||||
| Before the May 2018 safety signal* | |||||||
| Females aged 16–49 y | 12 169 | 2090 | 2182 | 7897 | 0.4 (0.3–0.5) | 6.7 (6.3–7.2) | 18.1 (17.4–18.9) |
| Males aged 16–49 y | 8342 | 4347 | 1779 | 2216 | 3.4 (3.0–3.8) | 35.8 (34.7–36.8) | 53.2 (52.0–54.3) |
| Females aged ≥50 y | 2174 | 1167 | 333 | 674 | 0.6 (0.3–0.9) | 37.9 (35.9–39.9) | 53.8 (51.7–55.9) |
| Males aged ≥50 y | 2266 | 1284 | 421 | 561 | 1.8 (1.3–2.4) | 40.8 (38.8–42.8) | 57.1 (55.0–59.1) |
| After the May 2018 safety signal† | |||||||
| Females aged 16–49 y | 17 027 | 3455 | 928 | 12 644 | NA | 1.7 (1.5–1.9) | 20.3 (19.7–20.9) |
| Males aged 16–49 y | 7396 | 2061 | 409 | 4926 | NA | 2.6 (2.3–3.0) | 27.9 (26.9–28.9) |
| Females aged ≥50 y | 4789 | 1417 | 149 | 3223 | NA | 1.3 (1.0–1.7) | 29.6 (28.3–30.9) |
| Males aged ≥50 y | 2963 | 930 | 109 | 1924 | NA | 1.9 (1.5–2.4) | 31.4 (29.8–33.1) |
ART = antiretroviral therapy.
Brazil, Cambodia, Rwanda, and Uganda.
Democratic Republic of the Congo, Haiti, Lesotho, Mozambique, Tanzania, and Zimbabwe. Because this category does not include Kenya, results are the same as the main analysis.
Appendix Figure. Patient assessment for eligibility, reasons for exclusion, sample included at the start of follow-up, and drop out.
*Reasons for exclusion are not mutually exclusive. ART = antiretroviral therapy.
Footnotes
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Contributor Information
Matthew L. Romo, Department of Epidemiology and Biostatistics, CUNY Graduate School of Public Health and Health Policy, City University of New York, and CUNY Institute for Implementation Science in Population Health, New York, New York.
Rena C. Patel, Department of Medicine and Department of Global Health, University of Washington, Seattle, Washington.
Jessie K. Edwards, Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
John M. Humphrey, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
Beverly S. Musick, Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana.
Caitlin Bernard, Department of Obstetrics & Gynecology, Indiana University School of Medicine, Indianapolis, Indiana.
Mercy W. Maina, Department of Pharmacy, Moi Teaching and Referral Hospital, Eldoret, Kenya.
Ellen Brazier, Department of Epidemiology and Biostatistics, CUNY Graduate School of Public Health and Health Policy, City University of New York, and CUNY Institute for Implementation Science in Population Health, New York, New York.
Barbara Castelnuovo, Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda.
Jeremy Penner, Family AIDS Care & Education Services, Kisumu, Kenya; Department of Family Practice, University of British Columbia, Vancouver, British Columbia, Canada.
Katarzyna Wyka, Department of Epidemiology and Biostatistics, CUNY Graduate School of Public Health and Health Policy, City University of New York, New York, New York.
Sandra Wagner Cardoso, Instituto Nacional de Infectologia, Laboratório de Pesquisa Clínica em HIV/AIDS, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
Penh Sun Ly, National Center for HIV/AIDS, Dermatology and STDs, Ministry of Health, Phnom Penh, Cambodia.
Cordelia Kunzekwenyika, SolidarMed, Masvingo, Zimbabwe.
Claudia P. Cortés, Departamento de Medicina, Universidad de Chile & Fundación Arriarán, Santiago, Chile.
Radoslaw Panczak, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
Elizabeth A. Kelvin, Department of Epidemiology and Biostatistics, CUNY Graduate School of Public Health and Health Policy, City University of New York, and CUNY Institute for Implementation Science in Population Health, New York, New York.
Kara K. Wools-Kaloustian, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
Denis Nash, Department of Epidemiology and Biostatistics, CUNY Graduate School of Public Health and Health Policy, City University of New York, and CUNY Institute for Implementation Science in Population Health, New York, New York.
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