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BackgroundLong-term retention of research participants in studies is challenging. In research in sub-Saharan Africa, phone calls are the most frequently used method to distantly engage with participants. ObjectiveWe aimed to get insight into the effectiveness of phone calls to retain contact with participants and evaluated determinants of reachability. MethodsA cross-sectional study was performed using the databases of two randomized controlled trials investigating different kinds of antiretroviral therapy in HIV-positive patients. One trial finished in 2018 (study 1), and the other finished in 2015 (study 2). A random sample size of 200 participants per study was obtained. There were up to 3 phone numbers available per participant collected during the studies. Participants received a maximum of 3 phone calls on every available number on different days and at different times. Voicemails were left, and emails sent wherever possible. We documented how many calls were answered, who answered, as well as after how many attempts participants were reached. To further increase our understanding of reachability, we conducted a short questionnaire assessing factors contributing to reachability. The study was approved by the Research Ethics Committee of the University of Witwatersrand, Johannesburg, South Africa (reference number M1811107). ResultsIn our sample size of n=200 per study, study 1, with a median time of 11 months since the last visit at the research site, had a response rate of 70.5% (141/200) participants while study 2, with a median duration of 55 months since the last visit, had a response rate of 50.0% (100/200; P

BackgroundSouth Africa provides free antiretroviral therapy for almost 5 million people living with HIV, but only 71% of the eligible people are on treatment, representing a shortfall in the care cascade, especially among men and youth. Many developing countries have expanded access to smartphones; success in health apps raises the possibility of improving this cascade. ObjectiveSmartLink is a health app for Android smartphones providing HIV-related laboratory results, information, support, and appointment reminders to engage and link patients to care. This study aimed to evaluate the ability of SmartLink to improve linkage to care for HIV-positive smartphone owners. MethodsThis study was a multisite randomized controlled trial in Johannesburg. The intervention arm received the app (along with referral to a treatment site) and the control arm received the standard of care (referral alone). Linkage to care was confirmed by an HIV-related blood test reported on the National Health Laboratory Service database between 2 weeks and 8 months after initiation. ResultsA total of 345 participants were recruited into the study; 64.9% (224/345) of the participants were female and 44.1% (152/345) were aged less than 30 years. In addition, 46.7% (161/345) were employed full time, 95.9% (331/345) had at least secondary school education, and 35.9% (124/345) were from Zimbabwe. Linkage to care between 2 weeks and 8 months was 48.6% (88/181) in the intervention arm versus 45.1% (74/164) in the control (P=.52) and increased to 64.1% (116/181) and 61.0% (100/164) (P=.55), respectively, after the initial 8-month period. Moreover, youth aged 18 to 30-years showed a statistically significant 20% increase in linkage to care for the intervention group. ConclusionsYouth aged less than 30 years have been historically difficult to reach with traditional interventions, and the SmartLink app provides a proof of concept that this population reacts to mobile health interventions that engage patients in HIV care. Trial RegistrationClinicalTrials.gov NCT02756949; https://clinicaltrials.gov/ct2/show/NCT02756949 (Archived by WebCite at http://www.webcitation.org/6z1GTJCNW)

BackgroundIn HIV treatment program, gaps in the “cascade of care” where patients are lost between diagnosis, laboratory evaluation, treatment initiation, and retention in HIV care, is a well-described challenge. Growing access to internet-enabled mobile phones has led to an interest in using the technology to improve patient engagement with health care. ObjectiveThe objectives of this trial were: (1) to assess whether a mobile phone–enabled app could provide HIV patients with laboratory test results, (2) to better understand the implementation of such an intervention, and (3) to determine app effectiveness in improving linkage to HIV care after diagnosis. MethodsWe developed and tested an app through a randomized controlled trial carried out in several primary health care facilities in Johannesburg. Newly diagnosed HIV-positive patients were screened, recruited, and randomized into the trial as they were giving a blood sample for initial CD4 staging. Trial eligibility included ownership of a phone compatible with the app and access to the internet. Trial participants were followed for a minimum of eight months to determine linkage to HIV care indicated by an HIV-related laboratory test result. ResultsThe trial outcome results are being prepared for publication, but here we describe the significant operational and technological lessons provided by the implementation. Android was identified as the most suitable operating system for the app, due to Android functionality and communication characteristics. Android also had the most significant market share of all smartphone operating systems in South Africa. The app was successfully developed with laboratory results sent to personal smartphones. However, given the trial requirements and the app itself, only 10% of screened HIV patients successfully enrolled. We report on issues such as patient eligibility, app testing in a dynamic phone market, software installation and compatibility, safe identification of patients, linkage of laboratory results to patients lacking unique identifiers, and present lessons and potential solutions. ConclusionsThe implementation challenges and lessons of this trial may assist future similar mHealth interventions to avoid some of the pitfalls. Ensuring sufficient expertise and understanding of the programmatic needs by the software developer, as well as in the implementation team, with adequate and rapid piloting within the target groups, could have led to better trial recruitment. However, the majority of screened patients were interested in the study, and the app was installed successfully in patients with suitable smartphones, suggesting that this may be a way to engage patients with their health care data in future. Trial RegistrationClinicalTrials.gov NCT02756949; https://clinicaltrials.gov/ct2/show/NCT02756949 (Archived by WebCite at http://www.webcitation.org/6z1GTJCNW)

: Introduction: Recent evidence has raised questions about whether newer HIV treatment regimens, including dolutegravir (DTG) and tenofovir alafenamide (TAF), are associated with increases in blood pressure (BP). Methods: We assessed changes in BP by treatment regimen and evaluated the relative contribution of kidney function and weight gain to these changes among participants in the ADVANCE phase‐3 trial clinical trial in South Africa (study dates: January 2017–February 2022). Our primary outcome of interest was a change in systolic BP (SBP) at 96 and 192 weeks, among those not receiving antihypertensive medication. The secondary outcome was treatment‐emergent hypertension at these same time points, defined as BP ≥140/90 mmHg on two occasions, or initiation of antihypertensive medication after week 4 among individuals without hypertension at enrolment. We used linear regression to evaluate the relationship between change in estimated glomerular filtration rate (eGFR) and change in SBP; and Poisson regression to evaluate the relationship between change in eGFR and treatment‐emergent hypertension at each time point. All models were adjusted for age, sex, treatment group and change in body mass index (BMI). Results: Over 96 weeks, the average changes in SBP were 1.7 mmHg (95% CI: 0.0−3.4), −0.5 mmHg (95% CI: −2.2 to 1.7) and −2.1 mmHg (95% CI: −3.8 to 0.4) in the TAF/emtricitabine (FTC)/DTG, tenofovir disoproxil fumarate (TDF)/FTC/DTG and TDF/FTC/efavirenz (EFV) groups, respectively. This difference was significant for the TAF/FTC/DTG compared to the TDF/FTC/EFV group (p = 0.002). Over 96 weeks, 18.2% (95% CI: 13.4–22.9), 15.4% (95% CI: 11.0–19.9) and 13.3% (95% CI: 8.9–17.6) of participants developed treatment‐emergent hypertension, respectively. In adjusted models, there was no significant relationship between change in eGFR and either outcome. Change in BMI was significantly associated with an increase in SBP, while age was associated with an increased risk of treatment‐emergent hypertension. Adjustment for BMI also mitigated the unadjusted relationship between HIV treatment regimen and SBP where present. Conclusions: In the ADVANCE cohort, weight gain and age accounted for increases in BP and risk of treatment‐emergent hypertension. HIV treatment programmes may need to integrate the management of obesity and hypertension into routine care. Clinical Trial Number: NCT03122262, INTRODUCTION The evolution of antiretroviral therapy in the last decade has seen the introduction of integrase‐strand transfer inhibitors (INSTIs) in fixed‐dose combinations with tenofovir prodrugs, either tenofovir disoproxil fumarate (TDF) [...]

: Introduction: Evidence‐based intervention strategies to improve adherence among individuals living with chronic conditions are critical in ensuring better outcomes. In this systematic review, we assessed the impact of interventions that aimed to promote adherence to treatment for chronic conditions. Methods: We systematically searched PubMed, Web of Science, Scopus, Google Scholar and CINAHL databases to identify relevant studies published between the years 2000 and 2023 and used the QUIPS assessment tool to assess the quality and risk of bias of each study. We extracted data from eligible studies for study characteristics and description of interventions for the study populations of interest. Results: Of the 32,698 total studies/records screened, 2814 were eligible for abstract screening and of those, 497 were eligible for full‐text screening. A total of 82 studies were subsequently included, describing a total of 58,043 patients. Of the total included studies, 58 (70.7%) were related to antiretroviral therapy for HIV, 6 (7.3%) were anti‐hypertensive medication‐related, 12 (14.6%) were anti‐diabetic medication‐related and 6 (7.3%) focused on medication for more than one condition. A total of 54/82 (65.9%) reported improved adherence based on the described study outcomes, 13/82 (15.9%) did not have clear results or defined outcomes, while 15/82 (18.3%) reported no significant difference between studied groups. The 82 publications described 98 unique interventions (some studies described more than one intervention). Among these intervention strategies, 13 (13.3%) were multifaceted (4/13 [30.8%] multi‐component health services‐ and community‐based programmes, 6/13 [46.2%] included individual plus group counselling and 3/13 [23.1%] included SMS or alarm reminders plus individual counselling). Discussion: The interventions described in this review ranged from adherence counselling to more complex interventions such as mobile health (mhealth) interventions. Combined interventions comprised of different components may be more effective than using a single component in isolation. However, the complexity involved in designing and implementing combined interventions often complicates the practicalities of such interventions. Conclusions: There is substantial evidence that community‐ and home‐based interventions, digital health interventions and adherence counselling interventions can improve adherence to medication for chronic conditions. Future research should answer if existing interventions can be used to develop less complicated multifaceted adherence intervention strategies., INTRODUCTION Patients on treatment for chronic conditions face multiple barriers to adherence, and no single intervention is deemed sufficient to ensure that high levels of adherence to treatment are maintained [...]

BACKGROUND:Uptake of antiretroviral treatment (ART) is expanding rapidly in low- and middle-income countries (LMIC). Monitoring of virological suppression is recommended at 6 months of treatment and annually thereafter. In case of confirmed virological failure, a switch to second-line ART is indicated. There is a paucity of data on virological suppression and clinical management of patients experiencing viremia in clinical practice in LMIC. We report a large-scale multicenter assessment of virological suppression over time and management of viremia under programmatic conditions. METHODS AND FINDINGS:Linked medical record and laboratory source data from adult patients on first-line ART at 52 South African centers between 1 January 2007 and 1 May 2018 were studied. Virological suppression, switch to second-line ART, death, and loss to follow-up were analyzed. Multistate models and Cox proportional hazard models were used to assess suppression over time and predictors of treatment outcomes. A total of 104,719 patients were included. Patients were predominantly female (67.6%). Median age was 35.7 years (interquartile range [IQR]: 29.9-43.0). In on-treatment analysis, suppression below 1,000 copies/mL was 89.0% at month 12 and 90.4% at month 72. Suppression below 50 copies/mL was 73.1% at month 12 and 77.5% at month 72. Intention-to-treat suppression was 75.0% and 64.3% below 1,000 and 50 copies/mL at month 72, respectively. Viremia occurred in 19.8% (20,766/104,719) of patients during a median follow-up of 152 (IQR: 61-265) weeks. Being male and below 35 years of age and having a CD4 count below 200 cells/μL prior to start of ART were risk factors for viremia. After detection of viremia, confirmatory testing took 29 weeks (IQR: 16-54). Viral resuppression to below 1,000 copies/mL without switch of ART occurred frequently (45.6%; 6,030/13,210) but was associated with renewed viral rebound and switch. Of patients with confirmed failure who remained in care, only 41.5% (1,872/4,510) were switched. The median time to switch was 68 weeks (IQR: 35-127), resulting in 12,325 person-years spent with a viral load above 1,000 copies/mL. Limitations of this study include potential missing data, which is in part addressed by the use of cross-matched laboratory source data, and the possibility of unmeasured confounding. CONCLUSIONS:In this study, 90% virological suppression below the threshold of 1,000 copies/mL was observed in on-treatment analysis. However, this target was not met at the 50-copies/mL threshold or in intention-to-treat analysis. Clinical management in response to viremia was profoundly delayed, prolonging the duration of viremia and potential for transmission. Diagnostic tools to establish the cause of viremia are urgently needed to accelerate clinical decision-making.

BACKGROUND:Antiretroviral therapy (ART) that enables suppression of HIV replication has been successfully rolled out at large scale to HIV-positive patients in low-income and middle-income countries. WHO guidelines for these regions define failure of ART with a lenient threshold of viraemia (HIV RNA viral load ≥1000 copies per mL). We investigated the occurrence of detectable viraemia during ART below this threshold and its effect on treatment outcomes in a large South African cohort. METHODS:In this observational cohort study, we included HIV-positive adults registered between Jan 1, 2007, and May 1, 2016, at 57 clinical sites in South Africa, who were receiving WHO-recommended ART regimens and viral load monitoring. Low-level viraemia was defined as the occurrence of at least one viral load measurement of 51-999 copies per mL during ART. Outcomes were WHO-defined virological failure (one or more viral load measurement of ≥1000 copies per mL) and switch to second-line ART. Risks were estimated with Cox proportional hazard models. FINDINGS:70 930 patients were included in the analysis, of whom 67 644 received first-line ART, 1476 received second-line ART, and 1810 received both. Median duration of follow-up was 124 weeks (IQR 56-221) for patients on first-line ART and 101 weeks (IQR 51-178) for patients on second-line ART. Low-level viraemia occurred in 16 013 (23%) of 69 454 patients, with an incidence of 11·5 per 100 person-years of follow-up (95% CI 11·4-11·7), during first-line ART. Virological failure during follow-up occurred in 14 380 (22%) of 69 454 patients on first-line ART. Low-level viraemia was associated with increased hazards of virological failure (hazard ratio [HR] 2·6, 95% CI 2·5-2·8; p

Introduction: Same-day initiation (SDI) of antiretroviral therapy (ART) for HIV consistently increases ART uptake, but concerns remain about higher attrition from care after initiation. We analysed 12-month retention in the SLATE SDI trials. Methods: SLATE I (Simplified Algorithms for Treatment Eligibility I, enrolment 06 March-28 July 2017) and SLATE II (enrolment 14 March-18 September 2018) were individually randomized trials at public outpatient clinics in Johannesburg that enrolled patients not yet on ART and administered the SLATE I or II algorithm. This included a symptom self-report, medical history, brief physical examination and readiness questionnaire to assess the eligibility for SDI. The studies compared the offer of SDI using the SLATE algorithms to standard of care initiation procedures. ART uptake and early retention were previously reported. Using routine clinic records, we conducted a pooled analysis of retention in care and HIV viral suppression 14 months after study enrolment, a time point equivalent to 12 months potential on ART, with an additional month allowed on either end to initiate ART and to return for the 12-month visit. Results and discussion: We enrolled 1193 study participants (standard arms, n = 599, 50%; intervention arms, n = 594, 50%) and analysed by originally assigned groups. By 14 months after enrolment, 50% of intervention arm patients and 46% of standard arm patients remained in care at the initiating site (crude risk difference 4% (95% confidence interval -196-10%); crude relative risk 1.10 (0.97-1.23), with similar viral suppression between arms. Observed attrition from care at site by 14 months was high in both study arms, but we found no evidence that the offer of SDI led to greater overall attrition or lower rates of viral suppression 1 year after starting ART and may have generated small improvements. SDI may have shifted some attrition from before to after dispensing of the first dose of medication. Conclusions: An offer of SDI of ART, following a carefully designed protocol to identify patients who are eligible and ready to start treatment, is not inherently associated with an overall increase in patient attrition from care and leads to similar rates of viral suppression. Trial registration: Clinicaltrials.gov NCT02891135, registered 01 September 2016. First participant enrolled 06 March 2017 in South Africa. Clinicaltrials.gov NCT03315013, registered 19 October 2017. First participant enrolled 14 March 2018. Keywords: implementation science; randomized trial; retention; same-day ART; South Africa; viral suppression, 1 | INTRODUCTION Since 2017, when the World Health Organization recommended 'same-day initiation' (SDI) of antiretroviral therapy (ART) for people living with HIV who are ready for treatment on the [...]

Introduction: Dolutegravir has replaced efavirenz in most low- and middle-income countries, due to better tolerability and formidable resistance profile, but dolutegravir side effects suggest alternatives are needed. We evaluated doravirine resistance in South Africa as a first step to assess whether doravirine may replace dolutegravir. Methods: A retrospective dataset was analysed for predicted doravirine susceptibility including sequences obtained from three patient groups. First, data from 277 patients initiating antiretroviral treatment (ART) were collected between February 2013 and October 2014 as part of a national survey. Second, data from 788 patients experiencing NNRTI-based ART failure were obtained between February 2013 and October 2014 as part of a national survey. Third, data derived from 584 patients who had genotypic drug resistance testing requested after NNRT-based failure as part of individual patient management between January 2016 and December 2019. Pol sequences were generated using validated population-based in-house genotyping and submitted to Stanford HIVdb v8.9. Results and discussion: Less than 5% of patients initiating ART presented with genotypic doravirine resistance, whereas most patients experiencing NNRTI-based ART failure presented with predicted intermediate (41.0%) or high-level resistance (43.8%) to doravirine. High-level resistance to doravirine was commonly predicted by the presence of at least three DRMs (79.7%). The predicted resistance profile to doravirine in ART-naive patients is promising, but less so in those experiencing failure to first-generation NNRTIs. Accumulation of NNRTI DRMs seems to be an important factor in the poor resistance prediction for doravirine. Conclusions: Although doravirine is approved as initial therapy in patients who are ART-naTve, it is currently recommended to obtain a genotype prior to the initiation of ART. Clinical studies are needed to ascertain whether predicted resistance profiles in ART naive and NNRTI-treated patients translate into poor clinical outcomes, especially in settings where genotypic resistance testing is not available. Keywords: HIV; drug resistance; antiretroviral treatment; doravirine; subtype C; South Africa, 1 | INTRODUCTION South Africa has the largest HIV epidemic globally with 7.5 million estimated infections and approximately 5.2 million HIV-infected people on antiretroviral treatment (ART) making it the biggest [...]

This paper compares the performance of three competing corridors serving landlocked SADC countries (Beira, Dar es Salaam, and Durban) based on total economic cost from the perspective of transporters, retailers, and manufacturers. The motivation for the research is the paradox that, while Beira is closest to the hinterland served by these corridors, it attracts the least cargo. Historical research compares corridors in terms of both direct costs and time delays, but without translating time delays and variability in time delays into the economic costs experienced by corridor users. Unpredictable time delays reduce the competitiveness of cargo owners forming part of global just-in-time value chains. Our novel TEC model includes direct costs and the cost impact of delays and variability in delays and quantifies the relative contributions of ports, border posts, and road travel. The Port's efficiency proved to be the biggest differentiator between these corridors, followed by border posts and road links. We found that while the Beira corridor has the lowest cost if only average travel time is considered, the Durban corridor proves to be the most competitive when variability in time delays is also considered, explaining why Durban enjoys the largest share of cargo transported to the landlocked hinterland., Author(s): Alwyn J. Hoffman (corresponding author) [1]; Crynos Mutendera [1]; Willem C. Venter [1] 1. Introduction The landlocked countries of the South African Development Community (SADC), comprising the Eastern Democratic [...]

Aims: Dolutegravir increases serum creatinine by inhibiting its renal tubular secretion and elimination. We investigated determinants of early changes in serum creatinine in a southern African cohort starting first‐line dolutegravir‐based antiretroviral therapy (ART). Methods: We conducted a secondary analysis of data from participants in a randomized controlled trial of dolutegravir, emtricitabine and tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide fumarate (TAF) (ADVANCE, NCT03122262). We assessed clinical, pharmacokinetic and genetic factors associated with change in serum creatinine from baseline to Week 4 using linear regression models adjusted for age, sex, baseline serum creatinine, HIV‐1 RNA concentration, CD4 T‐cell count, total body weight and co‐trimoxazole use. Results: We included 689 participants, of whom 470 had pharmacokinetic data and 315 had genetic data. Mean change in serum creatinine was 11.3 (SD 9.9) μmol.L−1. Factors that were positively associated with change in serum creatinine at Week 4 were increased log dolutegravir area under the 24‐h concentration–time curve (change in creatinine coefficient [β] = 2.78 μmol.L−1 [95% confidence interval (CI) 0.54, 5.01]), TDF use (β = 2.30 [0.53, 4.06]), male sex (β = 5.20 [2.92, 7.48]), baseline serum creatinine (β = −0.22 [−0.31, −0.12]) and UGT1A1 rs929596 A→G polymorphism with a dominant model (β = −2.33 [−4.49, −0.17]). The latter did not withstand correction for multiple testing. Conclusions: Multiple clinical and pharmacokinetic factors were associated with early change in serum creatinine in individuals initiating dolutegravir‐based ART. UGT1A1 polymorphisms may play a role, but further research on genetic determinants is needed. [ABSTRACT FROM AUTHOR]

Rapid advances in the potency, safety, and availability of modern HIV antiretroviral therapy (ART) have yielded a near-normal life expectancy for most people living with HIV (PLWH). Ironically, considering the history of HIV/AIDS (initially called "slim disease" because of associated weight loss), the latest dilemma faced by many people starting HIV therapy is weight gain and obesity, particularly Black people, women, and those who commenced treatment with advanced immunodeficiency. We review the pathophysiology and implications of weight gain among PLWH on ART and discuss why this phenomenon was recognized only recently, despite the availability of effective therapy for nearly 30 years. We comprehensively explore the theories of the causes, from initial speculation that weight gain was simply a return to health for people recovering from wasting to comparative effects of newer regimens vs prior toxic agents, to direct effects of agents on mitochondrial function. We then discuss the implications of weight gain on modern ART, particularly concomitant effects on lipids, glucose metabolism, and inflammatory markers. Finally, we discuss intervention options for PLWH and obesity, from the limitations of switching ART regimens or specific agents within regimens, weight-gain mitigation strategies, and potential hope in access to emerging antiobesity agents, which are yet to be evaluated in this population. [ABSTRACT FROM AUTHOR]

Introduction: Many African countries have had at least two years' experience with universal treatment eligibility for HIV. The iterature contains few descriptions, though, of populations starting treatment since adoption of universal eligibility. Using base-ine data from a clinical trial of same-day ART initiation, we describe the populations presenting for HIV testing or care at study clinics in Kenya and South Africa in 2017-18, during the era of same-day initiation. Methods: The Simplified Algorithm for Treatment Eligibility (SLATE) trials in Kenya (SLATE I) and South Africa (SLATE II) were multicenter, non-blinded, individually randomized, pragmatic trials evaluating simple, standardized algorithms to determine eligibility for same-day initiation of ART without relying on laboratory results, point of care tests or multiple clinic visits. In Kenya, enrolment occurred during July 2017 to April 2018. In South Africa, enrolment occurred during March to September 2018. We describe demographic, socioeconomic and clinical characteristics of patients randomized to the same-day initiation arm for both studies. Results and Discussion: A total of 240 and 296 participants were enrolled in Kenya and South Africa. The majority were female (59% and 64% respectively), with a median age of 35 years. In both countries, most subjects were newly diagnosed with HIV on the day of enrolment (62%, 55%), believed they already had adequate knowledge to begin ART (78%, 68%), and preferred to start ART immediately (same-day) (98% in both countries). About 40% of all patients had at least one symptom related to tuberculosis (cough, fever, night sweats, weight loss) and/or cryptococcal meningitis (continuous headache). More than a third of patients (37%, 36%) presented with advanced disease (CD4 Conclusions: Despite >2 years of universal eligibility for ART in Kenya and South Africa, in 2017-2018 more than half of HIV-positive patients presenting at public sector clinics were not yet aware of their status, and more than a third presented for care with advanced HIV disease. These proportions remain similar to those observed before the introduction of universa eligibility. Keywords: HIV/AIDS; presenting for care; patient characteristics; randomized trial; SLATE I Kenya; SLATE II South Africa, 1 | INTRODUCTION The World Health Organization's (WHO) 2016 consolidated guidelines recommended that all adults living with HIV should initiate antiretroviral treatment (ART) regardless of WHO clinical stage or CD4 [...]

Introduction: To adequately ascertain drug safety and efficacy drug trials need to include participants from all groups likely to receive the medication following approval. Pregnant women, however, are mostly excluded from trials, and women participating are often required to use highly effective contraception and taken off study product (even off study) if they conceive. There is little commercial incentive for including pregnant women in clinical trials, even when preclinical animal and human pharmacokinetic and safety data appear reassuring. With this conservative approach, large numbers of pregnant women are exposed to drug postlicensing with little known about drug safety and efficacy, and little done to systematically monitor outcomes of pregnancy exposure. Discussion: The article focuses on antiretrovirals for treating and preventing HIV, and presents potential approaches which could extend to other therapeutic areas, to obtaining adequate and timely data to inform use of these drugs in this population. Most importantly the pregnancy risk profile of investigational agents can be systematically stratified from low to high risk, based on guidelines from regulatory bodies. This stratification can determine the progress through preclinical work with animals and non-pregnant women to opportunistic studies among women who become pregnant on a clinical trial or within routine clinical treatment. Stratification can include pregnant women in clinical trials, concurrent with Phase II/III trials in nonpregnant adults, and ultimately to postmarketing surveillance for outcomes in pregnant women and their infants. Each step can be enabled by clear criteria from international and local regulatory bodies on progression through study phases, standardized protocols for collecting relevant data, collaborative data sharing, pregnancy outcomes surveillance systems supported by committed funding for these endeavours. Conclusions: A formalized step-wise approach to including pregnant women in antiretroviral drug research should become the new norm. Systematic implementation of this approach would yield more timely and higher quality pregnancy dosing, safety and efficacy data. Through more vigorous action, regulatory bodies could responsibly overcome reluctance to include pregnant women in drug trials. Funders, researchers and programme implementers need to be galvanized to progressively include pregnant women in research - the use of newer, more effective drugs in women is at stake (349). Keywords: HIV; teratogen; drug dosing; maternal health; child health; antiretroviral; pregnancy; dolutegravir; birth defects, 1 | INTRODUCTION Globally, antiretroviral (ARV) drug use in pregnancy has evolved from single and two-drug regimens for prevention of vertical infection, to three-drug regimens for all pregnant and breastfeeding [...]