Introduction
Since 2018, the WHO has recommended the first-line antiretroviral therapy (ART) to be a combination of tenofovir disoproxil fumarate (TDF) and either lamivudine (3TC) or emtricitabine (FTC) with the integrase strand transfer inhibitor (INSTI), dolutegravir (DTG) [1] [2] [3,4]
In the current WHO guidelines, tenofovir alafenamide (TAF) is included in the triple-drug therapy for patients with osteoporosis or impaired renal function, as a substitute for TDF [1] [5–8]
With ART drug resistance emerging in low-and-middle-income countries (LMICs), the low-cost generic formulations of DTG and TAF are attractive options that would allow LMICs to scale up their HIV treatment programmes [9–11] [12–16] .
The WHO defines obesity as a BMI of at least 30. It is calculated using the weight in kilograms divided by the height in metres squared (kg/m2 ) [17] [18] [19,20]
ADVANCE and NAMSAL are randomized controlled trials (RCTs) that are one of the few Phase III trials to investigate the effects of DTG, specifically on body weight, in a predominantly black, African population [4,14,16,21–24] [25]
ADVANCE is an ongoing trial that began in 2017, based in South Africa. The trial is comparing the efficacy and safety of two DTG-based regimens (TAF/FTC+DTG, TDF/FTC+DTG) against the previous standard treatment (TDF/FTC/EFV). There are 1053 participants who have been evenly assigned across the three treatment arms to receive long-term follow-ups. Currently, results have been published for Week 48 and Week 96 [14,26] [14] [21]
Aside from the recognized association between obesity and cardiovascular disease, there is extensive research highlighting an association between maternal obesity and adverse pregnancy outcomes. For example, a retrospective cohort study in Nigeria comparing adverse pregnancy outcomes in women with an obese BMI versus a normal BMI reported an increased risk of several adverse outcomes with obesity, including antepartum haemorrhage [odds ratio (OR): 2.78, 95% confidence interval (95% CI): 1.02–7.93], preeclampsia (OR: 2.31, 95% CI: 1.72–4.48) and postpartum haemorrhage (PPH, OR: 2.2, 95% CI: 1.18–5.20) [27] [28] [29–31]
Although current evidence shows DTG to be effective and well-tolerated during pregnancy (DolPHIN-1, DolPHIN-2, IMPAACT 2010) [32–34]
Therefore, this study aimed to assess the consequences of DTG-associated maternal obesity (at conception) on adverse pregnancy outcomes for a hypothetical population of 3000 women, evenly allocated to receive TAF/FTC+DTG, TDF/FTC+DTG or TDF/FTC/EFV.
Materials and methods
The method was divided into two steps, which are outlined as follows.
Meta-analysis
Firstly, a meta-analysis was performed to determine the effects of maternal obesity on adverse pregnancy outcomes. The methodology was carried out in line with the Cochrane Guidelines for Systematic Reviews and the PRISMA Guidelines [35,36]
Before performing the literature search for the meta-analysis, a scoping review of the literature was carried out to identify frequently reported adverse pregnancy outcomes in studies. This was used to decide the key outcomes to be measured in the meta-analysis and form parts of the inclusion criteria.
Four databases (MEDLINE, EMBASE, Maternal & Infant Care and Global Health) were searched to retrieve studies evaluating an association between adverse pregnancy outcomes and maternal obesity. A search strategy was developed using the ‘population, intervention, comparison, outcome’ framework. Search terms included ‘prepregnancy BMI’, ‘pregnancy complications’ and ‘maternal obesity’ . No language, country or date restrictions were applied (Supplementary 1: PRISMA Diagram, Supplementary 2: Search Terms, https://links.lww.com/QAD/C242 [37]
Study selection
Studies were required to assess at least one of the following adverse maternal pregnancy outcomes: preterm delivery, gestational hypertension, gestational diabetes mellitus, caesarean section or preeclampsia and at least one of the following adverse infant outcomes: small-for-gestational age (SGA), large-for-gestational age (LGA), low birthweight, macrosomia or stillbirth. Studies reporting neural tube defects (NTDs) were also selected.
Women with a normal BMI were compared against women with an obese BMI. Studies were required to define weight categories using the International WHO BMI classification (normal: 18.5–24.9, obese: ≥30) [17]
Studies were eligible for inclusion if they were cohort in design. Only studies with sufficient reporting of raw data values were selected to allow for appropriate data extraction and analysis. (Supplementary 3: Inclusion and Exclusion Criteria, https://links.lww.com/QAD/C242
Following the initial scoping review, there were a limited selection of cohort studies measuring an association between maternal obesity and NTDs. Therefore, the BMI classification inclusion criterion was not applied when screening the studies reporting this specific outcome. It was important to investigate this outcome in our meta-analysis considering the global safety signal that was released for DTG use during pregnancy in 2018. This occurred following the release of preliminary results from a birth surveillance programme in Botswana, which reported an increased risk of NTDs in infants exposed to DTG in utero . Fortunately, further analysis and research has now shown this risk to be nonsignificant and small [38,39]
The quality assessment of the cohort studies was done using the 9∗ Newcastle-Ottawa Tool [40]
Data extraction and analysis
The BMI classifications, outcome definitions and raw values were extracted from the selected studies. After the full-text assessments, PPH and neonatal deaths were adopted as additional outcomes for the meta-analysis, as these outcomes were consistently reported in many of the studies.
Statistical analysis was conducted using RevMan Software Version 5.3 [41] I 2 [42] I 2 I 2 < 75% as substantial and at least 75% as considerable.
Risk prediction
The risk prediction calculations were performed using a hypothetical sample based on the ADVANCE trial, across a 10-year time-frame. In the hypothetical sample, 3000 nonpregnant women with normal BMIs at baseline (i.e. at Week 0 of treatment) were evenly divided across the following treatment arms: TAF/FTC+DTG, TDF/FTC+DTG and TDF/FTC/EFV, to receive 96 weeks of treatment.
The rationale for this hypothetical sample is described as follows.
Firstly, we assumed that 3000 nonpregnant women with normal BMIs at baseline were evenly divided to use TAF/FTC+DTG, TDF/FTC+DTG or TDF/FTC/EFV. Within each treatment arm, an annual pregnancy rate of 10% was applied (based on the real annual pregnancy rate from the ADVANCE trial). Therefore, 100 women in each treatment arm were expected to become pregnant whilst receiving treatment. Across a 10-year timeframe, this created a sample of 1000 women in each treatment arm, with normal BMIs at baseline who became pregnant during treatment, resulting in a total sample of 3000 women.
The hypothetical sample requires the assumption that each woman became pregnant only once whilst taking the treatment. It also assumes that all the women were of reproductive age with no underlying conditions affecting their fertility and pregnancy.
We estimated the number of women expected to become obese or remain with a normal BMI at Week 96 of treatment in the hypothetical sample. The real ADVANCE treatment-associated obesity rates for Week 96 in women with a normal BMI at baseline were used for the calculation (14.1% for TAF/FTC+DTG, 7.9% for TDF/FTC+DTG and 1.5% for TDF/FTC/EFV) (Fig. 1 ). For example, in the hypothetical TAF/FTC+DTG arm, we estimated 141 women would have an obese BMI and 859 women would remain with a normal BMI at Week 96 of treatment.
Fig. 1: The treatment-associated obesity rates for women with a normal baseline BMI in each treatment arm of the ADVANCE trial.
From the meta-analysis, we extracted the RR and the absolute percentage of women with normal and obese BMIs experiencing each adverse pregnancy outcome. These results were combined with the hypothetical Week 96 BMI estimates to predict the number of women at risk of each adverse pregnancy outcome at Week 96 of treatment, assuming they conceived at Week 96 (i.e. at their Week 96 prepregnancy BMI)
We compared this to the number of women at risk of each adverse pregnancy outcome if they conceived at their baseline BMI (i.e. at their Week 0 prepregnancy BMI),
Finally, the number of women at risk of each adverse pregnancy outcome was aggregated for each treatment arm, for Week 0 and Week 96.
Figure 2 shows a flow-chart to aid the visualization of the methodology.
Fig. 2: A flow-chart to illustrate the methodology.
A 10-year timeframe was used for the risk prediction because we aimed to predict and illustrate the possible long-term health burden of treatment-associated weight gain (as seen in the results of the ADVANCE trial) on a large cohort of women becoming pregnant whilst receiving DTG-based ART.
The hypothetical sample only considered women with a normal BMI at baseline because it was based on the real participant demographics of the ADVANCE trial. In the ADVANCE trial, the normal baseline BMI category had the highest proportion of female participants. It would be areas for future research to perform similar risk prediction calculations for the other BMI categories. The 10% annual pregnancy rate from the ADVANCE trial was used over the 10-year time period for similar reasons.
The risk prediction calculations did not include the actual pregnancy outcomes experienced by women in the ADVANCE trial. The adverse pregnancy outcomes and predictions were derived from the studies found in the literature search. Details on the real pregnancy outcomes reported in the ADVANCE trial can be found in the published papers of the Week 48 and Week 96 results [14,26]
Results
Meta-analysis
The meta-analysis included 25 studies. The majority of the studies assessed women with singleton pregnancies. The studies were from a broad range of countries with the mean gestational age and gestational age at delivery being similar ( Supplementary 4: Study details, https://links.lww.com/QAD/C242
The RR for each adverse pregnancy outcome is displayed in Table 1 (Supplementary 5: Forest Plots, https://links.lww.com/QAD/C242 P = 0.98) had a statistically significant association with maternal prepregnancy obesity. Prepregnancy obesity increased the risk for all the measured adverse pregnancy outcomes apart from SGA infants. The risk of SGA infants was lower with obesity; the RR was 0.84 (95% CI: 0.76–0.94). Regarding adverse maternal pregnancy outcomes, obese mothers were at a higher risk of preeclampsia, gestational diabetes and gestational hypertension. Regarding adverse infant outcomes, obese mothers were at a higher risk of LGA infants or infants with macrosomia.
Table 1 -
Relative risk of adverse pregnancy outcomes.
Raw values (%)
Adverse pregnancy outcome
Normal BMI
Obese BMI
Relative risk (RR)
95% CI
P
Preterm delivery∗
24 998/359 032 (7.0)
6096/88 746 (6.9)
1.33
[1.19–1.48]
<0.0001
Gestational hypertension∗
7391/261 776 (2.8)
3845/63 123 (6.1)
3.68
[2.97–4.55]
<0.00001
Gestational diabetes mellitus∗
7986/514 908 (1.6)
6272/110 224 (5.7)
4.31
[3.18–5.85]
<0.00001
Preeclampsia∗
8898/361 935 (2.5)
4741/76 208 (6.2)
4.06
[3.09–5.33]
<0.00001
Postpartum haemorrhage∗
35 004/313 050 (11.2)
3895/47 933 (8.1)
1.23
[1.01–1.50]
0.04
Caesarean section∗
115 351/540 994 (21.3)
37 829/117 232 (32.3)
1.64
[1.55–1.73]
<0.00001
Small-for-gestational age∗
19 872/223 542 (8.9)
3500/44 757 (7.8)
0.84
[0.76–0.94]
0.0009
Large-for-gestational age∗
32 481/241 531 (13.5)
12 440/51 813 (24.0)
2.04
[1.65–2.52]
<0.00001
Macrosomia∗
13 050/427 496 (3.1)
5560/76 278 (7.3)
2.48
[2.10–2.93]
<0.00001
Low birthweight
1777/27 582 (6.5)
410/4969 (8.3)
1.01
[0.56–1.80]
0.98
Neonatal death∗
115/53 637 (0.2)
284/176 335 (0.2)
1.57
[1.00–2.48]
0.05
Stillbirth∗
1517/432 873 (0.4)
632/101 894 (0.6)
1.39
[1.01–1.92]
0.05
Neural tube defect∗
593/2 696 807 (0.02)
90/142 291 (0.06)
2.53
[1.15–5.55]
0.02
∗ Outcomes were statistically significant, P ≤ 0.05.
Risk prediction
As mentioned in the methodology, the ADVANCE treatment-associated obesity rates at Week 96 for women with a normal BMI at baseline were 14.1% for TAF/FTC+DTG, 7.9% for TDF/FTC+DTG and 1.5% for TDF/FTC/EFV (Fig. 1 ). Women in all three treatment arms gained weight after starting the ART regimens. Therefore, in our hypothetical sample, there was an overall rise in the number of women predicted to experience adverse pregnancy outcomes if they conceived at Week 96 versus Week 0 of treatment (i.e. at their Week 96 prepregnancy BMI versus Week 0 prepregnancy BMI), in all the treatment arms, across a 10-year timeframe.
Overall, the percentage increase in the number of women predicted to experience adverse pregnancy outcomes at their Week 0 BMI versus Week 96 BMI was 10% with TAF/FTC+DTG and 5% with TDF/FTC+DTG compared to only 1% with TDF/FTC/EV. The estimated predictions for each adverse pregnancy outcome are outlined in Table 2 .
Table 2 -
The number of women predicted to be at risk of each adverse pregnancy outcomes if they conceived at their baseline BMI (i.e. normal BMI at Week 0) and at their Week 96 BMI, for each treatment arm (TAF/FTC+DTG, TDF/FTC+DTG, TDF/FTC/EFV).
TAF/FTC+DTG
TDF/FTC+DTG
TDF/FTC/EFV
Adverse pregnancy outcome
Week 0
Week 96
Percentage change
Week 0
Week 96
Percentage change
Week 0
Week 96
Percentage change
Preterm delivery
70
73
+4%
70
71
+1%
70
70
±0%
Gestational hypertension
28
39
+39%
28
34
+21%
28
29
+4%
Gestational diabetes mellitus
16
23
+44%
16
19
+19%
16
16
±0%
Preeclampsia
25
35
+40%
25
30
+20%
25
26
+4%
Postpartum haemorrhage
112
115
+3%
112
114
+2%
112
112
±0%
Caesarean section
213
232
+9%
213
224
+5%
213
215
+1%
Small-for-gestational age
89
87
−2%
89
88
−1%
89
89
±0%
Large-for-gestational age
134
154
+15%
134
145
+8%
134
137
+2%
Low birthweight
64
65
+2%
64
64
±0%
64
64
±0%
Macrosomia
31
37
+19%
31
34
+10%
31
31
±0%
Stillbirth
4
4
±0%
4
4
±0%
4
4
±0%
Neonatal death
2
2
±0%
2
2
±0%
2
2
±0%
Neural tube defect
0
0
±0%
0
0
±0%
0
0
±0%
Total
788
866
+10%
788
829
+5%
788
795
+1%
DTG, dolutegravir; EFV, efavirenz; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.
Looking at specific outcomes, if women conceived at their Week 96 BMI, there would be 7/1000 additional predicted cases of gestational diabetes mellitus with TAF/FTC+DTG, 3/1000 cases with TDF/FTC+DTG and none with TDF/FTC/EFV across a 10-year time frame. Likewise, there would be 6/1000 additional predicted cases of macrosomia with TAF/FTC+DTG, 3/1000 with TDF/FTC+DTG and none with TDF/FTC/EFV across a 10-year time frame. No cases of NTDs were predicted to occur.
Discussion
Women in Africa already have a higher background risk to adverse pregnancy outcomes due to the high prevalence of maternal risk factors such as malaria, anaemia, sexually transmitted infections and HIV [43,44]
From the meta-analysis, it was concluded that maternal prepregnancy obesity is significantly associated with a higher risk of several adverse outcomes such as gestational hypertension (RR: 3.68, 95% CI: 2.97–4.55) and gestational diabetes mellitus (RR: 4.31, 95% CI: 3.18–5.85). However, maternal prepregnancy obesity was protective for adverse outcomes such as low birthweight and SGA infants. These results are in line with systematic reviews that have carried out similar assessments of maternal obesity and adverse pregnancy outcomes [29,45]
As higher rates of obesity occurred with DTG-based regimens in the ADVANCE trial, our calculations illustrated that ART regimen using DTG posed the highest predicted risk of adverse pregnancy outcomes in women.
The underlying mechanism for the DTG-associated weight gain is unclear, however, whilst most of the evidence suggests DTG has weight-inducing effects, it is important to consider a possible weight-suppression effect occurring with EFV. Participants in the ADVANCE trial with a mutation in the CYP2B6 metaboliser genotype, causing a slower metabolism of EFV, were suggested to have inhibited weight gain [46] [16]
DTG-associated obesity places users, particularly black women, at a higher risk of adverse outcomes. These adverse outcomes are not limited to pregnancy and may contribute to the development of metabolic syndrome and cardiac insufficiency [47] [48]
One of the limitations in this study is that we only considered a small selection of adverse pregnancy outcomes in the risk prediction calculations. In clinical practice, other important adverse pregnancy outcomes such as neonatal ICU admissions, antepartum haemorrhage and puerperal infections are seen but were not evaluated. We were also unable to account for the influence of other factors such as past medical and family history that would increase the underlying risk of some women for adverse pregnancy outcomes.
Similarly, we did not factor in the variation and confounding influence of ethnicity on adverse pregnancy outcomes. Ethnicity is known to create variation amongst populations and their risk of adverse pregnancy outcomes [49]
Furthermore, several assumptions were needed for our predictions to be valid. For example, we assumed that women became pregnant only once during their treatment, at Week 96 of treatment. We also assumed these women had no additional risk factors (apart from treatment-associated obesity) that may increase their chance of adverse pregnancy outcomes. We also assumed that there were no external factors apart from the ART that may cause fluctuations in their BMI.
The ADVANCE trial has extended past 96 weeks and the weight gain with TAF/FTC+DTG and TDF/FTC+DTG shows no indication of plateauing. At 144 weeks, though with incomplete data, women using TAF/FTC+DTG experienced an average weight gain of 12.8 kg compared with just 5.5 kg with TDF/FTC/EFV [50]
DTG-associated obesity is a slow-developing effect, with most of the DTG RCTs failing to have sufficient follow-up periods to see the manifestation of obesity-associated adverse events, including during and after pregnancy. Hence, these results should be interpreted with caution until adequately powered cohorts provide clinical data.
Weight gain is a complex issue before and during pregnancy (being underweight is also associated with poorer outcomes), and TAF and DTG are not the only antiretrovirals implicated. There is an urgent need to extend the follow-up period of ongoing and future DTG and other ART trials to assess the positive weight gain trend and understand the long-term and short-term implications of this drug. True safety and efficacy conclusions cannot be made until there is further information on the long-term impacts of this treatment.
Conclusion
DTG-associated obesity, especially in combination with TAF, may increase the risk of adverse pregnancy outcomes in women who are obese prior to conception, based on our predictions. Widespread use of TAF with DTG may need to be reconsidered until there are better long-term clinical data to inform decision-making.
There is a need for careful discussions on the benefits and risks of using newer antiretroviral agents and address the safety and efficacy of available alternatives amongst women of children-bearing age, without heightening the additional burden of obesity and the associated noncommunicable diseases. These discussions are essential for healthcare providers to make evidence-based decisions regarding ART regimens.
Acknowledgements
This study has been funded by the U.S. Agency for International Development (USAID) through its OPTIMIZE project.
The U.S. Agency for International Development (USAID) invests in OPTIMIZE through its support of a global consortium, led by Wits RHI, that includes ICAP at Columbia University, Mylan Laboratories, the University of Liverpool and the Medicines Patent Pool. USAID is a key implementing agency of the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) and is responsible for over half of all PEPFAR programs with activities focused in 35 priority countries and regions, mainly in sub-Saharan Africa and Asia. For more information, please visit: www.usaid.gov
The ADVANCE study is funded by the U.S. Agency for International Development, Unitaid, the South African Medical Research Council and ViiV Healthcare. Investigational drugs were donated by Gilead Sciences and ViiV Healthcare.
Funding for this AIDS journal supplement was provided by the US Agency for International Development (USAID) through the OPTIMIZE Cooperative Agreement AID-OAA-A-15–00069 to Ezintsha, Wits Reproductive Health & HIV Institute, University of the Witwatersrand. The content of this supplement is solely the responsibility of the authors and does not necessarily represent the official views of USAID, or any other agency.
Sumbul Asif performed the analysis and wrote the article. Evangelia Baxevanidi checked the analysis and reviewed the article. Andrew Hill ran the overall project, checked the analysis and the article. Celicia Serenata, Willem D.F. Venter, Lee Fairlie, Masebole Masenya, Simiso Sokhela and Nomathemba Chandiwana conducted the ADVANCE study in South Africa, collected the outcomes data and reviewed the article.
Conflicts of interest
There are no conflicts of interest.
References
1. Update of recommendations on first- and second-line antiretroviral regimens. Geneva, Switzerland: World Health Organization; 2019 (WHO/CDS/HIV/19.15). Licence: CC BY-NC-SA 3.0 IGO. [Internet]
https://apps.who.int/iris/bitstream/handle/10665/325892/WHO-CDS-HIV-19.15-eng.pdf?sequence=1&isAllowed=y [Accessed: 30 December 2020]
2. Doherty M, Ford N, Vitoria M, Weiler G, Hirnschall G.
The 2013 WHO guidelines for antiretroviral therapy: evidence-based recommendations to face new epidemic realities .
Curr Opin HIV AIDS 2013; 8:528–534.
3. Walmsley S, Baumgarten A, Berenguer J, Felizarta F, Florence E, Khuong-Josses M-A, et al.
Brief report: dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: week 96 and week 144 results from the SINGLE randomized clinical trial .
J Acquir Immune Defic Syndr 2015; 70:515–519.
4. Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutiérrez F, et al.
Dolutegravir plus abacavir–lamivudine for the treatment of HIV-1 infection .
N Engl J Med 2013; 369:1807–1818.
5. European guidelines for the treatment of HIV-positive adults (Version 10.0) [Internet].
https://www.eacsociety.org/files/2019_guidelines-10.0_final.pdf . [Accessed: 30 December 2020]
6. Saag MS, Benson CA, Gandhi RT, Hoy JF, Landovitz RJ, Mugavero MJ, et al.
Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2018 recommendations of the International Antiviral Society-USA Panel .
JAMA 2018; 320:379.
7. Ray AS, Fordyce MW, Hitchcock MJM.
Tenofovir alafenamide: a novel prodrug of tenofovir for the treatment of human immunodeficiency virus .
Antiviral Res 2016; 125:63–70.
8. Ruane PJ, DeJesus E, Berger D, Markowitz M, Bredeek UF, Callebaut C, et al.
Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults .
J Acquir Immune Defic Syndr 1999 2013; 63:449–455.
9. Gupta RK, Gregson J, Parkin N, Haile-Selassie H, Tanuri A, Andrade Forero L, et al.
HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis .
Lancet Infect Dis 2018; 18:346–355.
10. Vitoria M, Hill A, Ford N, Doherty M, Clayden P, Venter F, et al.
The transition to dolutegravir and other new antiretrovirals in low-income and middle-income countries: what are the issues? .
AIDS 2018; 32:1551–1561.
11. Vitoria M, Ford N, Clayden P, Pozniak AL, Hill AM.
When could new antiretrovirals be recommended for national treatment programmes in low-income and middle-income countries: results of a WHO Think Tank .
Curr Opin HIV AIDS 2017; 12:414–422.
12. Sax PE, Erlandson KM, Lake JE, Mccomsey GA, Orkin C, Esser S, et al.
Weight gain following initiation of antiretroviral therapy: risk factors in randomized comparative clinical trials .
Clin Infect Dis 2020; 71:1379–1389.
13. Bakal DR, Coelho LE, Luz PM, Clark JL, De Boni RB, Cardoso SW, et al.
Obesity following ART initiation is common and influenced by both traditional and HIV-/ART-specific risk factors .
J Antimicrob Chemother 2018; 73:2177–2185.
14. Venter WDF, Sokhela S, Simmons B, Moorhouse M, Fairlie L, Mashabane N, et al.
Dolutegravir with emtricitabine and tenofovir alafenamide or tenofovir disoproxil fumarate versus efavirenz, emtricitabine, and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection (ADVANCE): week 96 results from a randomised, phase 3, noninferiority trial .
Lancet HIV 2020; 7:e666–e676.
15. Taramasso L, Berruti M, Briano F, Di Biagio A.
The switch from tenofovir disoproxil fumarate to tenofovir alafenamide determines weight gain in patients on rilpivirine-based regimen .
AIDS 2020; 34:877–881.
16. Hill A, Waters L, Pozniak A.
Are new antiretroviral treatments increasing the risks of clinical obesity? .
J Virus Erad 2019; 5:41–43.
17. World Health Organization. WHO | What is overweight and obesity? [Internet]. WHO.
https://www.who.int/dietphysicalactivity/childhood_what/en/ . [Accessed: 30 October 2020]
18. World Health Organization. Obesity and overweight [Internet].
https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight . [Accessed: 30 October 2020]
19. National Department of Heath (NoDH), Statistics South Africa (Stats SA), South African Medical Research Council (SAMRC) and ICF.
South Africa Demographic and Health Surgery 2016: Key Indicators. 2017. Pretoria, South Africa and Rockville, Maryland, US: NoDH, Stats SA, SAMRC and ICF.
20. HIV and AIDS in South Africa [Internet]. Avert. 2015.
https://www.avert.org/professionals/hiv-around-world/sub-saharan-africa/south-africa . [Accessed: 30 October 2020]
21. Calmy A, Sanchez TT, Kouanfack C, Mpoudi-Etame M, Leroy S, Perrineau S, et al.
Dolutegravir-based and low-dose efavirenz-based regimen for the initial treatment of HIV-1 infection (NAMSAL): week 96 results from a two-group, multicentre, randomised, open label, phase 3 non-inferiority trial in Cameroon .
Lancet HIV [Internet] 2020; 7:e677–e687.
22. Orrell C, Hagins DP, Belonosova E, Porteiro N, Walmsley S, Falcó V, et al.
Fixed-dose combination dolutegravir, abacavir, and lamivudine versus ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate and emtricitabine in previously untreated women with HIV-1 infection (ARIA): week 48 results from a randomised, open-label, noninferiority, phase 3b study .
Lancet HIV 2017; 4:e536–e546.
23. Raffi F, Rachlis A, Stellbrink H-J, Hardy WD, Torti C, Orkin C, et al.
Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, noninferiority SPRING-2 study .
Lancet 2013; 381:735–743.
24. Cahn P, Madero JS, Arribas JR, Antinori A, Ortiz R, Clarke AE, et al.
Durable efficacy of dolutegravir plus lamivudine in antiretroviral treatment-naive adults with HIV-1 infection: 96-week results from the GEMINI-1 and GEMINI-2 randomized clinical trials .
J Acquir Immune Defic Syndr 2020; 83:310–318.
25. Pepperrell T, Hill A, Moorhouse M, Clayden P, McCann K, Sokhela S, et al.
Phase three trials of new antiretrovirals are not representative of the global HIV epidemic .
J Virus Erad 2020; 6:70–73.
26. Venter WDF, Moorhouse M, Sokhela S, Fairlie L, Mashabane N, Masenya M, et al.
Dolutegravir plus two different prodrugs of tenofovir to treat HIV .
N Engl J Med 2019; 381:803–815.
27. Iyoke CA, Ugwu GO, Ezugwu FO, Lawani OL, Onyebuchi AK.
Retrospective cohort study of the effects of obesity in early pregnancy on maternal weight gain and obstetric outcomes in an obstetric population in Africa .
Int J Womens Health 2013; 5:501–507.
28. Koyanagi A, Zhang J, Dagvadorj A, Hirayama F, Shibuya K, Souza JP, et al.
Macrosomia in 23 developing countries: an analysis of a multicountry, facility-based, cross-sectional survey .
Lancet Lond Engl 2013; 381:476–483.
29. O’Brien TE, Ray JG, Chan W-S.
Maternal body mass index and the risk of preeclampsia: a systematic overview .
Epidemiol Camb Mass 2003; 14:368–374.
30. Athukorala C, Rumbold AR, Willson KJ, Crowther CA.
The risk of adverse pregnancy outcomes in women who are overweight or obese .
BMC Pregnancy Childbirth 2010; 10:56.
31. Cresswell JA, Campbell OMR, De Silva MJ, Filippi V.
Effect of maternal obesity on neonatal death in sub-Saharan Africa: multivariable analysis of 27 national datasets .
Lancet 2012; 380:1325–1330.
32. Waitt C, Orrell C, Walimbwa S, Singh Y, Kintu K, Simmons B, et al.
Safety and pharmacokinetics of dolutegravir in pregnant mothers with HIV infection and their neonates: a randomised trial (DolPHIN-1 study) .
PLoS Med 2019; 16:e1002895.
33. Kintu K, Malaba TR, Nakibuka J, Papamichael C, Colbers A, Byrne K, et al.
Dolutegravir versus efavirenz in women starting HIV therapy in late pregnancy (DolPHIN-2): an open-label, randomised controlled trial .
Lancet HIV 2020; 7:332–339.
34. Chinula L, Brummel SS, Ziemba L, Stranix-Chibanda L, Coletti A, Krotje C,
et al. Safety and efficacy of DTG vs EFV and TDF vs TAF in pregnancy: IMPAACT 2010 TRIAL. [Abstract]. CROI Conference. 8–11 March 2020. Boston, Massachusetts.
35. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al.
The PRISMA 2020 statement: an updated guideline for reporting systematic reviews .
PLoS Med 2021; 18:e1003583.
36. Cumpston M, Li T, Page MJ, Chandler J, Welch VA, Higgins JP, et al.
Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions .
Cochrane Database Syst Rev [Internet] 2019.
37. Covidence systematic review software, Veritas Health Innovation, Melbourne, Australia [Internet]. Available at:
www.covidence.org . [Accessed: 30 October 2020]
38. Zash R.
Update on neural tube defects with antiretroviral exposure in the Tsepamo study, Botswana. AIDS 2020: 23rd International AIDS Conference Virtual . July 6–10, 2020.
https://cattendee.abstractsonline.com/meeting/9289/presentation/3500 .
39. Zash R, Holmes L, Diseko M, Jacobson DL, Brummel S, Mayondi G, et al.
Neural-tube defects and antiretroviral treatment regimens in Botswana .
N Engl J Med 2019; 381:827–840.
40. Ottawa Hospital Research Institute [Internet].
http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp . [Accessed: 30 October 2020]
41. RevMan [Internet]. online-learning/core-software-cochrane-reviews/revman. [Accessed 30 October 2020]
42. Cochrane Handbook. 9.5.2 Identifying and measuring heterogeneity [Internet].
https://handbook-5-1.cochrane.org/chapter_9/9_5_2_identifying_and_measuring_heterogeneity.htm . [Accessed: 30 October 2020]
43. Watson-Jones D, Weiss HA, Changalucha JM, Todd J, Gumodoka B, Bulmer J, et al.
Adverse birth outcomes in United Republic of Tanzania: impact and prevention of maternal risk factors .
Bull World Health Organ 2007; 85:9–18.
44. Adane AA, Ayele TA, Ararsa LG, Bitew BD, Zeleke BM.
Adverse birth outcomes among deliveries at Gondar University Hospital, Northwest Ethiopia .
BMC Pregnancy Childbirth 2014; 14:90.
45. Rahman MM, Abe SK, Kanda M, Narita S, Rahman MS, Bilano V, et al.
Maternal body mass index and risk of birth and maternal health outcomes in low- and middle-income countries: a systematic review and meta-analysis .
Obes Rev 2015; 16:758–770.
46. Griesel R, Maartens G, Chirehwa M, Sokhela S, Akpomiemie G, Moorhouse M, et al.
CYP2B6 genotype and weight gain differences between dolutegravir and efavirenz .
Clin Infect Dis [Internet] 2020.
47. Hill A, McCann K, Pilkington V, Moorhouse M, Sokhela S, Serenata C,
et al. Risks of metabolic syndrome, diabetes, and cardiovascular disease in Advance Trial [Abstract]. CROI Conference. 8–11 March 2020. Boston, Massachusetts.
48. Lynch AM, Hart JE, Agwu OC, Fisher BM, West NA, Gibbs RS.
Association of extremes of prepregnancy BMI with the clinical presentations of preterm birth .
Am J Obstet Gynecol 2014; 210:428e1-9.
49. Khalil A, Rezende J, Akolekar R, Syngelaki A, Nicolaides KH.
Maternal racial origin and adverse pregnancy outcome: a cohort study .
Ultrasound Obstet Gynecol 2013; 41:278–285.
50. Venter F, Moorhouse M, Sokhela S,
et al. The ADVANCE trial: Phase 3, randomised comparison of TAF/FTC+DTG, TDF/FTC+DTG or TDF/FTC/EFV for first-line treatment of HIV-1 infection [Abstract] .
AIDS 2020: 23rd International AIDS Conference Virtual . July 6–10, 2020. Abstract OAXLB0104.
