Early post-partum viremia predicts long-term non-suppression of viral load in HIV-positive women on ART in Malawi: Implications for the elimination of infant transmission

Megan Landes; Monique van Lettow; Joep J van Oosterhout; Erik Schouten; Andrew Auld; Thokozani Kalua; Andreas Jahn; Beth A Tippett Barr

doi:10.1371/journal.pone.0248559

. 2021 Mar 12;16(3):e0248559. doi: 10.1371/journal.pone.0248559

Early post-partum viremia predicts long-term non-suppression of viral load in HIV-positive women on ART in Malawi: Implications for the elimination of infant transmission

Megan Landes ^1,^2,^*, Monique van Lettow ^1,³, Joep J van Oosterhout ^1,^4,⁵, Erik Schouten ⁶, Andrew Auld ⁷, Thokozani Kalua ⁸, Andreas Jahn ^8,⁹, Beth A Tippett Barr ¹⁰

Editor: Graciela Andrei¹¹

PMCID: PMC7954347 PMID: 33711066

Abstract

Background

Long-term viral load (VL) suppression among HIV-positive, reproductive-aged women on ART is key to eliminating mother-to-child transmission (MTCT) but few data exist from sub-Saharan Africa. We report trends in post-partum VL in Malawian women on ART and factors associated with detectable VL up to 24 months post-partum.

Methods

1–6 months post-partum mothers, screened HIV-positive at outpatient clinics in Malawi, were enrolled (2014–2016) with their infants. At enrollment, 12- and 24-months post-partum socio-demographic and PMTCT indicators were collected. Venous samples were collected for determination of maternal VL (limit of detection 40 copies/ml). Results were returned to clinics for routine management.

Results

596/1281 (46.5%) women were retained in the study to 24 months. Those retained were older (p<0.01), had higher parity (p = 0.03) and more likely to have undetectable VL at enrollment than those lost to follow-up (80.0% vs 70.2%, p<0.01). Of 590 women on ART (median 30.1 months; inter-quartile range 26.8–61.3), 442 (74.9%) with complete VL data at 3 visits were included in further analysis. Prevalence of detectable VL at 12 and 24 months was higher among women with detectable VL at enrollment than among those with undetectable VL (74 detectable VL results/66 women vs. 19/359; p<0.001). In multivariable analysis (adjusted for age, parity, education, partner disclosure, timing of ART start and self-reported adherence), detectable VL at 24 months was 9 times more likely among women with 1 prior detectable VL (aOR 9.0; 95%CI 3.5–23.0, p<0.001) and 226 times more likely for women with 2 prior detectable VLs (aOR 226.4; 95%CI 73.0–701.8, p<0.001).

Conclusions

Detectable virus early post-partum strongly increases risk of ongoing post-partum viremia. Due to high loss to follow-up, the true incidence of detectable VL over time is probably underestimated. These findings have implications for MTCT, as well as for the mothers, and call for intensified VL monitoring and targeted adherence support for women during pregnancy and post-partum.

Introduction

In the last decade, prevention of maternal to child transmission of HIV (PMTCT) programs worldwide have transitioned from providing intermittent antiretroviral treatment (ART) for HIV-infected women during pregnancy, delivery and breastfeeding, to initiating lifelong ART (i.e., ‘Option B+’) [1]. This change has aligned PMTCT programs with evolving World Health Organization (WHO) universal test and treat guidelines for all persons living with HIV (i.e., ‘Treat All’) [2]. As a result, the number of women of reproductive age now initiating ART in sub-Saharan Africa has dramatically increased [3], and the benefit of long-term viral load suppression (VLS) during subsequent pregnancies, particularly in high fertility settings, has PMTCT outcomes now approaching those in high-income settings.

While pregnancy remains an important entry point for the current global ‘Treat All’ strategy, there is limited information regarding longitudinal VLS in this population [3]. Research studies reporting VLS estimates at various time points in the post-partum period signal particular challenges in reaching the UNAIDS goal of 90% VLS [4–7]. Further, among the few available population level estimates, we see a similar signal with Zimbabwe reporting VLS (<1000 copies/mL) in post-partum women on ART as 81.2% (CI: 79.4−83.1) at 4–12 weeks and 85.2% (CI: 82.9−87.4) at 12 months [8] and Uganda reporting a 3 year VLS (<1000 copies/mL) among post-partum women of 76% [9].

Several studies highlight difficulties in sustaining both adherence and VLS throughout the post-partum period. In Malawi, national routine program data demonstrate that only 30% women initiating ART during pregnancy or breastfeeding maintained adequate self-reported adherence at all visits over 2 years [10]. Data from South Africa show that during the first post-partum year, 30% of women on ART did not maintain VLS [11, 12], and in Zimbabwe, 50% of women did not maintain durable VLS over 12 months [8]. As detectable viremia determines risk of MTCT during pregnancy and breastfeeding [11, 13] as well as progression of illness in the mother, understanding and improving long-term VLS among women starting ART in pregnancy is key to eliminating MTCT and promoting the health of mothers.

In 2011, Malawi was the first country to implement ‘Option B+’ and has since shown large increases in women initiating ART in pregnancy [14], along with a remarkable reduction in early MTCT [15]. The National Evaluation of Malawi’s PMTCT Program (NEMAPP) study was launched in 2014 to evaluate the effectiveness of Option B+ by enrolling HIV-infected women and their infants at 4–26 weeks post-partum and following them annually for 2 years [16]. Within this nationally representative cohort, uptake of PMTCT services was very high at the time of enrollment: 97.8% of women knew their HIV status, 96.3% of these were on ART, and among a sub-set of these women 87.9% had achieved VLS (<1000 copies/ml) [13, 16]. Here we describe trends in detectable viral load (VL) among women on ART and retained until 24 months post-partum and we explore factors associated with VLS over time.

Methods

This is a nested study of HIV-infected mothers presenting with their 1 to 6-month-old infants at outpatient clinics in Malawi, where they were enrolled for longitudinal follow-up in the NEMAPP study between October 2014 and March 2016 (with follow-up visits till March 2018). The study period started three years after the national implementation of ‘Option B+’ PMTCT guidelines which provided lifelong ART (i.e., tenofovir/lamivudine/efavirenz) for all pregnant and breastfeeding women [17]. At the time of the study, the national HIV program was in the early stages of implementing routine VL monitoring and coverage was still limited.

NEMAPP used a multistage cluster design to sample 54 sites across Malawi [15] to provide national representative 24-month outcomes of MTCT. The subset included in this study, based on regional strata, were enrolled for intensive clinical and laboratory monitoring at 13 health facilities across 8 districts. A sub-set sample of 1324 HIV-positive mothers was calculated to estimate VLS based on an estimated 50% suppression rate and 50% loss to follow-up for a precision of 2.5% with a 95% confidence interval (95% CI) and an assumed design effect of 2.0.

Women in selected sites were simultaneously consented for enrolment in the main study and in this subset for more in-depth clinical and laboratory monitoring. Guardian-infant pairs were excluded from this current analysis (Fig 1). Mother-infant pairs were followed up at 12 and 24 months post-partum, with observed window periods of 10 to 18 and 20 to 28 months post-partum, respectively.

At enrolment, 12 and 24 months, mothers were interviewed by trained health facility staff using structured (pre-tested) questionnaires to obtain socio-demographic information, HIV status at screening, disclosure to partner status, uptake and timing of PMTCT/ART, self-reported health status and adherence to treatment (as self-reported number of days of missed ART in the last month, with ‘optimal adherence’ defined as 0–1 days of missed ART). ‘Durable adherence’ at any timepoint is defined as ‘optimal adherence’ at all time points. When possible, mothers’ health booklets and Ministry of Health registers were checked for accuracy of responses.

Maternal HIV VL testing was conducted on venous samples (Abbott Real-Time HIV-1 Assay, Abbott Laboratories, Chicago, IL) of all women regardless of ART status at enrollment, 12 and 24 months. VLS is defined as HIV 1-RNA <1000 copies/mL as per the Malawi national HIV guidelines [17]. We categorized VL results as ‘undetectable’ (<40 copies/mL) and ‘detectable’ (i.e., >40 copies/mL) with further sub-classification as ‘low-detectable’ (40–1000 copies/mL) and ‘unsuppressed’ (>1000 copies/mL). Further, we defined ‘durably undetectable VL’ as VL<40 copies/mL at all three study visits and ‘persistently detectable VL’ as VL>40 copies/mL at all three visits. The general term ‘viremia’ was used to describe the presence of any detectable virus in the blood.

Missing data were treated as additional categories. Crude percentages were calculated and comparisons between groups were made using chi-square tests for categorical variables and non-parametric tests for medians, using normal approximation (Wald) methods to calculate confidence intervals. Among women with complete VL observations, multivariable logistic regression analysis was used to identify characteristics associated with detectable vs. undetectable VL, with losing detectable VL vs. retaining undetectable VL, and with persistently detectable VL vs. those who had at least one undetectable VL. Univariate odds ratios (OR) with 95% CI were calculated for each variable in the model using normal approximation (Wald) methods. Adjusted OR (aOR) with 95% CI were calculated for each model after adjustment for age, parity, education level, partner disclosure, timing of ART initiation, previous VL results and adherence. All variables were simultaneously entered in the logistic regression model and tested for removal through backward stepwise selection. A 0.05 significance level was set for all statistical testing. Analyses were conducted using IBM SPSS Statistics 26 (IBM, Armonk, NY, USA).

Ethical approval was provided by Malawi’s National Health Sciences Research Committee (#1262) and the University of Toronto (#30448). The US Centers for Disease Control and Prevention (CDC) reviewed and approved as research according to human research protection procedures (#2014-054-7), but was not engaged. All participants provided written informed consent.

Results

Overall, 1281 HIV-infected mothers were enrolled in the study at 1–6 months post-partum with a median age of 29 years (interquartile range [IQR] 24–33) and parity of 3 (IQR 2–4) (data not shown). The majority of women (65.5%; n = 839) had either no formal or only primary level education. At enrollment, 94.3% (1208/1281) women already knew their HIV status and of these, 97.5% (1178/1208) were on ART. The median time on ART at enrollment was 8.3 months (IQR 5.2–39.5), with 47.6% (561/1178) of women having started ART pre-conception and 50.1% (590/1178) post-conception (Table 1).

Table 1. Characteristics of HIV-infected mothers enrolled for follow-up to 24 months.

	Enrolment	Annual visit 1	Annual visit 2
	1–6 months post-partum	12 months post-partum	24 months post-partum
N	1281	773	596
Region where mother resides and attends health care
North Central Rural	335 (26.2)	186 (24.1)	161 (27.0)
North Central Urban	392 (30.6)	193 (25.0)	131 (22.0)
South Rural	156 (12.2)	123 (15.9)	111 (18.6)
South Urban	398 (31.1)	271 (35.1)	193 (32.4)
Mothers’ age in years
≤19	79 (6.2)	50 (6.5)	35 (5.9)
20–24	287 (22.4)	145 (18 .8)	102(17.1)
25–29	335 (26.2)	197 (25.5)	152 (25.5)
≥ 30	576 (45.0)	379 (49.0)	305 (51.2)
Missing	4 (0.3)	2 (0.3)	2 (0.3)
Parity
1	192 (15.0)	108 (14.0)	76 (12.8)
2–3	633 (49.4)	366 (47.3)	275 (46.1)
≥ 4	454 (35.4)	298 (38.6)	244 (40.9)
Missing	2 (0.2)	1 (0.1)	1 (0.2)
Months post-partum at visit
1–3	931 (72.7)
4–6	350 (27.3)
10–16		713 (92.2)
17–18		60 (7.8)
20–26			568 (95.3)
27–28			28 (4.7)
Level of Education
None or primary education	839 (65.5)	492 (63.6)	385 (64.6)
Secondary or post-secondary education	440 (34.3)	280 (36.2)	211 (35.4)
Missing	2 (0.2)	1 (0.1)	0
Mothers’ HIV status at time of study screening (4–26 weeks post-partum)
Already known HIV-infected	1208 (94.3)	743 (96.1)	579 (97.1)
Newly diagnosed HIV-infected	73 (5.7)	30 (3.9)	17 (2.9)
Mothers’ reported disclosure of her HIV status to her partner at each visit
Yes, partner knows her HIV-positive status	1058 (82.6)	651 (84.2)	502 (84.2)
No, partner does not know her HIV-positive status	143 (11.2)	27 (3.5)	57 (9.6)
No partner	73 (5.7)	89 (11.5)	32 (5.4)
Missing	7 (0.5)	6 (0.8)	5 (0.8)
Mothers’ ART Initiation^$ (as reported at enrolment)
Started ART pre-conception	561 (43.8)	354 (45.8)	288 (48.3)
Started ART post-conception (during pregnany or post-partum)	590 (46.1)	362 (46.8)	278 (46.6)
Not started ART	87 (6.8)	53 (6.9)	29 (4.9)
Missing	43 (3.4)	4 (0.5)	1 (0.2)
Mothers’ ART status^$
On ART	1178 (92.0)	755^* (97.7)	590^** (99.0)
Not started ART	87 (6.8)	1 (0.1)	0
Started but Stopped ART	14 (1.1)	15 (1.9)	6 (1.0)
Missing	2 (0.2)	2 (0.3)	0
Time on ART in months (at time of visit) among those on ART, median (IQR)	8.3 (5.2–39.5)	19.2 (15.9–50.4)	30.1 (26.8–61.3)
Time on ART in months (at time of visit) among those on ART
≤3.0	75 (6.4)	3 (0.4)	0
3.1–6.0	275 (23.3)	3 (0.4)	0
6.1–12.0	229 (19.4)	49 (6.5)	4 (0.7)
12.1–18.0	31 (2.6)	238 (31.5)	6 (1.0)
18.1–24.0	39 (3.3)	89 (11.8)	47 (8.0)
≥24	345 (29.3)	297 (39.3)	483 (81.9)
Missing	184 (15.6)	76 (10.1)	50 (8.5)
Mothers’ self-reported health status
Well	1214 (94.8)	746 (96.5)	563 (94.5)
Minor Illness	52 (4.1)	23 (3.0)	17 (2.9)
Major Illness	8 (0.6)	0	0
Missing	7 (0.5)	4 (0.5)	16 (2.7)

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^$ Self-reported and verified/amended with clinical records when available.

* Including 39 women not (yet) on ART at enrolment of which 24 newly diagnosed at study enrolment.

** Including 27 women not (yet) on ART at enrolment of which 17 newly diagnosed at study enrolment.

Fig 1 describes follow-up and retention in the study. Overall, 773 (60.3%) women completed a 12 month study visit and 596 (46.5%) women completed a 24 month study visit, and of these, 97.7% (755/773) and 99.0% (590/596) were on ART, respectively (Table 2). Among women who did not complete the study, Ministry of Health registers confirmed that 91.5% (571/624) were known to be alive on ART at 24 months post-partum. In comparison to women alive and on ART but lost to follow-up from the study at 24 months, women remaining in the study at 24 months were more likely to be older (>30 years; p<0.01), have higher parity (p = 0.03) and more likely to be on ART at enrollment (p = 0.01). Further, women retained in the study had higher rates of undetectable VL at enrollment (VL <40 copies/mL) than those not (80.0% vs. 70.2%; p<0.01; S1 Table).

Table 2. Adherence and viral load over time among mothers on ART.

	Enrolment	12 months	24 months
N^*	1178	755^*	590^**
Nr of days having missed ART in the last month, among mothers on ART, at each visit
0	925 (78.5)	645 (85.4)	498 (84.4)
1 day	96 (8.1)	51 (6.8)	41 (6.9)
≥2 days	146 (12.4)	57 (7.5)	36 (6.1)
Missing	11 (0.9)	2 (0.3)	15 (2.5)
Combined self-reported adherence at 12 and 24 month
Fully optimal^# adherence over time		600 (79.5)	477 (80.8)
At least one sub-optimal^## adherence measure		131 (17.4)	104 (17.6)
Missing (data available for 1 visit only)		24 (3.2)	9 (1.5)
Viral load at each visit
<40	912 (77.4)	637 (84.4)	473 (80.2)
40–1000	90 (7.6)	21 (2.8)	19 (3.2)
>1000	145 (12.3)	61 (8.1)	48 (8.1)
Unknown/Missing	31 (2.6)	36 (4.8)	50 (8.5)
Nr of consecutive viral load observations
0	31 (2.6)	1 (0.1)
1	1147 (97.4)	53 (7.0)	8 (1.4)
2		701 (92.8)	140 (23.7)
3			442 (74.9)
Cumulative detectable viral loads^*	n = 1147	n = 701	n = 442^***
0 current and previous detectable (>40) VL	912 (79.5)	548 (78.2)	345 (78.1)
1 current or previous detectable (>40) VL	235 (20.5)	88 (12.6)	48 (10.9)
2 current and/or previous detectable (>40) VL		65 (9.3)	16 (3.6)
3 current and previous detectable (>40) VL			33 (7.5)

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* Including 39 women reported not on ART at enrolment of which 24 newly diagnosed at study enrolment.

** Including 27 women reported not on ART at enrolment of which 17 newly diagnosed at study enrolment.

*** Including 17 women reported not on ART at enrolment of which 10 newly diagnosed at study enrolment.

^# Reported to have missed ART 0 or 1 day in the last month in all visits (2 or 3).

^## Reported to have missed ART 2 or more days in the last month in 1 or more previous visits.

Overall, 86.7% (1021/1178) of women on ART had optimal adherence (i.e., 0–1 days missed ART in past month) at enrollment, 92.2% (696/755) at 12 months and 91.4% (539/590) at 24 months (Table 2). Further, 79.5% (600/755) of women retained had durable adherence at 12 months and 80.8% (477/590) had durable adherence at 24 months. Overall, among women with available VL data, VLS ratios (VL <1000 copies/mL) at enrollment, 12 and 24 months were 87.4% (1002/1147), 91.5% (658/719), 91.1% (492/540), respectively.

Table 3 describes VL trends among women with complete VL data over the 24 months post-partum period (N = 442), among whom 17 were not yet on ART at enrollment but subsequently started (10 were new diagnoses). Among women on ART at enrollment (n = 425), 80.7% (343/425) women had durable undetectable VL (<40 copies/mL) over 24 months, 11.8% (50/425) experienced at least one episode of viremia, and 7.5% (32/425) had persistently detectable VL. The prevalence of detectable VL at enrolment, 12 and 24 months were 15.5% (66/425), 9.9% (42/425) and 12.0% (51/425). The prevalence of detectable VL at 12 and 24 months was higher among women with detectable VL at enrollment than those with undetectable VL (74 detectable VL measures/66 women vs. 19/359; p<0.001).

Table 3. Viral load trends among women with complete viral load data.

Women on ART from Study Enrolment, n = 425						Women NOT on ART at study enrolment, n = 17
Enrolment		12-month visit		24-month visit		Enrolment		12-month visit		24-month visit
<40	359	<40	353	<40	343^$	<40	2^#	<40	2	<40	2
				40–1000	5					40–1000
				>1000	5					>1000
		40–1000	3	<40	2			40–1000		<40
				40–1000	1					40–1000
				>1000	0					>1000
		>1000	3	<40	1			>1000		<40
				40–1000	1					40–1000
				>1000	1					>1000
40–1000	27	<40	18	<40	15
				40–1000	3
				>1000	0
		40–1000	4	<40	0
				40–1000	2^*
				>1000	2^*
		>1000	5	<40	1
				40–1000	0^*
				>1000	4^*
>1000	39	<40	12	<40	9	>1000	15^##	<40	12	<40	11
				40–1000	0					40–1000	1
				>1000	3					>1000	0
		40–1000	3	<40	0			40–1000	1	<40
				40–1000	1^*					40–1000
				>1000	2^*					>1000	1
		>1000	24	<40	3			>1000	2	<40	2
				40–1000	1^*					40–1000
				>1000	20^*					>1000

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^$ Durable undetectable viral load.

* Persistent viremia (total:32).

^# Known HIV-positive mothers (1 not started, 1 stopped ART).

^## 10 newly diagnosed not yet on ART and 5 known HIV-positive mothers (3 not started and 2 stopped ART).

Further, Fig 2 shows the results of sequential VL testing at 1–6, 12 and 24 months post-partum where plots are of VL trajectories for individual mothers stratified by ART start at either pre-conception, post-conception or post-enrollment. Among the women starting ART pre- and post-conception, 16.3% (33/203) and 22.1% (49/222; p = 0.13), respectively, had at least one episode of viremia within 24 months. Overall, women with newly diagnosed HIV at enrollment experienced high loss to follow-up in the cohort (17/73 (23.3%) were retained to 24 months); however, the majority of women who started ART post-enrollment (15/17; 88.2%) gained VLS after ART initiation.

Table 4 describes factors associated with having a detectable VL at 24 months. In univariable analysis, both sub-optimal adherence measures and detectable VL in previous visits were associated with detectable VL at 24 months. In multivariable analysis (adjusted for age, parity, education, partner disclosure, timing of ART start and adherence), having detectable VL at 24 months was 9.0 times more likely among women with 1 prior detectable VL (95% CI 3.5–23.0, p<0.0001) and 226.4 times more likely for women with 2 prior detectable VLs (95% CI 73.0–701.8, p<0.0001).

Table 4. Factors associated with detectable viral load (VL >40) at 24 months post-partum among women on ART and having complete VL data (N = 442).

	VL>40 vs those with VL<40 around infant age 24 months
	n/n	%	Univariate (unadjusted)		Multivariable (adjusted)
			OR (95%CI)	p-value	aOR (95%CI)^#	p-value
Total	53/442	12.0
Mother’s age in years
≤24	11/104	10.6	0.8 (0.4–1.9)	0.60
≥25	42/336	12.5	ref
Missing	0/2
Parity, %
1–2	15/141	10.6	0.8 (0.4–1.5)	0.55
3+	38/301	2.6	ref
Level of Education
None or primary education	29/272	10.7	0.7 (0.4–1.3)	0.28
Secondary or post-secondary education	24/170	14.1	ref
Mother’s reported disclosure of her HIV status to her partner at any time during the study
Yes, partner knows her HIV-positive status	48/400	12.0	ref
No partner throughout study period or mother never disclosed during study period	5/42	12.2	1.0 (0.4–2.6)	0.98
Maternal ART Initiation
Pre-conception (started ART before last pregnancy)	24/203	11.8	ref
Post-conception (started ART during last pregnancy or post-partum)	27/222	12.2	1.0 (0.6–1.9)	0.91
New infections/not on ART at enrolment	2/17	11.8	0.99 (0.2–4.6)	0.99
Combined Self-reported adherence at 12 and 24 month (among those on ART)
Fully optimal^* adherence over time	37/358	10.3	ref
At least one sub-optimal^** adherence measure	16/83	19.3	2.1 (1.1–3.9)	0.03
Missing (data available for 1 visit only)	0/1	0.0
Cumulative detectable VLs
0 previous detectable (>40) VL	10/355	2.8	ref
1 previous detectable (>40) VL	10/48	20.8	9.1 (3.6–23.2)	0.0001	9.0 (3.5–23.0)	0.0001
2 previous detectable (>40) VL	33/39	84.6	189.8 (64.9–555.0)	0.0001	226.4 (73.0–701.8)	0.0001

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^# All variables were simultaneously entered in the logistic regression model as the first step and tested for removal one by one. In the multivariable analysis, only variables with significant associations in the last step are shown.

* Reported to have missed ART 0 or 1 day in the last month in all visits (2 or 3).

** Reported to have missed ART 2 or more days in the last month in 1 or more previous visits.

Table 5A describes risk factors associated with experiencing any further viremia during the post-partum period among women who had undetectable VL at enrollment (N = 361). In multivariable analysis, having at least one sub-optimal adherence measure tripled the risk of a having a viremic episode during the 24 months post-partum (aOR 3.2, 95% CI 1.1–9.4, p = 0.03; controlled for age, parity, education, partner disclosure and timing of ART initiation). Table 5B describes risk factors associated with having a persistent detectable VL through the post-partum period (vs. all others with at least one undetectable VL<40). In multivariable analysis, having at least one sub-optimal adherence measure more than doubled the risk of persistent viremia (aOR 2.3, 95% CI 1.1–4.9, p = 0.03; controlled for age, parity, education, partner disclosure and timing of ART initiation).

Table 5. a and b Factors associated with experiencing any viremia during the post-partum period and with persistent detectable VL load through the post-partum period.

	a. Losing VLS over time (ie. not maintaining it). Those with at least one VL measure >40 vs those that had 3/3 VLS<40						b. Persistent viremia Those on ART at 24 months with 3/3 >40 vs all others (who had at least one VL<40)
	n/n	%	Univariate (unadjusted)		Multivariable (adjusted)		n/n	%	Univariate (unadjusted)		Multivariable (adjusted)
			OR (95%CI)	p-value	aOR (95%CI)^*	p-value			OR (95%CI)	p-value	aOR (95%CI)^*	p-value
Total	16/361	4.4					33/422	7.8
Mothers’ age in years
≤24	5/80	6.3	1.6 (0.5–4.8)	0.38			7/104	6.7	0.9 (0.4–2.0)	0.73
25+	11/279	3.9	ref				26/336	7.7	ref
Missing							0/2
Parity
≤2	7/117	6.0	1.7 (0.6–4.6)	0.33			8/141	5.7	0.7 (0.3–1.5)	0.33
3+	9/244	3.7	ref				25/301	8.3	ref
Level of Education, %
None or Primary Education	10/225	4.4	1.0 (0.4–3.0)	0.99			17/272	6.3	0.6 (0.3–1.3)	0.22
Secondary and post-secondary education	6/136	4.4	ref				16/170	9.4	ref
Mothers’ reported disclosure of her HIV status to her partner at any time during the study
Yes, partner knows her HIV-positive status	15/326	4.6	ref				29/400	7.3	ref
No partner throughout study period or mother never disclosed during study period	1/35	2.9	0.6 (0.1–4.8)	0.64			4/42	9.5	1.3 (0.4–4.0)	0.59
Mothers’ ART initiation
Pre-conception (started ART before last pregnancy)	6/176	3.4	ref				14/203	6.9	ref
Post-conception (started ART during last pregnancy or post-partum)	10/183	5.5	1.6 (0.6–4.6)	0.35			18/222	8.1	1.2 (0.6–2.5)	0.64
New infections/not on ART (yet) at enrolment	0/2	0					1/17	5.9	0.8 (0.1–6.8)	0.87
Combined self-reported adherence at 12 and 24 month
Fully optimal^* adherence over time	10/302	3.3	ref		ref		22/358	6.1	ref		Ref
At least one sub-optimal^** adherence measure	6/59	10.2	3.3 (1.2–9.5)	0.03	3.2 (1.1–9.4)	0.03	11/83	13.3	2.3 (1.1–5.0)	0.03	2.3 (1.1–4.9)	0.03
Missing (data available for 1 visit only)							0/1

Open in a new tab

* All variables were simultaneously entered in the logistic regression model as the first step and tested for removal one by one. In the multivariable analysis, only variables with significant associations in the last step are shown.

** Reported to have missed ART 0 or 1 day in the last month in all visits (2 or 3).

Discussion

We present long-term VLS data among Malawian women living with HIV (WLHIV) to 24 months post-partum. While we document high ART coverage (>93%) among women retained in the study and that optimal adherence was high (87–92%) when measured at each time point, the proportion of women with durable adherence throughout post-partum was lower (80.8%). Similarly, while the proportion of women with VLS at each time point met the UNAIDS goal of >90%, fewer women were able to maintain durable VLS throughout the post-partum period: approximately 20% of women experienced at least one episode of viremia and 7.5% had persistently detectable VL. Among women with complete VL data, detectable VL in the early post-partum period signaled an increased risk of ongoing viremia at both 12 and 24 months post-partum. Sub-optimal adherence was significantly associated with both losing viral suppression among women who had VLS at enrollment and with having persistently detectable VL.

Currently, limited data exist regarding long-term VLS among women enrolled in PMTCT programs in sub-Saharan Africa [3]. The VLS proportions measured here at early post-partum, 12 and 24 months approximated UNAIDS 90-90-90 goals and are similar to VLS reported in other countries in the region [8, 9]. We additionally report that approximately 80% retained in this cohort had durable VLS to 24 months, which will confer increased benefit in preventing HIV transmission during breastfeeding and subsequent pregnancies, as well as preservation of health in mothers. However, the proportion of women achieving durable VLS in our study is higher than that reported in South Africa (70% (<50 copies/mL) at 12 months and 56% at 36–60 months (median 44 months post-partum)) [18] and in Kenya (67% (<1000 copies/mL) at 12months) [19]. These differences may be explained by diverse proportions of retention and loss to follow-up across these different settings, including that women retained to 24 months in our study may not reflect population-level VLS among all post-partum Malawian women.

However, despite comparatively higher rates of durable VLS over 24 months in this cohort, approximately 1 in 5 women still experienced at least one post-partum episode of viremia which likely has implications for MTCT, as well as the health of the mothers. While we cannot specifically comment on the duration or frequency of viremic episodes in relationship to individual level MTCT (as both were measured at yearly intervals over 24 months), we previously showed that non-suppressed VL, including low-level viremia (>40–1000 copies/ml) measured in the early post-partum period was predictive of MTCT at enrolment (4–26 weeks) in this same cohort of women [13]. Further, in Zimbabwe, a similar PMTCT program using a universal test and treat strategy linked non-durable VLS to increased MTCT risk to 18 months [8]. Considering this impact, and in light of emerging evidence here and in other studies in the region suggesting that women in pregnancy and post-partum may experience frequent episodes of viremia, this is an important finding for PMTCT programs [6].

What drives episodic viremia among post-partum women is likely to be challenges with adherence. Myer et al. [12] showed that ART non-adherence (versus drug-resistant mutations) explain the vast majority of new viremic episodes in pregnant and post-partum women with elevated VL after initial suppression. [12] Our study adds evidence that maintaining durable adherence is difficult in this period, with more than 20% of women retained to 24 months having at least one sub-optimal adherence measure [20, 21]. Literature has documented challenges in adherence, retention and achieving VLS in women initiating ART during pregnancy and breastfeeding [3, 7, 10] and highlights the role of post-partum physical, emotional and life role changes, including the increased care demands of an infant, as presenting particular challenges for this population [18, 20, 22]. Further studies highlight that non-adherence in pregnancy and the post-partum period is additionally related to biomedical, individual and health system-related factors, such as ART toxicity, comorbidities, stigma, HIV-status disclosure, mental health, food insufficiency, healthcare worker attitudes and the availability of supportive services [23–32].

While myriad interventions have been studied to support adherence, and subsequent loss of viral control in WLHIV in pregnancy and breastfeeding, finding ways to specifically identify women most at risk may be of benefit to programs to enable early targeted or differentiated care. Phillips et al. show that measures of self-reported adherence repeated over time are effective in identifying both current or pending elevated VL in HIV-infected pregnant and post-partum populations on ART [7, 18]. Further, we show that one VL measure early in the post-partum period strongly signals a risk of ongoing VL non-suppression up to 24 months. Currently, few countries implement a strategy of intensified VL monitoring during pregnancy, delivery, and post-partum, partly due to limited operational capacity and lack of a global consensus on best practices for VL testing during pregnancy and breastfeeding [33], however these results suggest that targeting at least one VL early in the post-partum period would identify women with high VL who are at highest risk of non-suppression through post-partum. The results of our study underline that further research is needed to determine the optimal timing and frequency of VL monitoring among pregnant and breastfeeding women to identify at-risk women and effective interventions that can achieve durable VLS in order to reach virtual elimination of MTCT.

Strengths and limitations

The strengths of this study are in estimating levels of VL suppression at three time points in the post-partum period within a nationally representative cohort as part of a programmatic evaluation of Option B+ in Malawi. However, loss to follow-up in this cohort was high over 24 months which may bias our results. While a portion of this analysis included a smaller subset of only women with complete data over 24 months, the characteristics of this sub-cohort as described in the results likely lead to an underestimation of the number and proportion of viremic episodes and resulting implications for MTCT rates. We showed that detectable VL at enrollment conferred significant risk of continuing viremia at 12 and 24 months among those retained in the study. The risk of ongoing viremia is likely higher in those lost to follow (who were younger with lower parity and were more likely to have detectable VL at enrolment) and subsequently in the WLHIV population. The NEMAPP study deliberately did not place dedicated study staff at health facilities as it aimed to evaluate routine circumstances in the field. This resulted in regularly missed study procedures during routine clinic visits. Ministry of Health staff, burdened with a heavy routine clinic workload, also had to conduct study defaulter tracing activities, which is likely to have led to higher loss-to follow up rates. Loss to follow-up was high but anticipated in the original sample size calculations. Finally, we did not examine the potential role of drug resistance.

Conclusion

Detectable VL early post-partum strongly increases risk of ongoing post-partum viremia with implications for infant HIV transmission, as well as for the health of the mother. While the proportion of women retained in the study met the UNAIDS 90-90-90 goals of >90% VLS, a significantly lower proportion achieved durable sustained VLS. Due to mothers with non-sustained VLS during the breastfeeding period, coupled with the likelihood of following pregnancies in a high fertility setting, large numbers of infants remain at risk of acquiring HIV infection. Additionally, with UNAIDS recently releasing new targets for 95% of pregnant and breastfeeding women to reach viral suppression to achieve the elimination of transmission [34], intensified and differentiated VL monitoring and targeted adherence support is required both during pregnancy and the breastfeeding period.

Supporting information

S1 Table. Baseline characteristics of women who completed the study versus those lost-to-follow from study.

(DOCX)

Click here for additional data file.^{(17.3KB, docx)}

S1 Data

(XLSX)

Click here for additional data file.^{(383KB, xlsx)}

S1 File

(PDF)

Click here for additional data file.^{(342.5KB, pdf)}

Acknowledgments

We would like to acknowledge Dr. Marie Louise Newell for her contributions to this manuscript.

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

This project has been supported by the President’s Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention (CDC) under the terms of cooperative agreement U2GGH000721. CDC staff were involved as co-investigators, assisting in protocol development and approval and manuscript authorship. The authors acknowledge full access to all the data and final responsibility for submission. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the funding agencies.

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PLoS One. doi: 10.1371/journal.pone.0248559.r001

Decision Letter 0

Graciela Andrei

15 Dec 2020

PONE-D-20-36329

Early post-partum viremia predicts long-term non-suppression of viral load in HIV-positive women on ART in Malawi : Implications for the elimination of infant transmission

PLOS ONE

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Reviewer #1: The authors present a well described analysis of post-partum HIV viral loads among women on ART in Malawi. Overall the analysis provides a good report from a setting that has had a recent significant scale up in viral load testing in a key population for the elimination of MTCT. I have only one major issue, which is surrounding the approach to the multivariable analysis, otherwise there are a few points that could be clarified.

Major:

Methods, lines 77. PPS sampling is implied here, but I don't think the analysis is weighted for this - this was not clear to me.

Methods, lines 116-119. Stepwise selection is known to be a historically bad method of variable selection. It has many issues and does not represent a sound method of reducing/selecting variables for consideration. This is the reason that I indicated the analysis was not correct. Usually when interested in associations or risk factors we should have considered carefully the potential exposures/risk factors, as well as measured confounders, and other adjustment factors and should estimate our model from that basis. In a strictly predictive setting, again, stepwise selection would be the incorrect approach - other methods such as penalisation would perform better, but also in a strictly predictive setting we would evaluate our model at least under some sort of internal validation process (such as k-fold cross validation).

Results:

The relatively small sample sizes and large OR & CI led me to question the stability of the estimates. Was any assessment for multi-collinearity and/or quasi-separation done?

This analysis primarily reports VLS among individuals retained - this needs to be emphasised much more in the discussion as it is very key to understanding the value of the analysis.

Table 3: Proportions might be useful here, and the authors could consider a flow diagram / alluvial type plot

Table 4 (and Table 5): It is unclear to me in the adjusted model if NS means not included, or not-significant. If the latter, the OR and CI intervals should be reported.

Minor comments:

Abstract: Please report OR estimates along with CI intervals (rather than just "9 times" etc)

Methods, lines 78-90: This is just not clear and I wonder if it could be rephrased so the sample size calculation for this can be better understood.

Reviewer #2: This is a well-written paper that presents important findings on postpartum viral load outcomes in a nationally representative sample of women living with HIV in Malawi. While the study reassuringly finds higher proportions of viral suppression than reported in other settings, these still remain below global targets and this study clearly shows that women who have one raised viral load remain at risk for subsequent viremia.

Overall, the paper is very clearly presented. I have a few comments for clarity.

1. I found the wording of the first sentence f the results section in the abstract to be confusing - can you revise to be more clear that this is comparing retained in study to lost from study- were 46.5% retained and older, or just retained?

2. I appreciate that the results have been clearly presented as being among women with completed viral loads. I do think that the point raised in lines 139-141 that women who were lost from the study largely were known to be alive and on ART through routine data is important. I think the authors could make this clearer perhaps by adding this into the Figure 1 flow diagram (lost from study but known to be in care) and also in the discussion around considering the impact of missing data. I agree that viremia if anything is underestimated but the fact that most women lost from the study were still in ART care is useful to support why other missing data methods have not been used.

3. For the models in Table 4 and 5, it’s not clear if the variables reported as NS in the adjusted models were included in the final model but results not reported as not significant, or if these variables were kicked out of the model in the backward stepwise process. I suggest the adjusted OR and 95% CI be reported for each variable that was in included in the final model following the stepwise selection rather than reporting as NS.

4. Do the authors have any thoughts on what could be done to best use the viral load information when it is available? When a woman has a raised VL postpartum she is at increased risk of either staying viremic or having subsequent viremia – what sort of interventions could be implemented at that time?

5. You may consider referencing the latest UNAIDS targets (in the 2020 world AIDS report) which include targets for viral suppression during breastfeeding (95% of pregnant and breastfeeding women living with HIV have suppressed viral loads). https://www.unaids.org/sites/default/files/media_asset/prevailing-against-pandemics_en.pdf

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PLoS One. 2021 Mar 12;16(3):e0248559. doi: 10.1371/journal.pone.0248559.r002

Author response to Decision Letter 0

4 Jan 2021

PONE-D-20-36329

Early post-partum viremia predicts long-term non-suppression of viral load in HIV-positive women on ART in Malawi: Implications for the elimination of infant transmission

Responses to reviewers’ comments:

When submitting your revision, we need you to address these additional requirements.

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Response: We have verified that the manuscript meets the requirements and made a few adjustments as needed

Response: We have included the relevant questionnaires (that include both English and the local language) as supporting information. Please note that only a selection of questions from these questionnaires were used for this sub-analysis.

3. In the Methods, please discuss whether and how the questionnaire was validated and/or pre-tested. If these did not occur, please provide the rationale for not doing so.

Response: questionnaires were pre-tested prior to study start. This has now been included in the method section.

Response: We believe that we described all the technical details and procedures required to reproduce the analysis. Post-hoc corrections were not performed/not deemed necessary. The statistical methods were reviewed and approved by 2 statisticians during CDC internal review.

5. Please include a caption for figure 2.

Response: thanks, this has now been included

6. We note that Supporting Information S2 Data with your paper includes detailed descriptions of individual patients/participants, i.e. data of birth.

Response: We belief that without any other data provided, participants cannot be identified through the date of birth only. However, we have taken out date of birth in the dataset. Please delete the current version from your depository.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

________________________________________

3. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

4. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

5. Review Comments to the Author

Reviewer #1: The authors present a well described analysis of post-partum HIV viral loads among women on ART in Malawi. Overall, the analysis provides a good report from a setting that has had a recent significant scale up in viral load testing in a key population for the elimination of MTCT. I have only one major issue, which is surrounding the approach to the multivariable analysis, otherwise there are a few points that could be clarified.

Major:

Methods, lines 77. PPS sampling is implied here, but I don't think the analysis is weighted for this - this was not clear to me.

Response: Thank you, this was not correctly described and has now been amended.

PPS sampling was for the total cohort. Indeed, for the total cohort we used weighted analyses to control for the survey design. However, for this sub-set weighted analysis would not be appropriate.

Response:

Thank you for your careful consideration of the analysis plan. We utilized the stepwise selection after discussion with CDC statisticians. After consulting again with them on receiving your review feedback, they advised that while from an academic standpoint it may not be ideal, the disadvantages are not considered ‘bad’ or ‘unsound’ as it remains a very practical approach in this context. In our early infant transmission (6-12wks of age) analysis conducted with study enrolment data, we developed and utilized a directed acyclic graph (DAG) to identify confounders and guide selection of variables (see Lancet article embedded and figure pasted below). These same variables were therefore most likely to be relevant in the model utilized at 24mos of age, and because we were able to use existing knowledge to a-priori determine what factors would be reasonable to include in the model, then the method chosen was appropriate.

If preferred, we would be happy to reference or reproduce this DAG in this paper as well, as the variables included are the same. Thank you in advance for your guidance.

Results:

The relatively small sample sizes and large OR & CI led me to question the stability of the estimates. Was any assessment for multi-collinearity and/or quasi-separation done?

Response: We agree that this final model represents a large OR and CI based on the relatively small sample size. We did not employ the methods suggested but have ensured that we are highlighting this in the limitations of our analysis.

This analysis primarily reports VLS among individuals retained - this needs to be emphasised much more in the discussion as it is very key to understanding the value of the analysis.

Response: we have emphasized this further in the discussion, as suggested.

Table 3: Proportions might be useful here, and the authors could consider a flow diagram / alluvial type plot

Response: We have tried several versions of charts but concluded that the current (sideways) flow chart is clearest. As there are several levels of comparisons, we did not complete proportions. These are described in the text.

Table 4 (and Table 5): It is unclear to me in the adjusted model if NS means not included, or not-significant. If the latter, the OR and CI intervals should be reported.

Response: Thank you – this was indeed not clear and has now been amended in tables and footnotes. “All variables were simultaneously entered in the logistic regression model as the first step and tested for removal one by one. In the multivariable analysis, only variables with significant associations in the last step are shown.”

Minor comments:

Abstract: Please report OR estimates along with CI intervals (rather than just "9 times" etc)

Response: The aORs have been added

Methods, lines 78-90: This is just not clear and I wonder if it could be rephrased so the sample size calculation for this can be better understood.

Response: this has now been rephrased.

Overall, the paper is very clearly presented. I have a few comments for clarity.

1. I found the wording of the first sentence of the results section in the abstract to be confusing - can you revise to be more clear that this is comparing retained in study to lost from study- were 46.5% retained and older, or just retained?

Response: this has now been made more clear

Response: Thank you – that is a good idea. We have now added those lost n study but know to be in care in Figure 1. The impact of missing data has also been further discussed in the Discussion

Response: the aORs and 95% CI have now been added to the tables for those that were not significant but included in the model.

Response: We have added our suggestion to the results – that where resources are limited for VL, targeting at least one in the PP period would allow for identification of those women at highest risk of non-suppression throughout PP. (Ideally this VL would be during pregnancy as well, but this is beyond the scope/implications of our PP findings).

Response: Thank you. This has been added as suggested

________________________________________

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Reviewer #1: No

Reviewer #2: No

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PLoS One. doi: 10.1371/journal.pone.0248559.r003

Decision Letter 1

Graciela Andrei

26 Jan 2021

PONE-D-20-36329R1

Early post-partum viremia predicts long-term non-suppression of viral load in HIV-positive women on ART in Malawi : Implications for the elimination of infant transmission

PLOS ONE

Dear Dr. van Lettow,

==============================

As suggested by Reviewer # 1, when preparing the second revised version, please remove from the manuscript the multivariable results, which are not relevant and actually misleading.

==============================

Please submit your revised manuscript by Mar 12 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

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We look forward to receiving your revised manuscript.

Kind regards,

Graciela Andrei

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: The analysis is not acceptable to me while there is inference made on a multivariable method where variable selection is by step wise regression was carried out. The multivariable analysis could be removed, and I would be happy to recommend the manuscript for publication.

Issues surrounding step wise selection of variables in multivariable regression include having biased upward R2 and biased downward standard errors where F and chi-2 test statistics do not have claimed distribution - this means the CI intervals around the parameter estimates are incorrect. The p-values are too low (and in fact not p-values as we understand them) because of multiple comparisons, but very difficult to correct because of the dependent nature of the steps. Parameter estimates tend to be biased high (in absolute value), and there is no guarantee that any or all of the variables with 'true' associations with the outcome will be identified.

Relevant references:

Altman DG, Andersen PK. 1989. Bootstrap investigation of the stability of a Cox regression model. Statistics in Medicine 8: 771–783.

Burnham KP, Anderson DR. (2002), Model selection and multimodel inference, Springer, New York.

Copas JB. 1983. Regression, prediction and shrinkage (with discussion). Journal of the Royal Statistical Society, Series B 45: 311–354.

Derksen S. Keselman HJ. 1992. Backward, forward and stepwise automated subset selection algorithms: frequency of obtaining authentic and noise variables. British Journal of Mathematical and Statistical Psychology 45: 265–282.

Harrell F E (2001), Regression modeling strategies: With applications to linear models, logistic regression, and survival

analysis, Springer-Verlag, New York.

Hurvich CM, Tsai CL. 1990. The impact of model selection on inference in linear regression. American Statistician 44: 214–217.

Judd, McClelland. Data Analysis: A Model Comparison Approach (Harcourt Brace Jovanovich, ISBN 0-15-516765-0)

Mantel N. 1970. Why stepdown procedures in variable selection. Technometrics 12: 621–625.

Roecker EB. 1991. Prediction error and its estimation for subset—selected models. Technometrics 33: 459–468.

Tibshirani R. 1996. Regression shrinkage and selection via the lasso. Journal of the Royal Statistical Society, Series B 58: 267–288.

Reviewer #2: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

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Reviewer #1: No

Reviewer #2: No

PLoS One. 2021 Mar 12;16(3):e0248559. doi: 10.1371/journal.pone.0248559.r004

Author response to Decision Letter 1

25 Feb 2021

PONE-D-20-36329R1

Early post-partum viremia predicts long-term non-suppression of viral load in HIV-positive women on ART in Malawi : Implications for the elimination of infant transmission

PLOS ONE

Response to comment Reviewer 1:

==============================

Reviewer # 1, when preparing the second revised version, please remove from the manuscript the multivariable results, which are not relevant and actually misleading.

==============================

Thank you for your thorough review.

We consulted with academic and programmatic statisticians and discussed the feedback received.

As described in the former response to reviewers’ comments we were advised that while from an academic standpoint our analyses may not be ideal, that the disadvantages were not considered ‘bad’ or ‘unsound’ as it remains a very practical approach in this context. We also explained that in our early infant transmission (6-12wks of age) analysis conducted with study enrolment data, we developed and utilized a directed acyclic graph (DAG) to identify confounders and guide selection of variables (see Lancet article: https://www.thelancet.com/pdfs/journals/lanhiv/PIIS2352-3018(18)30316-3.pdf). These same variables were therefore most likely to be relevant in the model utilized at 24mos of age, and because we were able to use existing knowledge to a-priori determine what factors would be reasonable to include in the model, then the method chosen was appropriate.

After careful consideration, we did not remove the multivariable results from the manuscript, as we disagree that the nuanced method changes would result in a measurable difference to the findings, and the paper would ultimately be of lower quality. As pragmatic researchers with a focus on creating evidence for programmatic improvement, we believe that our conclusions that women with non-suppressed viral load at early postpartum are likely to remain elevated at 12 months and 24 months needs to be published (ie. a single VL measure at this timepoint can identify the majority of women who remain unsuppressed).

Attachment

Submitted filename: Second Response to Reviewer PlosONe .docx

Click here for additional data file.^{(17.1KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0248559.r005

Decision Letter 2

Graciela Andrei

2 Mar 2021

Early post-partum viremia predicts long-term non-suppression of viral load in HIV-positive women on ART in Malawi : Implications for the elimination of infant transmission

PONE-D-20-36329R2

Dear Dr. van Lettow,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Graciela Andrei

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0248559.r006

Acceptance letter

Graciela Andrei

3 Mar 2021

PONE-D-20-36329R2

Early post-partum viremia predicts long-term non-suppression of viral load in HIV-positive women on ART in Malawi: Implications for the elimination of infant transmission

Dear Dr. van Lettow:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

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on behalf of

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PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. Baseline characteristics of women who completed the study versus those lost-to-follow from study.

(DOCX)

Click here for additional data file.^{(17.3KB, docx)}

S1 Data

(XLSX)

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S1 File

(PDF)

Click here for additional data file.^{(342.5KB, pdf)}

Attachment

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Click here for additional data file.^{(188.4KB, docx)}

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Data Availability Statement

All relevant data are within the paper and its Supporting Information files.

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Early post-partum viremia predicts long-term non-suppression of viral load in HIV-positive women on ART in Malawi: Implications for the elimination of infant transmission

Megan Landes

Monique van Lettow

Joep J van Oosterhout

Erik Schouten

Andrew Auld

Thokozani Kalua

Andreas Jahn

Beth A Tippett Barr

Roles

Abstract

Background

Methods

Results

Conclusions

Introduction

Methods

Fig 1. Mothers enrolled, followed and retained in the study up to 24 months post-partum.

Results

Table 1. Characteristics of HIV-infected mothers enrolled for follow-up to 24 months.

Table 2. Adherence and viral load over time among mothers on ART.

Table 3. Viral load trends among women with complete viral load data.

Fig 2. Sequential viral load testing in a cohort of 442 mothers who were tested at 1–6, 12 and 24 months post-partum in Malawi stratified by ART start as either pre-conception, post-conception or post-enrollment.

Table 4. Factors associated with detectable viral load (VL >40) at 24 months post-partum among women on ART and having complete VL data (N = 442).

Table 5. a and b Factors associated with experiencing any viremia during the post-partum period and with persistent detectable VL load through the post-partum period.

Discussion

Strengths and limitations

Conclusion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Graciela Andrei

Roles

Author response to Decision Letter 0

Decision Letter 1

Graciela Andrei

Roles

Author response to Decision Letter 1

Decision Letter 2

Graciela Andrei

Roles

Acceptance letter

Graciela Andrei

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

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RESOURCES

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