Postnatal HIV Transmission in breastfed infants of HIV-infected women on ART: a
systematic review and meta-analysis
Stephanie Bispo1§ , Lana Chikhungu2*, Nigel Rollins3*, Nandi Siegfried4*, Marie-Louise
Newell5*
Department of Social Statistics and Demography, University of Southampton, Southampton,
UK.
2
School of Languages and Area Studies, University of Portsmouth, Portsmouth, UK
3
Department of Maternal, New-born, Child and Adolescent Health, World Health
Organisation, Geneva, Switzerland
4
Medical Research Council, Cape Town, South Africa
5
Human Development and Health, Faculty of Medicine, University of Southampton,
Southampton, UK
§
Corresponding author: Stephanie Bispo
University Road
Southampton, SO17 1BJ, England.
Phone number: +44 7870545308
Email: [email protected]
*These authors have contributed equally to the work
Email addresses of authors:
SB: [email protected]
LC: [email protected]
NR: [email protected]
NS: [email protected]
MLN: [email protected]
Key words: Antiretroviral therapy; HIV; prevention of mother-to-child transmission; breast
feeding; systematic review; meta-analysis.
1
Abstract
2
Introduction: To systematically review the literature on mother-to-child transmission in
3
breastfed infants whose mothers received antiretroviral therapy and support the process of
4
updating the WHO infant feeding guidelines in the context of HIV and ART.
5
Methods: We reviewed experimental and observational studies; exposure was maternal HIV
6
antiretroviral therapy (and duration) and infant feeding modality; outcomes were overall and
7
postnatal HIV transmission rates in the infant at 6, 9, 12 and 18 months. English literature
8
from 2005 to 2015 was systematically searched in multiple electronic databases. Papers were
9
analysed by narrative synthesis; data were pooled in random effects meta-analyses. Postnatal
10
transmission was assessed from 4-6 weeks of life. Study quality was assessed using a
11
modified Newcastle-Ottawa Scale (NOS) and GRADE.
12
Results and discussion: Eleven studies were identified, from 1439 citations and review of 72
13
abstracts. Heterogeneity in study methodology and pooled estimates was considerable.
14
Overall pooled transmission rates at 6 months for breastfed infants with mothers on ART was
15
3.54% (95 confidence interval, CI, 1.15-5.93%) and at 12 months 4.23% (95% CI 2.97-
16
5.49%). Postnatal transmission rates were 1.08 (95% CI: 0.32-1.85) at six and 2.93 (95%CI:
17
0.68-5.18) at 12 months. ART was mostly provided for PMTCT only and did not continue
18
beyond 6 months postpartum. No study provided data on mixed feeding and transmission
19
risk.
20
Conclusions: There is evidence of substantially reduced postnatal HIV transmission risk
21
under the cover of maternal ART. However, transmission risk increased once PMTCT ART
22
stopped at 6 months, which supports the current WHO recommendations of life-long ART for
23
all.
24
25
PROSPERO Number: Not possible, completed reviews should not be registered (according to
26
Prospero website)
2
27
Introduction
28
29
The annual number of new HIV infections in children has decreased substantially, from an
30
estimated 520,000 in 2000 to
31
significant progress is consistent with
32
antiretroviral treatment (ART) programmes providing prevention of mother-to-child
33
transmission and treatment of HIV-positive adults [2, 3].
220,000 in 2014, representing a 58% decline [1]. This
improvements in the coverage and quality of
34
35
HIV transmission from mother to child can occur during pregnancy, delivery, and
36
breastfeeding [4]. Recognising the substantial benefit of breastfeeding for infant health and
37
survival, and the need to minimise the risk of postnatal transmission through breastfeeding
38
[5-7], the 2010 World Health Organization (WHO) guidelines recommended breastfeeding
39
for infants of HIV-positive mothers for at least one year under the cover of maternal or infant
40
ART [8].
41
42
In most African countries and some parts of India, health policy continues to advise mothers
43
living with HIV to breastfeed [9,10]. In such settings, exclusive breastfeeding (EBF) for the
44
first six months of life followed by complementary feeding and continued breastfeeding
45
(CBF) for up to one year, under the cover of ART to either the mother or the infant [6] is
46
recommended. However, these recommendations were drawn up supported by limited
47
information on the risk of postnatal HIV transmission when women or child or both were on
48
ART to prevent mother-to-child transmission (PMTCT). In addition, there was little or no
49
information on whether mixed feeding (MF), which had been associated with increased risk
50
of postnatal transmission in earlier studies, remained a risk even in the presence of ART
51
[6,11].
52
53
In the past five years, further evidence has become available from studies and programmes
54
where PMTCT postnatally was achieved through maternal ART or infant prophylaxis. The
55
risk of transmission when infants receive other feeds in addition to breastmilk in the first six
56
months of life is of particular interest for public health programmes [12]. To this end, we
57
present the results from a systematic review and GRADE Evidence summary tables,
58
addressing the question of HIV transmission rates at six, nine, 12 and 18 months in infants
59
born to women who were on ART from early-mid pregnancy until at least six months
60
postpartum, and whose infants breastfed in the first six months of life or longer. This study
3
61
was commissioned by the WHO and contributed to the formulation of the 2016 WHO HIV
62
Infant Feeding guidelines [13].
63
64
Methods
65
The review considered both experimental and observational studies, and included HIV-
66
positive mothers receiving ART and their breastfed children regardless of receipt of infant
67
antiretroviral prophylaxis. The exposures were HIV antiretroviral therapy and feeding
68
modality during breastfeeding (EBF, MF) and outcome measures were overall and postnatal
69
HIV transmission rate at six, 12 and 18 months.
70
71
We conducted searches in multiple electronic databases including PubMed, MEDLINE,
72
EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and CINAHL for
73
articles published between 2005 and 2015. Papers were selected from 2005, as triple
74
combination regimens were prescribed from 2004 (Ref).
75
studies, grey literature and conference abstracts available online from the International IAS
76
AIDS Conference in Melbourne 2014 and the 2013-2015 Conferences on Retroviruses and
77
Opportunistic Infections (CROI) were also searched.
Reference lists from relevant
78
79
Papers were firstly selected by SB and LC according to eligibility of abstracts, followed by
80
full text screening, where disagreements were solved by a third reviewer (MLN). Data was
81
collected independently by SB and revised by LC. We have used the reporting standards
82
described in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses
83
(PRISMA) statement [14], and the flow chart of the screening process is shown in Figure 1.
84
85
86
87
88
89
90
91
92
93
94
4
95
98
99
100
Identification
96
97
101
Records identified through database
searching
(n = 1439)
Additional records identified
through other sources
(n = 0)
1367 records excluded based on title because of being
duplicates, review, qualitative study and not providing data on
outcome of interest
Screening
104
Abstracts screened
(n = 73)
Records excluded for not
meeting review criteria
(n = 37)
Eligibility
103
Full-text articles assessed
for eligibility
(n = 36)
Full-text articles excluded,
with reasons - see
supplementary table 2
(n = 25)
Included
102
Studies included in the
systematic review
105
106
107
108
109
110
111
(n = 11)
112
113
Figure 1. Flowchart of screening process
114
115
To obtain further information regarding infant feeding, we contacted seven first authors of
116
studies identified for inclusion in this review, to solicit additional information regarding
117
infant feeding modality in the first six months of life. Questions related to the type and
118
duration of recommended feeding practice, type of infant feeding support provided to
119
mothers, collection of data on child feeding practices, and how this data was addressed in the
120
study (proportion, statistical model, rates of transmission or death). Response from three
121
authors was included in this study.
122
123
Assessment of study quality
5
124
A modified Newcastle-Ottawa Scale (NOS) was developed by the authors to assess the
125
quality of all studies included in the analysis, on the basis of selection of study participants
126
and outcome assessment [15]. Each study could score a maximum of five stars on Selection
127
and four on Outcome; considering representativeness of the study population, ascertainment
128
of exposure to ART and breastfeeding, report of maternal adherence to ART and feeding
129
modality.
130
131
The information obtained from the NOS was used to comment on the quality of the included
132
studies in the Grading of Recommendations Assessment, Development and Evaluation
133
system (GRADE), a system for rating quality of evidence and grading strength of
134
recommendations in systematic reviews[16]. In this study, NOS considered study limitations,
135
consistency of results, directness, imprecision and reporting bias.
136
137
Results are presented narratively and as pooled estimates with a heterogeneity score based on
138
a random effects meta-analysis using STATA 13 (Stata Corp, 2013). Random effects were
139
used because of differences among studies, such as rates of EBF, incentives to keep treatment
140
and time excluded from postnatal transmission, what allows the true transmission rate to
141
vary from study to study [17]. We summarised the information in graphs depicting overall
142
and postnatal HIV transmission rates at six and 12 months of age. Where no confidence
143
interval was available for estimates from the study report, a confidence interval was
144
calculated based on the number of events and those at risk using the formula described by
145
Eayres (2008) [18].
146
147
Results
148
The search process identified 1,439 citations, of which 1,367 were excluded on the basis of
149
being a duplicate, review, qualitative study or not evaluating transmission at six, 12 or 18
150
months according to feeding modality (Figure 1). The abstracts of 72 studies were evaluated
151
independently by three researchers (SB, LC and ML), and eleven studies were finally
152
selected for inclusion in this review; four of these were cohorts nested within randomised
153
clinical trials [11,19-21] and seven observational studies (include ref). In all studies mothers
154
started ART before or during pregnancy, and continued until at least six months postnatally,
155
according to the WHO recommendations at the time. Seven studies followed this
156
recommendation [5, 11,19,21-25] with six-month ART, three provided lifelong ART for all
157
women [26,27] while the remaining study [28] provided lifelong ART only for treatment6
158
eligible mothers with very low CD4 count (see Supplementary Table 1 for more details on
159
included studies).
160
161
HIV Transmission
162
Of the 11 studies, six reported the transmission rate at age six months [5,11,22-24,26], and
163
the remaining five reported HIV transmissions at a later age [19,21,25,27,28] (CHECK
164
NGOMA HERE)add 26 again. Two studies [26,23] did not provide a confidence interval
165
around the estimated transmission rate, which was calculated using the formula [18]. Two
166
studies reported the number of infections at six months and the number of children at risk:
167
one study [27] was a retrospective cohort and provided a single number as a denominator
168
(N=856); and for the second study [19] the number of children at risk was obtained from the
169
Kaplan-Meier graph. A further two studies reported the number of transmissions but not the
170
number of children at risk [21,28] and one study reported transmission only at age nine
171
months, but noted that all transmissions occurred during breastfeeding [25].
172
173
Overall transmission at age six months
174
For six studies overall transmission rates (including peripartum) at age six months were
175
provided [19,22-24,26,27] (Figure 2A).
176
177
In three studies ART was provided since 15 weeks of pregnancy [23, 26-27]. Ngoma et al [26]
178
reported three peripartum transmissions (before six weeks, number of children at risk=219),
179
and no postnatal transmissions between six weeks and six months, with an overall
180
transmission rate at six months of 1.4% (95% CI 0.5%-3.9%). Sagay et al. [27] reported a
181
total of four infections at six months (N=856; rate of transmission was calculated as 0.5%,
182
95%CI 0.2%-1.2%). Marazzi et al. [23] reported six transmissions at six months (N=313,
183
overall transmission rate 1.9%, 95% CI 0.9%-4.1%).
184
185
The subsequent studies started ART after 30 weeks pregnancy [19,22, 29]. Jamieson et al [19]
186
reported 67 infections; 21 infections after six weeks (N=849; overall transmission rate at age
187
six months 7.9%, 95% CI 6.2%-9.9%). Thomas et al. [22] reported 24 transmissions, of
188
which 20 occurred before six weeks, for an overall transmission rate of 5.0%, 95% CI 3.4%-
189
7.4% (N=487). Kilewo et al. [29] reported 22 infections at six months, 18 before six weeks
190
(N=423; overall transmission rate 5.0%, 95% CI 2.9%-7.1%).
191
7
192
The pooled estimate of overall transmission at six months was 3.54% (95% CI 1.15%-5.93%),
193
with considerable heterogeneity (I2 94.0%) (Figure 2A).
194
195
Postnatal transmission between 4/6 weeks and 6 months
196
Six studies provided estimates of postnatal transmission rates, excluding peripartum
197
infections, diagnosed before six weeks of age [5, 11,19,22,23,29] (Figure 2B), and among
198
those, three studies provided ART since the first antenatal visit [5,11,23]. Coovadia et al[11]
199
reported one infection (N=413, rate 0.2%; 95%CI 0%-1.4%); Marazzi et al [23] provided the
200
rate of transmission after four weeks of age (2/313, rate 0.6%; 95%CI 0.2%-2.3%). Alvarez-
201
Uria et al [5] reported four (N=127) infections for a transmission rate of 3.1% (95%CI 1.2%-
202
7.8%), noting that one of the infected infants was mixed fed.
203
204
In the other three studies, ART was given in later pregnancy, where in Jamieson et al [19]
205
ART could be given from first antenatal visit until 30 weeks pregnancy, and Thomas et al [22]
206
and Kilewo et al [29] ART was given at 34 weeks pregnancy. Jamieson et al. [19] reported 21
207
infections (N=769, rate 2.7%; 95%CI 1.80-4.10); Thomas et al [22] and Kilewo et al [29] did
208
not provide a rate of postnatal transmission at six months, but the number of transmissions
209
and number of children at risk were reported. In each study there were four transmissions
210
between six weeks and six months of age (N= 482 for Thomas et al, rate of postnatal
211
transmission 0.80%, 95% CI 0.3%-2.4%; and N=418 for Kilewo et al, rate of postnatal
212
transmission 0.90%, 95% CI 0.3%-2.1%). Figure 2B shows the pooled estimate for these six
213
studies, with a pooled transmission rate of 1.08% (95% CI 0.32%-1.85%). Heterogeneity was
214
substantial (I2 66.4%).
215
8
A)
B)
Study (Information)
Rate (95%CI)
%
Weight
%
Rate (95%CI) Weight
Study (Information)
Ngoma et al, 2015
(EBF:93%; N=219)
1.4 (0.5,3 .9)
16.7
Coovadia et al, 2012
(EBF:95%; N=413)
0.2(0.0,1.4)
22.3
Sagay et al, 2015
(EBF:73%; N=856)
0.5 (0.2, 1.2)
18.0
Jamieson et al, 2012
(EBF:89%; N=769)
2.7(1.8,4.1)
17.0
Jamieson et al, 2012 (EBF:89%; N=849)
7.9 (6.2, 9.9)
16.4
Alvarez-Uria et al, 2012
3.1(1.2,7.8)
4.5
(EBF:89%; N=482)
0.8(0.3,2.4)
18.1
(EBF:100%; N=313)
0.6(0.2,2.3)
18.1
0.9(0.3,2.1)
19.92
1.1(0.3,1.9)
100.0
(EBF:89%; N=487)
5.0 (3.4, 7.4)
16.1
Thomas et al, 2011
Marazzi et al, 2009 (EBF:100%; N=313)
1.9 (0.9, 4.1)
16.8
Marazzi et al, 2009
Kilewo et al, 2009
5.0 (2.9, 7.1)
15.9
Kilewo et al, 2009
Thomas et al, 2011
(EBF:80%; N=423)
Overall (I-squared=94%, p=0.000)
3.5 (1.2, 5.9) 100.0
(N=127)
(EBF:80%; N=418)
Overall (I-squared=66.4%, p=0.011)
Figure 2. Transmission rates at age six months: A) Overall transmission rate (including peripartum) at age six
months B) Postnatal transmission rate between 4-6 weeks of age and age six months, with 95% confidence
intervals, in children who were breastfed and whose mothers were on ART.
Note: A) Sagay et al (2015) and Jamieson et al (2012) did not provide a rate of transmission, but the rate was calculated on the basis
of the number of children at risk provided in the paper. For Jamieson et al (2012) transmission rate was provided at 28 weeks. For
Ngoma et al (2015) and Marazzi et al (2009), a confidence interval was not provided in the paper but calculated using the formula18.
216
B) Coovadia et al (2012), Alvarez-Uria et al (2012), Thomas et al (2011) and Kilewo et al (2009) excluded positive children at 6
weeks. Jamieson et al (2012) excluded transmission at 2 weeks and Marazzi et al (2009) excluded 4 weeks. Jamieson et al (2012),
Thomas et al (2011) and Kilewo et al (2009) did not provide rate of transmission, but rate was calculated considering number of
children at risk provided in the paper
9
217
Two studies reported the number of infections at six months but not the number of children at
218
risk. Thakwalakwa et al [21] reported three infections before six months (of 280 births but no
219
information provided on loss to follow up and deaths); Giuliano et al [28] reported four
220
transmissions before six months, 288 children were included in this study, but the number of
221
children at risk of transmission at six months was unclear.
222
223
Rate of transmission assessed after six months of age
224
Of the seven studies providing information on transmission rates at age 12 months, five
225
reported overall HIV transmission rates (including peripartum) [5,22-24,28] and two reported
226
postnatal transmission rates [11,19] (Figure 3). The pooled estimates showed an overall rate
227
of transmission at 12 months of 4.2% (95% CI 2.97%-5.5%); and a postnatal transmission
228
rate of 2.93% (95%CI 0.68%-5.18%) (Figure 3). Heterogeneity was higher in the postnatal
229
transmission (I2 71.2%) than in the overall HIV transmission group (I2 39.9%). The postnatal
230
pooled estimates included only two studies, one in which mothers initiated ART from first
231
antenatal visit, and the other in which ART was provided from 30 weeks.
Rate
(95%CI)
Study (Information)
232
%
Weight
1
233
Giuliano et al, 2013
(EBF:73%; N=288)
Alvarez-Uria et al, 2012 (N=127)
Thomas et al, 2011
234
235
19.9
3.7 (2.0, 6.7) 18.3
(EBF:89%; N=427)
5.7 (4.0, 8.3) 20.4
Marazzi et al, 2009
(EBF:100%; N=283)
2.8 (1.4, 5.5)
21.6
Kilewo et al, 2009
(EBF:80%; N=368)
5.8(3.6, 8.0)
19.9
4.2 (3.0,5.5)
100.0
Overall (I-squared=39.9%, p=0.155)
236
3.2 (1.0,5.4)
2
237
Coovadia et al, 2012
(EBF:95%; N=171)
1.7(0.3, 4.1)
46.7
Jamieson et al, 2012
(EBF:89%; N=662)
4.0(3.0, 6.0)
53.4
2.9 (0.7,5.2)
100.0
Overall (I-squared=71.2%, p=0.063)
238
NOTE: Weights are from random effect analysis
239
240
241
Figure 3. Transmission rates at 12 months of age, with 95% confidence intervals, in children
who were breastfed and whose mothers were on ART. Group 1: Overall transmission. Group 2:
Postnatal transmission between 4/6 weeks and 12 months of age
Note:
242
Coovadia et al (2012) excluded children HIV positive at 6 weeks. Jamieson et al (2012) excluded
transmission at 2 weeks. Marazzi et al (2009) did not provide the confidence interval, which was
thus calculated using the formula18.
243
10
244
Peltier et al [25] provided an overall transmission rate at nine months of age, including
245
perinatal transmission, with no transmission after cessation of breastfeeding. The total
246
number of children at risk was 227, with four infections (only 1 after 6 weeks). The overall
247
estimated rate of transmission at nine months was 1.8% (95%CI 0.7%-4.8%). Only 15
248
mothers were reported to have mixed fed their children, and none of these were infected.
249
Ngoma et al [26] was the only study which reported an estimated overall (including
250
peripartum) rate of transmission at 18 months, with lifelong ART provided for all mothers.
251
Nine transmissions were reported, with an overall transmission rate of 4.1% (95% CI 2.2%-
252
7.6%; N=219).
253
Additional information regarding feeding
254
No study provided a transmission rate according to infant feeding modality (EBF and MF); in
255
all studies mothers were recommended to (and assumed to have) exclusively breastfed their
256
infants for six months. Alvarez-Uria et al [5] noted that one of the infected children was
257
mixed-fed, but did not provide the rate of transmission by feeding modality.
258
259
Additional information was asked from each study regarding how feeding type was assessed
260
and supported during the study, with data also extracted from studies (Table 1).
261
262
263
264
265
266
267
268
269
270
271
11
272
Table 1. Responses regarding support for exclusive breastfeeding and type of data collection
Information from published papers
Additional
Information
273
Studies
Duration of BF
Frequency counselling
Local of
counselling
Type of support
Person
giving
support
Registered
nurse
Type of data
collection
Ngoma et al, 2015
12 months
Giuliano et al, 2013
4.5 months and
wean over a 1.5
months
4 wks post enrolment, 36 weeks gestation,
at birth, 2 weeks, 6 weeks, 3,6,9,12,15, 18
and 24 months
Every 2 wks in first 2 months pregnancy
and every month until BF cessation
2 week was home
visit, others
facility based.
Facility-based
Text message
reminders, food and
transportation stipends
Counselling
Skilled
personnel in
nutrition
practices
Self-report
Jamieson et al, 2012
6 months
1, 2, 4, 6, 8, 12, 18, 21, 24, 28 weeks postpartum
-
Alvarez-Uria et al,
2012
Coovadia et al, 2012
6 months
Not reported
Not reported
Counselling and
breast-milk
replacement food in
case of BF cessation
Not reported
Not reported
Not reported
6 months
7d, 2,5,6,8wks, 3,6,9,12,18 mo
Not reported
Not reported
Not reported
Self-report
Thomas et al, 2011
6 months
Not reported
Not reported
Not reported
Not reported
Marazzi et al, 2009
6 months
Weekly before delivery, and after delivery:
2,6,10, 14 weeks and 6, 9, 12, 15, 18, 24
months
Not reported
Not reported
nutritionists
Clinical data
Kilewo et al, 2009
6 months
1, 3, 6 weeks and 3, 4, 5, 6 months
Facility based
Counselling and
nutritional supplement
for pregnant and
lactating mothers
counselling
Not reported
Not reported
interview
Interview by
standard
questionnaire
274
275
276
12
277
GRADE PROFILE
278
An evaluation of the quality of the studies considered in this analysis is given in
279
Supplementary Table 3. The assessment of quality was based on study limitations/risk of bias
280
as per the evidence from the Newcastle-Ottawa Scale (Supplementary Table 4). We also
281
considered inconsistency, indirectness and publication bias. All studies are rated very low
282
quality. Initially, all studies were scored low quality due to being observational and were
283
downgraded for indirectness because their research areas were not directly in line with the
284
question. Where a pooled analysis was undertaken and a pooled estimate provided, studies
285
were further downgraded for inconsistency if the heterogeneity was not explained. In all
286
groups of studies there was at least one study with a risk of bias pertaining to lack of detailed
287
information on feeding leading to further downgrading as did the substantial heterogeneity in
288
transmission rate estimates between studies.
289
290
Discussion
291
This systematic review is the first synthesis of the HIV transmission risk in infants of HIV-
292
positive mothers including mothers receiving lifelong ART. The review provides evidence
293
for the low postnatal HIV transmission risk to infants in the presence of maternal ART. We
294
found a pooled estimated rate of overall transmission by age six months of 3.5% and a pooled
295
postnatal transmission rate by six months of age of 1.1% in women who were on ART from
296
early-mid pregnancy and who were recommended to breastfed their infants for six months.
297
The pooled estimate for postnatal transmission at 12 months of age was 3.0%; only one study
298
provided an estimated rate of transmission at 18 months, in women on lifelong ART, of 4.1%.
299
300
Our estimates compare favourably against estimates from studies in the pre-ART era, ranging
301
from 15% overall transmission at six weeks [30] and 32% at six months [31,32], highlighting
302
the efficacy of ART in reducing transmission risk following improved PMTCT services,
303
adherence to ART, and early initiation during pregnancy [2, 33].
304
305
Exclusive breastfeeding to six months of life is recommended for all infants because of its
306
major effect on reducing infant and child mortality and improving long term health outcomes.
307
In the context of postnatal HIV transmission and before WHO guidelines recommending
308
ART to reduce postnatal transmission, refraining from mixed-feeding in these first six
309
months was also considered important [12, 34] because of the associated increased risk of
13
310
postnatal transmission when compared to EBF [35-37]. However, we were unable to estimate
311
the rate of transmission associated with MF, since no study provided this data. Most studies
312
included in this review assumed that mothers exclusively breastfed up to six months as
313
recommended [6], however it has been reported by others that mixed feeding before six
314
months of age is common. [12,38]. Kilewo et al found that although at 16 weeks 80% of
315
mothers were still exclusively breastfeeding, this was only 51% at 24 weeks [22]; in the
316
Kisumo Breastfeeding Study exclusive breastfeeding at 5 months was 80.4% [39]. EBF was
317
found to be more common in women of higher parity, and less common in those not living
318
with the child’s father [40]. In a qualitative study in Nigeria investigating reasons for mixed
319
feeding, 42.8% of mothers reported pressure from family members relating to infant feeding
320
practice, with 28.5% following cultural practices, offering water and herbal medications to
321
the child [41].
322
In the included studies, women were recommended to exclusively breastfeed their infants for
323
six months in line with WHO guidelines, but there was no specific support provided for
324
mothers to exclusively breastfeed, and studies did not collect detailed information on infant
325
feeding modality. As such, the findings from this review thus reflect real-life situations.
326
However, the reports from two studies included in this systematic analysis shows that support
327
may increase adherence to exclusive breastfeeding. Marazzi et al offered nutritional
328
supplements to pregnant and lactating women, and at each clinic visit, EBF counselling could
329
be emphasised [23]; Ngoma et al sent text messages and offered food and transportation
330
stipends to mothers participating in the study [26]. Both studies had very high adherence to
331
EBF, with more than 90% of mothers reportedly exclusively breastfeeding during the first six
332
months.
333
WHO 2010 guidelines on HIV and infant feeding recommend exclusive breastfeeding in the
334
first 6 months of life primarily to protect against other non-HIV infectious causes of infant
335
mortality. Based on the available evidence at that time, ART was assumed to be effective at
336
reducing HIV transmission risk in this period. According to WHO guidelines, after six
337
months, appropriate complementary food needs to be introduced while breastfeeding
338
continues, although currently HIV-positive women are recommended to continue
339
breastfeeding for one year under the cover of ART [6,8]. Only two studies followed the
340
recommendation for HIV-positive women, with breastfeeding up to 12 months postpartum
341
and lifelong ART to mothers [26,27]. In the other studies mothers no longer received ART
342
after cessation of breastfeeding at six months, but there were reported transmissions beyond
14
343
six months due to continued breastfeeding in the absence of ART cover [19, 28]. Despite
344
providing lifelong ART and recommending breastfeeding up to 12 months, Ngoma et al [26] ,
345
reported high differences between transmission rate at six months (1.4%) and 18 months
346
(4.1%) due to poor adherence among mothers at taking ART. They report that 11.4% of
347
women who missed a dispensary visit transmitted HIV to the child, compared with 2.7%
348
women who did not miss any visit (p=0.038). On the other hand, the BREICHT study
349
conducted in Malawi [21] found a very similar rate of transmission between six and 12
350
months (three infections before six months, four infections at 12 months, N=280). This result
351
could be attributed to high adherence to ART when it was given together with food
352
supplements for the child after 6 months, a strategy that proved to be feasible and effective
353
for improving retention in care.
354
This review highlighted the considerable clinical and methodological heterogeneity in the
355
studies due to differences in the time of ART initiation during pregnancy, the recommended
356
duration of breastfeeding, the age at which infection in the infant was assessed, the details on
357
infant feeding modality and the definition of postnatal transmission. In addition, we
358
calculated transmission rates and/or confidence intervals, where these were not provided by
359
all studies, which contributed to the low quality of evidence for the estimated risk associated
360
with continued breastfeeding between six and 12 months post-delivery. However, this
361
systematic review and meta-analysis which includes studies published between 2005 and
362
2015 informs our understanding of the risk of transmission in the postnatal period in women
363
who receive ART. Although statistical inconsistency was considerable, the trends were in the
364
appropriate direction, and the findings provide evidence for public health programmes as well
365
as for new MTCT guidelines.
366
Conclusion
367
The findings of this review demonstrate the very low risk of postnatal transmission during
368
breastfeeding in women who are on ART lower risk of postnatal transmission when women
369
are on ART, despite considerable heterogeneity in pooled analyses. The overall quality of this
370
evidence is low. The new WHO guidelines on initiation of ART for all HIV-positive people
371
immediately upon the diagnosis of HIV infection will expand ART coverage among HIV-
372
positive pregnant and breastfeeding women [13]. Our results suggest that will be important
373
to provide women with ongoing support to adhere to the WHO EBF recommendations.
374
15
375
Competing interests
376
NR is a WHO employee. NS received funding for the methodological facilitation of the
377
WHO guidelines process. MLN, SB and LC received WHO funding to carry out the
378
systematic review. There are no competing interests in this submission.
379
380
Acknowledgements
381
This systematic review was commissioned and funded by the World Health Organization.
382
The authors alone are responsible for the views expressed in this article and they do not
383
necessarily represent the views, decisions or policies of the World Health Organization. We
384
thank Marina Giuliano, Michael Silverman and Timothy Thomas for the additional
385
information provided for this systematic review.
386
387
Author statement
388
NR and MLN conceived the idea, SB undertook the systematic review, supported by LC and
389
MLN. NS advised on methodological aspects. SB drafted the first version of the paper, LC,
390
NS, NR and MLN had substantial involvement in further drafts. All authors approve the final
391
draft for submission.
392
393
Additional Files
394
Box 1. Demonstration of search strategy for CENTRAL for the topic ‘mother-to-child-
395
transmission for HIV infected mothers receiving ART and infant feeding’.
396
Supplementary Table 1. Included papers: Descriptive information of studies providing
397
information on breastfeeding and ART
398
The table presented in word contains information about all included studies, such as: the type
399
of study, beginning/end of ART, type of child feeding, sample size, time of evaluation.
400
Supplementary Table 2. Studies excluded during full text screening and reasons for exclusion.
401
Supplementary Table 3. GRADE evidence profile
402
Grade profile includes quality assessment of each study, quality of information obtained and
403
importance, as well as information on reasons for downgrading studies. The table was used
16
404
for supporting the update of guidelines based on information provided by this systematic
405
review.
406
Supplementary Table 4. Modified Newcastle-Ottawa for assessment of HIV transmission in
407
breastfed infants whose mothers were on ART.
408
This table include information on how many stars each study received in selection or
409
outcome categories of NOS evaluation.
410
411
17
412
REFERENCES
413
414
415
416
417
1.
WHO. Global health sector response to HIV, 2000-2015: focus on innovations in Africa:
progress report: Geneva: World Health Organization; 2015.
418
419
420
421
422
423
424
425
426
427
428
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
459
460
461
3.
UNAIDS. Countdown to Zero: Global Plan Towards the Elimination of New HIV Infections
Among Children by 2015 and Keeping Their Mothers Alive, 2011-2015: Geneva: Joint United Nations
Programme on HIV/AIDS; 2011.
2.
WHO. Global update on the health sector response to HIV, 2014. Geneva: World Health
Organization; 2014.
4.
Newell M-L. Mechanisms and timing of mother-to-child transmission of HIV‐1. AIDS.
1998;12(8):831-837.
5.
Alvarez-Uria G, Midde M, Pakam R, Bachu L, Naik PK. Effect of Formula Feeding and
Breastfeeding on Child Growth, Infant Mortality, and HIV Transmission in Children Born to HIVInfected Pregnant Women Who Received Triple Antiretroviral Therapy in a Resource-Limited Setting:
Data from an HIV Cohort Study in India. Pediatrics. 2012 Jun; 763591.
6.
WHO. Guidelines on HIV and Infant Feeding 2010: Principles and Recommendations for
Infant Feeding in the Context of HIV and a Summary of Evidence: Geneva: World Health Organization;
2010.
7.
Taha TE, Kumwenda NI, Hoover DR, Kafulafula G, Fiscus SA, Nkhoma C, et al. The impact of
breastfeeding on the health of HIV-positive mothers and their children in sub-Saharan Africa. Bull
World Health Organ. 2006; 84(7):546-554.
8.
WHO. Antiretroviral drugs for treating pregnant women and preventing HIV infection in
infants: recommendations for a public health approach-2010 version: Geneva: World Health
Organization; 2010.
9.
Kuhn L, Aldrovandi G. Survival and health benefits of breastfeeding versus artificial feeding
in infants of HIV-infected women: developing versus developed world. Clin Perinatol.
2010;37(4):843-862.
10.
Coovadia H: Current issues in prevention of mother-to-child transmission of HIV-1. Curr Opin
HIV AIDS. 2009; 4(4):319-324.
11.
Coovadia HM, Brown ER, Fowler MG, Chipato T, Moodley D, Manji K, et al. Efficacy and
safety of an extended nevirapine regimen in infant children of breastfeeding mothers with HIV-1
infection for prevention of postnatal HIV-1 transmission (HPTN 046): a randomised, double-blind,
placebo-controlled trial. Lancet. 2012;379(9812):221-228.
12.
Coovadia HM, Rollins NC, Bland RM, Little K, Coutsoudis A, Bennish ML, et al. Mother-tochild transmission of HIV-1 infection during exclusive breastfeeding in the first 6 months of life: an
intervention cohort study. Lancet. 2007; 369(9567):1107-1116.
13.
WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing
HIV Infenction: What's new: Geneva: World Health Organization; 2015.
14.
Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews
and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264-269.
18
462
463
464
465
466
467
468
469
470
471
472
473
474
475
476
477
478
479
480
481
482
483
484
485
486
487
488
489
490
491
492
493
494
495
496
497
498
499
500
501
502
503
504
505
506
507
508
509
510
511
15.
Wells G, Shea B, O’connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa
Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2000 [cited 2015
March 17]. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
16.
Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, et al. Rating quality of
evidence and strength of recommendations: Going from evidence to recommendations. BMJ: Br
Med J. 2008;336(7652):1049.
17.
Borenstein M, Hedges LV, Higgins J, Rothstein HR. Introduction to meta-analysis: Wiley
Online Library; 2009.
18.
Eayres D. Technical Briefing 3. Commonly used public health statistics and their confidence
intervals. In. National Centre for Heath Outcomes Development; 2008.
19.
Jamieson DJ, Chasela CS, Hudgens MG, King CC, Kourtis AP, Kayira D, et al. Maternal and
infant antiretroviral regimens to prevent postnatal HIV-1 transmission: 48-week follow-up of the
BAN randomised controlled trial. Lancet. 2012;379(9835):2449-2458.
20.
Sellers CJ, Lee H, Chasela C, Kayira D, Soko A, Mofolo I, et al. Reducing lost to follow-up in a
large clinical trial of prevention of mother-to-child transmission of HIV: The Breastfeeding,
Antiretrovirals and Nutrition study experience. Clinical trials 2015, 12(2):156-165.
21.
Thakwalakwa C, Phiri A, Rollins N, Heikens GT, Barnell EK, Manary M. Growth and HIV-free
survival of HIV-exposed infants in Malawi: a randomized trial of two complementary feeding
interventions in the context of maternal antiretroviral therapy. J Acquir Immune Defic Syndr.
2014;66(2):181-187.
22.
Thomas TK, Masaba R, Borkowf CB, Ndivo R, Zeh C, Misore A, et al. Triple-antiretroviral
prophylaxis to prevent mother-to-child HIV transmission through breastfeeding--the Kisumu
Breastfeeding Study, Kenya: a clinical trial. PLoS Med. 2011;8(3):e1001015.
23.
Marazzi MC, Nielsen-Saines K, Buonomo E, Scarcella P, Germano P, Majid NA, et al.
Increased infant human immunodeficiency virus-type one free survival at one year of age in subsaharan Africa with maternal use of highly active antiretroviral therapy during breast-feeding.
Pediatr Infect Dis J. 2009;28(6):483-487.
24.
Kilewo C, Karlsson K, Ngarina M, Massawe A, Lyamuya E, Swai A, et al. Prevention of motherto-child transmission of HIV-1 through breastfeeding by treating mothers with triple antiretroviral
therapy in Dar es Salaam, Tanzania: the Mitra Plus study. J Acquir Immune Defic Syndr.
2009;52(3):406-416.
25.
Peltier CA, Ndayisaba GF, Lepage P, van Griensven J, Leroy V, Pharm CO, et al. Breastfeeding
with maternal antiretroviral therapy or formula feeding to prevent HIV postnatal mother-to-child
transmission in Rwanda. AIDS. 2009;23(18):2415-2423.
26.
Ngoma MS, Misir A, Mutale W, Rampakakis E, Sampalis JS, Elong A, et al. Efficacy of WHO
recommendation for continued breastfeeding and maternal cART for prevention of perinatal and
postnatal HIV transmission in Zambia. J Int AIDS Soc. 2015;18:19352.
19
512
513
514
515
516
517
518
519
520
521
522
523
524
525
526
527
528
529
530
531
532
533
534
535
536
537
538
539
540
541
542
543
544
545
546
547
548
549
550
551
552
553
554
555
556
557
558
559
560
561
27.
Sagay AS, Ebonyi AO, Meloni ST, Musa J, Oguche S, Ekwempu CC, et al. Mother-to-Child
Transmission Outcomes of HIV-Exposed Infants Followed Up in Jos North-Central Nigeria. Curr HIV
Res. 2015;13(3):193-200.
28.
Giuliano M, Andreotti M, Liotta G, Jere H, Sagno JB, Maulidi M, et al. Maternal antiretroviral
therapy for the prevention of mother-to-child transmission of HIV in Malawi: maternal and infant
outcomes two years after delivery. PLoS One. 2013;8(7):e68950.
29.
Kilewo C, Karlsson K, Ngarina M, Massawe A, Lyamuya E, Swai A, et al. Prevention of Motherto-Child Transmission of HIV-1 Through Breastfeeding by Treating Mothers With Triple Antiretroviral
Therapy in Dar es Salaam, Tanzania: The Mitra Plus Study. J Acquir Immune Defic Syndr.
2009;52(3):406-416.
30.
Leroy V, Sakarovitch C, Cortina-Borja M, McIntyre J, Coovadia H, Dabis F, et al. Is there a
difference in the efficacy of peripartum antiretroviral regimens in reducing mother-to-child
transmission of HIV in Africa? AIDS. 2005;19(16):1865-1875.
31.
Read JS: Late postnatal transmission of HIV-1 in breast-fed children: an individual patient
data meta-analysis. J Infect Dis. 2004; 189(12):2154-2166.
32.
Zijenah LS, Moulton LH, Iliff P, Nathoo K, Munjoma MW, Mutasa K, et al. Timing of motherto-child transmission of HIV-1 and infant mortality in the first 6 months of life in Harare, Zimbabwe.
AIDS. 2004;18(2):273-280.
33.
Finocchario-Kessler S, Clark KF, Khamadi S, Gautney BJ, Okoth V, Goggin K, et al. Progress
Toward Eliminating Mother to Child Transmission of HIV in Kenya: Review of Treatment Guideline
Uptake and Pediatric Transmission at Four Government Hospitals Between 2010 and 2012. AIDS
Behav. 2015:1-10.
34.
Becquet R, Bequet L, Ekouevi DK, Viho I, Sakarovitch C, Fassinou P, et al. Two-year morbiditymortality and alternatives to prolonged breast-feeding among children born to HIV-infected mothers
in Cote d'Ivoire. PLoS Med. 2007; 4(1):e17.
35.
Muluye D, Woldeyohannes D, Gizachew M, Tiruneh M. Infant feeding practice and
associated factors of HIV positive mothers attending prevention of mother to child transmission and
antiretroviral therapy clinics in Gondar Town health institutions, Northwest Ethiopia. BMC Public
Health. 2012;12:240.
36.
Becquet R, Ekouevi DK, Menan H, Amani-Bosse C, Bequet L, Viho I, et al. Early mixed feeding
and breastfeeding beyond 6 months increase the risk of postnatal HIV transmission: ANRS
1201/1202 Ditrame Plus, Abidjan, Cote d'Ivoire. Prev Med. 2008;47(1):27-33.
37.
Becquet R, Bland R, Leroy V, Rollins NC, Ekouevi DK, Coutsoudis A, et al. Duration, pattern of
breastfeeding and postnatal transmission of HIV: pooled analysis of individual data from West and
South African cohorts. PloS one. 2009;4(10):e7397.
38.
Bland RM, Little KE, Coovadia HM, Coutsoudis A, Rollins NC, Newell M-L. Intervention to
promote exclusive breast-feeding for the first 6 months of life in a high HIV prevalence area. AIDS.
2008;22(7):883-891.
20
562
563
564
565
566
567
568
569
570
571
572
39.
Okafor I, Ugwu E, Obi S, Odugu B. Virtual Elimination of Mother-to-Child Transmission of
Human Immunodeficiency Virus in Mothers on Highly Active Antiretroviral Therapy in Enugu, SouthEastern Nigeria. Ann Med Health Sci Res. 2014;4(4):615-618.
40.
Okanda JO, Borkowf CB, Girde S, Thomas TK, Lecher SL. Exclusive breastfeeding among
women taking HAART for PMTCT of HIV-1 in the Kisumu Breastfeeding Study. BMC pediatrics.
2014;14:280.
41.
Lawani LO, Onyebuchi AK, Iyoke CA, Onoh RC, Nkwo PO. The challenges of adherence to
infant feeding choices in prevention of mother-to-child transmission of HIV infections in South East
Nigeria. Patient Prefer Adherence. 2014;8:377-381.
573
21
Supplementary Files
Box 1.: Demonstration of search strategy for CENTRAL for the topic ‘mother-to-child-transmission for
HIV infected mothers receiving ART and infant feeding’
1 Maternal
2 mother
3 #1 OR #2
4 Antiretroviral therapy
5 Antiretroviral*
6 ART
7 HAART
8 #4 OR #5 OR #6 OR #7
9 HIV
10 Transmi*
11 Infec*
12 #9 OR #10 OR #11
13 Breastfeeding
14 Postnatal
15 Breast*
16 Feed*
17 Mixed
18 #13 OR #14 OR #15 OR #16 OR #17
19 #3 AND #8 AND #12 AND #18
22
Supplementary Table 1. Included papers: Descriptive information of studies providing information on breastfeeding and ART
Cohorts embedded on RCTs
First
Author/Study
Place of study
Randomised for
ARV
Other
Feeding
Beginning/ end
ART
Breastfeeding
duration
6 mo
12 mo
1527
Time
evaluation
N
Extracted information
Transmission 6
Exclude peripartum
mo
Given
Postnatal: excluding 6
weeks
HPTN046 trial
(Fowler, 2014;
Coovadia, 2012)
South Africa,
Tanzania, Uganda
and Zimbabwe
ART or not
Infant NVP or
not
All BF
From first
antenatal visit/ 6
mo
Jamieson, 2012
Antenatal clinics
in Malawi
ART† or
infant NVP
Nutritional
intervention
Majority
BF
30wks or less/ 6
mo
6 mo
12 mo
849
Calculated
Kisumu
Breastfeeding Study
(Okanda, 2014;
Thomas, 2011)
Thakwalakwaa,
2014
Kenya (antenatal
clinics)
ART
All BF
34 wks/ 6 mo‡
6 months
6 weeks, 6,
12 mo
502
Given
Malawi (Thyolo
District Hospital)
Only ART
All BF
From first
antenatal visit/
lifelong
6 mo
12 mo
248
Not given
Gives only number of
infected children with
no denominator
4.5 mo
12 mo
300
Not given
Gives only number of
infected children with no
denominator
6 mo
6 and 12 mo
318
Given
6 mo
9 mo
532
Not given
Nutritional
intervention
DREAM study
(Giuliano, 2013;
Palombi, 2007)
Malawi (two ante
natal clinics)
ART*
Alvarez-Uriaa,
2012
India (3 hospitals in
Antapur)
ART
Peltiera, 2009
Rwanda (four
government-run
health facilities)
Mozambique
ART
Observational studies
1st tremester and
lifelong
(CD4+<350) or
week 25/ 6 mo or
end BF
BF and RF
From first
antenatal visit / 6
mo (BF), post
labour (NBF)
BF and RF
28 wks / 7 mo‡
ART
All BF
15 wks/ 6 mo‡
5 mo
6 weeks, 6
and 12 mo
341
Given
Tanzania (Dar es
Salam)
Nigeria
Zambia
ART
All BF
34 wks/ 6 mo
6 mo
441
Given
ART
ART
All BF
All BF
lifelong
14 wks-lifelong
1 year
1 year
6 weeks, 6, 9,
12, 18 mo
18 mo
6 weeks, 6
and 12 mo
856
231
Calculated
Given
Marazzi, 2009
Kilewo, 2009
Sagay, 2015
Ngoma, 2015
All BF
Both measures.
Provides number of
infected children
before and after 2
weeks
Include peripartum.
Postnatal calculated.
Exclude 6 weeks
Provides Overall
transmission including
peripartum
Both, provides rates
including and excluding
peripartum (exclude 4
wks)
Include peripartum.
Postnatal calculated.
Include peripartum.
Include peripartum
23
BF= Breastfeeding; RF= Replacement feeding
a
Studies performed in rural environment
†Mothers with clinical stage 4 or CD4 <200 cells/mm3 were excluded
‡Mothers with CD4 count <200 cells/mm3 or stage III or IVdisease remained on ART throughout the study, and those who subsequently met the criteria after stopping ARVs were restarted, or when CD4 cell
counts were ≤350 cells/mm3 (Peltier, Marazzi)
*Mothers on ART based on disease progression or low CD4+ count
24
Supplementary Table 2. Full-text articles excluded from systematic review with reasons
No.
1.
Reference
Anoje C, Aiyenigba B, Suzuki C, Badru T, Akpoigbe K, Odo M, et al.
Reducing mother-to-child transmission of HIV: findings from an early infant
diagnosis program in south-south region of Nigeria. BMC Public Health.
2012;12:184.
2.
Becquet R, Bequet L, Ekouevi DK, Viho I, Sakarovitch C, Fassinou P, et al.
Two-year morbidity-mortality and alternatives to prolonged breast-feeding
among children born to HIV-infected mothers in Cote d'Ivoire. PLoS Med.
2007;4(1):e17
Becquet R, Ekouevi DK, Menan H, Amani-Bosse C, Bequet L, Viho I, et al.
Early mixed feeding and breastfeeding beyond 6 months increase the risk of
postnatal HIV transmission: ANRS 1201/1202 Ditrame Plus, Abidjan, Cote
d'Ivoire. Preventive Medicine. 2008;47(1):27-33.
Leroy V, Ekouevi DK, Becquet R, Viho I, Dequae-Merchadou L, Tonwe-Gold
B, et al. 18-month effectiveness of short-course antiretroviral regimens
combined with alternatives to breastfeeding to prevent HIV mother-to-child
transmission. PLoS One. 2008;3(2):e1645
Binagwaho A, Pegurri E, Drobac PC, Mugwaneza P, Stulac SN, Wagner CM, et
al. Prevention of mother-to-child transmission of HIV: cost-effectiveness of
antiretroviral regimens and feeding options in Rwanda. PLoS One.
2013;8(2):e54180
Chi BH, Musonda P, Lembalemba MK, Chintu NT, Gartland MG, Mulenga
SN, et al. Universal combination antiretroviral regimens to prevent mother-tochild transmission of HIV in rural Zambia: a two-round cross-sectional study.
Bulletin of the World Health Organization. 2014;92(8):582-92.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Derebe G, Biadgilign S, Trivelli M, Hundessa G, Robi ZD, Gebre-Mariam M,
et al. Determinant and outcome of early diagnosis of HIV infection among HIVexposed infants in southwest Ethiopia. BMC research notes. 2014;7:309
Goga AE, Dinh TH, Jackson DJ, Lombard C, Delaney KP. First populationlevel effectiveness evaluation of a national programme to prevent HIV
transmission from mother to child, South Africa. 2015;69(3):240-8
Gray GE, Urban M, Chersich MF, Bolton C, van Niekerk R, Violari A, et al. A
randomized trial of two postexposure prophylaxis regimens to reduce motherto-child HIV-1 transmission in infants of untreated mothers. AIDS (London,
England). 2005;19(12):1289-97
Kagaayi J, Gray RH, Brahmbhatt H, Kigozi G, Nalugoda F, Wabwire-Mangen
F, et al. Survival of infants born to HIV-positive mothers, by feeding modality,
in Rakai, Uganda. PLoS One. 2008;3(12):e387
Kouanda S, Tougri H, Cisse M, Simpore J, Pietra V, Doulougou B, et al. Impact
of maternal HAART on the prevention of mother-to-child transmission of HIV:
results of an 18-month follow-up study in Ouagadougou, Burkina Faso. AIDS
care. 2010;22(7):843-50
Kuhn L, Aldrovandi GM, Sinkala M, Kankasa C, Semrau K, Kasonde P, et al.
Differential effects of early weaning for HIV-free survival of children born to
HIV-infected mothers by severity of maternal disease. PLoS One.
2009;4(6):e6059
Magoni M, Bassani L, Okong P, Kituuka P, Germinario EP, Giuliano M, et al.
Mode of infant feeding and HIV infection in children in a program for
prevention of mother-to-child transmission in Uganda. AIDS (London,
England). 2005;19(4):433-7
Mandala J, Moyo T, Torpey K, Weaver M, Suzuki C, Dirks R, et al. Use of
service data to inform pediatric HIV-free survival following prevention of
mother-to-child transmission programs in rural Malawi. Bmc Public Health.
2012;12
Mwendo EM, Mtuy TB, Renju J, Rutherford GW, Nondi J, Sichalwe AW, et al.
Effectiveness of prevention of mother-to-child HIV transmission programmes
in Kilimanjaro region, northern Tanzania. Tropical medicine & international
health : TM & IH. 2014;19(3):267-74
Nagot N, Kankasa C, Meda N, Hofmeyr J, Nikodem C, Tumwine JK, et al.
Reason for Exclusion
The study combines both groups of
women on different types of ARV,
and do not provide infant HIV free
survival when mothers are
breastfeeding and on cART.
Mothers were not on cART, but on
dual ARV with single dose NVP on
labour.
Mothers are on short course cART,
and study does not provide rates of
HIV free survival. Focused on costs.
Provides only total HIV free
survival, not total number of mothers
on cART or infection only by cART.
No rates for breastfeeding and cART
together were provided.
It is very early diagnosis (4-6
weeks).
Mothers were not on cART, but on
dual ARV.
Mothers on different type of
antiretroviral therapy. Not possible to
identify HIV transmission and death
by mothers on cART.
Only 8 mothers on cART were
breastfeeding on the first exam.
Mothers received single-dose
nevirapine.
Mother receiving short course cART.
Mothers on single dose NVP.
Almost 50% of losses on the first
PCR test, and only 7 children
completed 18 months follow-up.
Mothers included on the study were
25
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
Lopinavir/Ritonavir versus Lamivudine peri-exposure prophylaxis to prevent
HIV-1 transmission by breastfeeding: the PROMISE-PEP trial Protocol ANRS
12174. BMC infectious diseases. 2012;12:246
Nlend AEN, Ekani BB. Preliminary assessment of breastfeeding practices in
HIV 1-infected mothers (prior to weaning) under the Djoungolo programme on
the prevention of mother-to-child transmission of HIV. Journal of tropical
pediatrics. 2010;56(6):436-9
Nyandiko WM, Otieno-Nyunya B, Musick B, Bucher-Yiannoutsos S, Akhaabi
P, Lane K, et al. Outcomes of HIV-exposed children in western Kenya: efficacy
of prevention of mother to child transmission in a resource-constrained setting.
Journal of acquired immune deficiency syndromes (1999). 2010;54(1):42-50
Omer SB. Twelve-month follow-up of Six Week Extended Dose Nevirapine
randomized controlled trials: differential impact of extended-dose nevirapine on
mother-to-child transmission and infant death by maternal CD4 cell count.
AIDS (London, England). 2011;25(6):767-76
Read JS. Prevention of mother-to-child transmission of HIV: antiretroviral
strategies. Clinics in perinatology. 2010;37(4):765-76.
Seth A, Chandra J, Gupta R, Kumar P, Aggarwal V, Dutta A. Outcome of HIV
exposed infants: experience of a regional pediatric center for HIV in North
India. Indian J Pediatr. 2012;79(2):188-93
Shah M, Johns B, Abimiku Al, Walker DG. Cost-effectiveness of new WHO
recommendations for prevention of mother-to-child transmission of HIV in a
resource-limited setting. AIDS. 2011;25(8):1093-102.
Simpore J, Pietra V, Pignatelli S, Karou D, Nadembega WM, Ilboudo D, et al.
Effective program against mother-to-child transmission of HIV at Saint Camille
Medical Centre in Burkina Faso. Journal of medical virology. 2007;79(7):873-9
Stringer JS, Stinson K, Tih PM, Giganti MJ, Ekouevi DK, Creek TL, et al.
Measuring coverage in MNCH: population HIV-free survival among children
under two years of age in four African countries. PLoS Med. 2013;10(5).
Taha TE, Li Q, Hoover DR, Mipando L, Nkanaunena K, Thigpen MC, et al.
Postexposure Prophylaxis of Breastfeeding HIV-Exposed Infants With
Antiretroviral Drugs to Age 14 Weeks: Updated Efficacy Results of the PEPIMalawi Trial. Jaids-Journal of Acquired Immune Deficiency Syndromes.
2011;57(4):319-25
Torpey K, Kabaso M, Weaver MA, Kasonde P, Mukonka V, Bweupe M, et al.
Infant feeding options, other nonchemoprophylactic factors, and mother-tochild transmission of HIV in Zambia. Journal of the International Association of
Physicians in AIDS Care (Chicago, Ill : 2002). 2012;11(1):26-33
Torpey K, Kasonde P, Kabaso M, Weaver MA, Bryan G, Mukonka V, et al.
Reducing pediatric HIV infection: estimating mother-to-child transmission rates
in a program setting in Zambia. Journal of acquired immune deficiency
syndromes (1999). 2010;54(4):415-22
van Lettow M, Bedell R, Landes M, Gawa L, Gatto S, Mayuni I, et al. Uptake
and outcomes of a prevention-of mother-to-child transmission (PMTCT)
program in Zomba district, Malawi. BMC Public Health. 2011;11:426
not eligible for cART.
The paper focus on breastfeeding,
mastitis and transmission, and
assessment of transmission done at
13 weeks.
Not possible to extract transmission
and death for cART and BF together.
Most mothers were not on cART.
Very small number of mothers on
cART.
Very small number of mothers on
cART, and no information provided
on whether those mothers were
breastfeeding or not.
Study based on models of % of
adherence in Nigeria.
Very small number of breastfed
children.
Only provide HIV free survival for
mothers on cART or dual ARV
together.
Mothers not on cART, comparison
among dual therapy
No data for mother on cART and
breastfeeding together
Very small number of mothers on
cART
26
Supplementary Table 3. GRADE evidence profile
Question: HIV transmission in breastfed infants of mothers on ART 1
Setting: Zambia, Nigeria, Malawi, South Africa, Tanzania, Uganda and Zimbabwe, India, Kenya, Mozambique
Quality assessment
№ of patients
№ of
Effect
Other
Study design
Risk of bias
Inconsistency Indirectness Imprecision
studies
[intervention]
Rate of transmission % (95% CI)
3175
Rate 3.54 (1.15- 5.93)
Quality
Importance
⨁◯◯◯
IMPORTANT
considerations
Overall transmission at 6 months (Perinatal and Postnatal transmission)
6
observational
very
studies2
serious
very serious
4
serious
5
not serious
none
3
VERY LOW 2 3 4 5
Postnatal transmission at 6 months
6
observational
very
studies 6
serious
very serious
8
serious
9
not serious
none
2109
7
rate 1.08
⨁◯◯◯
(0.32 to 1.85)
VERY LOW 7 8 9
rate 1.8
⨁◯◯◯
(0.7 to 4.8)
LOW11 12
CRITICAL
HIV transmission at 9 months
1
observational
studies10
serious11
not serious
serious 12
not serious
none
532
CRITICAL
27
Quality assessment
№ of patients
№ of
Effect
Quality
Other
Study design
Risk of bias
Inconsistency Indirectness Imprecision
studies
Importance
[intervention]
Rate of transmission % (95% CI)
1493
rate 4.23
⨁◯◯◯
(2.97 to 5.49)
VERY LOW 14 15 16
rate 2.93
⨁◯◯◯
considerations
Overall transmission at 12 months - including peripartum transmission
5
observational
serious
14
serious
15
studies 13
not
serious
not serious
none
16
CRITICAL
Postnatal transmission at 12 months (excluding peripartum transmission)
2
observational
serious
18
serious
19
serious
20
not serious
none
833
studies 17
(0.68 to 5.18)
VERY LOW
CRITICAL
18 19
20
Postnatal transmission at 18 months (lifelong ART, including all transmission)
1
observational
not serious 22
not serious
serious23
not serious
none
studies 21
1.
219
rate 4.1
⨁◯◯◯
(2.2 to 7.6 )
LOW 23
CRITICAL
There was no comparison that was in line with the PICO question. In all studies the recommendation was exclusive breastfeeding for the first six months of life and the majority of mothers breastfed their
children. Transmission according to mixed feeding was not provided by any of the studies.
28
2.
Studies included: Ngoma et al, 2015; Sagay et al, 2015; Jamieson et al, 2012; Thomas et al, 2011; Marazzi et al, 2009 and Kilewo et al, 2009. Of these, Jamieson et al (2012) and Thomas et al (2011)
were cohorts embedded in randomized control trials, while Ngoma et al, (2015), Sagay et al (2015), Marazzi et al (2009) and Kilewo et al (2009) were cohort studies
3.
Risk of bias: We downgraded once due to potential selection bias for lack of detailed feeding history in Sagay et al, 2015 and Marazzi et al. 2009. Adherence to ART was not provided in Sagay et al, 2015;
Marazzi et al, 2009 and Kilewo et al, 2009. Sagay et al, 2015 and Jamieson et al, 2012 did not provide a rate of transmission, but the rate of transmission was calculated from the number of children at
risk provided in the paper. Sagay et al, 2015 is a retrospective study, and only one denominator was provided for all rates provided in the study. Ngoma et al, 2015 and Marazzi et al, 2009 did not provide
confidence interval, which was calculated for both studies according to the formula provided in Appendix 6.
4.
Inconsistency: We downgraded twice due to substantial heterogeneity in rates of transmission provided or calculated. Rates ranged from 0.7% (95% CI 0.20%-1.20%) in Sagay et al, 2015, which was a
retrospective cohort, to 7.9% (95% CI 6.2%-9.90%) in Jamieson et al, 2012
5.
Indirectness: We downgraded once as the studies’ questions were not in line with the PICO question and covered different types of additional interventions. In Ngoma et al, 2015, Sagay et al, 2015,
Marazzi et al. 2009 and Kilewo et al. 2009 the only intervention was ART. Jamieson et al. 2012 compared transmission rates in children whose mothers were on ART, infants on NVP and a control group
and the three groups were further divided into those who were on a maternal nutrition supplement and those that were not.
6.
Studies included were: Coovadia et al, 2012, Jamieson et al, 2012, Alvarez-Uria et al, 2012, Thomas et al, 2011, Marazzi et al, 2009 and Kilewo et al, 2009. Coovadia et al (2012), Jamieson et al (2012)
and Thomas et al (2011) were cohorts embedded in randomized control trials, while Alvarez-Uria et al (2012), Marazzi et al (2009) and Kilewo et al (2009) were cohort studies.
7.
Risk of bias: We downgraded once due to potential selection bias for lack of detailed feeding history in Marazzi et al, 2009. Adherence to ART was not provided in Marazzi et al, 2009 and Kilewo et al,
2009. There were some differences regarding age in weeks as endpoint considered perinatal transmission. Coovadia et al (2012), Alvarez-Uria et al (2012), Thomas et al (2011) and Kilewo et al (2009)
excluded children positive at 6 weeks, Jamieson et al (2012) excluded at 2 weeks and Marazzi et al (2009) at 4 weeks. Jamieson et al (2012), Thomas et al (2011) and Kilewo et al (2009) did not provide
a rate of transmission, but the rate was calculated based on the number of children at risk provided in the paper. In Marazzi et al (2009) a confidence interval was not provided but was calculated using
the formula in Appendix 6.
8.
Inconsistency: We downgraded due to substantial heterogeneity in rates of transmission provided or calculated (I2=66.4%). Rates ranged from 0.24% (95% CI 0.0% to 1.40%) in Coovadia et al, 2012 to
3.10% (95% CI 1.20% to 7.80%) in Alvarez-Uria et al, 2012, the latter study had a very wide confidence interval due to the small sample of 127.
9.
Indirectness: We downgraded once as the studies’ questions were not in line with the PICO question and covered different types of co-interventions. In Alvarez-Uria et al., 2012, Marazzi et al. 2009 and
Kilewo et al. 2009 the only intervention was ART. Jamieson et al. 2012 compared HIV-free survival in children whose mothers were on ART, infants on NVP and a control group and the three groups
29
were further divided into those who were on a maternal nutrition supplement and those that were not. In Coovadia et al, infants were randomized to receive extended Nevirapine or placebo until 6 months
of life. In Alvarez-Uria et al. 2012 all women were on ART but newborns were also given prophylaxis, the study also compared transmission rates between infants being breastfed and receiving formula
feeding. In Thomas et al. 2011 all mothers were on ART but all infants received a single dose of NVP within 72 hours. Studies also varied with regard to initiation of maternal ART.
10. Single study included: Peltier et al, 2009, which was a cohort study.
11. Risk of bias: We downgraded once due to potential selection bias since this was a non-randomized intervention cohort in which the mother could choose the type of feeding for the infant. Only mothers
with low CD4 count (<350 cells/µl or WHO clinical stage 4) were eligible for lifelong ART. The study had good adherence to ART and ascertainment of feeding. Only 15 mothers were reported to be
mixed feeding their children, but no children were infected.
12. Indirectness: We downgraded once as the study research question was not in line with PICO questions and although the study compares breastfeeding and formula feeding, it did not study the effect of
ART by feeding.
13. Studies included were: Giuliano et al, 2013, Alvarez-Uria et al, 2012, Thomas et al, 2011, Marazzi et al, 2009 and Kilewo et al, 2009. Thomas et al (2011) was a cohort embedded in a randomized control
trial, while Giuliano et al (2013), Alvarez-Uria et al (2012), Marazzi et al (2009) and Kilewo et al (2009) were cohort studies
14. Risk of bias: We downgraded once due to potential selection bias for lack of detailed information regarding feeding in Marazzi et al, 2009.
15. Inconsistency: We downgraded once due to heterogeneity in rates of transmission (I2 =39.9%), which varied from 2.8% (95%CI 1.40% to 5.50%) in Marazzi et al, 2009 to 5.80% (95% CI 3.60% to 8.00%)
in Kilewo et al, 2009.
16. Indirectness: We downgraded once as the studies’ research questions were not in line with PICO questions and covered different types of co-interventions. In Giuliano et al, 2013, Alvarez-Uria et al, 2012,
Marazzi et al. 2009 and Kilewo et al. 2009 the only intervention was ART. Giuliano et al (2013) offered lifelong ART for mothers with low CD4 count. In Alvarez-Uria et al. 2012 all women were on ART but
newborns were also given prophylaxis. In Thomas et al. 2011 all mothers were on ART but all infants received a single dose of NVP within 72 hours. Studies also varied with regard to initiation of
maternal ART.
17. Studies include were: Coovadia et al, 2012 and Jamieson et al, 2012. Both studies were cohorts embedded in a randomized control trial.
18. Risk of bias: We downgraded once due to potential selection bias for lack of detail of feeding practices and adherence to ART in Coovadia et al, 2012. Jamieson et al, 2012 did not provide rate of
transmission. The studies also varied in the age in weeks as endpoint for peripartum transmission, Coovadia et al, 2012 excluded infants identified as infected at 6 weeks and Jamieson et al, 2012 at 2
weeks.
30
19. Inconsistency: We downgraded twice due to high heterogeneity in the pooled estimate (I2= 71.2%), with rates varying from 1.70% (95% CI 0.30% to 4.10%) in Coovadia et al, 2012 and 4.0% (95%Ci 1.94%
to 4.29%) in Jamieson et al, 2012..
20. Indirectness: We downgraded once because the studies’ research question was not in line with the PICO question and covered different types of co-interventions. . In Coovadia et al. 2012, infants were
randomised to receive either extended Nevirapine prophylaxis or placebo until 6 months or until breastfeeding cessation. Jamieson et al, 2012 compared HIV-free survival in children whose mothers were
on ART, infants on NVP and a control group and the three groups were further divided into those who were on a maternal nutrition supplement and those that were not.
21. Single study included: Ngoma et al, 2015.
22. Risk of bias: The study was not downgraded because the study had high adherence to ART, all mothers were receiving lifelong ART, and feeding was well-evaluated.
23. Indirectness: We downgraded once as the study’s research questions were not in line with the PICO question, and although all mothers were on lifelong ART, and ascertainment of ART and
breastfeeding were adequate, outcome was not stratified by feeding, and the number of infants who were mixed fed was not provided.
31
1
2
Supplementary Table 4. Modified Newcastle-Ottawa for assessment of HIV transmission in breastfed infants whose mothers were on ART
Author
Country
Selection
Outcome
Ngoma et al, 2015
Zambia
*****
**
Sagay et al, 2015
Nigeria
***
**
Thakwalakwa et al, 2014
Malawi
*
**
Giuliano et al, 2013
**
**
**
**
Jamieson et al, 2012
Malawi
South Africa, Tanzania, Uganda and
Zimbabwe
Malawi
****
***
Alvarez-Uria et al, 2012
India
**
****
Thomas et al, 2011
Kenya
****
***
Marazzi et al, 2009
Mozambique
**
**
Kilewo et al, 2009
Tanzania
***
***
Peltier et al, 2009
Rwanda
****
***
Coovadia et al, 2012
3
32