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      Two-Way Short Message Service (SMS) Communication May Increase Pre-Exposure Prophylaxis Continuation and Adherence Among Pregnant and Postpartum Women in Kenya

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          Abstract

          We evaluated a 2-way short messaging service (SMS) communication platform to improve continuation of pre-exposure prophylaxis (PrEP) for HIV prevention among Kenyan pregnant and postpartum women who initiated PrEP within routine maternal child health and family planning clinics. SMS increased support for PrEP, provided opportunities for dialogue beyond the clinic, and enabled women to ask and receive answers in real-time, which facilitated continued PrEP use.

          Abstract

          We evaluated a 2-way short messaging service (SMS) communication platform to improve continuation of pre-exposure prophylaxis (PrEP) for HIV prevention among Kenyan pregnant and postpartum women who initiated PrEP within routine maternal child health and family planning clinics. SMS increased support for PrEP, provided opportunities for dialogue beyond the clinic, and enabled women to ask and receive answers in real-time, which facilitated continued PrEP use.

          ABSTRACT

          Introduction:

          We evaluated a 2-way short message service (SMS) communication platform to improve continuation of pre-exposure prophylaxis (PrEP) for HIV prevention among Kenyan women who initiated PrEP within routine maternal child health (MCH) and family planning clinics.

          Methods:

          We adapted an existing SMS platform (Mobile WACh [mWACh]) to send PrEP-tailored, theory-based SMS and allow clients to communicate with a remote nurse. Women who did not have HIV and who were initiating PrEP at 2 MCH/family planning clinics in Kisumu County, Kenya, from February to October 2018, were offered enrollment into the mWACh-PrEP program; SMS communication was free. We evaluated acceptability, satisfaction, and implementation metrics. In a pre/postevaluation, we compared PrEP continuation at 1-month postinitiation among women who initiated PrEP in the period before (n=166) versus after mWACh-PrEP implementation, adjusting for baseline differences.

          Results:

          Of the 334 women who were screened for enrollment into the mWACh-PrEP program; 193 (58%) were eligible and of those, 190 (98%) accepted enrollment. Reasons for ineligibility (n=141) included no phone access (29%) and shared SIM cards (25%). Median age was 25 years (interquartile range=22–30), and 91% were MCH clients. Compared to women who initiated PrEP in the month before mWACh-PrEP implementation, women who enrolled in mWACh-PrEP were more likely to return for their first PrEP follow-up visit (40% vs. 53%; adjusted risk ratio [aRR]=1.26; 95% confidence interval [CI]= 1.06, 1.50; P=.008) and more likely to continue PrEP (22% vs. 43%; aRR=1.75; 95% CI=1.21, 2.55; P=.003). Among those who returned, 99% reported successful receipt of SMS through the mWACh-PrEP system and 94% reported that mWACh-PrEP helped them understand PrEP better. Concerns about PrEP use, how it works, and side effects accounted for the majority (80%) of issues raised by participants using SMS.

          Conclusions:

          Two-way SMS expanded support for PrEP and opportunities for dialogue beyond the clinic and enabled women to ask and receive answers in real time regarding PrEP, which facilitated its continued use.

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          Most cited references 32

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          Effects of a mobile phone short message service on antiretroviral treatment adherence in Kenya (WelTel Kenya1): a randomised trial.

          Mobile (cell) phone communication has been suggested as a method to improve delivery of health services. However, data on the effects of mobile health technology on patient outcomes in resource-limited settings are limited. We aimed to assess whether mobile phone communication between health-care workers and patients starting antiretroviral therapy in Kenya improved drug adherence and suppression of plasma HIV-1 RNA load. WelTel Kenya1 was a multisite randomised clinical trial of HIV-infected adults initiating antiretroviral therapy (ART) in three clinics in Kenya. Patients were randomised (1:1) by simple randomisation with a random number generating program to a mobile phone short message service (SMS) intervention or standard care. Patients in the intervention group received weekly SMS messages from a clinic nurse and were required to respond within 48 h. Randomisation, laboratory assays, and analyses were done by investigators masked to treatment allocation; however, study participants and clinic staff were not masked to treatment. Primary outcomes were self-reported ART adherence (>95% of prescribed doses in the past 30 days at both 6 and 12 month follow-up visits) and plasma HIV-1 viral RNA load suppression (<400 copies per mL) at 12 months. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00830622. Between May, 2007, and October, 2008, we randomly assigned 538 participants to the SMS intervention (n=273) or to standard care (n=265). Adherence to ART was reported in 168 of 273 patients receiving the SMS intervention compared with 132 of 265 in the control group (relative risk [RR] for non-adherence 0·81, 95% CI 0·69-0·94; p=0·006). Suppressed viral loads were reported in 156 of 273 patients in the SMS group and 128 of 265 in the control group, (RR for virologic failure 0·84, 95% CI 0·71-0·99; p=0·04). The number needed to treat (NNT) to achieve greater than 95% adherence was nine (95% CI 5·0-29·5) and the NNT to achieve viral load suppression was 11 (5·8-227·3). Patients who received SMS support had significantly improved ART adherence and rates of viral suppression compared with the control individuals. Mobile phones might be effective tools to improve patient outcome in resource-limited settings. US President's Emergency Plan for AIDS Relief. Copyright © 2010 Elsevier Ltd. All rights reserved.
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            Preexposure Prophylaxis for HIV Infection Integrated With Municipal- and Community-Based Sexual Health Services.

            Several randomized clinical trials have demonstrated the efficacy of preexposure prophylaxis (PrEP) in preventing human immunodeficiency virus (HIV) acquisition. Little is known about adherence to the regimen, sexual practices, and overall effectiveness when PrEP is implemented in clinics that treat sexually transmitted infections (STIs) and community-based clinics serving men who have sex with men (MSM).
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              Incident HIV during Pregnancy and Postpartum and Risk of Mother-to-Child HIV Transmission: A Systematic Review and Meta-Analysis

              Introduction Antenatal HIV testing is essential to identify HIV-infected women who need to start antiretrovirals (ARVs) both to decrease risk of mother-to-child HIV transmission (MTCT) and improve maternal health. As part of this process, women who test HIV negative during antenatal screening may feel reassured that neither they nor their infants are at risk for HIV. However, HIV may be acquired during pregnancy and postpartum and would not be detected unless repeat HIV testing is conducted. Despite guidelines recommending repeat HIV testing during the third trimester or at delivery in settings where the HIV epidemic is generalized [1],[2], repeat testing is rarely implemented or documented [3],[4]. The lack of retesting during pregnancy and postpartum represents a missed opportunity to identify women who have recently acquired HIV infection and have an increased risk of MTCT because of their high HIV viral loads during incident infection, and to initiate ARVs for prevention of mother-to-child HIV transmission (PMTCT) among HIV-infected women who did not access antenatal care and were not tested during pregnancy [5]. Several individual studies suggest that the incidence of HIV infection during pregnancy and the postpartum period is high, with some suggesting increased incidence among pregnant/postpartum women compared to non-pregnant women [3],[5],[6]. However, differences in antenatal and postpartum follow-up, study designs, assays used to detect infection, and underlying HIV prevalence have made it difficult to compare findings between studies. Potential mechanisms for increased susceptibility to HIV during pregnancy and postpartum include both biological and behavioral characteristics unique to this period [6]. If the risk of HIV acquisition is increased during the pregnancy and/or postpartum periods, this higher risk may translate to a substantial cumulative period of risk for women in areas where fertility rates and HIV prevalence are high. While a systematic review conducted in 1992 by Dunn et al. quantified risk of MTCT through breastfeeding among women infected postnatally, risk of in utero or intrapartum transmission among women who acquired HIV during pregnancy was not included [7]. In addition, the review was conducted prior to the implementation of ARV prophylaxis for PMTCT and was unable to characterize risk of MTCT among mothers with incident HIV infection in the era of PMTCT ARVs. Thus, the relative contribution of maternal HIV acquisition during pregnancy or postpartum and use of maternal PMTCT ARVs is unknown. In 2012, the World Health Organization announced a global plan to eliminate MTCT by 2015 that includes reducing HIV incidence among women and MTCT rates, and increasing uptake of maternal and infant ARVs for PMTCT [8]. However, achievement of these objectives will be hindered without a greater understanding of the risk of HIV infection in pregnant and postpartum populations, and the subsequent risk of MTCT both in the presence and absence of PMTCT ARVs. We performed a systematic review and meta-analysis to synthesize and compare the risk of HIV acquisition during pregnancy and the postpartum period, and risk of MTCT among women with incident HIV infection. Methods Systematic Review and Article/Abstract Selection We conducted a systematic review for all peer-reviewed published articles and conference abstracts on recent HIV infection during pregnancy or through 12 months postpartum (Figure 1). PubMed and Embase databases were searched from January 1, 1980, through October 31, 2013, to identify articles to review using combinations of the following terms: HIV infections, HIV seropositivity, pregnancy, human, incidence, acquisition, and acute. For PubMed (Medline) our search strategy was the following: (HIV infections[mh] or hiv-seropositivity[mh]) AND pregnancy[mh] AND human[mh] AND (incidence[mh] OR incidence[ti] OR acquisition[ti] OR acute[ti]). Our search strategy for Embase (excluding Medline results) was: ‘Human immunodeficiency virus infection’/exp AND ‘pregnancy’/exp AND (‘incidence’/exp OR ‘incidence’:ti OR ‘acquisition’:ti OR ‘acute’:ti) AND [embase]/lim NOT [medline]/lim. Titles of abstracts from the 19th and 20th Conference on Retroviruses and Opportunistic Infections (2011 and 2012), 6th and 7th International AIDS Society Conference (2011 and 2013), and 19th International AIDS Conference (2012) were also searched using the terms pregnancy, postpartum, and lactating. Titles of articles without abstracts were reviewed for consideration of full-text review; however, duplicate abstracts were not considered for full-text review. Articles were included in full-text review if the abstract or title mentioned HIV incidence, HIV seroconversion, or recent HIV infection during pregnancy, the postpartum period, or lactation. Review articles and articles on unrelated topics were excluded from full-text review. Titles of references cited in studies selected for full-text review were also evaluated for relevance and full-text review. Full-text articles and conference abstracts were excluded from analyses if (1) HIV incidence rates; cumulative HIV incidence; risk of HIV acquisition during pregnancy, postpartum, and/or during lactation; risk of MTCT during incident infection; or MTCT rates among women with incident infections were not reported and could not be calculated; (2) HIV infection preceded pregnancy; (3) HIV incidence estimates were based on mathematical modeling; (4) postpartum follow-up was >12 mo postpartum and HIV incidence during pregnancy was not reported; or (5) HIV prevalence and incidence could not be distinguished from one another. Additionally, conference abstracts that were subsequently published as articles were excluded, studies reporting results from the same cohort were compared and only the article with the most detailed data on incidence and follow-up was included, and articles in English were included if some or all of the data were also published in a different journal and in a language other than English. All other non-English articles/abstracts were considered for full-text review, but either were found to not be relevant based on review of English abstracts and titles, or did not have available abstracts to review. The combined search of articles and conference abstracts resulted in 1,176 studies for review: 626 articles and 559 conference abstracts. An additional nine articles were included for review from references cited in these articles, for a total of 1,185 studies identified to review. Among these, 78 studies (70 articles and eight conference abstracts) were identified for full-text review. 10.1371/journal.pmed.1001608.g001 Figure 1 Flowchart of studies reviewed and included in meta-analyses. **Not mutually exclusive. †One study excluded that reported relative risk rather than hazard ratio. Data Extraction and Statistical Analysis Two independent reviewers (A. L. D. and A. W.) reviewed full-text articles for inclusion and exclusion and abstracted data on the following outcomes occurring during pregnancy and/or postpartum periods: (1) HIV incidence rates; (2) cumulative incidence of HIV; (3) risk of HIV acquisition (hazard ratio [HR]); (4) risk of MTCT (odds ratio [OR]); and (5) MTCT rate. Variables extracted for analysis included sample size, number of incident HIV infections, number of women at risk of incident infection, person-time of follow-up, HIV incidence rates, cumulative HIV incidence, number of infant infections, assay used to detect incident infections, retesting and/or follow-up intervals, postpartum and lactation status, and study location. All postpartum follow-up time was restricted to 12 months postpartum unless women were reported to be lactating; there was no restriction on follow-up time for lactating women. Articles that did not report maximum postpartum follow-up time but presented a mean or median postpartum follow-up ≤12 months were also included in the analysis. Lactating women were combined with postpartum women for the meta-analysis; however, a separate subgroup analysis of postpartum women who were defined as lactating versus postpartum was also conducted. Incidence rates and cumulative incidence Incidence rates are reported as the number of new infections per 100 person-years; rates were calculated if data were available but not presented as an incidence rate. Cumulative incidence was calculated as the number of new infections per number at risk for studies with repeat testing. Cumulative incidence based on cross-sectional testing of HIV-positive samples using assay algorithms designed to detect incident infections was included as presented in the article or abstract. Assays included in the cumulative incidence meta-analysis included serological testing algorithm for recent HIV seroconversion (STARHS) using BED capture enzyme immunoassay or bioMerieux Vironosticka less sensitive enzyme immunoassay, avidity index, nucleic acid amplification tests, and p24 antigen tests. Studies presenting annual cumulative incidence were summarized for the meta-analysis by calculating a weighted incidence based on sample size. We calculated 95% CIs if they were not presented in the study. The Poisson distribution was used to calculate 95% CIs for incidence rates using person-time denominators, and the binomial distribution was used to calculate 95% CIs for cumulative incidence using individuals as the denominator. 95% CIs were calculated using the weighted estimate if annual cumulative incidence was calculated by weighting. Authors were contacted if additional information was required to calculate incidence rates or cumulative incidence. Pooled summary statistics and plots Meta-analyses were conducted to summarize cumulative HIV incidence and incidence rates of HIV during pregnancy and postpartum, MTCT rates among women with incident HIV infections, the association between pregnancy/postpartum periods and HIV acquisition, and the association between incident maternal HIV infection during pregnancy/postpartum periods and MTCT. Pooled HRs were calculated to summarize the association between pregnancy and postpartum periods and HIV acquisition if HRs were presented, and pooled ORs were used to summarize the association between incident infection during pregnancy/postpartum periods and MTCT. Fixed effects models were constructed to pool HIV incidence rates, cumulative incidence, MTCT rates, HRs, and ORs; models were tested for heterogeneity using the I 2 statistic. Models pooling HIV incidence rates, MTCT rates, and HRs for HIV acquisition were a priori stratified by pregnancy, postpartum period, or pregnancy and postpartum periods combined. Significant heterogeneity was detected in all models, and the models were reconstructed with random effects using estimates of heterogeneity from the Mantel-Haenszel model to calculate pooled measures. We conducted both a priori and post hoc analyses to identify sources of heterogeneity. Pooled incidence rates during pregnancy and the postpartum period for studies conducted in Africa were a priori stratified by region (south, southeast, east, central, and west; in descending order of HIV prevalence) as a strategy to adjust for differences in HIV prevalence between these regions. We compared cumulative incidence detected by assay algorithms versus repeat testing and MTCT risk by use of maternal or infant ARV prophylaxis through additional stratified analysis. We also conducted post hoc stratified analysis of MTCT rates, MTCT risk, and cumulative incidence by study location (Africa or outside of Africa), and multivariate meta-regression for cumulative incidence by study location and testing algorithm. Forest plots of HIV incidence rates, cumulative HIV incidence, HRs, ORs, and MTCT rates were generated for individual articles, pooled subgroup estimates (when indicated), and pooled overall estimates. Meta-regression was used to compare log-transformed incidence, log-transformed cumulative incidence, MTCT rates, ORs, and HRs between subgroups and in multivariate models. Statistical analysis was performed using Stata version 13.1 (StataCorp). The Newcastle-Ottawa Scale was used to assess the quality of the studies included in the meta-analyses that compared MTCT risk or risk of maternal HIV acquisition between groups; this scale ranges from 0 to 9 and assesses study quality based on study characteristics for selection of the cohort, comparability of exposed and unexposed groups, and outcome ascertainment. The quality of studies for studies with comparison groups was not compared statistically since quality scoring adds subjective bias to the results unless individual score components are used in the meta-regression, and adding several covariates for individual score components would result in over-stratification [9],[10]. Two independent reviewers (A. L. D. and A. W.) scored each study, and the average score for all studies, stratified by outcome, was calculated [11]. Results Study Selection for Review Among the 1,176 studies identified, 78 were selected for further review of the full-text article or conference abstract, and 47 were included in the analysis (41 articles and six conference abstracts) (Figure 1). Characteristics of studies included in the meta-analysis and data summaries are presented in Table 1. Studies were identified from six continents: 35 from Africa; four each from Asia, North America, and South America; and one each from Australia and Europe. Only ten studies comparing MTCT risk (n = 5) or risk of maternal HIV acquisition (n = 5) between groups were eligible for evaluation by the Newcastle-Ottawa Scale. Studies evaluated by the Newcastle-Ottawa Scale received a mean score of 7.4 for studies comparing risk of MTCT and a mean score of 8.2 for studies comparing risk of maternal HIV acquisition, indicating that the quality of included studies was high; individual Newcastle-Ottawa Scores for MTCT and risk of maternal HIV acquisition are shown in Table 1. 10.1371/journal.pmed.1001608.t001 Table 1 Study characteristics and data included in meta-analyses and data summaries. Study Location First Author, Year [Reference] Study Years Country Methodology Sample Size or Person-Years Incidence Measure (Pregnancy or Postpartum) Repeat Testing Intervals HIV Acquisition MTCT Measures (Pregnancy or Postpartum)a Newcastle-Ottawa Score (Analysis) Africa South Bernasconi, 2010 [53] 2004–2006 Swaziland Assay n = 3,029 CI (pregnancy) — — — — Boly, 2011 [54] 2010 Namibia Retesting n = 196 CI (pregnancy) — — — — Hargrove, 2008 [14] 1997–2000 Zimbabwe Assay n = 6,829 CI (postpartum) — — — — Humphrey, 2006 [46] 1997–2001 Zimbabwe Prospective cohort 7,763 PY IR (postpartum) Postpartum (quarterly/biannually until 12 mo postpartum) — — — Humphrey, 2010 [21] 1997–2000 Zimbabwe Prospective cohort n = 334 — — — Rate and risk (pregnancy) 7 (MTCT) Kharsany, 2010 [55] 2007–2008 South Africa Assay n = 467 CI (pregnancy) — — — — Kieffer, 2011 [56] 2008–2009 Swaziland Prospective cohort 346 PY IR (pregnancy) — — — — Lu, 2011 [16] Not reported Botswana Retesting n = 417 (incidence), n = 17 (MTCT) CI (pregnancy and postpartum) — — Rate (pregnancy and postpartum) — Mbizvo, 2001 [57] 1991–2005 Zimbabwe Prospective cohort 1,093 PY IR (pregnancy and postpartum) Postpartum (12 mo postpartum) — — — Moodley, 2009 [3] 2006–2007 South Africa Retesting 679 PY Pregnancy (36–40 wk gestation) — — — Moodley, 2011b [5] 2005–2007 South Africa Prospective cohort 1,946 PY, n = 39 IR (pregnancy and postpartum) Pregnancy and postpartum (≤6 mo antenatally and 12 mo postpartum) — Rate and risk (pregnancy and postpartum combined) 7 (MTCT) Morrison, 2007c [42] 1994–2004 Zimbabwe Prospective cohort 2,004 PY, n = 4,415 IR (pregnancy and postpartum) Pregnancy (≤24 mo after enrollment) Pregnancy and postpartum — 9 (HIV acquisition) Munjoma, 2010 [58] 2002–2008 Zimbabwe Prospective cohort 298 PY IR (pregnancy) — — — — Rehle, 2007 [13] 2005 South Africa Assay n = 135 CI (pregnancy) — — — — Reid, 2010 [59] 2003–2007 3 African countries Prospective cohort n = 228 — — Pregnancy — 8 (HIV acquisition) Rollins, 2002 [60] 2000 South Africa Assay n = 418 — — — — — Wand, 2011 [39] 2002–2005 South Africa Prospective cohort n = 2,523 — — Pregnancy — 8 (HIV acquisition) Southeast De Schacht, 2011 [61] Not reported Mozambique Prospective cohort 226 PY IR (pregnancy) — — — — Gay, 2010 [62] 2000–2004 Malawi Assay n = 2,327 CI (pregnancy) — — — — Hira, 1990 [20] 1987 Zambia Retesting n = 1,954 (incidence), n = 19 (MTCT) CI (pregnancy and postpartum) Postpartum (12 mo postpartum) — Rate (postpartum) — Mugo, 2011 [38] 2004–2007 7 African countries Prospective cohort 231 PY, n = 1,085 IR (pregnancy) — Pregnancy — 9 (HIV acquisition) Taha, 1998 [45] Recruited 1990, 1993 Malawi Prospective cohort 338 PY IR (pregnancy) — — — — Central Colebunders, 1988 [19] Not reported Zaire Case series n = 3 — — — Rate (postpartum) — East Braunstein, 2011c [63] 2006–2009 Rwanda Prospective cohort 625 PY, n = 397 IR (pregnancy and postpartum) Postpartum (2 y after enrollment) Pregnancy and postpartum — 7 (HIV acquisition) Gray, 2005c [6] 1994–1999 Uganda Prospective cohort 4,040 PY IR (pregnancy and postpartum) Postpartum (until lactation stopped) — — — Keating, 2012 [43] 2009 Malawi Retrospective cohort 275 PY IR (pregnancy) — — — — Kinuthia, 2010 [64] Not reported Kenya Retesting 779 PY IR (pregnancy) Pregnancy (6 wk postpartum) — — — Leroy, 1994 [65] 1988–1992 Rwanda Prospective cohort 204 PY IR (postpartum) Postpartum (quarterly until 12 mo postpartum) — — — Tabu, 2013 [4] 2012 Uganda Retesting 312 PY IR (pregnancy) — — — — Van de Perre, 1991 [22] 1988–1991 Rwanda Prospective cohort n = 12 — — — Rate (pregnancy and postpartum) — Wawer, 1999 [66] 1994 Uganda Prospective cohort 1,280 PY IR (pregnancy and postpartum) Postpartum, retested 8 mo postpartum (mean) — — — Wolday, 2007 [67] 1995–2003 Ethiopia Assay n = 6,394 CI (pregnancy) — — — — West Imade, 2012 [68] 2010–2012 Nigeria Assay 235 PY IR (pregnancy) — — — — Kim, 2010 [12] 1998–2004 Côte d'Ivoire Assay n = 10,616 CI (pregnancy) — — — — Traore, 2012 [69] 2010–2011 Burkina Faso Prospective cohort 126 PY IR (pregnancy) — — — — Asia Duan, 2010 [70] 2004–2008 China Assay n = 84,144 CI (pregnancy) — — — — Liang, 2009 [15] 2000–2008 China Retrospective cohort n = 106 — — — Rate (postpartum) — Roongpisuthipong, 2001 [24] 1992–1994 Thailand Retesting n = 15 — — — Rate and risk (pregnancy) 7 (MTCT) Saphonn, 2005 [71] 1999–2002 Cambodia Assay n = 19,467 — — — — — North America Birkhead, 2010 [25] 2002–2006 United States (New York) Prospective cohort n = 41 — — — Rate and risk (pregnancy) 9 (MTCT) Nesheim, 2005 [72] 1990–1998 United States (Georgia) Assay n = 48,018 CI (pregnancy) — — — — Nesheim, 2007 [26] 2001–2005 United States Retesting n = 4 — — — Rate (pregnancy) — Singh, 2012 [18] 2005–2010 United States Surveillance cohort n = 124 — — — Rate and risk (pregnancy) 7 (MTCT) South America de Freitas, 2005 [73] 1991–2002 Brazil Assay n = 4,327 CI (pregnancy) — — — — Pando, 2011 [74] 2006–2008 Argentina Assay n = 8,560 CI (pregnancy) — — — — Australia Palasanthiran, 1993 [17] 1984–1990 Australia Retrospective cohort n = 11 — — — Rate (postpartum) — Europe Tovo, 1991 [23] Not reported Italy Prospective cohort n = 10 — — — Rate (pregnancy) — a MTCT rates measured as proportions, and risk measured as ORs. b Antenatal and postpartum periods combined. c Postpartum women were defined as lactating. CI, cumulative incidence; IR, incidence rate; PY, person-years. Incidence Rates during Pregnancy and Postpartum Nineteen studies reported HIV incidence rates during pregnancy and/or the postpartum period: 16 during pregnancy, seven during the postpartum period, and one during pregnancy and postpartum periods combined (Figure 2), representing 19 cohorts and 22,803 person-years in total. All incidence rates were from publications reported from sub-Saharan Africa. Incidence rates during pregnancy ranged from 0 to 16.8 per 100 person-years, with a pooled incidence rate of 4.7 (95% CI 3.3–6.1). During the postpartum period, the pooled incidence rate was 2.9 (95% CI 1.8–4.0) and not significantly different from the pooled incidence rate during pregnancy (4.7, 95% CI 3.3–6.1; p = 0.18). After combining results from all studies, the pooled incidence during pregnancy and/or the postpartum period was 3.8 (95% CI 3.0–4.6). In subgroup analyses separating postpartum women who were defined as lactating versus postpartum, stratified pooled incidence rates among women defined as lactating (2.0, 95% CI 0.2–3.8) or postpartum (3.2, 95% CI 2.2–4.2) were not significantly different from that of the overall postpartum population combining these groups. Incidence rates during pregnancy and/or postpartum were also stratified by African region (Figure 3). Pooled incidence was highest in southeast Africa (6.2, 95% CI 4.2–8.1), followed by south Africa (4.8, 95% CI 3.5–6.2), east Africa (2.7, 95% CI 1.8–3.6), and west Africa (0.7, 95% CI 0–2.3); the pooled incidence rate was significantly lower in east Africa than in southeast Africa (p = 0.04), but there were no other significant differences by region. 10.1371/journal.pmed.1001608.g002 Figure 2 Forest plot of HIV incidence rates, by pregnancy and postpartum status. PY, person-years. *Defined as lactating. 10.1371/journal.pmed.1001608.g003 Figure 3 Forest plot of HIV incidence rates during pregnancy and postpartum, by African region. PY, person-years. *Defined as lactating. Cumulative HIV Incidence during Pregnancy and Postpartum Cumulative HIV incidence during pregnancy was reported in 16 studies, during the postpartum period in three studies, and during the combined pregnancy/postpartum period in one study (Figure 4). Thirteen studies reported cumulative incidence based on assay-specific algorithms from cross-sectional testing, two studies were based on repeat testing, and one study reported both assay and repeat testing results during pregnancy, delivery, or postpartum. Incident infections from assays were detected using an avidity index, STARHS, p24 antigen detection, or nucleic acid amplification tests. The estimate of cumulative incidence using BED capture enzyme immunoassay as the assay for STARHS was adjusted to account for assay sensitivity and specificity in the studies by Kim et al. [12], Rehle et al. [13], and Hargrove et al. [14], as reported in the articles. Pooled cumulative incidence was 1.4% (95% CI 1.1%–1.7%) when infections were detected by assay algorithms from cross-sectional testing and 2.7% (95% CI 1.0%–4.4%) among populations retested (p = 0.4). Cumulative incidence was significantly higher in African countries (3.6%, 95% CI 1.9%–5.3%) than in non-African countries (0.3%, 95% CI 0.1%–0.4%; p 200 cells/mm3 and antiretroviral therapy (ART) for women with CD4 count ≤200 cells/mm3, one used zidovudine and nevirapine regimens for women and infants, and the last did not specify ARV regimen. MTCT rates across all studies ranged from 12.9% in the United States to 58.0% in Rwanda, with a pooled rate of 22.7% (95% CI 17.5%–27.8%). A similar MTCT rate (23.5%) resulted from the pooled analysis of the subset of these studies that did not use ARVs (p = 0.70); MTCT rates also did not differ by African versus non-African countries (23.6% versus 22.0%, respectively; p = 0.49). The pooled MTCT rate among women with incident infection during pregnancy was 17.8% (95% CI 12.2%–23.4%), compared to 26.9% (95% CI 19.3%–34.5%) among women with incident infection postpartum (p = 0.10). 10.1371/journal.pmed.1001608.g006 Figure 6 Forest plot of mother-to-child HIV transmission rates among women with incident infection during pregnancy/postpartum. *No PMTCT ARVs. **Unspecified ARV regimen. †Single-dose nevirapine if maternal CD4 count >200 cells/mm3 and ART for women with CD4 count ≤200 cells/mm3. ††Zidovudine and nevirapine regimens for women and infants. Five studies compared risk of MTCT among women with incident versus chronic HIV infection (Figures 7 and 8). MTCT risk was 9- to 15-fold higher among US women who seroconverted during pregnancy than among women with chronic HIV infection, because of effective early ART treatment of chronically HIV-infected mothers. In African cohorts, compared to women with chronic HIV, MTCT risk was 2- to 3-fold higher among women with incident HIV infection in the postpartum period (pooled OR 2.9, 95% CI 2.2–3.9) or in the pregnancy and postpartum periods combined (pooled OR 2.3, 95% CI 1.2–4.4). The pooled OR for MTCT with incident HIV versus chronic HIV among mothers was 2.8 (95% CI 0.9–4.7) (Figure 8); the pooled OR after adjusting for maternal or infant ARV prophylaxis was 5.6 (95% CI 0.1–311.5). 10.1371/journal.pmed.1001608.g007 Figure 7 Effect of incident maternal HIV infection and antiretroviral prophylaxis on mother-to-child HIV transmission. Incident infection defined as maternal HIV acquisition during pregnancy or postpartum; chronic infection defined as established HIV infection during pregnancy or postpartum. MTCT rates and ORs are derived from the studies indicated in parentheses; PMTCT ARVs represent the regimens available during the studies. For Moodley [5], women with CD4 count >200 cells/mm3 were eligible to receive ART; all other women received single-dose nevirapine regimens. For Singh [18], women were assumed to receive ART as per national guidelines in place during the study. 10.1371/journal.pmed.1001608.g008 Figure 8 Forest plot of risk of mother-to-child HIV transmission and maternal HIV infection status. Discussion In this meta-analysis we found that HIV incidence rates were high among pregnant and postpartum women, with pooled incidence rates of 4.7 per 100 person-years among pregnant women and 2.9 per 100 person-years among postpartum women. In our pooled analysis, we did not find a significantly higher risk of HIV infection among pregnant or postpartum women compared to non-pregnant women. The pooled MTCT rate was high, 22.7%, among pregnant and postpartum women with incident HIV infection, and risk of MTCT was 2.8-fold higher among these women compared to women with chronic HIV infection. Pooled MTCT rate was non-significantly higher among women with postpartum versus antenatal incident infections (26.9% versus 17.8%, respectively). The highest HIV incidence estimates during pregnancy/postpartum were >10 per 100 person-years and were from South Africa and Swaziland, countries with high HIV prevalence (>15%) [27] and in which high incidence has been noted in non-pregnant adults [28],[29]. The pooled incidence rates we observed are comparable to, or higher than, those of non-pregnant “high risk” individuals, including female sex workers (2.7 per 100 person-years), HIV-discordant couples (2.0 to 3.6 per 100 person-years) from south and east Africa, and men who have sex with men (6.1 per 100 person-years) from North and South America [30]–[35]. Studies of discordant couples involve a known HIV-infected partner, which would be expected to result in higher HIV incidence than in pregnant women with unknown partner status, the majority of whom presumably have HIV-uninfected partners. However, discordant couples in cohort studies, by virtue of knowing their status, have reinforced messages to use condoms, access ART treatment, and decrease risk, leading to lower HIV incidence. Similarly, studies in female sex workers have noted dramatic reductions in HIV incidence following initial enrollment in cohort studies [36],[37], because of either increased HIV preventive measures or selective inclusion of relatively resistant individuals in the cohort. While single studies have noted increased risk of HIV acquisition during pregnancy/postpartum compared to non-pregnant women [38],[39], the pooled estimate did not suggest that pregnancy or the postpartum period significantly elevated risk. However, it is difficult to design a study that would definitively determine the incremental risk of the pregnancy/postpartum periods compared to non-pregnant time periods because of a variety of confounding factors. One notable potential confounder is use of contraceptives in the non-pregnant/postpartum comparison group, some of which (injectable and oral contraceptives) have also been linked to higher risk of HIV acquisition [40],[41]. One study in this meta-analysis included hormonal contraception within the multivariate model and found that the effect of pregnancy on HIV acquisition risk was attenuated when potential confounders were included in the model [38], whereas another study did not observe any difference in risk when non-pregnant/non-lactating women using versus not using hormonal contraception were used as comparison groups [42]. In addition, differential risk during early versus late pregnancy may modify the association between pregnancy and HIV risk. Studies included in this meta-analysis included both early and late stages of pregnancy in their risk intervals, but did not capture associations with specific periods in pregnancy, for example, whether risk increases as hormone levels rise. Mugo et al. [38] did not observe any difference in associations, based on stage of pregnancy, but the sample size was small, limiting the power to detect effect modification by pregnancy stage. Finally, while HIV incidence was non-significantly higher during pregnancy versus non-pregnant time periods, the lower coital frequency among pregnant and postpartum African women previously reported [6],[43],[44] may indicate that pregnancy is associated with increased per-coital-act susceptibility to HIV, as has been observed in a study conducted in Uganda [6]. Thus, an alternative approach to determining the impact of the pregnancy/postpartum periods would be to pool estimates of risk per coital act, as was done in the Ugandan study, which estimated 1.4-fold higher HIV risk per coital act during pregnancy/postpartum compared to non-pregnant/non-lactating periods [6]. However, detailed data on frequency of intercourse were not provided in the studies reviewed, limiting ability to estimate risk per coital act. Both biological and behavioral changes have been hypothesized to explain the potentially higher risk of HIV acquisition observed during pregnancy and the postpartum period. Behavioral factors were not associated with HIV acquisition in two prior studies of pregnant and postpartum women [3],[6]; however, behavior changes in male partners during the pregnancy/postpartum period have not been well characterized and could play a role in maternal HIV risk, particularly if partners increase sexual activity outside of the relationship. Pregnancy-induced physiological changes have been hypothesized to increase HIV susceptibility, through changes in systemic and mucosal immunity, disturbances in vaginal flora, and alterations of the genital mucosa. However, prospective studies to examine biological risk factors for HIV acquisition during pregnancy and postpartum have been limited. Taha et al. showed that sexually transmitted infections (gonorrhea and trichomoniasis) and other genital tract infections (bacterial vaginosis) were associated with increased risk of HIV acquisition during pregnancy and postpartum: risk was 2-fold higher for trichomonas infection during pregnancy or postpartum, and 4-fold higher for gonorrhea during pregnancy [45]. Other potential biological risk factors for HIV acquisition include vitamin A deficiency, severe anemia, and younger age [46]. Incident maternal infections during pregnancy/postpartum may increase MTCT because of high levels of maternal viral load during incident infection, low levels of passively transferred maternal antibody, and absence of PMTCT ARVs because maternal infection is initially undetected. While half of the studies included in our MTCT rate analysis were conducted prior to implementation of PMTCT ARV prophylaxis, transmission rates were similar among women receiving and not receiving ARVs. In addition, although current World Health Organization guidelines for PMTCT are shifting from short-course ARV regimens to lifelong maternal ART, short-course regimens continue to be used in many resource-limited settings [47]. Thus, our pooled MTCT rates remain relevant to pregnant and postpartum women with both undiagnosed and treated incident infections, and highlight the need to improve detection of infections and early initiation of PMTCT ARVs. In early MTCT studies, prior to PMTCT interventions, the increased relative risk for incident versus chronic maternal infection was due to high maternal viral load and lower maternal HIV-specific immune responses in incident infection. With PMTCT ARVs, rates of transmission among women with chronic HIV decreased from ∼20%–35% to 1%–5%. Since incident maternal HIV is typically detected weeks after infection, there is a relative delay in the initiation and effect of ARVs, amplifying the relative risk in incident versus chronic MTCT rates. Thus, earlier studies comparing MTCT in incident versus chronic maternal infection noted 2- to 3-fold increased MTCT, while later studies note 6- to >15-fold increased MTCT because of differential PMTCT. A recent modeling study projected that the absolute number of MTCT events could be reduced by 28% in South Africa if HIV screening was repeated during late pregnancy or at 6-week infant immunization visits, demonstrating a greater need for identification and early treatment for women acquiring HIV during pregnancy [48]. Our systematic review and meta-analysis had several strengths. We used a broad search strategy that included peer-reviewed articles in addition to conference abstracts presented at recent HIV conferences. We also contacted authors to acquire additional data for some summary measures. Two independent reviewers evaluated full-text articles for relevance and abstraction of data. HIV incidence rates, cumulative HIV incidence, and risk of HIV acquisition were pooled separately by pregnancy and postpartum status, as well as together, to better understand risks specific to pregnancy versus the postpartum period. To complement the meta-analysis of HIV incidence, we also pooled MTCT rates among mothers with incident infection, and compared the risk of MTCT for women with incident versus chronic infection. Our analysis is subject to limitations resulting from pooling data from studies with heterogeneous research methodologies. Incident HIV infections reported in the studies were estimated using tests that varied in sensitivity and with different intervals for follow-up testing. Variability in test performance has previously been noted to result in overestimation of incidence when lower sensitivity tests are used initially and higher sensitivity tests for subsequent tests [49]. Timing of seroconversion is also related to timing of testing; women seeking antenatal care and testing earlier in their pregnancy have more person-time and opportunity to be detected as an incident rather than chronic infection. Conversely, seroconversions early in pregnancy are not captured as incident infections if antenatal care is sought later. Another limitation of this analysis is that cumulative incidence based on repeat testing was estimated from cohorts with differing duration of follow-up and cross-sectional testing using sensitive assays. While the performance of assays for detecting recent infections has been shown to vary across HIV clades and subpopulations, a recent study suggests pregnancy does not influence performance of BED or avidity assays [50],[51]. However, there is considerable evidence that early iterations of testing algorithms for incident infection misclassified a proportion of individuals with chronic infections as incident infections (false recent rate) and prompted the World Health Organization to issue guidance on conducting assays, with specific criteria for appropriate sampling designs, sample size, and statistical analysis considerations [51]. Thus, inclusion of different assays and testing algorithms likely overestimates our pooled cumulative incidence. These differences partially explain why our estimates of pooled cumulative incidence and pooled incidence rate differ. While we were unable to adjust for national HIV prevalence at the time of the study—since HIV prevalence estimates are not available for all countries and years included in this meta-analysis—we did consider African region as a marker of HIV prevalence; however, this approach may result in residual confounding. In addition, none of the included studies were primarily designed to estimate HIV incidence in pregnancy and the postpartum period; most studies excluded pregnant women from initial study participation, and report HIV incidence during pregnancy and postpartum as a secondary research objective, limiting generalizability. Finally, the number of studies included in our meta-regression models was small; therefore, the models may lack power to detect associations and are unable to ascertain multiple potential sources of confounding. In conclusion, HIV incidence among pregnant and postpartum populations was high in this meta-analysis and may substantially increase risk of MTCT. Our results have several implications for antenatal care/PMTCT programs. First, women in high prevalence settings should be offered repeat HIV testing to detect incident infections and to diagnose women in the postpartum period who did not receive antenatal care. This approach is beneficial because it detects maternal HIV infection while women are accessing the health care system and prompts referral to appropriate HIV care and treatment. While specific recommendations regarding ARV regimens for women with incident infection do not currently exist, maternal ART during pregnancy is likely the best option given high maternal viral loads during incident infection. Second, there is a need for wider distribution of more sensitive HIV tests, such as the fourth generation rapid tests, to enhance early detection of incident HIV. These more sensitive assays, which detect both HIV antibodies and HIV p24 antigen, can reduce the number of women who have early HIV infection and are incorrectly classified as HIV negative. Third, since pregnant and postpartum women are a vulnerable population at risk of HIV and sexually transmitted infections, they should receive continued counseling on the need for condoms to prevent transmission during this time. Pregnant and postpartum populations should also be considered, and included early in the process, of developing and evaluating female-controlled prevention methods, such as microbicides, for safety and efficacy [52]. Supporting Information Checklist S1 PRISMA checklist. (DOC) Click here for additional data file.
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                Author and article information

                Journal
                Glob Health Sci Pract
                Glob Health Sci Pract
                ghsp
                ghsp
                Global Health: Science and Practice
                Global Health: Science and Practice
                2169-575X
                30 March 2020
                30 March 2020
                : 8
                : 1
                : 55-67
                Affiliations
                [a ]Department of Global Health, University of Washington , Seattle, Washington, USA.
                [b ]Department of Biobehavioral Nursing and Health Informatics, University of Washington , Seattle, WA, USA.
                [c ]Department of Obstetrics/Gynecology, Kenyatta National Hospital , Nairobi, Kenya.
                [d ]Department of Epidemiology, University of Washington , Seattle, Washington, USA.
                [e ]Department of Medicine, University of Washington , Seattle, Washington, USA.
                [f ]Department of Pediatrics, University of Washington , Seattle, Washington, USA.
                [g ]Department of Obstetrics/Gynecology, University of Washington , Seattle, Washington, USA.
                Author notes
                Correspondence to: Jillian Pintye ( jpintye@ 123456uw.edu ).
                Article
                GHSP-D-19-00347
                10.9745/GHSP-D-19-00347
                7108943
                32139420
                © Pintye et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly cited. To view a copy of the license, visit http://creativecommons.org/licenses/by/4.0/. When linking to this article, please use the following permanent link: https://doi.org/10.9745/GHSP-D-19-00347

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