The Presence of Hemoglobin in Cervicovaginal Lavage Is Not Associated With Genital Schistosomiasis in Zambian Women From the BILHIV Study.

Background: Female genital schistosomiasis (FGS) occurs when Schistosoma haematobium eggs are deposited in reproductive tissue. Female genital schistosomiasis in the cervical mucosa is associated with increased vascularity. If FGS is associated with the presence of hemoglobin in cervicovaginal lavage (CVL), the use of urinary reagent strips to detect hemoglobin in CVL could supplement FGS diagnosis. Methods: Nonmenstruating, nonpregnant, sexually active women aged 18-31 participating in the HPTN 071 (PopART) Population-Cohort were invited in 2 Zambian communities. Genital self-swabs and a urine specimen were collected at a home visit, and CVL and hand-held colposcopy were performed at a midwife led clinic visit. Urinary reagent strips were used to identify hemoglobin in CVL. Eggs and circulating anodic antigen (CAA) were detected from urine. Visual-FGS was defined as the presence of sandy patches, rubbery papules, or abnormal blood vessels. Polymerase chain reaction (PCR)-FGS was defined as Schistosoma deoxyribonucleic acid detected by real-time PCR on CVL or cervical or vaginal swab. Results: Of 209 women with home genital swabs and companion CVL specimens, 66% (138 of 209) had detectable CVL hemoglobin, 13.4% (28 of 209) had PCR-defined FGS, and 17.2% (36 of 209) had visual-FGS. Active Schistosoma infection, diagnosed by CAA or urine microscopy, was present in 21.0% (44 of 209) participants. Active Schistosoma infection (P = .4), PCR-FGS (P = 0.7), and visual-FGS (P = 0.3) were not associated with CVL hemoglobin presence. Results did not differ in subgroups with high infection burden (cycle threshold < 35 or 2-3 positive genital PCR). Conclusions: Polymerase chain reaction-FGS, visual-FGS, and active Schistosoma infection were not associated with the presence of CVL hemoglobin. Further research is needed to establish accessible community-based FGS diagnostics.

Validation of the isothermal Schistosoma haematobium Recombinase Polymerase Amplification (RPA) assay, coupled with simplified sample preparation, for diagnosing female genital schistosomiasis using cervicovaginal lavage and vaginal self-swab samples.

BACKGROUND: Female genital schistosomiasis (FGS) is a neglected and disabling gynecological disease that can result from infection with the parasitic trematode Schistosoma haematobium. Accurate diagnosis of FGS is crucial for effective case management, surveillance and control. However, current methods for diagnosis and morbidity assessment can be inaccessible to those at need, labour intensive, costly and unreliable. Molecular techniques such as PCR can be used to reliably diagnose FGS via the detection of Schistosoma DNA using cervicovaginal lavage (CVL) samples as well as lesser-invasive vaginal self-swab (VSS) and cervical self-swab samples. PCR is, however, currently unsuited for use in most endemic settings. As such, in this study, we assessed the use of a rapid and portable S. haematobium recombinase polymerase amplification (Sh-RPA) isothermal molecular diagnostic assay, coupled with simplified sample preparation methodologies, to detect S. haematobium DNA using CVL and VSS samples provided by patients in Zambia. METHODOLOGY/PRINCIPAL FINDINGS: VSS and CVL samples were screened for FGS using a previously developed Sh-RPA assay. DNA was isolated from VSS and CVL samples using the QIAamp Mini kit (n = 603 and 527, respectively). DNA was also isolated from CVL samples using two rapid and portable DNA extraction methods: 1) the SpeedXtract Nucleic Acid Kit (n = 223) and 2) the Extracta DNA Tissue Prep Kit (n = 136). Diagnostic performance of the Sh-RPA using VSS DNA extacts (QIAamp Mini kit) as well as CVL DNA extracts (QIAamp Mini kit, SpeedXtract Nucleic Acid Kit and Extracta DNA Tissue Prep Kit) was then compared to a real-time PCR reference test. Results suggest that optimal performance may be achieved when the Sh-RPA is used with PuVSS samples (sensitivity 93.3%; specificity 96.6%), however no comparisons between different DNA extraction methods using VSS samples could be carried out within this study. When using CVL samples, sensitivity of the Sh-RPA ranged between 71.4 and 85.7 across all three DNA extraction methods when compared to real-time PCR using CVL samples prepared using the QIAamp Mini kit. Interestingly, of these three DNA extraction methods, the rapid and portable SpeedXtract method had the greatest sensitivity and specificity (85.7% and 98.1%, respectively). Specificity of the Sh-RPA was >91% across all comparisons. CONCLUSIONS/SIGNIFICANCE: These results supplement previous findings, highlighting that the use of genital self-swab sampling for diagnosing FGS should be explored further whilst also demonstrating that rapid and portable DNA isolation methods can be used to detect S. haematobium DNA within clinical samples using RPA. Although further development and assessment is needed, it was concluded that the Sh-RPA, coupled with simplified sample preparation, shows excellent promise as a rapid and sensitive diagnostic tool capable of diagnosing FGS at the point-of-care in resource-poor schistosomiasis-endemic settings.

An update on female and male genital schistosomiasis and a call to integrate efforts to escalate diagnosis, treatment and awareness in endemic and non-endemic settings: The time is now.

The last decades have brought important insight and updates in the diagnosis, management and immunopathology of female genital schistosomiasis (FGS) and male genital schistosomiasis (MGS). Despite sharing a common parasitic aetiological agent, FGS and MGS have typically been studied separately. Infection with Schistosoma haematobium manifests with gender-specific clinical manifestations and consequences of infection, albeit having a similar pathogenesis within the human genital tract. Schistosoma haematobium is a known urinary bladder carcinogen, but its potential causative role in other types of neoplasia, such as cervical cancer, is not fully understood. Furthermore, the impact of praziquantel treatment on clinical outcomes remains largely underexplored, as is the interplay of FGS/MGS with relevant reproductive tract infections such as HIV and Human Papillomavirus. In non-endemic settings, travel and immigrant health clinics need better guidance to correctly identify and treat FGS and MGS. Our review outlines the latest advances and remaining knowledge gaps in FGS and MGS research. We aim to pave a way forward to formulate more effective control measures and discuss elimination targets. With a growing community awareness in health practitioners, scientists and epidemiologists, alongside the sufferers from these diseases, we aspire to witness a new generation of young women and men free from the downstream disabling manifestations of disease.

Association of Female Genital Schistosomiasis With the Cervicovaginal Microbiota and Sexually Transmitted Infections in Zambian Women.

BACKGROUND: The cervicovaginal microbiota, including sexually transmitted infections (STIs), have not been well described in female genital schistosomiasis (FGS). METHODS: Women (aged 18-31, sexually active, nonpregnant) were invited to participate at the final follow-up of the HPTN 071 (PopART) Population Cohort in January-August 2018. We measured key species of the cervicovaginal microbiota (Lactobacillus crispatus, L. iners, Gardnerella vaginalis, Atopobium vaginae, and Candida) and STIs (Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, and Mycoplasma genitalium) using quantitative PCR (qPCR). We evaluated associations of the microbiota and STI presence and concentration with FGS (qPCR-detected Schistosoma DNA in any of 3 genital specimens). RESULTS: The presence and concentration of key cervicovaginal species did not differ between participants with (n = 30) or without FGS (n = 158). A higher proportion of participants with FGS had T. vaginalis compared with FGS-negative women (P = .08), with further analysis showing that T. vaginalis was more prevalent among women with ≥2 Schistosoma qPCR-positive genital specimens (50.0%, 8/16) than among FGS-negative women (21.5%, 34/158; P = .01). CONCLUSIONS: We found weak evidence of an association between the presence of T. vaginalis and FGS, with a stronger association in women with a higher-burden FGS infection. Additional research is needed on potential between-parasite interactions, especially regarding HIV-1 vulnerability.

Female Genital Schistosomiasis and HIV-1 Incidence in Zambian Women: A Retrospective Cohort Study.

BACKGROUND: Female genital schistosomiasis (FGS) has been associated with prevalent HIV-1. We estimated the incidence of HIV-1 infection in Zambian women with and without FGS. METHODS: Women (aged 18-31, nonpregnant, sexually active) were invited to participate in this study in January-August 2018 at the final follow-up of the HPTN 071 (PopART) Population Cohort. HIV-1-negative participants at enrollment (n = 492) were included in this analysis, with testing to confirm incident HIV-1 performed in HPTN 071 (PopART). The association of incident HIV-1 infection with FGS (Schistosoma DNA detected by polymerase chain reaction [PCR] in any genital specimen) was assessed with exact Poisson regression. RESULTS: Incident HIV-1 infections were observed in 4.1% (20/492) of participants. Women with FGS were twice as likely to seroconvert as women without FGS but with no statistical evidence for a difference (adjusted rate ratio, 2.16; 95% CI, 0.21-12.30; P = .33). Exploratory analysis suggested an association with HIV-1 acquisition among women with ≥2 positive genital PCR specimens (rate ratio, 6.02; 95% CI, 0.58-34.96; P = .13). CONCLUSIONS: Despite higher HIV seroconversion rates in women with FGS, there was no statistical evidence of association, possibly due to low power. Further longitudinal studies should investigate this association in a setting with higher schistosomiasis endemicity.

Cervicovaginal Immune Activation in Zambian Women With Female Genital Schistosomiasis.

HIV-1 infection disproportionately affects women in sub-Saharan Africa, where areas of high HIV-1 prevalence and Schistosoma haematobium endemicity largely overlap. Female genital schistosomiasis (FGS), an inflammatory disease caused by S. haematobium egg deposition in the genital tract, has been associated with prevalent HIV-1 infection. Elevated levels of the chemokines MIP-1α (CCL-3), MIP-1ß (CCL-4), IP-10 (CXCL-10), and IL-8 (CXCL-8) in cervicovaginal lavage (CVL) have been associated with HIV-1 acquisition. We hypothesize that levels of cervicovaginal cytokines may be raised in FGS and could provide a causal mechanism for the association between FGS and HIV-1. In the cross-sectional BILHIV study, specimens were collected from 603 female participants who were aged 18-31 years, sexually active, not pregnant and participated in the HPTN 071 (PopART) HIV-1 prevention trial in Zambia. Participants self-collected urine, and vaginal and cervical swabs, while CVLs were clinically obtained. Microscopy and Schistosoma circulating anodic antigen (CAA) were performed on urine. Genital samples were examined for parasite-specific DNA by PCR. Women with FGS (n=28), defined as a positive Schistosoma PCR from any genital sample were frequency age-matched with 159 FGS negative (defined as negative Schistosoma PCR, urine CAA, urine microscopy, and colposcopy imaging) women. Participants with probable FGS (n=25) (defined as the presence of either urine CAA or microscopy in combination with one of four clinical findings suggestive of FGS on colposcope-obtained photographs) were also included, for a total sample size of 212. The concentrations of 17 soluble cytokines and chemokines were quantified by a multiplex bead-based immunoassay. There was no difference in the concentrations of cytokines or chemokines between participants with and without FGS. An exploratory analysis of those women with a higher FGS burden, defined by ≥2 genital specimens with detectable Schistosoma DNA (n=15) showed, after adjusting for potential confounders, a higher Th2 (IL-4, IL-5, and IL-13) and pro-inflammatory (IL-15) expression pattern in comparison to FGS negative women, with differences unlikely to be due to chance (p=0.037 for IL-4 and p<0.001 for IL-5 after adjusting for multiple testing). FGS may alter the female genital tract immune environment, but larger studies in areas of varying endemicity are needed to evaluate the association with HIV-1 vulnerability.

Acceptability and feasibility of genital self-sampling for the diagnosis of female genital schistosomiasis: a cross-sectional study in Zambia.

Background: Female genital schistosomiasis (FGS) is a neglected and disabling gynaecological disorder that is difficult to diagnose and is part of the wider spectrum of urogenital disease caused by the waterborne parasite  Schistosoma haematobium. Over 90% of human schistosomiasis cases are found in sub-Saharan Africa with 3.8 million people infected with schistosomes in Zambia. Reported FGS prevalence ranges from 33-75% of those with urinary schistosomiasis in endemic areas, suggesting a potentially high FGS burden in Zambia alone. The Bilharzia and HIV (BILHIV) study evaluated home self-sampling genital collection methods for the diagnosis of FGS. Methods: Eligible participants included non-pregnant, sexually active women aged 18-31 who were previously recruited for the HPTN 071 (PopART) trial in Livingstone, Zambia. Household demographic and symptom questionnaires were administered by community workers. Participants were offered vaginal and cervical self-swabs and a urine cup. Cervicovaginal lavage (CVL) was performed in clinic by midwives. Information was collected from participants on the acceptability and feasibility of genital self-sampling. Results: From January-August 2018, 603 women were enrolled, and 87.3% (527/603) completed clinic follow up. A high proportion of participants indicated that self-collection of specimens was "easy" or "very easy" on a 5-point Likert scale. A high proportion of women would be willing to self-collect all three specimens again in future: vaginal swab 96.7% (583/603), cervical swab 96.5% (582/603), and urine 96.2% (580/603). Home-based self-sampling was preferred over provider-based sampling in the clinic due to greater privacy 58.5% (353/603), convenience 46.3% (279/603) and need for transportation 15.9% (96/603). Conclusions: Home based genital self-sampling for FGS diagnosis is highly acceptable. This scalable method may inform future efforts for community-based diagnosis of FGS.

Genital self-sampling compared with cervicovaginal lavage for the diagnosis of female genital schistosomiasis in Zambian women: The BILHIV study.

BACKGROUND: Given the potentially causal association of female genital schistosomiasis (FGS) with HIV-1 infection, improved diagnostics are urgently needed to scale-up FGS surveillance. The BILHIV (bilharzia and HIV) study assessed the performance of home-based self-collection methods (cervical and vaginal swabs) compared to cervicovaginal lavage (CVL) for the detection of Schistosoma DNA by real-time polymerase chain reaction (PCR). METHODS: Between January and August 2018, a consecutive series of female participants from the Population-Cohort of the previous HIV prevention trial HPTN 071 (PopART), resident in Livingstone, Zambia were invited to take part in BILHIV if they were 18-31 years old, non-pregnant and sexually active. Genital self-collected swabs and a urine specimen were obtained and a questionnaire completed at home visits. CVL was obtained at clinic follow-up. RESULTS: 603 women self-collected genital swabs. Of these, 527 women had CVL performed by a mid-wife during clinic follow-up. Schistosoma DNA was more frequently detected in genital self-collected specimens (24/603, 4.0%) compared to CVL (14/527, 2.7%). Overall, 5.0% (30/603) women had female genital schistosomiasis, defined as a positive PCR by any genital sampling method (cervical swab PCR, vaginal swab PCR, or CVL PCR) and 95% (573/603) did not have a positive genital PCR. The sensitivity of any positive genital self-collected swab against CVL was 57.1% (95% CI 28.9-82.3%), specificity 97.3% (95.5-98.5%). In a subset of participants with active schistosome infection, determined by detectable urine Circulating Anodic Antigen (CAA) (15.1%, 91/601), positive PCR (4.3%, 26/601), or positive microscopy (5.5%, 33/603), the sensitivity of any positive self-collected specimen against CVL was 88.9% (51.8-99.7%). CONCLUSIONS: Genital self-sampling increased the overall number of PCR-based FGS diagnoses in a field setting, compared with CVL. Home-based sampling may represent a scalable alternative method for FGS community-based diagnosis in endemic resource limited settings.

Temporal trends in otolaryngologic findings among HIV-1-infected children in a population-based cohort.

BACKGROUND: Otolaryngologic conditions are common among HIV-1-infected children. In this study, we provide data regarding prevalence of pediatric HIV-1 otolaryngologic manifestations in the era of antiretroviral therapy (ART). METHODS: We conducted population-based, prospective, multicenter pediatric HIV-1 surveillance among 276 children with perinatally acquired HIV-1 from 1988 to 2009. All Center for Disease Control (CDC) mild, moderate and severe otolaryngologic conditions were evaluated. RESULTS: CDC-defined, HIV-1-related otolaryngologic conditions among the 276 children were: 103, mild; 50, moderate and 20, severe. The majority [23.3% (24/103), 40.0% (20/50) and 50% (10/20)] of mild, moderate and severe diagnoses, respectively, occurred in the first year of life, with 53.4% (55/103), 66.0% (33/50) and 70% (14/20), respectively, occurring in the first 2 years of life. The most frequent diagnoses were otitis media [21% (58/276)] and oropharyngeal thrush [17.4% (48/276)]. There was a temporal decline by cohort in prevalence of mild and moderate otolaryngologic diagnoses which was significant for mild conditions: 90, pre-ART cohort and 13, ART cohort (P < 0.001) and moderate conditions: 47, pre-ART and 3, ART (P < 0.001). CONCLUSIONS: In our study, many CDC-defined, HIV-related otolaryngologic conditions occur in the first 2 years of life. Over 22 years of longitudinal follow up, there was a significant decline in prevalence of CDC-defined otolaryngologic conditions by temporal cohorts when comparing pre-ART and ART eras. This finding supports early ART administration to decrease morbidity in HIV-1-positive infants and children as well as current US and World Health Organization guidelines to prevent early HIV disease progression.

Temporal trends in mucocutaneous findings among human immunodeficiency virus 1-infected children in a population-based cohort.

The objective of the study was to determine the prevalence of pediatric human immunodeficiency virus 1 (HIV-1) mucocutaneous manifestations in the era of highly active antiretroviral therapy (HAART). We conducted population-based, prospective, multicenter pediatric HIV-1 surveillance in 276 children with perinatally acquired HIV-1 from 1988 to 2009. Centers for Disease Control and Prevention (CDC)-defined HIV-1 related mucocutaneous conditions among the 276 children were: category A (n = 152), B (n = 60), and C (n = 1). Nearly half of the category A and B diagnoses (43.4% [66/152] and 35.0% [21/60], respectively) occurred in the first year of life, with 59.2% (90/152) and 61.7% (37/60), respectively, occurring in the first 2 years of life. The most frequent infectious diagnosis was oropharyngeal thrush (n = 117, 42.4%); the most common inflammatory diagnosis was diaper dermatitis (n = 71, 25.7%). There was a temporal decline in the prevalence of A (pre-HAART cohort, 123; post-HAART cohort, 29; p < 0.01) and B (pre-HAART, 55; post-HAART, 5; p < 0.01) mucocutaneous diagnoses. In children with perinatal HIV-1, there was a significant decline in CDC category A and B mucocutaneous diagnoses by temporal cohort, consistent with the introduction of antiretroviral medications and HAART. Clinical category A and B mucocutaneous diagnoses were most common in the first 2 years of life, emphasizing the importance of early HIV-1 testing and HAART initiation.

Timing of antiretroviral therapy initiation and its impact on disease progression in perinatal human immunodeficiency virus-1 infection.

OBJECTIVE: Treatment with highly active antiretroviral therapy (HAART) reduces overall perinatal human immunodeficiency virus (HIV) type 1-related mortality. The effect of timing of HAART initiation on reduction of morbidity is not well defined. We evaluated the association of timing of HAART initiation on progression to moderate or severe disease. METHODS: Retrospective, population-based study of 196 perinatally HIV-infected children followed from birth in northern California from 1988 to 2009. RESULTS: Of 196 children, 58% received HAART and were followed for a median of 6.2 years after HAART initiation. HAART use was associated with improved survival to the age of 5 years: no HAART, 50% versus HAART, 88%; P < 0.0001. However, the advantage of initial HAART over mono or dual therapy transitioning to HAART was small and not statistically significant (P = 0.23). Starting HAART before the development of moderate or severe disease delayed the median age of diagnosis of moderate disease from 0.4 years (interquartile range, [0.3-0.8]) without HAART to 3.0 years ([interquartile range, 1.9-5.8]; P < 0.0001) with HAART. HAART initiation after progression to moderate or severe disease was associated with decreased progression to severe disease or death, respectively (moderate to severe: 8% [3/36] with HAART vs. 84% [70/83] with no HAART, P < 0.0001; severe to death: 9% [6/68] with HAART vs. 73% [49/67] with no HAART, P < 0.0001). CONCLUSIONS: In perinatal HIV infection, HAART is associated with delayed progression and reduced mortality regardless of disease severity at HAART initiation. This finding reinforces US guidelines regarding HAART initiation at >1 year of age if children present with most clinical category B diagnoses, regardless of CD4 measurements or plasma HIV RNA level.

Antiretroviral use during pregnancy for treatment or prophylaxis.

INTRODUCTION: Antiretrovirals are recommended for all pregnant women either for treatment of HIV-1 infection or for prevention of mother-to-child transmission. Distinguishing between HIV-1-infected pregnant women who meet treatment criteria and those who do not (who use antiretrovirals during pregnancy for prophylaxis) is accomplished by assessing the HIV-1 disease stage and has important implications regarding when antiretroviral drugs are initiated during pregnancy, what drugs are used and antiretroviral use after delivery. AREAS COVERED: This review addresses antiretroviral use by HIV-1-infected women during pregnancy. Specifically, the review focuses on antiretroviral therapy for HIV-1-infected pregnant women who meet criteria for treatment and antiretroviral prophylaxis for HIV-1-infected pregnant women (to prevent mother-to-child transmission of HIV-1). The review primarily addresses antiretroviral use in resource-rich settings, but use in resource-poor settings is briefly addressed. EXPERT OPINION: Antiretrovirals represent only one component of the overall management of HIV-1 infected pregnant women and, therefore, cannot be viewed in isolation from other components of optimal care for HIV-1-infected women and from other efficacious interventions to prevent mother-to-child transmission of HIV-1. Antiretrovirals can be used safely and effectively during pregnancy. We concur with current guidelines regarding the threshold that differentiates which women need antiretroviral therapy for HIV-1 infection for their own health versus those who need prophylaxis to prevent transmission of HIV-1 infection to their child. We thus recommend that lifelong antiretroviral therapy be initiated in patients with an AIDS-defining illness, a CD4 count < 350 cells/mm(3) or other co-morbid conditions such as acute opportunistic infections, HIV-1-associated nephropathy or hepatitis B co-infection. Irrespective of whether or not antiretrovirals are used during pregnancy, or whether antiretrovirals during pregnancy are used for treatment or prophylaxis, all infants of HIV-1-infected women should receive antiretroviral post-exposure prophylaxis.

Streptococcus gallolyticus subspecies pasteurianus (biotype II/2), a newly reported cause of adult meningitis.

We report the first case of adult meningitis confirmed to be due to Streptococcus gallolyticus subsp. pasteurianus. Phenotypically reported as Streptococcus bovis biotype II/2, 16S rRNA sequencing revealed S. gallolyticus subsp. pasteurianus. Because of taxonomic uncertainties, S. gallolyticus subsp. pasteurianus may be an underrecognized agent of systemic infections.

Antiretroviral therapy (ART) for treating HIV infection in ART-eligible pregnant women.

BACKGROUND: This systematic review focuses on antiretroviral therapy (ART) for treating human immunodeficiency virus (HIV) infection in ART-eligible pregnant women. Mother-to-child transmission (MTCT) is the primary means by which children worldwide acquire HIV infection. MTCT occurs during three major timepoints during pregnancy and the postpartum period: in utero, intrapartum, and during breastfeeding. Strategies to reduce MTCT focus on these periods of exposure and include maternal and infant use of ART, caesarean section before onset of labour or rupture of membranes, and complete avoidance of breastfeeding. Where these combined interventions are available, the risk of MTCT is as low as 1-2%. Thus, ART used among mothers who require treatment of HIV for their own health also plays a significant role in decreasing MTCT.This review is one in a series of systematic reviews performed in preparation for the revision of the 2006 World Health Organization (WHO) Guidelines regarding "Antiretroviral Drugs for Treating Pregnant Women and Preventing HIV Infection in Infants" and "Antiretroviral therapy (ART) for HIV Infections in Adults and Adolescents." The findings from these reviews were discussed with experts, key stakeholders, and country representatives at the 2009 WHO guideline review meeting. The resulting WHO 2009 "rapid advice" preliminary guidance on adult and adolescent ART now recommends lifelong treatment for all adults with HIV infection and CD4 counts <350 cells/mm(3). These recommendations also apply to pregnant women who are HIV-infected and they place a high value on early ART to benefit the mother's own health (WHO 2009). The "rapid advice" preliminary guidance also aims to minimize side effects for mothers and their infants (WHO 2009). OBJECTIVES: Our objective was to assess the current literature regarding the treatment of HIV infection in pregnant women who are clinically or immunologically eligible for ART. This review includes an evaluation of the optimal time to start therapy in relation to the woman's laboratory parameters and/or gestational age. It also includes an analysis of which specific antiretroviral medications to start in women who are not yet on ART and which agents to continue in women who are already on ART. SEARCH STRATEGY: In June 2009, electronic searches were undertaken in these databases: Cochrane's "CENTRAL," EMBASE, PubMed, LILACS, and Web of Science/Web of Social Science. Hand searches were performed of the reference lists of all pertinent reviews and studies identified. Abstracts from relevant conferences were searched. Experts in the field were contacted to locate additional studies. The search strategy was iterative. SELECTION CRITERIA: We selected randomized controlled trials and observational studies that evaluated pregnant women with HIV infection who were eligible for ART according to criteria defined by the WHO guideline review committee. Studies were included in the systematic review when a comparison group was clearly defined and where the intervention comprised triple ART. For a study to be considered, each medication in the ART regimen needed to be clearly described. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the selected studies for relevance and inclusion. Relevant data was then extracted from included studies, and the risk of bias assessed. In each included study, the relative risk (RR) for the intervention versus the comparison group was calculated for each outcome, as appropriate, with 95% confidence intervals (CIs). MAIN RESULTS: To our knowledge, there are no randomized controlled trials or observational studies that address the optimal time to start antiretroviral drugs in ART-eligible pregnant women in relation to the woman's laboratory parameters and/or gestational age. The medications to continue in ART-eligible pregnant women who are already receiving ART also have not been evaluated systematically in the current literature. The long-term mortality of HIV-positive pregnant women on ART for their own health, and the long-term virologic or clinical efficacy of ART in treating them, has not been evaluated in randomized clinical trials. In this review, surrogate outcomes for long-term mortality and virologic and clinical efficacy (e.g. MTCT and infant HIV transmission or death) were evaluated to determine the efficacy of specific antiretroviral regimens to start in women who are not yet on ART.Three randomized controlled trials and six observational studies were selected. No studies addressed comparative maternal mortality, which regimens to continue in women already on ART, or the laboratory parameters and gestational age at which to start therapy. The use of zidovudine (AZT), lamivudine (3TC) and lopinavir/ritonavir (LPV-r) starting at 28-36 weeks gestation in a breastfeeding population reduced infant HIV-transmission or death at 12 months compared to a short-course regimen (RR 0.64, 95% CI: 0.44-0.92) (deVincenzi, 2009). Starting AZT, 3TC, and nevirapine (NVP) at 34 weeks in a mixed-feeding population reduced infant HIV-transmission or death at 7 months compared to a short-course regimen (RR 0.39, 95% CI: 0.12-0.85) (Bae, 2008).In the Mma Bana study (a randomized controlled trial in a breastfeeding population) there was no difference in MTCT at six months between the AZT/3TC/LPV-r and AZT, 3TC, and abacavir (ABC) arms (RR 0.17, 95% CI: 0.02-1.44) (Shapiro, 2009). Both regimens also showed 92-95% efficacy in virologic suppression at delivery and during the breastfeeding period. In the Kesho Bora study there was a significant difference in MTCT at 12 months between breastfeeding women who initiated AZT/3TC/LPV-r starting between 28 and 36 weeks and those receiving a short course regimen (RR 0.58, 95% CI: 0.34-0.97) (deVincenzi, 2009). MTCT also decreased significantly when AZT/3TC/NVP was compared with a short-course regimen at seven months in a feeding intervention study (RR 0.15, 95% CI: 0.04-0.62) (Bae, 2008) and 12 months in a population where either exclusive breastfeeding or replacement feeding was encouraged (RR 0.14, CI: 0.04-0.47) (Ekouevi, 2008).In the Mma Bana study, there was increased risk of prematurity among infants born to women receiving AZT/3TC/LPV-r (RR 1.52, CI: 1.07- 2.17) compared with AZT/3TC/ABC (Shapiro, 2009). Ekouevi 2008 showed higher rates of infant low birth weight on AZT/3TC/NVP started at 24 weeks compared to a short course regimen started between 32 and 36 weeks (RR 1.81, 95% CI: 1.09- 3.0). Tonwe-Gold 2007 showed an increase in maternal severe adverse events among the women receiving AZT/3TC/NVP compared with a short-course regimen (RR 25.33, CI 1.49- 340.51). AUTHORS' CONCLUSIONS: In ART-eligible pregnant women with HIV infection, ART is a safe and effective means of providing maternal virologic suppression, decreasing infant mortality, and reducing MTCT. Specifically, AZT/3TC/NVP, AZT/3TC/LPV-r, and AZT/3TC/ABC have been shown to decrease MTCT. More research is needed regarding the use of specific regimens and their maternal and infant side-effect profiles.