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1.  Risk Factors for Mortality among HIV-exposed and HIV-unexposed Infants Admitted to a Neonatal Intensive Care Unit in Botswana 
Aim
Newborns admitted to neonatal intensive care units (NNU) in resource limited settings face high risk of mortality but the epidemiology of these deaths is poorly understood. We describe risk factors for NNU mortality in an area with high prevalence of HIV.
Methods
We performed a prospective cohort study of infants admitted to the NNU at a public referral hospital in Gaborone, Botswana. The primary outcome was neonatal death, defined as death within 28 days of a live delivery. Cox proportional hazard models were used to evaluate risk factors for mortality.
Results
From October 2008 to April 2009, 449 neonates were admitted to the NNU. Cumulative mortality was 24.5% (110/449). Factors associated with increased risk of death included lack of enteral feeding (HR 18.8, 95% CI 10.3, 34.2), gestational age <28 weeks (HR 2.0, 95% CI 1.1, 3.8) and APGAR score <7 at 10 minutes (HR 2.5, 95% CI 1.5, 4.2). Among 348 (78%) infants who were fed, there was no difference in mortality between infants who were breastfed compared with those who were formula fed or had mixed feeding (p=0.76). There was no significant mortality difference by HIV exposure status; 35 (28%) of 128 HIV-exposed infants died compared with 55 (21%) of 272 HIV-unexposed infants (p=0.19).
Conclusions
This study identified low Apgar scores, extreme prematurity, and lack of enteral feeding as the most important risk factors for mortality in this NNU setting. HIV exposure and formula feeding were not significantly associated with death in neonates who were very ill.
doi:10.1111/jpc.12454
PMCID: PMC4310460  PMID: 24372811
Botswana; neonatal intensive care units; neonatal mortality; HIV; feeding method
2.  No Clinically Significant Drug Resistance Mutations In HIV-1 subtype C Infected Women After Discontinuation Of NRTI-Based Or PI-Based HAART For PMTCT In Botswana 
Risk of developing drug resistance after stopping antiretroviral regimens to prevent mother-to-child HIV-1 transmission (PMTCT) is unknown. Mma Bana Study randomized treatment-naïve pregnant women with CD4 ≥200 cells/mm3 to receive either abacavir/zidovudine/lamivudine (triple NRTI arm) or lopinavir/ritonavir/zidovudine/lamivudine (PI arm). Drugs were discontinued after 6 months breastfeeding. One month post-discontinuation, 29 NRTI arm samples and 25 PI arm samples were successfully genotyped. No clinically significant antiretroviral resistance mutations were detected. Eight minor resistance mutations were found among 11(20%) women (3 from NRTI arm, 8 from PI arm), occurring at similar frequencies to those reported in HIV-1 subtype C treatment naive cohorts.
doi:10.1097/QAI.0b013e31829308f8
PMCID: PMC3762949  PMID: 23542639
Mother-to-Child HIV transmission; Highly Active Antiretroviral Therapy; Minor drug resistance mutations; Botswana
3.  HIV transmission and 24-month survival in a randomized trial of HAART to prevent MTCT during pregnancy and breastfeeding in Botswana (The Mma Bana Study) 
AIDS (London, England)  2013;27(12):1911-1920.
Objectives
Highly active antiretroviral therapy (HAART) for prevention of mother-to-child HIV transmission (MTCT) may impact long-term survival of mothers and children.
Design
Randomized clinical trial.
Methods
HIV–infected pregnant women with CD4 ≥200 cells/mm3 were randomly assigned to abacavir, zidovudine, lamivudine (Arm A) or lopinavir–ritonavir, zidovudine–lamivudine (Arm B) from week 26–34 gestation through planned weaning by 6 months postpartum. Women with baseline CD4 <200 received nevirapine–zidovudine–lamivudine indefinitely (Obs arm), as did randomized women later qualifying for treatment.
Results
Among 560 randomized and 170 observational women enrolled, there were 14 deaths (1.9%); 1 antenatally (Obs), 3 from delivery though 6 months postpartum (1 Arm A, 2 Obs), and 10 from 6–24 months postpartum (5 Arm A, 3 Arm B, 2 Obs). Time to death or CD4 <200 was shorter in Arm A vs. B (p=0.03). Of 709 live-born children, 97% breastfed for median 5.8 months. Of 37 (5.2%) deaths by 24 months, 9 were before breastfeeding initiated (3 Arm A, 2 Arm B, 4 Obs); 6 while breastfeeding (1 Arm A, 2 Arm B, 3 Obs); and 22 after weaning (9 Arm A, 11 Arm B, 2 Obs). Only 8 children (1.1%) were HIV-infected at 24 months (6 Arm A, 1 Arm B, 1 Obs), all before 6 months.
Conclusions
Low MTCT was maintained through extended follow-up in all arms. Disease progression appeared slower after discontinuing protease inhibitor-based HAART, but a concerning number of maternal deaths occurred after stopping either regimen. Strategies to improve maternal and child survival in the post-intervention period are required.
PMCID: PMC3987116  PMID: 24180000
HIV; MTCT; Botswana; Africa; Antiretrovirals; Infant Survival; Maternal Health
4.  Predictors of suboptimal CD4 response among women achieving virologic suppression in a randomized antiretroviral treatment trial, Africa 
BMC Infectious Diseases  2014;14:331.
Background
A subset of HIV-1 infected patients starting highly active antiretroviral treatment (HAART) experience suboptimal CD4 response (SCR) despite virologic suppression. We studied the rate of and risk factors for SCR among women starting HAART in the ACTG A5208 study conducted in 7 African countries. 741 HAART-naive women with screening CD4 count <200 cells/μL were randomized to start HAART with Tenofovir/Emtricitabine plus either Nevirapine or Lopinavir/Ritonavir.
Methods
This analysis includes the 625 women who remained on-study through 48 weeks without experiencing protocol-defined virologic failure. We defined SCR as < 100 CD4 cells/μL increase from baseline and absolute CD4 cell count < 350 cells/μL, both at 48 weeks after HAART initiation.
Results
The baseline characteristics for the 625 women prior to HAART initiation were: median age 33 years, screening CD4 count 134 cells/μL, and HIV-1 RNA 5.1 log10 copies/mL; 184 (29%) were WHO Stage 3 or 4.
Seventy one (11%) of these 625 women experienced SCR. Baseline factors independently associated with increased odds of SCR included older age, lower HIV-1 RNA, positive Hepatitis B surface antigen, and site location. At 96 weeks, only 6% of the SCR group had CD4 ≥ 350 cells/μL compared with 67% in the non SCR group.
Conclusion
After starting HAART, 11% of women with virologic suppression through 48 weeks experienced SCR. These patients were also less likely to achieve CD4 ≥ 350 cells/μL by 96 weeks. The underlying causes and long term clinical implications of SCR deserve further investigation.
Trial registration
Clinicaltrials.gov Identifier: NCT00089505
doi:10.1186/1471-2334-14-331
PMCID: PMC4083139  PMID: 24938526
HIV; Antiretroviral therapy; HAART; Immune response; CD4
5.  Impact of Antiretroviral Drugs in Pregnant Women and Their Children in Africa: HIV Resistance and Treatment Outcomes 
The Journal of Infectious Diseases  2013;207(Suppl 2):S93-S100.
The global community has committed itself to eliminating new pediatric HIV infections by 2015 and improving maternal, newborn, and child health and survival in the context of HIV. Such objectives require regimens to prevent mother-to-child transmission (pMTCT) which, while being highly efficacious, protect the efficacy of future first-line antiretroviral therapy (ART). Major obstacles to eliminating vertical transmissions globally include low rates of adherence to ART and non-completion of the ‘pMTCT cascade’ due to programmatic and structural challenges faced by healthcare systems in low-income countries. Providing all pregnant women with lifelong ART regardless of CD4 count/disease stage (Option B+) could be the most effective option to prevent both HIV transmission and resistance, assuming adherence is successfully maintained. This strategy is more likely to achieve sustained undetectable HIV viremia, does not involve ART interruptions, is simpler to implement, and is cost-effective. Where Option B+ is not available, options A (short course zidovudine with single-dose nevirapine and an ARV “tail”) and B (combination ART during pregnancy and breastfeeding, with ART cessation after weaning in women not qualifying for ART for their own health) are also efficacious, highly cost-effective and associated with infrequent resistance selection if taken properly.
doi:10.1093/infdis/jit110
PMCID: PMC3657116  PMID: 23687295
mother-to-child transmission; HIV; prophylaxis; antiretroviral therapy; resistance
6.  A Randomized Trial of Mogen Clamp versus Plastibell for Neonatal Male Circumcision in Botswana 
Background
Male circumcision can reduce the risk of heterosexually-acquired HIV-1 infection in men. Neonatal male circumcision (NMC) has many potential advantages over circumcision at older ages but little is known about its feasibility and safety in resource-limited settings.
Methods
We performed a randomized trial in southeastern Botswana of Mogen clamp and Plastibell, two commonly used devices for NMC. Follow-up visits occurred at six weeks and four months postpartum. Adverse events, parental satisfaction and staff impressions were recorded.
Results
Of 302 male neonates randomized, 300 (99%) underwent circumcision, 153 (51%) with Mogen clamp and 147 (49%) with Plastibell. There were no major adverse events in the Mogen clamp arm but there were two major adverse events in the Plastibell arm (both were a proximally migrated ring that had to be removed by study staff). Minor adverse events were more common with the Mogen clamp compared with the Plastibell, specifically removal of too little skin and formation of skin bridges or adhesions (12 vs. 1 and 11 vs. 3, respectively, all P<0.05). Five (3%) infants in the Mogen clamp arm and none in the Plastibell arm had minor bleeding (P=0.03). More than 94% of mothers reported being highly or completely satisfied with the procedure.
Conclusions
NMC can be performed in Botswana with a low rate of adverse events and high parental satisfaction. Although the risk of migration and retention of the Plastibell is small, the Mogen clamp may be safer for NMC in regions where immediate emergent medical attention is not available.
doi:10.1097/QAI.0b013e318285d449
PMCID: PMC3683122  PMID: 23314413
7.  Immune Activation Markers in Peripartum Women in Botswana: Association with Feeding Strategy and Maternal Morbidity 
PLoS ONE  2014;9(3):e89928.
Hormone levels shift the immune state in HIV-uninfected pregnant and breastfeeding women away from Th1 responses and toward regulation to permit fetal tolerance. Limited data exist on inflammation during pregnancy or postpartum in HIV-infected women, though certain inflammatory markers are associated with adverse health outcomes among HIV-infected persons.
We measured hsCRP, D-dimer, IFN-γ, IL-6, IL-10 and TNF-α at 34 weeks gestation and six months postpartum in HIV-infected women from the Botswana Mashi PMTCT trial who were randomized to breastfeeding or formula-feeding. Differences in inflammatory markers between gestation and postpartum periods, and by randomized feeding method, were estimated using generalized estimating equations, adjusting for baseline plasma HIV-1 viral load, CD4 count, calendar time, and antiretroviral treatment status. Additionally, we studied the association between marker concentrations at six months postpartum and major adverse clinical events over the following 4.5 years, using case-cohort sampling and adjusted Cox proportional hazards models.
In 86 breastfeeding and 75 formula-feeding women, hsCRP and D-dimer decreased significantly between 34 weeks gestation and six months postpartum, while IFN-γ increased. There was no significant association between inflammatory marker change and randomized feeding method after adjusting for multiple comparisons and removing outliers. In univariate analysis, TNF-α, D-dimer, and IFN-γ concentrations at six months postpartum were significant predictors of subsequent clinical events, and TNF-α remained significant in multivariate analysis (HR = 4.16, p = 0.001).
In young HIV-infected women in Botswana inflammatory marker concentrations did not differ significantly between women who breast- vs. formula-fed. However, postpartum TNF-α level was predictive of subsequent adverse clinical event.
doi:10.1371/journal.pone.0089928
PMCID: PMC3962339  PMID: 24657960
8.  Acceptability of Male Circumcision Among Adolescent Boys and their Parents, Botswana 
AIDS and behavior  2012;16(2):340-349.
Little is known of the acceptability of male circumcision (MC) to adolescent boys, a key target group for HIV prevention. We conducted a cluster design survey among adolescent boys and their parents/guardians in two villages in Botswana. Of 1300 households visited, 398 boys were eligible; 269 boys and 210 parents/guardians participated. MC was described correctly by 80% of boys, and 76% identified that MC reduces the risk of male HIV acquisition. After a brief informational session, 75% of boys stated that they would definitely want to be circumcised and 96% of parents/guardians would want their boy circumcised. Boys most frequently reported pain (49%) and possible health problems (19%) as concerns undergoing MC; concerns about peer or partner acceptance, sexual function, or cultural appropriateness were uncommon. Adolescent MC is likely to be highly acceptable in Botswana if done safely, for free and with adequate pain control in a hospital setting.
doi:10.1007/s10461-011-9929-7
PMCID: PMC3951752  PMID: 21437725
HIV/AIDS prevention; Male circumcision; Acceptability; Adolescent boys; Botswana
9.  Loss of Anatomical Landmarks with Eutectic Mixture of Local Anesthetic Cream for Neonatal Male Circumcision 
Journal of pediatric urology  2012;9(1):e86-e90.
We report two cases of newborns who developed marked local edema after application of a eutectic mixture of local anesthetic (EMLA) topical anesthetic cream for neonatal male circumcision (NMC). Although local edema and erythema are known potential side effects of EMLA cream, a common anesthetic used for NMC, the loss of landmarks precluding safe NMC has not previously been reported, and is described here. Although we cannot recommend an alternate local anesthetic for neonates with this reaction to EMLA, based on a review of the published data we think that serious systemic adverse events related to EMLA are extremely rare.
doi:10.1016/j.jpurol.2012.09.013
PMCID: PMC3568457  PMID: 23102766
Male circumcision; neonatal; EMLA; Eutectic Mixture of Local Anesthetic; adverse events; edema
10.  Characterization of HIV-HBV co-infection in a multi-national HIV-infected cohort 
AIDS (London, England)  2013;27(2):191-201.
Objective
To understand the HIV-hepatitis B virus (HBV) epidemic from a global perspective by clinically and virologically characterizing these viruses at the time of antiretroviral therapy (ART) initiation in a multi-national cohort.
Methods and design
HIV-infected subjects enrolled in two international studies were classified as HIV-HBV co-infected or HIV monoinfected prior to ART. HIV-HBV co-infected subjects were tested for HBV characteristics, hepatitis D virus (HDV), a novel non-invasive marker of liver disease, and drug-resistant HBV. Comparisons between discrete covariates used chi-square or Fisher’s exact tests (and Jonchkheere-Terpstra for trend tests) while continuous covariates were compared using Wilcoxon Rank-Sum Test.
Results
Of the 2105 HIV-infected subjects from 11 countries, the median age was 34 years and 63% were Black. The 115 HIV-HBV co-infected subjects had significantly higher ALT and AST values, lower body mass index, and lower CD4+ T-cell counts than HIV monoinfected subjects (median 159 cells/mL and 137 cells/mL, respectively, P=0.04). In the co-infected subjects, 49.6% had HBeAg-negative HBV, 60.2% had genotype A HBV, and 13% were HDV positive. Of the HBeAg-negative subjects, 66% had HBV DNA ≤2000 IU/ml compared to 5.2% of the HBeAg-positive subjects. Drug-resistant HBV was not detected.
Conclusions
Screening for HBV in HIV-infected patients in resource-limited settings is important since it is associated with lower CD4+ T-cell counts. In settings where HBV DNA is not available, HBeAg may be useful to assess the need for HBV treatment. Screening for drug-resistant HBV is not needed prior to starting ART in settings where this study was conducted.
doi:10.1097/QAD.0b013e32835a9984
PMCID: PMC3763734  PMID: 23032418
HIV; HBV; coinfection; global
11.  Phylogenetic Relatedness of Circulating HIV-1C Variants in Mochudi, Botswana 
PLoS ONE  2013;8(12):e80589.
Background
Determining patterns of HIV transmission is increasingly important for the most efficient use of modern prevention interventions. HIV phylogeny can provide a better understanding of the mechanisms underlying HIV transmission networks in communities.
Methods
To reconstruct the structure and dynamics of a local HIV/AIDS epidemic, the phylogenetic relatedness of HIV-1 subtype C env sequences obtained from 785 HIV-infected community residents in the northeastern sector of Mochudi, Botswana, during 2010–2013 was estimated. The genotyping coverage was estimated at 44%. Clusters were defined based on relatedness of HIV-1C env sequences and bootstrap support of splits.
Results
The overall proportion of clustered HIV-1C env sequences was 19.1% (95% CI 17.5% to 20.8%). The proportion of clustered sequences from Mochudi was significantly higher than the proportion of non-Mochudi sequences that clustered, 27.0% vs. 14.7% (p = 5.8E-12; Fisher exact test). The majority of clustered Mochudi sequences (90.1%; 95% CI 85.1% to 93.6%) were found in the Mochudi-unique clusters. None of the sequences from Mochudi clustered with any of the 1,244 non-Botswana HIV-1C sequences. At least 83 distinct HIV-1C variants, or chains of HIV transmission, in Mochudi were enumerated, and their sequence signatures were reconstructed. Seven of 20 genotyped seroconverters were found in 7 distinct clusters.
Conclusions
The study provides essential characteristics of the HIV transmission network in a community in Botswana, suggests the importance of high sampling coverage, and highlights the need for broad HIV genotyping to determine the spread of community-unique and community-mixed viral variants circulating in local epidemics. The proposed methodology of cluster analysis enumerates circulating HIV variants and can work well for surveillance of HIV transmission networks. HIV genotyping at the community level can help to optimize and balance HIV prevention strategies in trials and combined intervention packages.
doi:10.1371/journal.pone.0080589
PMCID: PMC3859477  PMID: 24349005
12.  Highly Active Antiretroviral Therapy and Adverse Birth Outcomes Among HIV-Infected Women in Botswana 
The Journal of Infectious Diseases  2012;206(11):1695-1705.
Background. It is unknown whether adverse birth outcomes are associated with maternal highly active antiretroviral therapy (HAART) in pregnancy, particularly in resource-limited settings.
Methods. We abstracted obstetrical records at 6 sites in Botswana for 24 months. Outcomes included stillbirths (SBs), preterm delivery (PTD), small for gestational age (SGA), and neonatal death (NND). Among human immunodeficiency virus (HIV)–infected women, comparisons were limited to HAART exposure status at conception, and those with similar opportunities for outcomes. Comparisons were adjusted for CD4+ lymphocyte cell count.
Results. Of 33 148 women, 32 113 (97%) were tested for HIV, of whom 9504 (30%) were HIV infected. Maternal HIV was significantly associated with SB, PTD, SGA, and NND. Compared with all other HIV-infected women, those continuing HAART from before pregnancy had higher odds of PTD (adjusted odds ratio [AOR], 1.2; 95% confidence interval [CI], 1.1, 1.4), SGA (AOR, 1.8; 95% CI, 1.6, 2.1) and SB (AOR, 1.5; 95% CI, 1.2, 1.8). Among women initiating antiretroviral therapy in pregnancy, HAART use (vs zidovudine) was associated with higher odds of PTD (AOR, 1.4; 95% CI, 1.2, 1.8), SGA (AOR, 1.5; 95% CI, 1.2, 1.9), and SB (AOR, 2.5; 95% CI, 1.6, 3.9). Low CD4+ was independently associated with SB and SGA, and maternal hypertension during pregnancy with PTD, SGA, and SB.
Conclusions. HAART receipt during pregnancy was associated with increased PTD, SGA, and SB.
doi:10.1093/infdis/jis553
PMCID: PMC3488194  PMID: 23066160
13.  Env sequence determinants in CXCR4-using human immunodeficiency virus type-1 subtype C 
Virology  2012;433(2):296-307.
HIV-1 subtype C (HIV-1C) CXCR4-using virus is isolated infrequently and is poorly characterized. Understanding HIV-1C env characteristics has implications for the clinical use of antiretrovirals that target viral entry. A total of 209 env clones derived from 10 samples with mixed CCR5-(R5), CXCR4-using (X4) or dual-tropic HIV-1C were phenotyped for coreceptor usage. Intra-patient X4 and R5 variants generally formed distinct monophyletic phylogenetic clusters. X4 compared to R5 envs had significantly greater amino acid variability and insertions, higher net positive charge, fewer glycosylation sites and increased basic amino acid substitutions in the GPGQ crown. Basic amino acid substitution and/or insertion prior to the crown are highly sensitive characteristics for predicting X4 viruses. Chimeric env functional studies suggest that the V3 loop is necessary but often not sufficient to impart CXCR4 utilization. Our studies provide insights into the unique genotypic characteristics of X4 variants in HIV-1C.
doi:10.1016/j.virol.2012.08.013
PMCID: PMC3616623  PMID: 22954962
HIV-1; Subtype C; CCR5; CXCR4; Phylogenetic; Envelope
14.  Cotrimoxazole Prophylaxis and Risk of Severe Anemia or Severe Neutropenia in HAART-Exposed, HIV-Uninfected Infants 
PLoS ONE  2013;8(9):e74171.
Background
Prophylactic cotrimoxazole is recommended for infants born to HIV-infected mothers. However, cotrimoxazole may increase the risk of severe anemia or neutropenia.
Methods
We compared the proportion of HIV-exposed uninfected (HIV-EU) infants experiencing incident severe anemia (and separately, severe neutropenia) between a prospective cohort receiving prophylactic cotrimoxazole from 1 to 6 months vs. infants from two prior trials who did not receive cotrimoxazole. Infants were from rural and urban communities in southern Botswana.
Results
A total of 1705 HIV-EU infants were included. Among these 645 (37.8%) were fed with iron-supplemented formula from birth. Severe anemia developed in 87 (5.1%) infants, and severe neutropenia in 164 (9.6%) infants. In an analysis stratified by infant feeding method, there were no significant differences in the risk of severe anemia by prophylactic cotrimoxazole exposure–risk difference, −0.69% (95% confidence interval [CI] −2.1 to 0.76%). Findings were similar in multivariable analysis, adjusted odds ratio (aOR) 0.35 (95% CI 0.07 to 1.65). There were also no significant differences observed for severe neutropenia by cotrimoxazole exposure, risk difference 2.0% (95% CI −1.3 to 5.2%) and aOR 0.80 (95% CI 0.33 to 1.93).
Conclusions
Severe anemia and severe neutropenia were infrequent among HIV-exposed uninfected infants receiving cotrimoxazole from 1–6 months of age. Concerns regarding hematologic toxicity should not limit the use of prophylactic cotrimoxazole in HIV-exposed uninfected infants.
ClinicalTrials.gov Registration Numbers
NCT01086878 (http://clinicaltrials.gov/show/NCT01086878), NCT00197587 (http://clinicaltrials.gov/show/NCT00197587), and NCT00270296 (http://clinicaltrials.gov/show/NCT00270296).
doi:10.1371/journal.pone.0074171
PMCID: PMC3781096  PMID: 24086319
15.  Infant Feeding Practices Were Not Associated with Breast Milk HIV-1 RNA Levels in a Randomized Clinical Trial in Botswana 
AIDS and behavior  2012;16(5):1260-1264.
Exclusive breastfeeding has been associated with a reduced risk of late vertical HIV transmission as compared to an infant diet composed of breast milk mixed with supplemental foods or liquids. Hypothesized mechanisms include increased infectivity of breast milk from mothers who practice mixed breastfeeding (MBF), or mechanisms such as increased gastrointestinal permeability in the infant caused by mixed feeding. It has been proposed that MBF may result in subclinical mastitis and higher breast milk HIV titers. However, little is known about the relationship between feeding strategy and breast milk viral load. We measured the HIV-1 concentration in breast milk in a sub-cohort of women enrolled in a mother-to-child HIV transmission prevention trial (the "Mashi" study). We report no observed relationship between MBF and measured breast milk viral RNA load. Our findings suggest that the increased transmission risk associated with higher breast milk HIV-1 RNA during MBF is unlikely.
doi:10.1007/s10461-011-0035-7
PMCID: PMC3523667  PMID: 21901486
exclusive; mixed; PMTCT; breast feeding; vertical HIV transmission
16.  High Viral Load and Elevated Angiogenic Markers Associated with Increased Risk of Preeclampsia among Women Initiating Highly Active Antiretroviral Therapy (HAART) in Pregnancy in the Mma Bana Study, Botswana 
Background
Risk factors associated with preeclampsia in HIV-infected women remain largely unknown. Systemic angiogenic imbalance contributes to preeclampsia in HIV-uninfected women, but changes in angiogenic markers after HAART initiation have not been studied.
Methods
The Mma Bana study randomized 560 HIV-infected, HAART-naive pregnant women with CD4 counts ≥ 200 cells/mm3 between 26–34 weeks gestation to lopinavir/ritonavir/zidovudine/lamivudine or abacavir/zidovudine/lamivudine. Another 170 participants with CD4 counts < 200 cells/mm3 initiated nevirapine/zidovudine/lamivudine between 18–34 weeks gestation. Characteristics of 11 women who developed preeclampsia were compared with the remaining722 Mma Bana participants who delivered, using logistic regression. Plasma samples drawn at HAART initiation and one month later from 60 women without preeclampsia and at HAART initiation for all11 preeclamptic women were assayed for placental growth factor (PlGF) and soluble FMS toll-like tyrosine kinase-1 (sFlt-1),
Results
Pre-HAART viral load > 100,000 copies/ml was associated with preeclampsia (OR 5.8; 95% CI 1.8, 19.4; p = 0.004). Median pre-HAART PlGF level was lower and sFLT-1 was higher in women who developed preeclampsia versus those who did not (130 vs 992 pg/ml, p=0.001; 17.5 vs 9.4 pg/ml, p=0.03, respectively). In multivariate analysis, PlGF and viral load remained significantly associated with preeclampsia. No significant changes in angiogenic factors were noted after 1 month of HAART treatment among non-preeclamptic women.
Conclusions
Pre-HAART viral load > 100,000 copies/ml and PlGF predicted preeclampsia among women starting HAART in pregnancy. Among non-preeclamptic women, HAART treatment did not significantly alter levels of PlGF or sFlt-1 one month into treatment.
doi:10.1097/QAI.0b013e318286d77e
PMCID: PMC3683097  PMID: 23344545
HIV-1; viral load; pregnancy; preeclampsia; HAART
17.  Nevirapine (NVP) Pharmacokinetics (PK) and Risk of Rash and Hepatitis among HIV-Infected Sub-Saharan African Women 
AIDS (London, England)  2012;26(7):833-841.
Objectives
To estimate nevirapine pharmacokinetics and examine its association with rash and/or hepatotoxicity in women starting antiretroviral treatment in the ACTG A5208/OCTANE study in Africa.
Design
In HIV-infected, non-pregnant women with screening CD4<200 cells/mm3 randomized to nevirapine (twice daily, after 14-day once-daily lead-in period) plus tenofovir/emtricitabine, single nevirapine blood samples were collected 14 and 28 days following randomization. Rash and hepatotoxicity that occurred during therapy, or within 7 days after the last dose of nevirapine, were defined as toxicity.
Methods
Nevirapine pharmacokinetics were modeled by population pharmacokinetic analysis. Individual Bayesian pharmacokinetic estimates were used to calculate clearance, 24-hour area under the curve, and predicted plasma concentrations.
Results
Median week 4 nevirapine clearance was 2.0 L/hr. Among the 359 women, 194 (54%) developed a rash of any grade; 82 (23%) had grade 2+ and 9 (3%) had grade 3+ rash. Median clearance was 1.7L/hr for subjects exhibiting 3+ rash versus 2.0 L/hr in women without 3+ rash (p=0.046). The odds of developing 3+ rash was 50% higher for every 20% decrease in clearance (p=0.046). Nevirapine discontinuation due to rash/liver toxicity was significantly more common among women with pretreatment CD4 count > 250 cells/mm3 (p=0.003).
Conclusions
In this study, HIV-infected African women starting a nevirapine-based antiretroviral regimen had a lower nevirapine clearance compared to previous reports. Severe rash, but not hepatotoxicity, was associated with higher NVP exposure. Albeit observed in a small number of women, baseline CD4≥250 cells/mm3 was significantly associated with NVP toxicity.
doi:10.1097/QAD.0b013e328351a521
PMCID: PMC3506024  PMID: 22301417
nevirapine; pharmacokinetics; rash; hepatotoxicity; drug toxicity
18.  Highly Active Antiretroviral Therapy versus Zidovudine for Prevention of Mother-to-Child Transmission in a Programmatic Setting, Botswana 
Few studies have compared the programmatic effectiveness of the recommended strategies of antenatal highly-active antiretroviral therapy (HAART) and zidovudine for prevention of mother-to-child transmission (MTCT). We prospectively followed infants (93% formula-fed) whose mothers who took either HAART (258 infants) or zidovudine (170 infants) during pregnancy in the Botswana national program. Overall, 10 infants (2.5%) acquired HIV— 9 infants in the zidovudine group (5.5%, 95%CI 2.6-10.2%) and 1 infant in the HAART group (0.4%, 95%CI 0.0-2.2%). Maternal HAART was associated with decreased MTCT (P=0.001) and improved HIV-free survival (P=0.040) compared with zidovudine (with or without single-dose nevirapine) in a programmatic setting.
doi:10.1097/QAI.0b013e31822d4063
PMCID: PMC3196679  PMID: 21792062
19.  Prevalence of human papillomavirus genotypes and associated cervical squamous intraepithelial lesions in HIV-infected women in Botswana 
Journal of medical virology  2011;83(10):1689-1695.
Background
Human papillomaviruses (HPV) constitute one of the most prevalent sexually transmitted infections and are the etiological agents for invasive cervical cancer, the predominant cancer among women in Botswana. However, the prevalence of HPV genotypes in Botswana has yet to be reported
Methods
139 endocervical swabs were taken at baseline from HIV-1 infected, HSV-2 seropositive women enrolled in a longitudinal cohort study designed to assess the influence of herpes simplex virus-2 (HSV-2) infection on genital tract shedding of HIV-1. Extracted DNA was evaluated for the presence of low-risk and high-risk HPV using the Roche Linear Array.
Results
Genotyping identified HPV in 95 of 139 women of which 61/95 were infected with high-risk HPV and 56/95 with low-risk HPV. The median number of genotypes was 2 (IQR: 1–4). The most prevalent HPV genotype in HIV-infected women was HPV 58. Abnormal cervical cytology was detected in 87/127 women and was associated with contemporaneous HPV infection (RR=1.43, 95% CI: 1.05–1.93) (p=0.02).
Conclusions
HPV prevalence was high among HIV-infected women with infection by multiple genotypes being widespread. The associations attributed to specific oncogenic HPV subtypes and cervical squamous intraepithelial lesions presented here provide critical information to inform future vaccine policy within Botswana.
doi:10.1002/jmv.22178
PMCID: PMC3156037  PMID: 21837784
HIV; Human Papillomavirus; co-infection; cervical cancer
20.  Increased Risk of Preterm Delivery Among HIV-Infected Women Randomized to Protease Versus Nucleoside Reverse Transcriptase Inhibitor-Based HAART During Pregnancy 
The Journal of Infectious Diseases  2011;204(4):506-514.
(See the editorial commentary by Kourtis, on pages 493–4.)
Background. Protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) use in pregnancy has been associated with preterm deliveries in some observational studies.
Methods. HIV-infected, HAART-naive pregnant women with CD4+ counts ≥200 cells/mm3 were randomized between 26 and 34 weeks gestation to lopinavir/ritonavir/zidovudine/lamivudine (PI group) or abacavir/zidovudine/lamivudine (NRTI group) in a clinical trial to prevent mother-to-child HIV transmission. Risk factors for preterm delivery (<37 weeks) and differences by randomization arm were evaluated for live infants by logistic regression.
Results. Preterm delivery rates were higher among 267 women in the PI group than 263 women in the NRTI group (21.4% vs 11.8%, P = .003). PI-based HAART was the most significant risk factor for preterm delivery [odds ratio = 2.03, 95% confidence interval 1.26–3.27, P = .004]. Mean change in maternal body mass index (BMI) 1 month after HAART initiation was lower in the PI group (P < .001); however, this was not significantly associated with preterm delivery. Neither infant hospitalizations nor mortality through 6 months of life differed by maternal regimen.
Conclusions. PI-based HAART was associated with increased preterm delivery but not increased infant hospitalizations or mortality in a clinical trial setting. The association between PI use and lower increase in BMI in late pregnancy warrants further study.
doi:10.1093/infdis/jir307
PMCID: PMC3144169  PMID: 21791651
21.  HIV-1 Protease Inhibitors and Clinical Malaria: a Secondary Analysis of the AIDS Clinical Trials Group A5208 Study 
HIV-1 protease inhibitors (PIs) have antimalarial activity in vitro and in murine models. The potential beneficial effect of HIV-1 PIs on malaria has not been studied in clinical settings. We used data from Adult AIDS Clinical Trials Group A5208 sites where malaria is endemic to compare the incidence of clinically diagnosed malaria among HIV-infected adult women randomized to either lopinavir/ritonavir (LPV/r)-based antiretroviral therapy (ART) or to nevirapine (NVP)-based ART. We calculated hazard ratios and 95% confidence intervals. We conducted a recurrent events analysis that included both first and second clinical malarial episodes and also conducted analyses to assess the sensitivity of results to outcome misclassification. Among the 445 women in this analysis, 137 (31%) received a clinical diagnosis of malaria at least once during follow-up. Of these 137, 72 (53%) were randomized to LPV/r-based ART. Assignment to the LPV/r treatment group (n = 226) was not consistent with a large decrease in the hazard of first clinical malarial episode (hazard ratio = 1.11 [0.79 to 1.56]). The results were similar in the recurrent events analysis. Sensitivity analyses indicated the results were robust to reasonable levels of outcome misclassification. In this study, the treatment with LPV/r compared to NVP had no apparent beneficial effect on the incidence of clinical malaria among HIV-infected adult women. Additional research concerning the effects of PI-based therapy on the incidence of malaria diagnosed by more specific criteria and among groups at a higher risk for severe disease is warranted.
doi:10.1128/AAC.05322-11
PMCID: PMC3264273  PMID: 22123685
22.  Abacavir alters the transcription of inflammatory cytokines in virologically suppressed, HIV-infected women 
Background
Abacavir (ABC) may be associated with a small, increased risk of myocardial infarction in HIV-infected adults, possibly related to cytokine-mediated inflammation.
Methods
To evaluate the induction of inflammatory cytokine transcription by ABC, we used samples from women randomized to receive zidovudine/lamivudine/ABC (Trizivir) or lopinavir/ritonavir and zidovudine/lamividine (Kaletra/Combivir) from the third trimester through six-months postpartum for the prevention of mother-to-child transmission (PMTCT). Women were matched by CD4 count and baseline HIV RNA. All women attained viral suppression (<50 copies/ml) by the time of sampling.
Results
Four cytokines showed a difference in expression between the treatment arms, all in a proinflammatory direction for the ABC arm: CD40LG 1.82-fold, (p=.027); IL-8 3.16-fold (p=.020); LTA 2.82-fold, (p=.008); and CCL5 −1.67-fold, (p=.035). At 12-months postpartum, 6-months after antiretroviral discontinuation, cytokine expression was similar by treatment arm.
Conclusions
We conclude that ABC may upregulate proinflammatory cytokines at the transcriptional level in this population.
doi:10.7448/IAS.15.2.17393
PMCID: PMC3499794  PMID: 22789611
HIV; abacavir; cytokine; transcription; antiretroviral; inflammation; AIDS
23.  Nevirapine- Versus Lopinavir/Ritonavir-Based Initial Therapy for HIV-1 Infection among Women in Africa: A Randomized Trial 
PLoS Medicine  2012;9(6):e1001236.
In a randomized control trial, Shahin Lockman and colleagues compare nevirapine-based therapy with lopinavir/ritonavir-based therapy for HIV-infected women without previous exposure to antiretroviral treatment.
Background
Nevirapine (NVP) is widely used in antiretroviral treatment (ART) of HIV-1 globally. The primary objective of the AA5208/OCTANE trial was to compare the efficacy of NVP-based versus lopinavir/ritonavir (LPV/r)-based initial ART.
Methods and Findings
In seven African countries (Botswana, Kenya, Malawi, South Africa, Uganda, Zambia, and Zimbabwe), 500 antiretroviral-naïve HIV-infected women with CD4<200 cells/mm3 were enrolled into a two-arm randomized trial to initiate open-label ART with tenofovir (TDF)/emtricitabine (FTC) once/day plus either NVP (n = 249) or LPV/r (n = 251) twice/day, and followed for ≥48 weeks. The primary endpoint was time from randomization to death or confirmed virologic failure ([VF]) (plasma HIV RNA<1 log10 below baseline 12 weeks after treatment initiation, or ≥400 copies/ml at or after 24 weeks), with comparison between treatments based on hazard ratios (HRs) in intention-to-treat analysis. Equivalence of randomized treatments was defined as finding the 95% CI for HR for virological failure or death in the range 0.5 to 2.0. Baseline characteristics were (median): age = 34 years, CD4 = 121 cells/mm3, HIV RNA = 5.2 log10copies/ml. Median follow-up = 118 weeks; 29 (6%) women were lost to follow-up. 42 women (37 VFs, five deaths; 17%) in the NVP and 50 (43 VFs, seven deaths; 20%) in the LPV/r arm reached the primary endpoint (HR 0.85, 95% CI 0.56–1.29). During initial assigned treatment, 14% and 16% of women receiving NVP and LPV/r experienced grade 3/4 signs/symptoms and 26% and 22% experienced grade 3/4 laboratory abnormalities. However, 35 (14%) women discontinued NVP because of adverse events, most in the first 8 weeks, versus none for LPV/r (p<0.001). VF, death, or permanent treatment discontinuation occurred in 80 (32%) of NVP and 54 (22%) of LPV/r arms (HR = 1.7, 95% CI 1.2–2.4), with the difference primarily due to more treatment discontinuation in the NVP arm. 13 (45%) of 29 women tested in the NVP versus six (15%) of 40 in the LPV/r arm had any drug resistance mutation at time of VF.
Conclusions
Initial ART with NVP+TDF/FTC demonstrated equivalent virologic efficacy but higher rates of treatment discontinuation and new drug resistance compared with LPV/r+TDF/FTC in antiretroviral-naïve women with CD4<200 cells/mm3.
Trial registration
ClinicalTrials.gov NCT00089505
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 34 million people (mostly living in low- or middle-income countries) are currently infected with HIV, the virus that causes AIDS. HIV destroys CD4 lymphocytes and other immune cells, leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within 10 years of infection. Then, in 1996, antiretroviral therapy (ART)—cocktails of drugs that attack different parts of HIV—became available. For people living in affluent countries, HIV/AIDS became a chronic condition. But, because ART was expensive, for people living in developing countries, HIV/AIDS remained a fatal illness. In 2006, the international community set a target of achieving universal access to ART by 2010 and, although this target has not been reached, by the end of 2010, 6.6 million of the estimated 15 million people in need of ART in developing countries were receiving one of the ART regimens recommended by the World Health Organization (WHO) in its 2010 guidelines.
Why Was This Study Done?
A widely used combination for the initial treatment of HIV-infected people (particularly women) in resource-limited settings is tenofovir and emtricitabine (both nucleotide reverse transcriptase inhibitors; reverse transcriptase is essential for HIV replication) and nevirapine (NVP, a non-nucleoside reverse transcriptase inhibitor). However, little is known about the efficacy of this NVP-based ART combination. Moreover, its efficacy and toxicity has not been compared with regimens containing lopinavir/ritonavir (LPV/r). LPV/r, which inhibits the viral protease that is essential for HIV replication, is available in resource-limited settings but is usually reserved for second-line treatment. LPV/r-based ART is more expensive than NVP-based ART but if it were more effective or better tolerated than NVP-based ART, then first-line treatment with LPV/r-based ART might be cost-effective in resource-limited settings. Conversely, evidence of the clinical equivalence of NVP-based and LPV/r-based ART would provide support for NVP-based ART as an initial therapy. In this randomized equivalence trial, the researchers compare the efficacy and toxicity of NVP-based and LVP/r-based initial therapy for HIV infection among antiretroviral-naïve African women. In a randomized trial, patients are assigned different treatments by the play of chance and followed to compare the effects of these treatments; an equivalence trial asks whether the effects of two treatments are statistically equivalent.
What Did the Researchers Do and Find?
The researchers followed 500 antiretroviral-naïve HIV-infected women with a low CD4 cell count living in seven African countries, half of whom received NVP-based ART and half of whom received LPV/r-based ART, for an average of 118 weeks and recorded the time to virologic failure (the presence of virus in the blood above pre-specified levels) or death among the participants. Forty-two women in the NVP arm reached this primary endpoint (37 virologic failures and five deaths) compared to 50 women in the LPV/r arm (43 virologic failures and seven deaths), a result that indicates equivalent virologic efficacy according to preset statistical criteria. During the initial assigned treatment, similar proportions of women in both treatment arms developed serious drug-related signs and symptoms and laboratory abnormalities. However, whereas 14% of the women in the NVP arm discontinued treatment because of adverse effects, none of the women in the LPV/r arm discontinued treatment. Finally, nearly half of the women tested in the NVP arm but only 15% of the women tested in the LVP/r arm had developed any drug resistance at the time of virologic failure.
What Do These Findings Mean?
These findings indicate that, among HIV-infected, treatment-naïve African women, initial NVP-based ART is as effective as LPV/r-based ART in terms of virologic failure and death although more women in the NVP arm discontinued treatment or developed new drug resistance than in the LPV/r arm. Several limitations of this study may affect the accuracy of these findings. In particular, some of the study participants may have been exposed to single-dose NVP during childbirth to prevent mother-to-child transmission of HIV; in a parallel randomized trial, the researchers found that LPV/r-based ART was superior to NVP-based ART among women with prior exposure to single-dose NVP. Moreover, the duration of the current study means the long-term effects of the two treatments cannot be compared. Nevertheless, these findings support the WHO recommendation of NVP-based ART with careful early toxicity monitoring as an initial affordable and effective HIV treatment regiment in resource-limited settings, until access to better-tolerated and more potent regimens is possible.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001236.
Information is available from the US National Institute of Allergy and Infectious Diseases on all aspects of HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment (in several languages)
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including detailed information on HIV treatment and care (in English and Spanish)
WHO provides information about universal access to AIDS treatment (in English, French and Spanish); its 2010 ART guidelines can be downloaded
More information about this trial, the OCTANE trial, is available
MedlinePlus provides detailed information about nevirapine and lopinavir/ritinovir (in English and Spanish)
Patient stories about living with HIV/AIDS are available through Avert; the nonprofit website Healthtalkonline also provides personal stories about living with HIV, including stories about taking anti-HIV drugs and the challenges of anti-HIV drugs
doi:10.1371/journal.pmed.1001236
PMCID: PMC3373629  PMID: 22719231
24.  Prevalence and clinical associations of CXCR4-using HIV-1 among treatment-naive subtype C-infected women in Botswana 
Human immunodeficiency virus type 1 (HIV-1) coreceptor usage was determined using a phenotypic assay in plasma samples from treatment-naive women infected with subtype C virus who had CD4 cell counts below 200 cells/mm3. Of 148 women 14.9% were infected with dual/mixed (DM) virus; the remainder had R5 virus. A greater proportion of women in the lowest CD4 cell count stratum had DM virus (p=0.026); change in coreceptor use after ART exposure was uncommon. CXCR4-using HIV-1 was less common in subtype C-infected women than reported in subtype B cohorts, but was most prevalent in women with the lowest CD4 cell counts.
doi:10.1097/QAI.0b013e318214fe27
PMCID: PMC3353541  PMID: 21346588
AIDS; HIV-1 tropism; CCR5; CXCR4; subtype C; antiretroviral therapy
25.  Increased Risk of Severe Infant Anemia Following Exposure to Maternal HAART, Botswana 
Background
Maternal highly-active antiretroviral therapy (HAART) reduces mother-to-child HIV transmission (MTCT), but may increase the risk for infant anemia.
Methods
The incidence of first severe anemia (Grade 3 or 4, Division of AIDS 2004 Toxicity Table) was assessed among HIV-uninfected infants in the Mashi and Mma Bana MTCT prevention trials in Botswana. Severe anemia rates were compared between 3 groups: infants exposed to maternal HAART in utero and during breastfeeding and 1 month of postnatal zidovudine (HAART-BF); infants exposed to maternal zidovudine (ZDV) in utero, 6 months of postnatal ZDV, and breastfeeding (ZDV-BF); and infants exposed to maternal ZDV in utero, 1 month of postnatal ZDV, and formula-feeding (ZDV-FF).
Results
A total of 1719 infants were analyzed— 691 HAART-BF, 503 ZDV-BF, and 525 ZDV-FF. Severe anemia was detected in 118 infants (7.4%). By 6 months, 12.5% of HAART-BF infants experienced severe anemia, compared with 5.3% of ZDV-BF (P<0.001) and 2.5% of ZDV-FF infants (P<0.001). In adjusted analysis, HAART-BF infants were at greater risk of severe anemia than ZDV-BF or ZDV-FF infants (adjusted odds ratios 2.6 and 5.8, respectively; P < 0.001). Most anemias were asymptomatic and improved with iron/multivitamin supplementation and cessation of ZDV exposure. However, 11 infants (0.6% of all infants) required transfusion for symptomatic anemia. Microcytosis and hypochromia were common among infants with severe anemia.
Conclusions
Exposure to maternal HAART starting in utero was associated with severe infant anemia. Confirmation of this finding and possible strategies to mitigate hematologic toxicity warrant further study.
Trial Registration
ClinicalTrials.gov identifiers: NCT00197587 and NCT00270296.
doi:10.1097/QAI.0b013e31820bd2b6
PMCID: PMC3112252  PMID: 21266910
Mother-to-Child Transmission; Anemia; Antiretroviral Therapy; Fetal Drug Exposure; Human Immunodeficiency Virus; Infant

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