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1.  Evaluation of the False Recent Classification Rates of Multiassay Algorithms in Estimating HIV Type 1 Subtype C Incidence 
Abstract
Laboratory cross-sectional assays are useful for the estimation of HIV incidence, but are known to misclassify individuals with long-standing infection as recently infected. The false recent rate (FRR) varies widely across geographic areas; therefore, accurate estimates of HIV incidence require a locally defined FRR. We determined FRR for Botswana, where HIV-1 subtype C infection is predominant, using the BED capture enzyme immunoassay (BED), a Bio-Rad Avidity Index (BAI) assay (a modification of the Bio-Rad HIV1/2+O EIA), and two multiassay algorithms (MAA) that included clinical data. To estimate FRR, stored blood samples from 512 antiretroviral (ARV)-naive HIV-1 subtype C-infected individuals from a prospective cohort in Botswana were tested at 18–24 months postenrollment. The following FRR mean (95% CI) values were obtained: BED 6.05% (4.15–8.48), BAI 5.57% (3.70–8.0), BED-BAI 2.25% (1.13–4.0), and a combination of BED-BAI with CD4 (>200) and viral load (>400) threshold 1.43% (0.58–2.93). The interassay agreement between BED and BAI was 92.8% (95% CI, 90.1–94.5) for recent/long-term classification. Misclassification was associated with viral suppression for BED [adjusted OR (aOR) 10.31; p=0.008], BAI [aOR 9.72; p=0.019], and MAA1 [aOR 16.6; p=0.006]. Employing MAA can reduce FRR to <2%. A local FRR can improve cross-sectional HIV incidence estimates.
doi:10.1089/aid.2013.0055
PMCID: PMC3887420  PMID: 23937344
2.  Undisclosed Antiretroviral Drug Use in a Multinational Clinical Trial (HIV Prevention Trials Network 052) 
The Journal of Infectious Diseases  2013;208(10):1624-1628.
The HIV Prevention Trials Network 052 study enrolled serodiscordant couples. Index participants infected with human immunodeficiency virus reported no prior antiretroviral (ARV) treatment at enrollment. ARV drug testing was performed retrospectively using enrollment samples from a subset of index participants. ARV drugs were detected in 45 of 96 participants (46.9%) with an undetectable viral load, 2 of 48 (4.2%) with a low viral load, and 1 of 65 (1.5%) with a high viral load (P < .0001); they were also detected in follow-up samples from participants who were not receiving study-administered treatment. ARV drug testing may be useful in addition to self-report of ARV drug use in some clinical trial settings.
doi:10.1093/infdis/jit390
PMCID: PMC3805242  PMID: 23908493
HIV; antiretroviral drug; self-report; HPTN 052; Africa; clinical trial
3.  Daily Acyclovir to Decrease Herpes Simplex Virus Type 2 (HSV-2) Transmission from HSV-2/HIV-1 Coinfected Persons: A Randomized Controlled Trial 
The Journal of Infectious Diseases  2013;208(9):1366-1374.
Background. Daily suppressive therapy with valacyclovir reduces risk of sexual transmission of herpes simplex virus type 2 (HSV-2) in HSV-2–serodiscordant heterosexual couples by 48%. Whether suppressive therapy reduces HSV-2 transmission from persons coinfected with HSV-2 and human immunodeficiency virus type 1 (HIV-1) is unknown.
Methods. Within a randomized trial of daily acyclovir 400 mg twice daily in African HIV-1 serodiscordant couples, in which the HIV-1–infected partner was HSV-2 seropositive, we identified partnerships in which HIV-1–susceptible partners were HSV-2 seronegative to estimate the effect of acyclovir on risk of HSV-2 transmission.
Results. We randomly assigned 911 HSV-2/HIV-1–serodiscordant couples to daily receipt of acyclovir or placebo. We observed 68 HSV-2 seroconversions, 40 and 28 in acyclovir and placebo groups, respectively (HSV-2 incidence, 5.1 cases per 100 person-years; hazard ratio [HR], 1.35 [95% confidence interval, .83–2.20]; P = .22). Among HSV-2–susceptible women, vaginal drying practices (adjusted HR, 44.35; P = .004) and unprotected sex (adjusted HR, 9.91; P = .002) were significant risk factors for HSV-2 acquisition; having more children was protective (adjusted HR, 0.47 per additional child; P = .012). Among HSV-2–susceptible men, only age ≤30 years was associated with increased risk of HSV-2 acquisition (P = .016).
Conclusions. Treatment of African HSV-2/HIV-1–infected persons with daily suppressive acyclovir did not decrease risk of HSV-2 transmission to susceptible partners. More-effective prevention strategies to reduce HSV-2 transmission from HIV-1–infected persons are needed.
doi:10.1093/infdis/jit333
PMCID: PMC3789565  PMID: 23901094
HSV-2; HIV-1; acyclovir; transmission; serodiscordant couples; Africa
4.  Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial 
The Lancet. Infectious diseases  2014;14(4):281-290.
Summary
Background
Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes.
Methods
The HPTN 052 trial is a randomised controlled trial done at 13 sites in nine countries. We enrolled HIV-1-serodiscordant couples to the study and randomly allocated them to either early or delayed antiretroviral treatment by use of permuted block randomisation, stratified by site. Random assignment was unblinded. The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study (early treatment group) or after a decline in CD4 count or with onset of an AIDS-related illness (delayed treatment group). Primary events were AIDS clinical events (WHO stage 4 HIV-1 disease, tuberculosis, and severe bacterial infections) and the following serious medical conditions unrelated to AIDS: serious cardiovascular or vascular disease, serious liver disease, end-stage renal disease, new-onset diabetes mellitus, and non-AIDS malignant disease. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00074581.
Findings
1763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group (two individuals were excluded from this group after randomisation). Median CD4 counts at randomisation were 442 (IQR 373–522) cells per μL in patients assigned to the early treatment group and 428 (357–522) cells per μL in those allocated delayed antiretroviral treatment. In the delayed group, antiretroviral treatment was initiated at a median CD4 count of 230 (IQR 197–249) cells per μL. Primary clinical events were reported in 57 individuals assigned to early treatment initiation versus 77 people allocated to delayed antiretroviral treatment (hazard ratio 0·73, 95% CI 0·52–1·03; p=0·074). New-onset AIDS events were recorded in 40 participants assigned to early antiretroviral treatment versus 61 allocated delayed initiation (0·64, 0·43–0·96; p=0·031), tuberculosis developed in 17 versus 34 patients, respectively (0·49, 0·28–0·89, p=0·018), and primary non-AIDS events were rare (12 in the early group vs nine with delayed treatment). In total, 498 primary and secondary outcomes occurred in the early treatment group (incidence 24·9 per 100 person-years, 95% CI 22·5–27·5) versus 585 in the delayed treatment group (29·2 per 100 person-years, 26·5–32·1; p=0·025). 26 people died, 11 who were allocated to early antiretroviral treatment and 15 who were assigned to the delayed treatment group.
Interpretation
Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes. The clinical benefits recorded, combined with the striking reduction in HIV-1 transmission risk previously reported, provides strong support for earlier initiation of antiretroviral treatment.
Funding
US National Institute of Allergy and Infectious Diseases.
doi:10.1016/S1473-3099(13)70692-3
PMCID: PMC4144040  PMID: 24602844
5.  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
6.  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
7.  Persistently Elevated Serum Interleukin-6 Predicts Mortality Among Adults Receiving Combination Antiretroviral Therapy in Botswana: Results from a Clinical Trial 
Abstract
Elevated serum levels of inflammatory biomarkers have been associated with increased mortality and morbidity among HIV-infected individuals receiving combination antiretroviral therapy (cART) in European and U.S. cohorts. Few similar data are available from sub-Saharan Africa, where most cART-treated adults reside and the prevalence of advanced immunosuppression and opportunistic infections (OIs) at cART initiation is higher. This was a retrospective nested case-control analysis of clinical trial data from the completed Adult Antiretroviral Treatment and Drug Resistance (“Tshepo”) study, 2002–2007, Gaborone, Botswana. We measured pretreatment serum levels of interleukin-6 (IL-6), high sensitivity C-reactive protein, and D-dimer in stored plasma samples from 32 deceased participants (cases) and 64 survivors (controls), matched for age, sex, baseline CD4+ cell count, and plasma HIV-1 RNA. Multivariate conditional logistic regression analyses were used to compare inflammatory biomarker levels, adjusting for pretreatment body mass index (BMI) and the presence of OIs. A total of 37 (5.7%) of 650 patients died on study, for a crude mortality rate of 20.6/1,000 person-years. Of 37 (86%) study participants who died on study 32 were included in this analysis. Causes of death (n=32) included non-AIDS-defining events (31.3%), HIV-related OIs (28.1%), cART/toxicity-related (21.9%), other infectious etiologies (15.6%), and unknown (3.1%). Median time to death was 31 weeks [interquartile range (IQR) 14–64]. Median baseline levels of all three biomarkers were higher in cases compared to matched controls. After adjusting for BMI and the presence of OIs, only baseline and most recent (near time of event) levels of IL-6 remained as significant predictors of all-cause mortality [adjusted OR (aOR)=1.25, 95% CI (1.05–1.48); p=0.012; and aOR=1.48 (1.05–2.09); p=0.027, respectively]. Serum IL-6 levels are important predictors of all-cause mortality in this adult urban sub-Saharan African cART-treated population. Future translational studies are warranted to better elucidate pathophysiology and inform the design of novel interventions to ameliorate the risk of death among these “at-risk” individuals.
doi:10.1089/aid.2012.0309
PMCID: PMC3685692  PMID: 23590237
8.  Short Communication: Effect of Short-Course Antenatal Zidovudine and Single-Dose Nevirapine on the BED Capture Enzyme Immunoassay Levels in HIV Type 1 Subtype C Infection 
Abstract
Cross-sectional prevalence studies based on immunoassays that discriminate between recent and long-term infections, such as the BED assay, have been widely used to estimate HIV incidence. However, individuals receiving highly active antiretroviral therapy tend to have lower BED levels and are associated with a higher risk for being mistakenly classified as recent infections. To assess the effect of short-term antenatal zidovudine (ZDV) and single-dose nevirapine (sdNVP) on the BED levels in HIV-1C infection, we measured longitudinal BED normalized optical density (OD-n) levels using stored plasma samples collected prenatally and postnatally from 159 pregnant HIV-infected women in Botswana who participated in the randomized clinical Mother-to-Child-Prevention study, the Mashi study. All women received ZDV from 34 weeks gestation through delivery and were randomized to receive either sdNVP or placebo during labor. Among 159 subjects, the OD-n levels decreased from baseline to delivery in 93 subjects (p=0.039), suggesting that short-course ZDV may decrease OD-n levels. sdNVP at delivery did not affect longitudinal BED OD-n levels postdelivery. However, sdNVP appeared to modify the association between CD4 count at delivery and OD-n levels postdelivery. When estimating HIV incidence with the BED assay, special care may be required regarding women who received short-term ZDV for prevention of mother-to-child transmission.
doi:10.1089/aid.2012.0294
PMCID: PMC3653368  PMID: 23521375
10.  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
11.  Plasma Viral Loads During Early HIV-1 Infection Are Similar in Subtype C– and Non-Subtype C–Infected African Seroconverters 
The Journal of Infectious Diseases  2013;207(7):1166-1170.
Recent data suggest that infection with human immunodeficiency virus type 1 (HIV-1) subtype C results in prolonged high-level viremia (>5 log10 copies/mL) during early infection. We examined the relationship between HIV-1 subtype and plasma viremia among 153 African seroconverters. Mean setpoint viral loads were similar for C and non-C subtypes: 4.36 vs 4.42 log10 copies/mL (P = .61). The proportion of subtype C–infected participants with viral loads >5 log10 copies/mL was not greater than the proportion for those with non-C infection. Our data do not support the hypothesis that higher early viral load accounts for the rapid spread of HIV-1 subtype C in southern Africa.
doi:10.1093/infdis/jit015
PMCID: PMC3583276  PMID: 23315322
HIV-1; group M subtype; plasma viral load; early infection; Africa
12.  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
13.  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
14.  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
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.  Immunohaematological reference values for HIV-negative healthy adults in Botswana 
Background
Clinical laboratories in Botswana have relied entirely on the reference intervals for normal immunohaematological values provided by manufacturers' kits and textbooks.
Objectives
The aim of this study was to determine the means, medians, 2.5th and 97.5th percentile reference intervals, for normal immunohaematological values in healthy adults in Botswana.
Method
A total of 261 healthy participants comprising 126 men (48%) and 135 (52%) women were enrolled in the southern part of Botswana, and immunological and haematological laboratory parameters were measured.
Results
The mean age was 28.8 (95% Confidence Interval [CI] 27.7–29.8) years, with a median of 27 years and a range 18–66 years. The mean haemoglobin level was significantly lower for women (12.4 g/dL; 95% CI 12.1% – 12.7%) than men (15.1 g/dL; 95% CI 14.9% – 15.3%). The women's haemoglobin reference values (9.0 g/dL – 15.0 g/dL) levels were lower than observed in predominantly White populations (12.0 g/dL – 16.0 g/dL), but comparable with regional consensus reference intervals (9.5 g/dL – 15.8 g/dL) recently defined for East and Southern Africa.
Conclusion
The established values provide an important tool for patient management and could influence decisions on inclusion of participants and adverse events in clinical trials conducted locally.
PMCID: PMC3682757  PMID: 23772402
17.  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
18.  Extended High Viremics: A Substantial Fraction of Individuals Maintain High Plasma Viral RNA Levels after Acute HIV-1 Subtype C Infection 
AIDS (London, England)  2011;25(12):1515-1522.
Objective
This study addressed two questions: (1) What fraction of individuals maintain a sustained high HIV-1 RNA load after the acute HIV-1C infection peak? and (2) How long is a high HIV-1 RNA load maintained after acute HIV-1C infection in this subpopulation?
Design/Methods
Plasma HIV-1 RNA dynamics were studied in 77 subjects with primary HIV-1C infection from African cohorts in Gaborone, Botswana, and Durban, South Africa. HIV-infected individuals who maintained mean viral load of ≥ 100,000 (5.0 log10) copies/ml after 100 days post-seroconversion (p/s) were termed Extended High Viremics. Individuals were followed longitudinally for a median (IQR) of 573 (226;986) days p/s.
Results
The proportion of Extended High Viremics was 34% (95% CI: 23%–44%) during the period 100 to 300 days p/s and 19% (95% CI: 9%–29%) over the period of 200 to 400 days p/s. The median (IQR) duration of HIV-1 RNA load ≥ 100,000 copies/ml among Extended High Viremics was 271 (188;340) days p/s. For the subset with average viral load ≥ 100,000 copies/ml during 200–400 days p/s, the median (IQR) duration was 318 (282;459) days. The Extended High Viremics had a significantly shorter time to CD4 decline to 350 cells/μl (median: 88 vs. 691 days p/s for those not designated as Extended High Viremics; p<0.0001, Gehan-Wilcoxon test).
Conclusions
A high proportion of Extended High Viremics – individuals maintaining high plasma HIV-1 RNA load after acute infection – has been identified during primary HIV-1 subtype C infection. These Extended High Viremics likely contribute disproportionately to HIV-1 incidence.
doi:10.1097/QAD.0b013e3283471eb2
PMCID: PMC3544358  PMID: 21505307
HIV-1 subtype C; primary infection; viral HIV-1 RNA load; Southern Africa; HIV-1 transmission
19.  Evolutionary Gamut of in vivo Gag Substitutions during Early HIV-1 Subtype C Infection 
Virology  2011;421(2):119-128.
Two analyses of HIV-1 subtype C Gag quasispecies were performed in a prospective cohort of 42 acutely and recently infected individuals by SGA on viral RNA/proviral DNA templates. First, in vivo Gag substitutions were assessed in relation to the HIV-1C consensus sequence, which revealed that 29.3% of detected amino acid substitutions can be classified as reversions to subtype consensus, 61.3% as forward substitutions from subtype consensus, and 9.3% as polymorphisms not associated with the subtype consensus sequence. Second, the proportion, dynamics, and relationships within individual pools of viral quasispecies were analyzed. Among reverse substitutions, 16.1% were minor, 11.0% transient, 13.6% dominant, and 59.2% fixed. In contrast, 31.6% of forward substitutions were minor, 59.3% transient, 3.8% dominant, and 5.3% fixed. The distinct patterns in the spectrum and dynamics of reverse and forward Gag substitutions suggest that these differences should be considered in HIV-1 evolutionary studies and analyses of viral mutational pathways.
doi:10.1016/j.virol.2011.09.020
PMCID: PMC3210886  PMID: 22014506
20.  Analysis of Genetic Linkage of HIV From Couples Enrolled in the HIV Prevention Trials Network 052 Trial 
The Journal of Infectious Diseases  2011;204(12):1918-1926.
Background. The HIV Prevention Trials Network (HPTN) 052 trial demonstrated that early initiation of antiretroviral therapy (ART) reduces human immunodeficiency virus (HIV) transmission from HIV-infected adults (index participants) to their HIV-uninfected sexual partners. We analyzed HIV from 38 index-partner pairs and 80 unrelated index participants (controls) to assess the linkage of seroconversion events.
Methods. Linkage was assessed using phylogenetic analysis of HIV pol sequences and Bayesian analysis of genetic distances between pol sequences from index-partner pairs and controls. Selected samples were also analyzed using next-generation sequencing (env region).
Results. In 29 of the 38 (76.3%) cases analyzed, the index was the likely source of the partner’s HIV infection (linked). In 7 cases (18.4%), the partner was most likely infected from a source other than the index participant (unlinked). In 2 cases (5.3%), linkage status could not be definitively established.
Conclusions. Nearly one-fifth of the seroconversion events in HPTN 052 were unlinked. The association of early ART and reduced HIV transmission was stronger when the analysis included only linked events. This underscores the importance of assessing the genetic linkage of HIV seroconversion events in HIV prevention studies involving serodiscordant couples.
doi:10.1093/infdis/jir651
PMCID: PMC3209811  PMID: 21990420
21.  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
22.  Validation of A Point-of-Care Lactate Device For Screening At-Risk Adults Receiving Combination Antiretroviral Therapy In Botswana 
Background
Nucleoside reverse-transcriptase inhibitors (NRTIs) are a major component of combination antiretroviral therapy (cART) worldwide but they have been associated with mitochondrial toxicities, with one of the most significant being lactic acidosis. In southern Africa, being female and overweight (BMI > 25) as well as receiving d4T and/or ddI-based cART are risk factors for the development of this potentially life-threatening complication. It is challenging in many resource-limited settings to obtain reliable serum lactate measurements while screening for the presence of lactic acidosis. Point-of-care devices, however, are now available that provide simple, accurate measurements of serum lactate levels at relatively low cost. The objective of this study was to assess the agreement of the portable (Accutrend™ handheld) lactate analyzer to the conventional laboratory system for obtaining serum lactate.
Methods
Eighty two “at-risk” cART-treated adults were evaluated, having their lactate levels tested in parallel using both modalities.
Results
The mean (range) lactate level for the portable device was 2.28 (0.9-5.0) compared to 1.96 (0.7-5.4) using the conventional method. There was a strong correlation (p<0.05) between the portable device and the conventional means with a Pearson correlation coefficient of 0.92 [95% CI: 0.88-0.95]. The mean bias was 0.33 [95% CI: -0.39-1.04], with the portable device having slightly higher values.
Conclusion
The use of a portable lactate device provides an accurate and user-friendly means of screening at-risk patients for the presence of lactic acidosis in resource-limited settings with limited laboratory capacity.
PMCID: PMC3475318  PMID: 23087782
HIV/AIDS; lactic acidosis; Botswana; Point-of-care devices; Complications of combination antiretroviral therapy (cART)
23.  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
24.  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
25.  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

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