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.
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.
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.
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.
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.
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.
HIV-1; Subtype C; CCR5; CXCR4; Phylogenetic; Envelope
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.
exclusive; mixed; PMTCT; breast feeding; vertical HIV transmission
Clinical laboratories in Botswana have relied entirely on the reference intervals for normal immunohaematological values provided by manufacturers' kits and textbooks.
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.
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.
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.
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.
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.
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),
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.
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.
HIV-1; viral load; pregnancy; preeclampsia; HAART
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?
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.
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).
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.
HIV-1 subtype C; primary infection; viral HIV-1 RNA load; Southern Africa; HIV-1 transmission
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.
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.
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.
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.
Eighty two “at-risk” cART-treated adults were evaluated, having their lactate levels tested in parallel using both modalities.
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.
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.
HIV/AIDS; lactic acidosis; Botswana; Point-of-care devices; Complications of combination antiretroviral therapy (cART)
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
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.
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).
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.
HIV; Human Papillomavirus; co-infection; cervical cancer
(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.
Abacavir (ABC) may be associated with a small, increased risk of myocardial infarction in HIV-infected adults, possibly related to cytokine-mediated inflammation.
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.
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.
We conclude that ABC may upregulate proinflammatory cytokines at the transcriptional level in this population.
HIV; abacavir; cytokine; transcription; antiretroviral; inflammation; AIDS
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.
AIDS; HIV-1 tropism; CCR5; CXCR4; subtype C; antiretroviral therapy
Maternal highly-active antiretroviral therapy (HAART) reduces mother-to-child HIV transmission (MTCT), but may increase the risk for infant anemia.
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).
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.
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.
ClinicalTrials.gov identifiers: NCT00197587 and NCT00270296.
Mother-to-Child Transmission; Anemia; Antiretroviral Therapy; Fetal Drug Exposure; Human Immunodeficiency Virus; Infant
Increased stillbirth rates occur among HIV-infected women, but no studies have evaluated the pathological basis for this increase, or whether highly active antiretroviral therapy (HAART) influences the etiology of stillbirths. It is also unknown whether HIV infection of the fetus is associated with stillbirth.
HIV-infected women and a comparator group of HIV-uninfected women who delivered stillbirths were enrolled at the largest referral hospital in Botswana between January and November 2010. Obstetrical records, including antiretroviral use in pregnancy, were extracted at enrollment. Verbal autopsies; maternal HIV, CD4 and HIV RNA testing; stillbirth HIV PCR testing; and placental pathology (blinded to HIV and treatment status) were performed.
Ninety-nine stillbirths were evaluated, including 62 from HIV-infected women (34% on HAART from conception, 8% on HAART started in pregnancy, 23% on zidovudine started in pregnancy, and 35% on no antiretrovirals) and 37 from a comparator group of HIV-uninfected women. Only 2 (3.7%) of 53 tested stillbirths from HIV-infected women were HIV PCR positive, and both were born to women not receiving HAART. Placental insufficiency associated with hypertension accounted for most stillbirths. Placental findings consistent with chronic hypertension were common among HIV-infected women who received HAART and among HIV-uninfected women (65% vs. 54%, p = 0.37), but less common among HIV-infected women not receiving HAART (28%, p = 0.003 vs. women on HAART).
In utero HIV infection was rarely associated with stillbirths, and did not occur among women receiving HAART. Hypertension and placental insufficiency were associated with most stillbirths in this tertiary care setting.
Antiretroviral therapy that reduces viral replication could limit the transmission of human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples.
In nine countries, we enrolled 1763 couples in which one partner was HIV-1–positive and the other was HIV-1–negative; 54% of the subjects were from Africa, and 50% of infected partners were men. HIV-1–infected subjects with CD4 counts between 350 and 550 cells per cubic millimeter were randomly assigned in a 1:1 ratio to receive antiretroviral therapy either immediately (early therapy) or after a decline in the CD4 count or the onset of HIV-1–related symptoms (delayed therapy). The primary prevention end point was linked HIV-1 transmission in HIV-1–negative partners. The primary clinical end point was the earliest occurrence of pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death.
As of February 21, 2011, a total of 39 HIV-1 transmissions were observed (incidence rate, 1.2 per 100 person-years; 95% confidence interval [CI], 0.9 to 1.7); of these, 28 were virologically linked to the infected partner (incidence rate, 0.9 per 100 person-years, 95% CI, 0.6 to 1.3). Of the 28 linked transmissions, only 1 occurred in the early-therapy group (hazard ratio, 0.04; 95% CI, 0.01 to 0.27; P<0.001). Subjects receiving early therapy had fewer treatment end points (hazard ratio, 0.59; 95% CI, 0.40 to 0.88; P = 0.01).
The early initiation of antiretroviral therapy reduced rates of sexual transmission of HIV-1 and clinical events, indicating both personal and public health benefits from such therapy.
The impact of in utero exposure to highly active antiretroviral therapy (HAART) on longitudinal growth of HIV-uninfected infants is unknown.
The Mashi and Mma Bana PMTCT intervention trials enrolled HIV-infected pregnant women at four sites in Botswana. Breastfed (BF), HIV-uninfected infants born ≥37 weeks were included in this analysis. Weight-for-age (WAZ), length-for-age (LAZ), and weight-for-length (WLZ) z-scores were calculated using WHO Child Growth Standards. Mean z-scores were compared between in utero ARV exposure groups using student’s t-test, response profiles analysis and general linear mixed effects modeling.
Growth of 619 HAART-exposed and 440 ZDV-exposed, HIV-uninfected infants was evaluated. Mean birth weights (BW) were 3.01 kg for HAART and 3.15 kg for ZDV-exposed infants (p<.001), with lower mean birth WAZ, LAZ, and WLZ among HAART-exposed infants (all p<.001). HAART-exposed infants had greater improvement in WAZ and WLZ from birth through 2 months (p=0.03, p <.001 respectively). WAZ did not differ between groups from 3 through 6 months (p=0.26). LAZ remained lower in HAART-exposed infants but the incidence of wasting or stunting did not differ between exposure groups.
Lower weights in HAART-exposed uninfected infants at birth were rapidly corrected during the first 6 months of life.
Prevention of mother-to-child transmission; HIV; growth
Recent in vitro studies suggest that acyclovir may directly inhibit HIV-1 replication and can select for a specific HIV-1 reverse transcriptase mutation (V75I) with concomitant loss of an anti-HIV-1 effect. We tested for HIV-1 genotypic resistance at reverse transcriptase codon 75 in plasma from 168 HIV-1 infected persons from Botswana, Kenya, Peru, and the US taking daily acyclovir or valacyclovir for between 8 weeks and 24 months. No V75I cases were detected (95% confidence interval: 0-2.2%). These prospective in vivo studies suggest that standard-dose acyclovir or valacyclovir does not select for HIV-1 resistance.
HSV-2; HIV-1 resistance; V75I
Recent in vitro studies suggest that acyclovir may directly inhibit HIV-1 replication and can select for a specific HIV-1 reverse transcriptase mutation (V75I) with concomitant loss of an anti-HIV-1 effect. We tested for HIV-1 genotypic resistance at reverse transcriptase codon 75 in plasma from 168 HIV-1–infected persons from Botswana, Kenya, Peru, and the United States taking daily acyclovir or valacyclovir for between 8 weeks and 24 months. No V75I cases were detected (95% confidence interval, 0%–2.2%). These prospective in vivo studies suggest that standard-dose acyclovir or valacyclovir does not select for HIV-1 resistance.
Standard values for birth weight by gestational age are not available for sub-Saharan Africa, but are needed to evaluate incidence and risk factors for intrauterine growth retardation in settings where HIV, antiretrovirals, and other in utero exposures may impact birth outcomes.
Birth weight data were collected from six hospitals in Botswana. Infants born to HIV-negative women between 26-44 weeks gestation were analyzed to construct birth weight for gestational age charts. These data were compared with published norms for black infants in the United States.
During a 29 month period from 2007-2010, birth records were reviewed in real-time from 6 hospitals and clinics in Botswana. Of these, 11,753 live infants born to HIV-negative women were included in the analysis. The median gestational age at birth was 39 weeks (1st quartile 38, 3rd quartile 40 weeks), and the median birth weight was 3100 grams (1st quartile 2800, 3rd quartile 3400 grams). We constructed estimated percentile curves for birth weight by gestational age which demonstrate increasing slope during the third trimester and leveling off beyond 40 weeks. Compared with black infants in the United States, Botswana-born infants had lower median birth weight for gestational age from weeks 37 through 42 (p < .02).
We present birth weight for gestational age norms for Botswana, which are lower at term than norms for black infants in the United States. These findings suggest the importance of regional birth weight norms to identify and define risk factors for higher risk births. These data serve as a reference for Botswana, may apply to southern Africa, and may help to identify infants at risk for perinatal complications and inform comparisons among infants exposed to HIV and antiretrovirals in utero.
Adult male circumcision reduces a man's risk for heterosexual HIV acquisition. Infant circumcision is safer, easier and less costly but not widespread in southern Africa. Questionnaires were administered to sixty mothers of newborn boys in Botswana: 92% responded they would circumcise if the procedure were available in a clinical setting, primarily to prevent future HIV infection, and 85% stated the infant's father must participate in the decision. Neonatal male circumcision appears to be acceptable in Botswana and deserves urgent attention in resource-limited regions with high HIV prevalence, with the aim to expand services in safe, culturally acceptable and sustainable ways.
Neonatal; Infant; Male circumcision; Acceptability; Botswana; HIV; Prevention
Single-dose nevirapine (sdNVP) is widely used to prevent mother-to-child transmission (PMTCT) of HIV-1. This may result in NVP resistance in both mother and infant. The significance of low levels of NVP resistance mutations in infants treated with NVP-containing antiretroviral treatment (ART) is unknown.
To determine the presence of pre-treatment NVP resistance in HIV-infected infants with and without prior NVP exposure.
33 HIV-1-infected infants in a PMTCT trial received NVP-containing ART (26 infants with prior NVP exposure). Plasma and buffy coat samples obtained prior to ART initiation were evaluated for drug resistance by bulk sequencing and allele-specific PCR (ASPCR).
ViroSeq™ identified NVP resistance in 3 of 33 infants; all failed first-line therapy. Pre-ART plasma NVP resistance by ASPCR was detected in 9 of 16 children experiencing virologic failure compared to 4 of 17 children without virologic failure (risk ratio 2.4, CI 0.94-7.8, p=0.08). Proviral resistance was not associated with virologic failure (risk ratio 1.2, CI 0.8-2.0, p= 0.40). In the nevirapine-exposed infants, those who started ART before 7 months had higher risk of virologic failure (RR 2.3; CI 0.96-9.2; p=0.11).
Low level drug resistance detected in plasma after NVP exposure prior to ART initiation may be associated with virologic failure on ART, while resistance in the DNA reservoir was not predictive of treatment outcome.
HIV; minor variant; drug resistance; nevirapine; PMTCT
National initiatives offering NNRTI-based combination antiretroviral therapy (cART) have expanded in sub-Saharan Africa (SSA). The Tshepo study is the first clinical trial evaluating the long-term efficacy and tolerability of EFV- vs. NVP-based cART among adults in Botswana.
Three year randomized study (n = 650) using a 3×2×2 factorial design comparing efficacy and tolerability among: A: ZDV/3TC vs. ZDV/ddI vs. d4T/3TC; B: EFV vs. NVP, and C: Com-DOT vs. standard adherence strategies. This manuscript focuses on comparison B.
There was no significant difference by assigned NNRTI in time to virologic failure with resistance (log-rank p = 0.14), NVP vs. EFV risk ratio (RR) = 1.54 [0.86-2.70]. Rates of virologic failure with resistance were 9.6% NVP-treated [6.8-13.5] vs. 6.6% EFV-treated [4.2-10.0] at 3 years. Women receiving NVP-based cART trended towards higher virological failure rates when compared to EFV-treated women, Holm-corrected log-rank p = 0.072, NVP vs. EFV RR = 2.22 [0.94-5.00]. 139 patients had 176 treatment modifying toxicities, with shorter time to event in NVP-treated vs. EFV-treated, RR = 1.85 [1.20-2.86], log-rank p = 0.0002.
Tshepo-treated patients had excellent overall immunologic and virologic outcomes, and no significant differences were observed by randomized NNRTI comparison. NVP-treated women trended towards higher virologic failure with resistance compared to EFV-treated women. NVP-treated adults had higher treatment modifying toxicity rates when compared to those receiving EFV. NVP-based cART can continue to be offered to women in SSA if routine safety monitoring chemistries are done and the potential risk of EFV-related teratogenicity is considered.
HIV/AIDS; HAART; non-nucleoside reverse transcriptase inhibitors (NNRTI’s); nevirapine versus efavirenz; sub-Saharan Africa; randomized clinical trial