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1.  Lipid Changes in Kenyan HIV-1-Infected Infants Initiating Highly Active Antiretroviral Therapy by One Year of Age 
Background
Early highly active antiretroviral therapy (HAART) is recommended for HIV-1 infected infants. There are limited data on lipid changes during infant HAART.
Methods
Non-fasting total (TC), low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol, and triglycerides (TG) were measured at 0, 6 and 12 months. Correlates of lipid levels and changes post-HAART were assessed using linear regression.
Results
Among 115 infants, pre-HAART median age was 3.8 months, CD4% was 19%, and weight-for-age z-score (WAZ) was −2.42. Pre-HAART median lipid levels were: TC, 108.7 mg/dl, LDL, 42.5 mg/dl, HDL, 29.4 mg/dl and TG, 186.9 mg/dl. Few infants had abnormally high TC (6.2%) or LDL (5.6%), but many had low HDL (76.5%) or high TG (69.6%). Higher pre-HAART WAZ and HAZ were each associated with higher pre-HAART TC (P=0.04 and P=0.01) and LDL (P=0.02 and P=0.008). From 0–6 months post-HAART, TC (P<0.0001), LDL (P<0.0001), and HDL (P<0.0001) increased significantly, and 23.1% (P=0.002), 14.0% (P=0.2), 31.3% (P<0.0001), and 50.8% (P=0.2) of infants had abnormally high TC, high LDL, low HDL, and high TG, respectively. Changes in TC and HDL were each associated with higher gain in WAZ (P=0.03 and P=0.01) and HAZ (P=0.01 and P=0.007). Increased change in LDL was associated with higher gain in HAZ (P=0.03). Infants on protease inhibitor (PI)-HAART had smaller HDL increase (P=0.004).
Conclusions
Infants had substantive increases in lipids, which correlated with growth. Increases in HDL were attenuated by PI-HAART. It is important to determine clinical implications of these changes.
doi:10.1097/INF.0b013e31828afb2a
PMCID: PMC3737429  PMID: 23385950
lipids; pediatric HIV-1; highly active antiretroviral therapy; infants; Africa
2.  Clinical and Virologic Manifestations of Primary Epstein-Barr Virus (EBV) Infection in Kenyan Infants Born to HIV-Infected Women 
The Journal of Infectious Diseases  2013;207(12):1798-1806.
Background. Human immunodeficiency virus (HIV) infection is a risk factor for Epstein-Barr virus (EBV)–associated lymphomas. Characterizing primary infection may elucidate risk factors for malignancy.
Methods. To describe clinical and virologic manifestations of primary EBV infection among infants born to HIV-infected women, specimens were utilized from a cohort study conducted in Nairobi, Kenya. HIV and EBV viral loads were measured serially in plasma. EBV serology was performed on EBV DNA–negative infants. Monthly clinical examinations were performed by pediatricians.
Results. The probability of EBV infection by 1 year of age was .78 (95% CI, .67–.88) in HIV-infected and .49 (95% CI, .35–.65) in HIV-uninfected infants (P < .0001). At 2 years, probability of EBV infection was .96 (95% CI, .89–.99) in HIV-infected infants. Peak EBV loads were higher in HIV-infected versus HIV-uninfected infants (median 2.6 vs 2.1 log10 copies/mL; P < .0001). The majority of HIV-infected infants had detectable EBV DNA for >3 months (79%). Primary EBV infection was associated with cough, fever, otitis media, pneumonia, hepatomegaly, splenomegaly, and hospitalization in HIV-infected infants; conjunctivitis and rhinorrhea in HIV-uninfected infants.
Conclusions. EBV infection occurs early in infants born to HIV-infected women. HIV infection was associated with more frequent and higher quantity EBV DNA detection.
doi:10.1093/infdis/jit093
PMCID: PMC3654744  PMID: 23493724
EBV; primary infection; HIV; pediatric; herpesviruses
3.  A prospective cohort study comparing the effect of single-dose 2g metronidazole on Trichomonas vaginalis infection in HIV-seropositive versus HIV-seronegative women 
Sexually transmitted diseases  2013;40(6):499-505.
Background
This analysis compared the frequency of persistent Trichomonas vaginalis (TV) among HIV-seropositive and HIV-seronegative women.
Methods
Data were obtained from women enrolled in an open cohort study of sex workers in Kenya. Participants were examined monthly, and those diagnosed with TV by saline microscopy were treated with single-dose 2g oral metronidazole. All women on antiretroviral therapy (ART) used nevirapine-based regimens. Generalized estimating equations with a logit link were used to compare the frequency of persistent TV (defined as the presence of motile trichomonads by saline microscopy at the next exam visit within 60 days) by HIV status.
Results
Three-hundred and sixty participants contributed 570 infections to the analysis (282 HIV-seropositive and 288 HIV-seronegative). There were 42 (15%) persistent infections among HIV-seropositive participants versus 35 (12%) among HIV-seronegative participants (adjusted odds ratio [aOR]=1.14; 95% confidence interval [CI] (0.70, 1.87)). Persistent TV was highest among HIV-seropositive women using ART (21/64 [33%]) compared to HIV-seropositive women not using ART (21/217 [10%]). Concurrent bacterial vaginosis (BV) at TV diagnosis was associated with an increased likelihood of persistent TV (aOR=1.90; 95% CI 1.16, 3.09).
Conclusions
The frequency of persistent TV infection following treatment with single-dose 2g oral metronidazole was similar by HIV status. Alternative regimens, including multi-day antibiotic treatment, may be necessary to improve cure rates for women using nevirapine-based ART and women with TV and concurrent BV.
doi:10.1097/OLQ.0b013e31828fce34
PMCID: PMC3676301  PMID: 23677023
Trichomonas vaginalis; metronidazole; efficacy; persistence; HIV infection; nevirapine; antiretroviral therapy
4.  Antibody-dependent cell-mediated virus inhibition (ADCVI) antibody activity does not correlate with risk of HIV-1 superinfection 
Previous studies of HIV-infected women with high risk behavior have indicated that neither neutralizing antibody nor cellular immunity elicited by an initial HIV-1 infection is associated with protection against superinfection with a different HIV-1 strain. Here, we measured antibody-dependent cell-mediated virus inhibition (ADCVI) antibody activity in the plasma of 12 superinfected cases and 36 singly infected matched controls against 2 heterologous viruses. We found no association between plasma ADCVI activity and superinfection status. ADCVI antibody activity against heterologous virus elicited by the original infection may not contribute to preventing a superinfecting HIV-1.
doi:10.1097/QAI.0b013e3182874d41
PMCID: PMC3625514  PMID: 23344546
antibody-dependent cell-mediated virus inhibition; ADCVI; HIV-1; superinfection; primary infection; clade A
5.  Appropriateness of hydroxyethylcellulose gel as a placebo control in vaginal microbicide trials: A comparison of the two control arms of HPTN 035 
Objective
To compare the two control arms of HPTN 035 (a hydroxyethylcellulose (HEC) gel control arm and a no gel control arm) to assess behavioral effects associated with gel use and direct causal effects of the HEC gel on STIs, pregnancy, and genital safety.
Design
Randomized trial with one blinded (HEC gel) and one open label (no gel) control arms.
Methods
HIV-uninfected, sexually active women were randomized into the HEC gel arm (n=771) and into the no gel arm (n=772) in five countries. Participants in the HEC gel arm were instructed to insert the study gel intravaginally <1 hour before each vaginal sex act. Data on sexual behavior, adherence, safety, pregnancy, and STIs were collected quarterly for 12 to 30 months of follow-up.
Results
During follow-up, mean reported condom use in the past week was significantly higher in the no gel arm (81% versus 70%, p<0.001). There were no significant differences, after adjusting for this differential condom use, between the two arms in rates of genital safety events, pregnancy outcomes, or STIs, including HIV-1.
Conclusions
In this large randomized trial, we found no significant differences between the no gel and HEC gel arms in rates of genital safety events, pregnancy outcomes, or STIs. These results aid interpretation of the results of previous vaginal microbicide trials that used the HEC gel as a control. The HEC gel is suitable as a control for ongoing and future vaginal microbicide studies.
doi:10.1097/QAI.0b013e31828607c5
PMCID: PMC3625489  PMID: 23334506
HIV prevention; vaginal microbicide; placebo; women; sexually transmitted infections
6.  Incidence and Correlates of Chlamydia trachomatis Infection in a High Risk Cohort of Kenyan Women 
Sexually transmitted diseases  2013;40(3):10.1097/OLQ.0b013e318272fe45.
BACKGROUND
In Africa, data on Chlamydia trachomatis infection are scarce because reliable diagnosis is costly and not widely available. Our objective was to evaluate the incidence and correlates of C. trachomatis infection among high-risk Kenyan women.
METHODS
We conducted prospective cohort analyses using data from a cohort of women who reported transactional sex. C. trachomatis testing was performed using the Gen-Probe Aptima GC/CT Detection System. We used Andersen-Gill proportional hazards modeling to evaluate correlates of C. trachomatis.
RESULTS
Between August 2006 and December 2010, 865 women contributed 2011 person-years of observation. Sixty-four women experienced 101 episodes of C. trachomatis infection (incidence rate of 5.0/100 person-years). There was a large difference in incidence by age group: those below 25 years had an incidence of 27.6 per 100 person-years (95% CI 16.3 – 46.5), those 25 to 34 years old had an incidence of 8.4 per 100 person-years (95% CI 6.4 – 11.0), and those 35 years old and above had an incidence of 2.6 per 100 person-years (95% CI 1.8 – 3.6). In multivariate analyses, younger age (<25 years and 25–34 years versus ≥35 years; hazard ratio [HR] 8.49 95% CI 4.1–17.7 and HR 2.9 95% CI 1.7–5.0 respectively), depot medroxyprogesterone acetate use (HR 1.8 95% CI 1.1–3.0) and recent Neisseria gonorrhoeae infection (HR 3.3 95% CI 1.5–7.4) were significantly associated with increased risk of acquiring C. trachomatis infection.
CONCLUSIONS
The high incidence of C. trachomatis among younger high-risk women suggests the need for screening as an important public health intervention for this population.
doi:10.1097/OLQ.0b013e318272fe45
PMCID: PMC3831875  PMID: 23407467
Chlamydia trachomatis; incidence; risk factors; women; Africa
7.  Incident HIV during Pregnancy and Postpartum and Risk of Mother-to-Child HIV Transmission: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(2):e1001608.
Alison Drake and colleagues conduct a systematic review and meta-analysis to estimate maternal HIV incidence during pregnancy and the postpartum period and to compare mother-to-child HIV transmission risk among women with incident versus chronic infection.
Please see later in the article for the Editors' Summary
Background
Women may have persistent risk of HIV acquisition during pregnancy and postpartum. Estimating risk of HIV during these periods is important to inform optimal prevention approaches. We performed a systematic review and meta-analysis to estimate maternal HIV incidence during pregnancy/postpartum and to compare mother-to-child HIV transmission (MTCT) risk among women with incident versus chronic infection.
Methods and Findings
We searched PubMed, Embase, and AIDS-related conference abstracts between January 1, 1980, and October 31, 2013, for articles and abstracts describing HIV acquisition during pregnancy/postpartum. The inclusion criterion was studies with data on recent HIV during pregnancy/postpartum. Random effects models were constructed to pool HIV incidence rates, cumulative HIV incidence, hazard ratios (HRs), or odds ratios (ORs) summarizing the association between pregnancy/postpartum status and HIV incidence, and MTCT risk and rates. Overall, 1,176 studies met the search criteria, of which 78 met the inclusion criterion, and 47 contributed data. Using data from 19 cohorts representing 22,803 total person-years, the pooled HIV incidence rate during pregnancy/postpartum was 3.8/100 person-years (95% CI 3.0–4.6): 4.7/100 person-years during pregnancy and 2.9/100 person-years postpartum (p = 0.18). Pooled cumulative HIV incidence was significantly higher in African than non-African countries (3.6% versus 0.3%, respectively; p<0.001). Risk of HIV was not significantly higher among pregnant (HR 1.3, 95% CI 0.5–2.1) or postpartum women (HR 1.1, 95% CI 0.6–1.6) than among non-pregnant/non-postpartum women in five studies with available data. In African cohorts, MTCT risk was significantly higher among women with incident versus chronic HIV infection in the postpartum period (OR 2.9, 95% CI 2.2–3.9) or in pregnancy/postpartum periods combined (OR 2.3, 95% CI 1.2–4.4). However, the small number of studies limited power to detect associations and sources of heterogeneity.
Conclusions
Pregnancy and the postpartum period are times of persistent HIV risk, at rates similar to “high risk” cohorts. MTCT risk was elevated among women with incident infections. Detection and prevention of incident HIV in pregnancy/postpartum should be prioritized, and is critical to decrease MTCT.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, about 3.4 million children younger than 15 years old (mostly living in sub-Saharan Africa) are infected with HIV, the virus that causes AIDS by gradually destroying immune system cells, thereby leaving infected individuals susceptible to other serious infections. In 2012 alone, 230,000 children (more than 700 every day) were newly infected with HIV. Most HIV infections among children are the result of mother-to-child HIV transmission (MTCT) during pregnancy, delivery, or breastfeeding. The rate of MTCT (and deaths among HIV-positive pregnant women from complications related to HIV infection) can be greatly reduced by testing women for HIV infection during pregnancy (antenatal HIV testing), treating HIV-positive women with antiretroviral drugs (ARVs, powerful drugs that control HIV replication and allow the immune system to recover) during pregnancy, delivery, and breastfeeding, and giving ARVs to their newborn babies.
Why Was This Study Done?
The World Health Organization and the Joint United Nations Programme on HIV/AIDS (UNAIDS) have developed a global plan that aims to move towards eliminating new HIV infections among children by 2015 and towards keeping their mothers alive. To ensure the plan's success, the incidence of HIV (the number of new infections) among women and the rate of MTCT must be reduced by increasing ARV uptake by mothers and their infants for the prevention of MTCT. However, the risk of HIV infection among pregnant women and among women who have recently given birth (postpartum women) is poorly understood because, although guidelines recommend repeat HIV testing during late pregnancy or at delivery in settings where HIV infection is common, pregnant women are often tested only once for HIV infection. The lack of retesting represents a missed opportunity to identify pregnant and postpartum women who have recently acquired HIV and to prevent MTCT by initiating ARV therapy. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic) and meta-analysis (a study that uses statistical methods to combine the results of several studies), the researchers estimate maternal HIV incidence during pregnancy and the postpartum period, and compare the risk of MTCT among women with incident (new) and chronic (long-standing) HIV infection.
What Did the Researchers Do and Find?
The researchers identified 47 studies (35 undertaken in Africa) that examined recent HIV acquisition by women during pregnancy and the 12-month postpartum period. They used random effects statistical models to estimate the pooled HIV incidence rate and cumulative HIV incidence (the number of new infections per number of people at risk), and the association between pregnancy/postpartum status and HIV incidence and MTCT risk and rates. The pooled HIV incidence rate among pregnant/postpartum women estimated from 19 studies (all from sub-Saharan Africa) that reported HIV incidence rates was 3.8/100 person-years. The pooled cumulative HIV incidence was significantly higher in African countries than in non-African countries (3.6% and 0.3%, respectively; a “significant” difference is one that is unlikely to arise by chance). In the five studies that provided suitable data, the risk of HIV acquisition was similar in pregnant, postpartum, and non-pregnant/non-postpartum women. Finally, among African women, the risk of MTCT was 2.9-fold higher during the postpartum period among those who had recently acquired HIV than among those with chronic HIV infection, and 2.3-fold higher during the pregnancy/postpartum periods combined.
What Do These Findings Mean?
These results suggest that women living in regions where HIV infection is common are at high risk of acquiring HIV infection during pregnancy and the postpartum period and that mothers who acquire HIV during pregnancy or postpartum are more likely to pass the infection on to their offspring than mothers with chronic HIV infections. However, the small number of studies included in this meta-analysis and the use of heterogeneous research methodologies in these studies may limit the accuracy of these findings. Nevertheless, these findings have important implications for the global plan to eliminate HIV infections in children. First, they suggest that women living in regions where HIV infection is common should be offered repeat HIV testing (using sensitive methods to enhance early detection of infection) during pregnancy and in the postpartum period to detect incident HIV infections, and should be promptly referred to HIV care and treatment. Second, they suggest that prevention of HIV transmission during pregnancy and postpartum should be prioritized, for example, by counseling women about the need to use condoms to prevent transmission during this period of their lives.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001608.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on children and HIV/AIDS and on the prevention of mother-to-child transmission of HIV (in English and Spanish)
The 2013 UNAIDS World AIDS Day Report provides information about the AIDS epidemic and efforts to halt it; the 2013 UNAIDS Progress Report on the Global Plan provides information on progress towards eliminating new HIV infections among children; the UNAIDS Believe it. Do it website provides information about the campaign to support the UNAIDS global plan
Personal stories about living with HIV/AIDS, including stories from young people infected with HIV, are available through Avert, NAM/aidsmap, and Healthtalkonline
doi:10.1371/journal.pmed.1001608
PMCID: PMC3934828  PMID: 24586123
8.  Maternal Valacyclovir and Infant Cytomegalovirus Acquisition: A Randomized Controlled Trial among HIV-Infected Women 
PLoS ONE  2014;9(2):e87855.
Background
Studies in HIV-1-infected infants and HIV-1-exposed, uninfected infants link early cytomegalovirus (CMV) acquisition with growth delay and cognitive impairment. We investigated maternal valacyclovir to delay infant acquisition of CMV.
Methods
Pregnant women with HIV-1, HSV-2 and CD4 count >250 cells/µl were randomized at 34 weeks gestation to 500 mg twice-daily valacyclovir or placebo for 12 months. Maternal CMV DNA was measured in plasma at 34 weeks gestation, in cervical secretions at 34 and 38 weeks gestation, and in breast milk at 7 postpartum timepoints; infant CMV DNA was measured in dried blood spots at 8 timepoints including birth.
Results
Among 148 women, 141 infants were compared in intent-to-treat analyses. Maternal and infant characteristics were similar between study arms. Infant CMV acquisition did not differ between study arms, with 46/70 infants (66%) in placebo arm and 47/71 infants (66%) in the valacyclovir arm acquiring CMV; median time to CMV detection did not differ. CMV DNA was detected in 92% of 542 breast milk specimens with no difference in CMV level between study arms. Change in cervical shedding of CMV DNA between baseline and 38 weeks was 0.40-log greater in the placebo arm than the valacyclovir arm (p = 0.05).
Conclusions
In this cohort of HIV-1-seropositive mothers, two-thirds of infants acquired CMV by one year. Maternal valacyclovir had no effect on timing of infant CMV acquisition or breast milk CMV viral loads, although it modestly reduced cervical CMV shedding. Maternal prophylaxis to reduce infant CMV acquisition warrants further evaluation in trials with antiviral agents.
Trials Registration
ClinicalTrials.gov NCT00530777
doi:10.1371/journal.pone.0087855
PMCID: PMC3913686  PMID: 24504006
9.  Adherence and acceptability in MTN 001: A randomized cross-over trial of daily oral and topical tenofovir for HIV prevention in women 
AIDS and behavior  2013;17(2):737-747.
We compared adherence to and acceptability of daily topical and oral formulations of tenofovir (TFV) used as pre-exposure prophylaxis (PrEP) for HIV prevention among women in South Africa, Uganda and the United States. 144 sexually active, HIV-uninfected women participated in a cross-over study of three regimens: oral tablet, vaginal gel, or both. We tested for differences in adherence and evaluated product acceptability. Self-reported adherence for all regimens was high (94%), but serum TFV concentrations indicated only 64% of participants used tablets consistently. Most women in the U.S. (72%) favored tablets over gel; while preferences varied at the African sites (42% preferred gel and 40% tablets). Findings indicate a role for oral and vaginal PrEP formulations and highlight the importance of integrating pharmacokinetics-based adherence assessment in future trials. Biomedical HIV prevention interventions should consider geographic and cultural experience with product formulations, partner involvement, and sexual health benefits that ultimately influence use.
doi:10.1007/s10461-012-0333-8
PMCID: PMC3562423  PMID: 23065145
anti-infective agents; HIV; patient compliance; sexual behavior; vaginal creams, foams and jellies; administration, oral; PrEP; microbicide
10.  A Prospective Study of Risk Factors for Bacterial Vaginosis in HIV-1-Seronegative African Women 
Sexually transmitted diseases  2008;35(6):617-623.
Background
Bacterial vaginosis (BV) is common and has been associated with increased HIV-1 susceptibility. The objective of this study was to identify risk factors for BV in African women at high risk for acquiring HIV-1.
Methods
We conducted a prospective study among 151 HIV-1-seronegative Kenyan female sex workers. Non-pregnant women were eligible if they did not have symptoms of abnormal vaginal itching or discharge at the time of enrollment. At monthly follow-up, a vaginal examination and laboratory testing for genital tract infections were performed. Multivariate Andersen-Gill proportional hazards analysis was used to identify correlates of BV.
Results
Participants completed a median of 378 (interquartile range 350–412) days of follow-up. Compared to women reporting no vaginal washing, those who reported vaginal washing 1–14 (adjusted hazard ratio [aHR] 1.29, 95% confidence interval [CI] 0.88–1.89), 15–28 (aHR 1.60, 95% CI 0.98–2.61), and >28 times/week (aHR 2.39, 95% CI 1.35–4.23) were at increased risk of BV. Higher BV incidence was also associated with the use of cloth for intravaginal cleansing (aHR 1.48, 95% CI 1.06–2.08) and with recent unprotected intercourse (aHR 1.75, 95% CI 1.47–2.08). Women using depot medroxyprogesterone acetate contraception were at lower risk for BV (aHR 0.59, 95% CI 0.48–0.73).
Conclusions
Vaginal washing and unprotected intercourse were associated with increased risk of BV. These findings could help to inform the development of novel vaginal health approaches for HIV-1 risk reduction in women.
doi:10.1097/OLQ.0b013e31816907fa
PMCID: PMC3902781  PMID: 18418290
Bacterial vaginosis; vaginal washing; intravaginal practices; women; Africa
11.  Correlates and outcomes of preterm birth, low birth weight, and small for gestational age in HIV-exposed uninfected infants 
Background
Preterm birth (PTB), low birth weight (LBW) and small for gestational age (SGA) contribute to neonatal mortality. Maternal HIV-1 infection has been associated with an increased risk of PTB, but mechanisms underlying this association are undefined. We describe correlates and outcomes of PTB, LBW, and SGA in HIV-exposed uninfected infants.
Methods
This was a retrospective analysis of cohort study. Between 1999–2002, pregnant, HIV-infected women were enrolled into an HIV-1 transmission study. Logistic regression was used to identify correlates of PTB, LBW and SGA in HIV-negative, spontaneous singleton deliveries. Associations between birth outcomes and mortality were measured using survival analyses.
Results
In multivariable models, maternal plasma (OR = 2.1, 95% CI = 1.1-3.8) and cervical HIV-1 RNA levels (OR = 1.6, 95% CI = 1.1-2.4), and CD4 < 15% (OR = 2.4, 95% CI = 1.0-5.6) were associated with increased odds of PTB. Abnormal vaginal discharge and cervical polymorphonuclear leukocytes were also associated with PTB. Cervical HIV-1 RNA level (OR = 2.4, 95% CI = 1.5-6.7) was associated with an increased odds of LBW, while increasing parity (OR = 0.46, 95% CI = 0.24-0.88) was associated with reduced odds. Higher maternal body mass index (OR = 0.75, 95% CI = 0.61-0.92) was associated with a reduced odds of SGA, while bacterial vaginosis was associated with >3-fold increased odds (OR = 3.2, 95% CI = 1.4-7.4). PTB, LBW, and SGA were each associated with a >6-fold increased risk of neonatal death, and a >2-fold increased rate of infant mortality within the first year.
Conclusions
Maternal plasma and cervical HIV-1 RNA load, and genital infections may be important risk factors for PTB in HIV-exposed uninfected infants. PTB, LBW, and SGA are associated with increased neonatal and infant mortality in HIV-exposed uninfected infants.
doi:10.1186/1471-2393-14-7
PMCID: PMC3897882  PMID: 24397463
Preterm birth; Low birth weight; Small for gestational age; Pediatric HIV
12.  Short Communication: T Cell Activation in HIV-1/Herpes Simplex Virus-2-Coinfected Kenyan Women Receiving Valacyclovir 
Abstract
Herpes simplex virus-2 (HSV-2) suppression with acyclovir or valacyclovir reduces HIV-1 viral RNA levels; one hypothesis is that HSV-2 suppression reduces immune activation. We measured T cell immune activation markers among women participating in a randomized placebo-controlled trial of valacyclovir to reduce HIV-1 RNA levels among pregnant women. Although valacyclovir was associated with lower HIV-1 RNA levels, the distribution of both CD4+ and CD8+ CD38+HLA-DR+ T cells was not different among women taking valacyclovir when compared to women taking placebo. Further study is needed to understand the mechanism of HIV-1 RNA reduction following herpes suppression among those coinfected with HIV-1 and HSV-2.
doi:10.1089/aid.2012.0071
PMCID: PMC3537320  PMID: 22852760
13.  Mucosal Escherichia coli Bactericidal Activity and Immune Mediators Are Associated With HIV-1 Seroconversion in Women Participating in the HPTN 035 Trial 
The Journal of Infectious Diseases  2012;206(12):1931-1935.
The mucosal environment may impact the risk for human immunodeficiency virus type 1 (HIV-1) acquisition. Immune mediators were measured in vaginal fluid collected from HPTN 035 participants who acquired HIV-1 and from those who remained HIV-1 negative (controls). Mediator concentrations were similar in samples obtained before as compared to after HIV-1 acquisition in the 8 seroconverters. Compared with controls, seroconverters were more likely to have detectable levels of HβD-2 (odds ratio [OR], 2.39; P = .005) and greater Escherichia coli bactericidal activity (OR, 1.22; P = .01) prior to seroconversion. E. coli bactericidal activity remained significant in a multivariable analysis (P = .02) and may be a biomarker for HIV-1 acquisition.
doi:10.1093/infdis/jis555
PMCID: PMC3502373  PMID: 22966121
14.  Impact of Helminth Diagnostic Test Performance on Estimation of Risk Factors and Outcomes in HIV-Positive Adults 
PLoS ONE  2013;8(12):e81915.
Background
Traditional methods using microscopy for the detection of helminth infections have limited sensitivity. Polymerase chain reaction (PCR) assays enhance detection of helminths, particularly low burden infections. However, differences in test performance may modify the ability to detect associations between helminth infection, risk factors, and sequelae. We compared these associations using microscopy and PCR.
Methods
This cross-sectional study was nested within a randomized clinical trial conducted at 3 sites in Kenya. We performed microscopy and real-time multiplex PCR for the stool detection and quantification of Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale, Strongyloides stercoralis, and Schistosoma species. We utilized regression to evaluate associations between potential risk factors or outcomes and infection as detected by either method.
Results
Of 153 HIV-positive adults surveyed, 55(36.0%) and 20(13.1%) were positive for one or more helminth species by PCR and microscopy, respectively (p<0.001). PCR-detected infections were associated with farming (Prevalence Ratio 1.57, 95% CI: 1.02, 2.40), communal water source (PR 3.80, 95% CI: 1.01, 14.27), and no primary education (PR 1.54, 95% CI: 1.14, 2.33), whereas microscopy-detected infections were not associated with any risk factors under investigation. Microscopy-detected infections were associated with significantly lower hematocrit and hemoglobin (means of -3.56% and -0.77 g/dl) and a 48% higher risk of anemia (PR 1.48, 95% CI: 1.17, 1.88) compared to uninfected. Such associations were absent for PCR-detected infections unless infection intensity was considered, Infections diagnosed with either method were associated with increased risk of eosinophilia (PCR PR 2.42, 95% CI: 1.02, 5.76; microscopy PR 2.92, 95% CI: 1.29, 6.60).
Conclusion
Newer diagnostic methods, including PCR, improve the detection of helminth infections. This heightened sensitivity may improve the identification of risk factors for infection while reducing ability to discriminate infections associated with adverse clinical outcomes. Quantitative assays can be used to differentiate infection loads and discriminate infections associated with sequelae.
doi:10.1371/journal.pone.0081915
PMCID: PMC3852669  PMID: 24324729
15.  Genital Inflammation Predicts HIV-1 Shedding Independent of Plasma Viral Load and Systemic Inflammation 
In women, genital HIV-1 RNA levels predict the risk of HIV-1 transmission independent of plasma viral load. To better understand the factors that contribute to genital HIV-1 shedding, we evaluated the relationships between genital and plasma cytokine concentrations and HIV-1 RNA levels. Vaginal, but not plasma, levels of interferon gamma-induced protein 10 (IP-10) were significantly associated with vaginal viral load, independent of plasma viral load. Thus, efforts to decrease HIV-1 transmission must take into account the role of local inflammation, which is not necessarily reflected in plasma measurements.
doi:10.1097/QAI.0b013e31826c2edd
PMCID: PMC3494808  PMID: 22878424
HIV-1; inflammation; cytokine; genital; shedding; transmission
16.  Male, Mobile, and Moneyed: Loss to Follow-Up vs. Transfer of Care in an Urban African Antiretroviral Treatment Clinic 
PLoS ONE  2013;8(10):e78900.
Objectives
The purpose of this study was to analyze characteristics, reasons for transferring, and reasons for discontinuing care among patients defined as lost to follow-up (LTFU) from an antiretroviral therapy (ART) clinic in Nairobi, Kenya.
Design
The study used a prospective cohort of patients who participated in a randomized, controlled ART adherence trial between 2006 and 2008.
Methods
Participants were followed from pre-ART clinic enrollment to 18 months after ART initiation, and were defined as LTFU if they failed to return to clinic 4 weeks after their last scheduled visit. Reasons for loss were captured through phone call or home visit. Characteristics of LTFU who transferred care and LTFU who did not transfer were compared to those who remained in clinic using log-binomial regression to estimate risk ratios.
Results
Of 393 enrolled participants, total attrition was 83 (21%), of whom 75 (90%) were successfully traced. Thirty-seven (49%) were alive at tracing and 22 (59%) of these reported having transferred their antiretroviral care. In the final model, transfers were more likely to have salaried employment [Risk Ratio (RR), 2.7; 95% confidence interval (CI), 1.2-6.1; p=0.020)] and pay a higher monthly rent (RR, 5.8; 95% CI, 1.3-25.0; p=0.018) compared to those retained in clinic. LTFU who did not transfer care were three times as likely to be men (RR, 3.1; 95% CI, 1.1-8.1; p=0.028) and nearly 4 times as likely to have a primary education or less (RR, 3.8; 95% CI, 1.3-10.6; p=0.013). Overall, the most common reason for LTFU was moving residence, predominantly due to job loss or change in employment.
Conclusion
A broad definition of LTFU may include those who have transferred their antiretroviral care and thereby overestimate negative effects on ART continuation. Interventions targeting men and considering mobility due to employment may improve retention in urban African ART clinics.
Clinical Trials
The study’s ClinicalTrials.gov identifier is NCT00273780.
doi:10.1371/journal.pone.0078900
PMCID: PMC3812001  PMID: 24205345
17.  Survival Benefit of Early Infant Antiretroviral Therapy is Compromised when Diagnosis is Delayed 
Late presentation is common among African HIV-1-infected infants. Incidence and correlates of mortality were examined in 99 infants with HIV-1 diagnosis by age 5 months. Twelve-month survival was 66.8% (95% confidence interval, 55.9%, 75.6%). WHO stage 3/4, underweight, wasting, microcephaly, low hemoglobin, pneumonia, and gastroenteritis predicted mortality. Early HIV-1 diagnosis with ART before symptomatic disease is critical for infant survival.
doi:10.1097/INF.0b013e3182587796
PMCID: PMC3756892  PMID: 22544051
Pediatric; Infant; HIV-1; Antiretroviral therapy; Mortality
18.  HIV-1 Superinfection Occurs Less Frequently Than Initial Infection in a Cohort of High-Risk Kenyan Women 
PLoS Pathogens  2013;9(8):e1003593.
HIV superinfection (reinfection) has been reported in several settings, but no study has been designed and powered to rigorously compare its incidence to that of initial infection. Determining whether HIV infection reduces the risk of superinfection is critical to understanding whether an immune response to natural HIV infection is protective. This study compares the incidence of initial infection and superinfection in a prospective seroincident cohort of high-risk women in Mombasa, Kenya. A next-generation sequencing-based pipeline was developed to screen 129 women for superinfection. Longitudinal plasma samples at <6 months, >2 years and one intervening time after initial HIV infection were analyzed. Amplicons in three genome regions were sequenced and a median of 901 sequences obtained per gene per timepoint. Phylogenetic evidence of polyphyly, confirmed by pairwise distance analysis, defined superinfection. Superinfection timing was determined by sequencing virus from intervening timepoints. These data were combined with published data from 17 additional women in the same cohort, totaling 146 women screened. Twenty-one cases of superinfection were identified for an estimated incidence rate of 2.61 per 100 person-years (pys). The incidence rate of initial infection among 1910 women in the same cohort was 5.75 per 100pys. Andersen-Gill proportional hazards models were used to compare incidences, adjusting for covariates known to influence HIV susceptibility in this cohort. Superinfection incidence was significantly lower than initial infection incidence, with a hazard ratio of 0.47 (CI 0.29–0.75, p = 0.0019). This lower incidence of superinfection was only observed >6 months after initial infection. This is the first adequately powered study to report that HIV infection reduces the risk of reinfection, raising the possibility that immune responses to natural infection are partially protective. The observation that superinfection risk changes with time implies a window of protection that coincides with the maturation of HIV-specific immunity.
Author Summary
HIV-infected individuals with continued exposure are at risk of acquiring a second infection, a process known as superinfection. Superinfection has been reported in various at-risk populations, but how frequently it occurs remains unclear. Determining the frequency of superinfection compared with initial infection can help clarify whether the immune response developed against HIV can protect from reinfection – critical information for understanding whether such responses should guide HIV vaccine design. In this study, we developed a sensitive high-throughput method to identify superinfection and used this to conduct a screen for superinfection in 146 women in a high-risk cohort. This enabled us to determine if first HIV infection affects the risk of second infection by comparing the incidence of superinfection in this group to the incidence of initial infection in 1910 women in the larger cohort. We found that the incidence of superinfection was approximately half that of initial infection after controlling for behavioral and clinical differences that might affect infection risk. These results suggest that the immune response elicited in natural HIV infection may provide partial protection against subsequent infection and indicate the setting of superinfection may shed light on the features of a protective immune response and inform vaccine design.
doi:10.1371/journal.ppat.1003593
PMCID: PMC3757054  PMID: 24009513
19.  Breast milk cellular HIV-specific interferon γ responses are associated with protection from peripartum HIV transmission 
AIDS (London, England)  2012;26(16):2007-2016.
Objective
Breast milk is a major route of infant HIV infection, yet the majority of breast-fed, HIV-exposed infants escape infection by unknown mechanisms. This study aimed to investigate the role of HIV-specific breast milk cells in preventing infant HIV infection.
Design
A prospective study was designed to measure associations between maternal breast milk HIV-specific interferon-γ (IFN-γ) responses and infant HIV-1 detection at 1 month of age.
Methods
In a Kenyan cohort of HIV-infected mothers, blood and breastmilk HIV-gag IFN-γ ELISpot responses were measured. Logistic regression was used to measure associations between breast milk IFN-γ responses and infant HIV infection at 1 month of age.
Results
IFN-γ responses were detected in breast milk from 117 of 170 (69%) women. IFN-γ responses were associated with breast milk viral load, levels of macrophage inflammatory protein (MIP) 1α, MIP-1β, regulated upon activation, normal T-cell expressed, and secreted and stromal-cell derived factor 1 and subclinical mastitis. Univariate factors associated with infant HIV infection at 1 month postpartum included both detection and breadth of breast milk IFN-γ response (P =0.08, P =0.04, respectively), breast milk MIP-1β detection (P =0.05), and plasma (P =0.004) and breast milk (P =0.004) viral load. In multivariate analyses adjusting for breast milk viral load and MIP-1β, breast milk IFN-γ responses were associated with an approximately 70% reduction in infant HIV infection [adjusted odds ratio (aOR) 0.29, 95% confidence interval (CI) 0.092–0.91], and each additional peptide pool targeted was associated with an approximately 35% reduction in infant HIV (aOR 0.65, 95% CI 0.44–0.97).
Conclusion
These data show breast milk HIV-gag-specific IFN-γ cellular immune responses are prevalent and may contribute to protection from early HIV transmission. More broadly, these data suggest breast milk cellular responses are potentially influential in decreasing mother-to-child transmission of viruses.
doi:10.1097/QAD.0b013e328359b7e0
PMCID: PMC3718292  PMID: 22948269
breastfeeding; breast milk cytotoxic T lymphocytes; cytokines; early postnatal transmission; infant; MIP-1β; pediatric; sub-Saharan Africa
20.  The post-trial effect of oral periodic presumptive treatment for vaginal infections on the incidence of bacterial vaginosis and Lactobacillus colonization 
Sexually Transmitted Diseases  2012;39(5):361-365.
Background
We previously demonstrated a decrease in bacterial vaginosis (BV) and an increase in Lactobacillus colonization among randomized controlled trial (RCT) participants who received monthly oral periodic presumptive treatment (PPT) [2g metronidazole + 150mg fluconazole]. Post-trial data were analyzed to test the hypothesis that the treatment effect would persist following completion of one year of PPT.
Methods
Data were obtained from women who completed all 12 RCT visits and attended ≥1 post-trial visit within 120 days following completion of the RCT. We used Andersen-Gill proportional hazards models to estimate the post-trial effect of the intervention on the incidence of BV by Gram stain and detection of Lactobacillus species by culture.
Results
The analysis included 165 subjects (83 active and 82 placebo). The post-trial incidence of BV was 260 per 100 person-years in the intervention arm versus 358 per 100 person-years in the placebo arm (hazard ratio [HR]=0.76; 95% confidence interval [CI]: 0.51–1.12). The post-trial incidence of Lactobacillus colonization was 180 per 100 person-years in the intervention arm versus 127 per 100 person-years in the placebo arm (HR=1.42; 95% CI: 0.85–2.71).
Conclusions
Despite a decrease in BV and an increase in Lactobacillus colonization during the RCT, the effect of PPT was not sustained at the same level following cessation of the intervention. New interventions that reduce BV recurrence and promote Lactobacillus colonization without the need for ongoing treatment are needed.
doi:10.1097/OLQ.0b013e31824790d7
PMCID: PMC3335440  PMID: 22504600
Bacterial vaginosis; Lactobacillus; periodic presumptive treatment; suppressive treatment
21.  HIV-1-Specific Enzyme-Linked Immunosorbent Spot Assay Responses in HIV-1-Exposed Uninfected Partners in Discordant Relationships Compared to Those in Low-Risk Controls 
Clinical and Vaccine Immunology : CVI  2012;19(11):1798-1805.
A number of studies of highly exposed HIV-1-seronegative individuals (HESN) have found HIV-1-specific cellular responses. However, there is limited evidence that responses prevent infection or are linked to HIV-1 exposure. Peripheral blood mononuclear cells (PBMC) were isolated from HESN in HIV-1-discordant relationships and low-risk controls in Nairobi, Kenya. HIV-1-specific responses were detected using gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assays stimulated by peptide pools spanning the subtype A HIV-1 genome. The HIV-1 incidence in this HESN cohort was 1.5 per 100 person years. Positive ELISpot responses were found in 34 (10%) of 331 HESN and 14 (13%) of 107 low-risk controls (odds ratio [OR] = 0.76; P = 0.476). The median immunodominant response was 18.9 spot-forming units (SFU)/106 peripheral blood mononuclear cells (PBMC). Among HESN, increasing age (OR = 1.24 per 5 years; P = 0.026) and longer cohabitation with the HIV-1-infected partner (OR = 5.88 per 5 years; P = 0.003) were associated with responses. These factors were not associated with responses in controls. Other exposure indicators, including the partner's HIV-1 load (OR = 0.99 per log10 copy/ml; P = 0.974) and CD4 count (OR = 1.09 per 100 cells/μl; P = 0.238), were not associated with responses in HESN. HIV-1-specific cellular responses may be less relevant to resistance to infection among HESN who are using risk reduction strategies that decrease their direct viral exposure.
doi:10.1128/CVI.00179-12
PMCID: PMC3491560  PMID: 22971780
22.  Acute Cytomegalovirus Infection Is Associated with Increased Frequencies of Activated and Apoptosis-Vulnerable T Cells in HIV-1-Infected Infants 
Journal of Virology  2012;86(20):11373-11379.
Cytomegalovirus (CMV) coinfection is associated with infant HIV-1 disease progression and mortality. In a cohort of Kenyan HIV-infected infants, the frequencies of activated (CD38+ HLA-DR+) and apoptosis-vulnerable (CD95+ Bcl-2−) CD4+ and CD8+ T cells increased substantially during acute CMV infection. The frequency of activated CD4+ T cells was strongly associated with both concurrent CMV coinfection (P = 0.001) and HIV-1 viral load (P = 0.05). The frequency of apoptosis-vulnerable cells was also associated with CMV coinfection in the CD4 (P = 0.02) and CD8 (P < 0.001) T cell subsets. Similar observations were made in HIV-exposed uninfected infants. CMV-induced increases in T cell activation and apoptosis may contribute to the rapid disease progression in coinfected infants.
doi:10.1128/JVI.00790-12
PMCID: PMC3457128  PMID: 22875969
23.  A Combination of Broadly Neutralizing HIV-1 Monoclonal Antibodies Targeting Distinct Epitopes Effectively Neutralizes Variants Found in Early Infection 
Journal of Virology  2012;86(19):10857-10861.
Neutralizing antibody protection against HIV-1 may require broad and potent antibodies targeting multiple epitopes. We tested 7 monoclonal antibodies (MAbs) against 45 viruses of diverse subtypes from early infection. The CD4 binding site MAb NIH45-46W was most broad and potent (91% coverage; geometric mean 50% inhibitory concentration [IC50], 0.09 μg/ml). Combining NIH45-46W and a V3-specific MAb, PGT128, neutralized 96% of viruses, while PGT121, another V3-specific MAb, neutralized the remainder. Thus, 2 or 3 antibody specificities may prevent infection by most HIV-1 variants.
doi:10.1128/JVI.01414-12
PMCID: PMC3457273  PMID: 22837204
24.  Cellular Immune Responses and Susceptibility to HIV-1 Superinfection: A Case-Control Study 
AIDS (London, England)  2012;26(5):643-646.
A case control study was performed to determine the effects of HIV-1-specific cellular immune responses on the odds of acquiring a second HIV-1 infection (superinfection). Changes in the frequency of cytokine-producing or cytolytic CD8+ or CD4+ T cells were not associated with significant alterations in the odds of superinfection, suggesting that HIV-1 specific cellular immune responses at the level induced by chronic infection do not appear to significantly contribute to protection from HIV-1 superinfection.
doi:10.1097/QAD.0b013e3283509a0b
PMCID: PMC3511787  PMID: 22210637
HIV-1; cellular immunity; T cells; superinfection; re-infection
25.  Valacyclovir Suppressive Therapy Reduces Plasma and Breast Milk HIV-1 RNA Levels During Pregnancy and Postpartum: A Randomized Trial 
The Journal of Infectious Diseases  2011;205(3):366-375.
Background. The effect of herpes simplex virus type 2 (HSV-2) suppression on human immunodeficiency virus type 1 (HIV-1) RNA in the context of prevention of mother-to-child transmission (PMTCT) interventions is unknown.
Methods. Between April 2008 and August 2010, we conducted a randomized, double-blind trial of twice daily 500 mg valacyclovir or placebo beginning at 34 weeks gestation in 148 HIV-1/HSV-2 coinfected pregnant Kenyan women ineligible for highly active antiretroviral therapy (CD4 > 250 cells/mm3). Women received zidovudine and single dose nevirapine for PMTCT and were followed until 12 months postpartum.
Results. Mean baseline plasma HIV-1 RNA was 3.88 log10 copies/mL. Mean plasma HIV-1 was lower during pregnancy (−.56 log10 copies/mL; 95% confidence interval [CI], −.77 to −.34) and after 6 weeks postpartum (−.51 log10 copies/mL; 95% CI, −.73 to −.30) in the valacyclovir arm than the placebo arm. Valacyclovir reduced breast milk HIV-1 RNA detection at 6 and 14 weeks postpartum compared with placebo (30% lower, P = .04; 46% lower, P = .01, respectively), but not after 14 weeks. Cervical HIV-1 RNA detection was similar between arms (P = .91).
Conclusions. Valacyclovir significantly decreased early breast milk and plasma HIV-1 RNA among women receiving PMTCT.
Clinical Trials Registration. NCT00530777.
doi:10.1093/infdis/jir766
PMCID: PMC3256951  PMID: 22147786

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