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Jared M Baeten,
Deborah Donnell,
Patrick Ndase,
Nelly R Mugo,
James D Campbell,
Jonathan Wangisi,
Jordan W Tappero,
Elizabeth A Bukusi,
Craig R Cohen,
Elly Katabira, [......],
Lisa Ondrejcek,
Robert W Coombs,
Lisa Frenkel,
Craig Hendrix,
Namandjé N Bumpus,
David Bangsberg,
Jessica E Haberer,
Wendy S Stevens,
Jairam R Lingappa,
Connie Celum
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ABSTRACT: Antiretroviral preexposure prophylaxis is a promising approach for preventing human immunodeficiency virus type 1 (HIV-1) infection in heterosexual populations.
We conducted a randomized trial of oral antiretroviral therapy for use as preexposure prophylaxis among HIV-1-serodiscordant heterosexual couples from Kenya and Uganda. The HIV-1-seronegative partner in each couple was randomly assigned to one of three study regimens--once-daily tenofovir (TDF), combination tenofovir-emtricitabine (TDF-FTC), or matching placebo--and followed monthly for up to 36 months. At enrollment, the HIV-1-seropositive partners were not eligible for antiretroviral therapy, according to national guidelines. All couples received standard HIV-1 treatment and prevention services.
We enrolled 4758 couples, of whom 4747 were followed: 1584 randomly assigned to TDF, 1579 to TDF-FTC, and 1584 to placebo. For 62% of the couples followed, the HIV-1-seronegative partner was male. Among HIV-1-seropositive participants, the median CD4 count was 495 cells per cubic millimeter (interquartile range, 375 to 662). A total of 82 HIV-1 infections occurred in seronegative participants during the study, 17 in the TDF group (incidence, 0.65 per 100 person-years), 13 in the TDF-FTC group (incidence, 0.50 per 100 person-years), and 52 in the placebo group (incidence, 1.99 per 100 person-years), indicating a relative reduction of 67% in the incidence of HIV-1 with TDF (95% confidence interval [CI], 44 to 81; P<0.001) and of 75% with TDF-FTC (95% CI, 55 to 87; P<0.001). Protective effects of TDF-FTC and TDF alone against HIV-1 were not significantly different (P=0.23), and both study medications significantly reduced the HIV-1 incidence among both men and women. The rate of serious adverse events was similar across the study groups. Eight participants receiving active treatment were found to have been infected with HIV-1 at baseline, and among these eight, antiretroviral resistance developed in two during the study.
Oral TDF and TDF-FTC both protect against HIV-1 infection in heterosexual men and women. (Funded by the Bill and Melinda Gates Foundation; Partners PrEP ClinicalTrials.gov number, NCT00557245.).
New England Journal of Medicine 07/2012; 367(5):399-410. · 53.30 Impact Factor
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ABSTRACT: Early sexual partnerships place young women in sub-Saharan Africa at high risk for HIV. Few studies have examined both individual- and partnership-level characteristics of sexual relationships among adolescent girls. A cross-sectional survey of sexual history and partnerships was conducted among 761 adolescent girls aged 15-19 years in Nairobi, Kenya. Rapid HIV testing was conducted and correlates of HIV infection were determined using multivariate logistic regression. The HIV prevalence was 7% and seropositive adolescents had a younger age at sexual debut (P < 0.01), more sexual partners in 12 months (P = 0.03), and were more likely to report transactional or non-consensual sex (P < 0.01). Girls who reported not knowing their partner's HIV status were 14 times as likely to be HIV-seropositive than girls who knew their partner's status (adjusted odds ratio: 14.2 [1.8, 109.3]). Public health messages to promote HIV testing and disclosure within partnerships could reduce sexual risk behaviours and HIV transmission among adolescents.
International Journal of STD & AIDS 07/2012; 23(7):468-74. · 1.09 Impact Factor
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ABSTRACT: 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.
AIDS research and human retroviruses. 01/2012;
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ABSTRACT: Summary Among 288 HIV-1-infected, breastfeeding women who received zidovudine prophylaxis and were followed with their infants in Nairobi, we found no associations between maternal genetic polymorphisms in CCR5 (59029G/A, 59353T/C, 59356T/C, 59402G/A), RANTES (-403G/A) and SDF-1 (3'801G/A) and mother-to-child HIV-1 transmission; plasma, cervical and breastmilk viral loads; or breastmilk chemokine concentrations.
International Journal of Immunogenetics 08/2010; 37(4):301-5. · 1.29 Impact Factor
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ABSTRACT: HIV-infected women with sexually transmitted infections (STIs) or bacterial vaginosis (BV) during pregnancy are at increased risk for poor obstetric outcomes. In resource-limited settings, diagnostic testing for STIs and BV is often not available and most pregnant women are managed using syndromic algorithms. As part of a Nairobi perinatal cohort, HIV-1-infected pregnant women were interviewed and samples were collected for STIs and BV testing. Diagnostic accuracy of STIs and BV by syndromic algorithms was evaluated with comparison to the reference standard. Among 441 women, prevalence of BV was 37%, trichomoniasis 16%, chlamydia 4%, syphilis 3% and gonorrhoea 2%. Significantly more women with STIs were aged 21-years-old, had not attended secondary school and had a history of STIs. Syndromic diagnosis of STIs and BV demonstrated a sensitivity of 45% and 57%, and positive predictive value of 30% and 42%, respectively. Among these HIV-infected, pregnant women, STIs and vaginal infections were common and syndromic diagnosis was insensitive, resulting in missed opportunities to intervene and improve infant and maternal health.
International Journal of STD & AIDS 08/2010; 21(8):549-52. · 1.09 Impact Factor
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R Y Choi, C Farquhar,
J Juno,
D Mbori-Ngacha,
B Lohman-Payne,
F Vouriot,
S Wayne,
J Tuff,
R Bosire,
G John-Stewart,
K Fowke
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ABSTRACT: The C868T single nucleotide polymorphism (SNP) in the CD4 receptor encodes an amino acid change that could alter its structure and influence human immunodeficiency virus (HIV-1) infection risk. HIV-1-infected pregnant women in Nairobi were followed with their infants for 1 year postpartum. Among 131 infants, those with the 868T allele were more likely than wild-type infants to acquire HIV-1 overall [hazard ratio (HR) = 1.92, 95% confidence interval (CI) 1.05, 3.50, P = 0.03; adjusted HR = 2.03, 95% CI 1.03, 3.98, P = 0.04], after adjusting for maternal viral load. This SNP (an allele frequency of approximately 15% in our cohort) was associated with increased susceptibility to mother-to-child HIV-1 transmission, consistent with a previous study on this polymorphism among Nairobi sex workers.
Clinical & Experimental Immunology 06/2010; 160(3):461-5. · 3.36 Impact Factor
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C Celum,
A Wald,
J R Lingappa,
A S Magaret,
R S Wang,
N Mugo,
A Mujugira,
J M Baeten,
J I Mullins,
J P Hughes, [......],
W Stevens,
M S Campbell,
K K Thomas,
R W Coombs,
R Morrow,
W L H Whittington,
M J McElrath,
L Barnes,
R Ridzon,
L Corey
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ABSTRACT: Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1.
We conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, > or = 250 cells per cubic millimeter) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrollment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses.
A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimeter. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval [CI], 0.60 to 1.41; P=0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log(10) copies per milliliter (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2-positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed.
Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log(10) copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.)
New England Journal of Medicine 02/2010; 362(5):427-39. · 53.30 Impact Factor
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ABSTRACT: Prevention of infant HIV is a powerful incentive for maternal HIV diagnosis and an opportunity to increase male HIV testing and disclosure of HIV status within couples. We examined male HIV disclosure in couples who attended a Nairobi antenatal clinic (ANC), had individual HIV testing, and were counselled to disclose to their partner. At two-week follow-up, men and women independently reported HIV disclosure. Of 2104 women, 1993 requested partner attendance; 313 male partners came, of whom 183 chose individual HIV testing. Of 106 couples who followed up, 93% of both partners reported disclosure by women versus 71% by men (P < 0.0001); 27% of men reported disclosure while their female partner reported not knowing partner HIV status. In these couples, male ANC HIV testing did not result in shared knowledge of HIV status. Couple counselling models that incorporate disclosure may yield greater HIV prevention benefits than offering individual partner HIV testing services at ANC.
International Journal of STD & AIDS 11/2009; 20(11):765-7. · 1.09 Impact Factor
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ABSTRACT: The sensitivity and specificity of rapid HIV-1 tests may be altered during pregnancy and postpartum. We conducted a study to determine the prevalence and correlates of false-positive Abbott Determine and false-negative Uni-Gold rapid HIV-1 test results among antenatal and postnatal mothers attending a primary care clinic in Nairobi, Kenya. Mothers were tested for HIV-1 using Abbott Determine and non-reactive results were considered HIV-1 antibody negative. Reactive samples by Determine were re-tested by Uni-Gold. Vironostika HIV-1 and Uni-FORM II Enzyme-linked immunosorbent assays were used to confirm samples that had positive Abbott Determine and negative Uni-Gold. Among 2311 women who accepted HIV-1 testing, 1238 (54%) were tested antenatally and 1073 (46%) were tested postnatally. Of tested women, 274 (12%) women were reactive by Abbott Determine and on retesting with Uni-Gold 30 (11%) had indeterminate results. The prevalence of indeterminate results was significantly higher in antenatal women than in postnatal women (2% versus 1%, P = 0.03). In conclusion, indeterminate rapid HIV-1 test results are more common in the antenatal period and appropriate safeguards to confirm HIV-1 infection status should be implemented in antenatal programmes.
International Journal of STD & AIDS 11/2009; 20(11):790-2. · 1.09 Impact Factor
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ABSTRACT: Infants infected with HIV-1 after the first month of life have a lower viral set-point and slower disease progression than infants infected before 1 month. We investigated the kinetics of HIV-1-specific CD8(+) T lymphocyte secretion of interferon (IFN)-gamma in infants infected before 1 month of life compared with those infected between months 1 and 12 (late infection). HIV-1 infection was assessed at birth and at months 1, 3, 6, 9 and 12 and timing of infection was determined by HIV-1 gag DNA from dried blood spots and verified by plasma HIV-1 RNA levels. HIV-1 peptide-specific IFN-gamma responses were measured by enzyme-linked immunospot at months 1, 3, 6, 9 and 12. Timing of development of IFN-gamma responses was compared using the log-rank test and Kaplan-Meier survival curves. Infants infected late developed HIV-1-specific CD8(+) T cell responses 2.8 months sooner than infants infected peripartum: 2.3 versus 5.1 months after HIV-1 infection (n = 52, P = 0.04). Late-infected infants had more focused epitope recognition than early-infected infants (median 1 versus 2 peptides, P = 0.03); however, there were no differences in the strength of IFN-gamma responses. In infants infected with HIV-1 after the first month of life, emergence of HIV-1-specific CD8(+) IFN-gamma responses is coincident with the decline in viral load, nearly identical to what is observed in adults and more rapid than in early-infected infants.
Clinical & Experimental Immunology 07/2009; 156(3):511-7. · 3.36 Impact Factor
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ABSTRACT: Humoral immunity, and specifically immunoglobulin A (IgA) that is directed against human immunodeficiency virus (HIV)-1, may contribute to protection against HIV-1 acquisition at mucosal surfaces. HIV-1-specific IgA has been detected in genital tract secretions of HIV-1-uninfected commercial sex workers with HIV-1 exposure, and may be produced in parotid saliva by infants exposed orally to HIV-1 during delivery and breastfeeding. To explore this hypothesis, we collected saliva from 145 infants aged < or = 6 months enrolled in a perinatal HIV-1 transmission study in Nairobi and from 55 control infants without HIV-1 exposure who were born to HIV-1-seronegative mothers. Among the 145 infants, 115 (79%) remained uninfected during the 12-month study period and 30 (21%) became HIV-1-infected during follow-up. Nine (8%) of the 115 HIV-1-exposed, uninfected infants had detectable levels of HIV-1 gp160-specific IgA compared with four (13%) of 30 infected infants and none of 55 control infants (P = 0.47 and P = 0.03 respectively). Among the nine HIV-1-exposed, uninfected infants with positive assays, median age was 1 month and none acquired HIV-1 during follow-up. We conclude that HIV-1-specific salivary IgA responses may be generated by very young infants exposed perinatally to maternal HIV-1. Mucosal responses would be an appropriate target for paediatric vaccines against breast milk HIV-1 transmission.
Clinical & Experimental Immunology 07/2008; 153(1):37-43. · 3.36 Impact Factor
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ABSTRACT: To identify potential predictors of mortality, to determine mortality rate and to identify prevalent causes of death in a cohort of HIV-1 exposed uninfected infants.
Prospective cohort study.
Kenyatta National Hospital, Nairobi, Kenya.
Three hundred and fifty one HIV-1 exposed uninfected post-neonatal infants who survived to one year of age.
Sixteen infants died (post-neonatal mortality rate of 47/1000 live births), 14 (88%) before six months of age. The most frequently identified medical conditions at death included bronchopneumonia, diarrhoea and failure to thrive. In multivariate analysis, prematurity (RR=10.5, 95%CI 3.8-29.1, p<0.001), teenage motherhood (RR=3.6, Cl 1.0-13.2, p=0.05) and symptomatic maternal HIV-1 disease (RR=2.7, CI 0.9-7.7, p=0.06) were associated with infant mortality.
Prematurity, teenage motherhood and symptomatic HIV-1 maternal disease were important predictors for post-neonatal mortality in this cohort of HIV-1 exposed uninfected infants. These factors should be considered in monitoring and follow up in prevention of mother-to-child HIV-1 transmission (PMTCT) programs.
East African medical journal 10/2005; 82(9):447-51.
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Clinical & Experimental Immunology 01/2004; 134(3):367-77. · 3.36 Impact Factor
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AIDS 05/2001; 15(6):815-7. · 6.24 Impact Factor
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JR Lingappa,
JP Hughes,
D Donnel,
JM Baeten,
JI Mullins,
MS Campbell,
GE Gray, C Farquhar,
H Rees,
A Wald,
L Corey,
C Celum,
Myron Elmer Essex
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ABSTRACT: Background: Non-sterilizing HIV-1 vaccines may provide public health benefits if they significantly reduce plasma HIV-1 RNA, thus potentially reducing infectiousness. Quantification of reduction in plasma HIV-1 RNA needed to decrease HIV-1 transmission is useful for design of efficacy trials of candidate HIV-1 vaccines. We modeled the relationship between plasma HIV-1 RNA and HIV-1 transmission using data from a prospective study of African heterosexual HIV-1 serodiscordant couples. Methods: 3408 HIV-1-infected participants with CD4 counts ≥250 cells/mm3 enrolled in the Partners in Prevention HSV/HIV Transmission Study and their partners were followed for ≤24 months. HIV-1 transmission events were assessed for viral genetic linkage within the enrolled partnership by determining HIV-1 env and gag sequences from partners. The relationship between plasma HIV-1 RNA over time and risk of genetically linked HIV-1 transmission was evaluated with a Cox model with a natural cubic spline. Results: 84 post-enrollment linked HIV-1 transmissions were observed. HIV-1 incidence increased rapidly and non-linearly with higher plasma HIV-1: from 0.53 transmissions per 100 person-years for plasma HIV-1 RNA <10,000 copies/mL to 6.2 for HIV-1 RNA >1,000,000 copies/mL (p<0.0001). Baseline HIV-1 RNA in men was, on average, 0.4 log10 higher than in women; no significant difference in risk of transmission for a given HIV-1 level was observed between men and women (p = 0.17). Given the distribution of plasma HIV-1 RNA in this population of stable cohabiting couples, our modeling predicts that a 0.74 log10 reduction in average plasma HIV-1 RNA in the population would be required for a 50% reduction in HIV-1 transmission risk. Conclusion: This analysis provides a detailed description of the relationship between plasma HIV-1 RNA and risk of heterosexual HIV-1 transmission. These findings suggest targets for reduction in HIV-1 RNA for use in evaluating non-sterilizing HIV-1 vaccine candidates in HIV-1 infected persons to reduce risk of heterosexual HIV-1 transmission.
