PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-16 (16)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
Document Types
1.  Hormonal Contraceptive Use Among HIV-Positive Women and HIV Transmission Risk to Male Partners, Zambia, 1994–2012 
The Journal of Infectious Diseases  2016;214(7):1063-1071.
Background. Evidence on the association between female-to-male human immunodeficiency virus (HIV) transmission risk and hormonal contraception is sparse and conflicting.
Methods. Heterosexual HIV-discordant couples from Lusaka, Zambia, were followed longitudinally at 3 month-intervals from 1994 to 2012. The impact of hormonal contraception on time to HIV transmission from HIV-positive women to their HIV-negative male partners (M−F+) was evaluated.
Results. Among 1601 M−F+ couples, 171 genetically linked HIV transmissions occurred in men over 3216 couple-years (5.3 transmissions/100 couple-years; 95% confidence interval [CI], 4.5–6.2). In multivariable Cox models, neither injectable (adjusted hazard ratio [aHR], 0.6; 95% CI, .4–1.2), oral contraceptive pill (aHR, 0.8; 95% CI, .3–2.1), nor implant (aHR, 0.8; 95% CI, .5–1.4) use was associated with HIV transmission, relative to nonhormonal methods, after controlling for the man's age at baseline and time-varying measures of pregnancy, self-reported unprotected sex with the study partner, sperm present on a vaginal swab wet mount, genital inflammation of either partner, genital ulceration of the man, and first follow-up interval. Sensitivity analyses, including marginal structural modeling and controlling for viral load and fertility intentions available in a subset of couples, led to similar conclusions.
Conclusions. Our findings suggest null associations between hormonal contraception and risk of female-to-male HIV transmission. We support efforts to increase the contraceptive method mix for all women, regardless of HIV serostatus, along with reinforced condom counseling for HIV-serodiscordant couples.
doi:10.1093/infdis/jiw322
PMCID: PMC5021237  PMID: 27462093
HIV discordant couples; HIV risk; hormonal contraception; longitudinal cohort; Zambia
2.  Hormonal contraception does not increase women's HIV acquisition risk in Zambian discordant couples, 1994–2012 
Contraception  2015;91(6):480-487.
Objective
To determine the impact of hormonal contraceptive methods on risk of HIV acquisition among HIV-negative women cohabiting with HIV-positive male partners.
Study design
From 1994–2012, HIV discordant couples recruited from a couples’ voluntary HIV counseling and testing center in Lusaka, Zambia were followed longitudinally. HIV-negative partners were tested quarterly. This analysis is restricted to couples in which the man was HIV-positive and the woman was HIV-negative at enrollment and the man was not on antiretroviral treatment. Multivariate Cox models evaluated associations between time-varying contraceptive methods and HIV acquisition among women. Sensitivity analyses explored exposure misclassification and time-varying confounder mediation.
Results
Among 1393 couples, 252 incident infections occurred in women over 2842 couple-years (8.9 infections per 100 couple-years; 95% CI, 7.8–10.0). Multivariate Cox models indicated that neither injectable [adjusted hazard ratio (aHR)=1.2; 95% CI, 0.8–1.7], oral contraceptive pill (OCP, aHR=1.3; 95% CI, 0.9–1.8), or implant (aHR=1.1; 95% CI, 0.5–2.2) use was significantly associated with HIV acquisition relative to non-hormonal contraception controlling for woman's age, literacy and time-varying measures of genital ulceration/inflammation. This remained true when only looking at the subset of infections acquired from the spouse (82% of infections) and additionally controlling for baseline HIV viral load of the male partner, pregnancy status, and time-varying measures of sperm on a vaginal swab wet prep and self-reported unprotected sex. OCP and injectable users reported more unprotected sex (p<.001), and OCP users were more likely to have sperm on vaginal swab (p=.1) than nonhormonal method users.
Conclusions
We found no association between hormonal contraception and HIV acquisition risk in women. Condom use and reinforced condom counseling should always be recommended for HIV discordant couples. HIV testing of sex partners together is critical to establish HIV risk, ascertain couple fertility intentions and counsel appropriately.
Implications
These findings add to a controversial literature and uniquely address several common design and analytic challenges faced by previous studies. After controlling for confounders, we found no association between hormonal contraception and HIV acquisition risk in women. We support promoting condoms for HIV prevention and increasing the contraceptive method mix to decrease unintended pregnancy.
doi:10.1016/j.contraception.2015.02.004
PMCID: PMC4442041  PMID: 25708502
Discordant couples; HIV risk; Hormonal contraception; Longitudinal cohort; Women; Zambia
3.  Hormonal Contraception, Pregnancy, Breastfeeding, and Risk of HIV Disease Progression Among Zambian Women 
Background:
Some studies suggest that hormonal contraception, pregnancy, and/or breastfeeding may influence rates of HIV disease progression.
Methods:
From 1994 to 2012, HIV discordant couples recruited at couples' voluntary HIV counseling and testing centers in Lusaka were followed 3-monthly. Multivariate survival analyses explored associations between time-varying contraception, pregnancy, and breastfeeding and 2 outcomes among HIV-positive women: (1) time to death and (2) time to antiretroviral treatment (ART) initiation.
Results:
Among 1656 female seropositive, male seronegative couples followed for 3359 person-years (PY), 224 women died [6.7/100 PY; 95% confidence interval (CI): 5.8 to 7.6]. After 2003, 290 women initiated ART (14.5/100 PY; 95% CI: 12.9 to 16.2). In a multivariate model of time to death, hormonal implant [adjusted hazard ratio (aHR) = 0.30; 95% CI: 0.10 to 0.98] and injectable (aHR = 0.59; 95% CI: 0.36 to 0.97) were significantly protective relative to nonhormonal method use, whereas oral contraceptive pill (OCP) use was not (aHR = 1.08; 95% CI: 0.74 to 1.57) controlling for baseline HIV disease stage, time-varying pregnancy, time-varying breastfeeding, and year of enrollment. In a multivariate model of time-to-ART initiation, implant was significantly protective (aHR = 0.54; 95% CI: 0.31 to 0.95), whereas OCP (aHR = 0.70; 95% CI: 0.44 to 1.10) and injectable (aHR = 0.85; 95% CI: 0.55 to 1.32) were not relative to nonhormonal method use controlling for variables above, woman's age, and literacy. Pregnancy was not significantly associated with death (aHR = 1.07; 95% CI: 0.68 to 1.66) or ART initiation (aHR = 1.24; 95% CI: 0.83 to 1.86), whereas breastfeeding was protective for death (aHR = 0.34; 95% CI: 0.19 to 0.62) and ART initiation (aHR = 0.49; 95% CI: 0.29 to 0.85).
Conclusions:
Hormonal implants and injectables significantly predicted lower mortality; implants were protective for ART initiation. OCPs and pregnancy were not associated with death or ART initiation, whereas breastfeeding was protective for both. Findings from this 18-year cohort study suggest that (1) HIV-positive women desiring pregnancy can be counseled to do so and breastfeed and (2) all effective contraceptive methods, including injectables and implants, should be promoted to prevent unintended pregnancy.
doi:10.1097/QAI.0000000000000848
PMCID: PMC4752415  PMID: 26379070
breastfeeding; HIV disease progression; hormonal contraception; longitudinal cohort; pregnancy; Zambia
4.  Family history of hematologic malignancies and risk of multiple myeloma: differences by race and clinical features 
Cancer Causes & Control  2015;27:81-91.
Purpose
Multiple myeloma (MM) is the most common hematologic malignancy affecting Blacks in the USA, with standardized incidence rates that are twofold to threefold higher than Whites. The rationale for the disparity is unclear.
Methods
Using participants enrolled in the Molecular And Genetic Epidemiology study of myeloma (259 MM cases; 461 controls), we examined the risk of MM associated with family history of cancer, differences by race and among cases, defining clinical features. Risk estimates were calculated using odds ratios and corresponding 95% confidence intervals from logistic regression adjusted for confounders.
Results
Overall, MM risk in cases with relatives affected with any hematologic malignancy was significantly elevated compared to controls (OR 1.89, 95% CI 1.25–2.86). Myeloma risk associated with a family history of MM was higher than the risk associated with any hematologic malignancy (OR 3.75, 95% CI 1.75–8.05), and the effect was greater for Blacks (OR 20.9, 95% CI 2.59–168) than Whites (OR 2.04, 95% 0.83–5.04), among cases with early onset (≤60 years; OR 4.58, 95% CI 1.21–17.3) and with increasing numbers of affected relatives (p trend = 0.001). Overall, frequencies of end organ damage differed in cases with relatives affected with any hematologic malignancy and significantly more cases exhibited κ light chain restriction (OR 3.23, 95% CI 1.13–9.26).
Conclusions
The excess risk of MM observed in Blacks and the variation in clinical features observed in MM patients according to family history of hematologic malignancy may be attributed to a shared germline and environmental susceptibility.
Electronic supplementary material
The online version of this article (doi:10.1007/s10552-015-0685-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s10552-015-0685-2
PMCID: PMC4703620  PMID: 26596855
Multiple myeloma; Family history; Genetic; Black; African American
5.  Immunogenetic influences on acquisition of HIV-1 infection: Consensus findings from two African cohorts point to an enhancer element in IL19 (1q32.2) 
Genes and immunity  2015;16(3):213-220.
Numerous reports have suggested that immunogenetic factors may influence HIV-1 acquisition, yet replicated findings that translate between study cohorts remain elusive. Our work aimed to test several hypotheses about genetic variants within the IL10-IL24 gene cluster that encodes interleukin (IL)-10, IL-19, IL-20, and IL-24. In aggregated data from 515 Rwandans and 762 Zambians with up to 12 years of follow-up, 190 single nucleotide polymorphisms (SNPs) passed quality control procedures. When HIV-1-exposed seronegative subjects (n = 486) were compared with newly seroconverted individuals (n = 313) and seroprevalent subjects (n = 478) who were already infected at enrollment, rs12407485 (G>A) in IL19 showed a robust association signal in adjusted logistic regression models (odds ratio = 0.64, P = 1.7 × 10−4, and q = 0.033). Sensitivity analyses demonstrated that (i) results from both cohorts and subgroups within each cohort were highly consistent; (ii) verification of HIV-1 infection status after enrollment was critical; and (iii) supporting evidence was readily obtained from Cox proportional hazards models. Data from public databases indicate that rs12407485 is part of an enhancer element for three transcription factors. Overall, these findings suggest that molecular features at the IL19 locus may modestly alter the establishment of HIV-1 infection.
doi:10.1038/gene.2014.84
PMCID: PMC4409473  PMID: 25633979
Africa; HIV-1 infection; IL19; SNP; association; validation
6.  Creating an African HIV Clinical Research and Prevention Trials Network: HIV Prevalence, Incidence and Transmission 
PLoS ONE  2015;10(1):e0116100.
HIV epidemiology informs prevention trial design and program planning. Nine clinical research centers (CRC) in sub-Saharan Africa conducted HIV observational epidemiology studies in populations at risk for HIV infection as part of an HIV prevention and vaccine trial network. Annual HIV incidence ranged from below 2% to above 10% and varied by CRC and risk group, with rates above 5% observed in Zambian men in an HIV-discordant relationship, Ugandan men from Lake Victoria fishing communities, men who have sex with men, and several cohorts of women. HIV incidence tended to fall after the first three months in the study and over calendar time. Among suspected transmission pairs, 28% of HIV infections were not from the reported partner. Volunteers with high incidence were successfully identified and enrolled into large scale cohort studies. Over a quarter of new cases in couples acquired infection from persons other than the suspected transmitting partner.
doi:10.1371/journal.pone.0116100
PMCID: PMC4300215  PMID: 25602351
7.  Contraceptive discontinuation and switching among couples receiving integrated HIV and family planning services in Lusaka, Zambia 
AIDS (London, England)  2013;27(0 1):S93-103.
Objective
To describe predictors of contraceptive method discontinuation and switching behaviors among HIV positive couples receiving couples' voluntary HIV counseling and testing services in Lusaka, Zambia.
Design
Couples were randomized in a factorial design to two family planning educational intervention videos, received comprehensive family planning services, and were assessed every 3-months for contraceptive initiation, discontinuation and switching.
Methods
We modeled factors associated with contraceptive method upgrading and downgrading via multivariate Andersen-Gill models.
Results
Most women continued the initial method selected after randomization. The highest rates of discontinuation/switching were observed for injectable contraceptive and intrauterine device users. Time to discontinuing the more effective contraceptive methods or downgrading to oral contraceptives or condoms was associated with the women's younger age, desire for more children within the next year, heavy menstrual bleeding, bleeding between periods, and cystitis/dysuria. Health concerns among women about contraceptive implants and male partners not wanting more children were associated with upgrading from oral contraceptives or condoms. HIV status of the woman or the couple was not predictive of switching or stopping.
Conclusions
We found complicated patterns of contraceptive use. The predictors of contraception switching indicate that interventions targeted to younger couples that address common contraception-related misconceptions could improve effective family planning utilization. We recommend these findings be used to increase the uptake and continuation of contraception, especially long acting reversible contraceptive (LARC) methods, and that fertility-goal based, LARC-focused family planning be offered as an integral part of HIV prevention services.
doi:10.1097/QAD.0000000000000039
PMCID: PMC4070372  PMID: 24088689
Contraceptive discontinuation; couples' voluntary HIV counseling and testing; family planning; long-acting reversible contraception; Zambia
8.  Impact of long-term contraceptive promotion on incident pregnancy: a randomized controlled trial among HIV positive couples in Lusaka, Zambia 
Objectives
To evaluate the impact of family planning promotion on incident pregnancy in a combined effort to address Prongs 1 and 2 of Prevention of Mother-to-Child Transmission of HIV.
Design
We conducted a factorial randomized controlled trial of two video-based interventions.
Methods
“Methods-focused” and “Motivational” messages promoted long-term contraceptive use among 1060 couples with HIV in Lusaka, Zambia.
Results
Among couples not using contraception prior to randomization (N=782), the video interventions had no impact on incident pregnancy. Among baseline contraceptive users, viewing the “Methods” video which focused on the IUD and contraceptive implant was associated with a significantly lower pregnancy incidence (HR=0.38; 95%CI:0.19–0.75) relative to those viewing control and/or motivational videos. The effect was strongest in concordant positive couples (HR=0.22; 95%CI:0.08–0.58) and couples with HIV+ women (HR=0.23; 95%CI:0.09–0.55).
Conclusions
The “Methods video” intervention was previously shown to increase uptake of longer-acting contraception and to prompt a shift from daily oral contraceptives to quarterly injectables and long-acting methods such as the IUD and implant. Follow-up confirms sustained intervention impact on pregnancy incidence among baseline contraceptive users, in particular couples with HIV positive women. Further work is needed to identify effective interventions to promote long-acting contraception among couples who have not yet adopted modern methods.
doi:10.1097/QAI.0b013e31827ee19c
PMCID: PMC3625483  PMID: 23202814
Couples’ voluntary HIV counseling and testing; family planning; long-term contraception; randomized controlled trial; Zambia
9.  Unintended Pregnancy among HIV Positive Couples Receiving Integrated HIV Counseling, Testing, and Family Planning Services in Zambia 
PLoS ONE  2013;8(9):e75353.
Objective
We describe rates of unintended pregnancy among HIV positive couples in Lusaka, Zambia. We also identify factors associated with unintended pregnancy among oral contraceptive pill (OCP) using couples in this cohort.
Design
Data were analyzed from couples randomized in a factorial design to two family planning intervention videos.
Methods
Rates of unintended pregnancy were stratified by contraceptive method used at time of pregnancy. Predictors of time to unintended pregnancy among OCP users were determined via multivariate Cox modeling.
Results
The highest rates of unintended pregnancy were observed among couples requesting condoms only (26.4/100CY) or OCPs (20.7/100CY); these rates were not significantly different. OCP users accounted for 37% of the couple-years (CY) observed and 87% of unintended pregnancies. Rates of unintended pregnancy for injectable (0.7/100CY) and intrauterine device (1.6/100CY) users were significantly lower relative to condom only users. No pregnancies occurred among contraceptive implant users or after tubal ligation. Factors associated (p<0.05) with time to unintended pregnancy among OCP users in multivariate analysis included the man wanting more children, the woman being HIV negative versus having stage IV HIV disease, and the woman reporting: younger age, no previous OCP use, missed OCPs, or sex without a condom.
Conclusions
Long-acting reversible contraceptive methods were effective in the context of integrated couples HIV prevention and contraceptive services. Injectable methods were also effective in this context. Given the high user failure rate of OCPs, family planning efforts should promote longer-acting methods among OCP users wishing to avoid pregnancy. Where other methods are not available or acceptable, OCP adherence counseling is needed, especially among younger and new OCP users.
Trial registration
ClinicalTrials.gov NCT00067522
doi:10.1371/journal.pone.0075353
PMCID: PMC3787093  PMID: 24098692
10.  Genetic Variations and Heterosexual HIV-1 Infection: Analysis of Clustered Genes Encoding CC-motif Chemokine Ligands 
Genes and immunity  2011;13(2):202-205.
Several CC-motif chemokine ligands (CCLs) can block HIV-1 binding sites on CC-motif chemokine receptor 5 (CCR5) and inhibit viral entry. We studied single nucleotide polymorphisms (SNPs) in genes encoding three CCR5 ligands [CCL3 (MIP-1α), CCL4 (MIP-1β), and CCL5 (RANTES)] along with an adjacent gene encoding a CCR2 ligand [CCL2 (MCP-1)] to identify candidate markers for HIV-1 infection and pathogenesis. Analyses of 567 HIV-1 serodiscordant Zambian couples revealed that rs5029410C (in CCL3 intron 2) was associated with lower viral load (VL) in seroconverters, adjusted for gender and age (regression β=−0.57 log10, P=4×10−6). In addition, rs34171309A in CCL3 exon 3 was associated with increased risk of HIV-1 acquisition in exposed seronegatives (hazard ratio=1.52, P=0.006 when adjusted for donor VL and genital ulcer/inflammation). The CCL3 exon 3 SNP, encoding a conservative Glu-to-Asp substitution, and five neighboring SNPs in tight linkage disequilibrium all showed similar associations with HIV-1 acquisition. How these multiple CCL3 SNPs may alter the occurrence or course of HIV-1 infection remains to be determined.
doi:10.1038/gene.2011.70
PMCID: PMC3559129  PMID: 21975429
HIV-1 transmission; CCL2; CCL3; CCL4; CCL5; SNP
11.  Disparate Associations of HLA Class I Markers with HIV-1 Acquisition and Control of Viremia in an African Population 
PLoS ONE  2011;6(8):e23469.
Background
Acquisition of human immunodeficiency virus type 1 (HIV-1) infection is mediated by a combination of characteristics of the infectious and the susceptible member of a transmission pair, including human behavioral and genetic factors, as well as viral fitness and tropism. Here we report on the impact of established and potential new HLA class I determinants of heterosexual HIV-1 acquisition in the HIV-1-exposed seronegative (HESN) partners of serodiscordant Zambian couples.
Methodology/Principal Findings
We assessed the relationships of behavioral and clinically documented risk factors, index partner viral load, and host genetic markers to HIV-1 transmission among 568 cohabiting couples followed for at least nine months. We genotyped subjects for three classical HLA class I genes known to influence immune control of HIV-1 infection. From 1995 to December 2006, 240 HESNs seroconverted and 328 remained seronegative. In Cox proportional hazards models, HLA-A*68:02 and the B*42-C*17 haplotype in HESN partners were significantly and independently associated with faster HIV-1 acquisition (relative hazards = 1.57 and 1.55; p = 0.007 and 0.013, respectively) after controlling for other previously established contributing factors in the index partner (viral load and specific class I alleles), in the HESN partner (age, gender), or in the couple (behavioral and clinical risk score). Few if any previously implicated class I markers were associated here with the rate of acquiring infection.
Conclusions/Significance
A few HLA class I markers showed modest effects on acquisition of HIV-1 subtype C infection in HESN partners of discordant Zambian couples. However, the striking disparity between those few markers and the more numerous, different markers found to determine HIV-1 disease course makes it highly unlikely that, whatever the influence of class I variation on the rate of infection, the mechanism mediating that phenomenon is identical to that involved in disease control.
doi:10.1371/journal.pone.0023469
PMCID: PMC3157381  PMID: 21858133
12.  Association of chemokine receptor gene (CCR2-CCR5) haplotypes with acquisition and control of HIV-1 infection in Zambians 
Retrovirology  2011;8:22.
Background
Polymorphisms in chemokine (C-C motif) receptors 2 and 5 genes (CCR2 and CCR5) have been associated with HIV-1 infection and disease progression. We investigated the impact of CCR2-CCR5 haplotypes on HIV-1 viral load (VL) and heterosexual transmission in an African cohort. Between 1995 and 2006, cohabiting Zambian couples discordant for HIV-1 (index seropositive and HIV-1 exposed seronegative {HESN}) were monitored prospectively to determine the role of host genetic factors in HIV-1 control and heterosexual transmission. Genotyping for eight CCR2 and CCR5 variants resolved nine previously recognized haplotypes. By regression and survival analytic techniques, controlling for non-genetic factors, we estimated the effects of these haplotypic variants on a) index partner VL, b) seroconverter VL, c) HIV-1 transmission by index partners, d) HIV-1 acquisition by HESN partners.
Results
Among 567 couples, 240 virologically linked transmission events had occurred through 2006. HHF*2 homozygosity was associated with significantly lower VL in seroconverters (mean beta = -0.58, log10 P = 0.027) and the HHD/HHE diplotype was associated with significantly higher VL in the seroconverters (mean beta = 0.54, log10 P = 0.014) adjusted for age and gender in multivariable model. HHD/HHE was associated with more rapid acquisition of infection by the HESNs (HR = 2.0, 95% CI = 1.20-3.43, P = 0.008), after adjustments for index partner VL and the presence of genital ulcer or inflammation in either partner in Cox multivariable models. The HHD/HHE effect was stronger in exposed females (HR = 2.1, 95% CI = 1.14-3.95, P = 0.018).
Conclusions
Among Zambian discordant couples, HIV-1 coreceptor gene haplotypes and diplotypes appear to modulate HIV-1 VL in seroconverters and alter the rate of HIV-1 acquisition by HESNs. These associations replicate or resemble findings reported in other African and European populations.
doi:10.1186/1742-4690-8-22
PMCID: PMC3075214  PMID: 21429204
13.  Genotypes and haplotypes in the insulin-like growth factors, their receptors and binding proteins in relation to plasma metabolic levels and mammographic density 
Background
Increased mammographic density is one of the strongest independent risk factors for breast cancer. It is believed that one third of breast cancers are derived from breasts with more than 50% density. Mammographic density is affected by age, BMI, parity, and genetic predisposition. It is also greatly influenced by hormonal and growth factor changes in a woman's life cycle, spanning from puberty through adult to menopause. Genetic variations in genes coding for hormones and growth factors involved in development of the breast are therefore of great interest. The associations between genetic polymorphisms in genes from the IGF pathway on mammographic density and circulating levels of IGF1, its binding protein IGFBP3, and their ratio in postmenopausal women are reported here.
Methods
Samples from 964 postmenopausal Norwegian women aged 55-71 years were collected as a part of the Tromsø Mammography and Breast Cancer Study. All samples were genotyped for 25 SNPs in IGF1, IGF2, IGF1R, IGF2R, IGFALS and IGFBP3 using Taqman (ABI). The main statistical analyses were conducted with the PROC HAPLOTYPE procedure within SAS/GENETICS™ (SAS 9.1.3).
Results
The haplotype analysis revealed six haploblocks within the studied genes. Of those, four had significant associations with circulating levels of IGF1 or IGFBP3 and/or mammographic density. One haplotype variant in the IGF1 gene was found to be associated with mammographic density. Within the IGF2 gene one haplotype variant was associated with levels of both IGF1 and IGFBP3. Two haplotype variants in the IGF2R were associated with the level of IGF1. Both variants of the IGFBP3 haplotype were associated with the IGFBP3 level and indicate regulation in cis.
Conclusion
Polymorphisms within the IGF1 gene and related genes were associated with plasma levels of IGF1, IGFBP3 and mammographic density in this study of postmenopausal women.
doi:10.1186/1755-8794-3-9
PMCID: PMC2853484  PMID: 20302654
14.  Human Leukocyte Antigens and HIV Type 1 Viral Load in Early and Chronic Infection: Predominance of Evolving Relationships 
PLoS ONE  2010;5(3):e9629.
Background
During untreated, chronic HIV-1 infection, plasma viral load (VL) is a relatively stable quantitative trait that has clinical and epidemiological implications. Immunogenetic research has established various human genetic factors, especially human leukocyte antigen (HLA) variants, as independent determinants of VL set-point.
Methodology/Principal Findings
To identify and clarify HLA alleles that are associated with either transient or durable immune control of HIV-1 infection, we evaluated the relationships of HLA class I and class II alleles with VL among 563 seroprevalent Zambians (SPs) who were seropositive at enrollment and 221 seroconverters (SCs) who became seropositive during quarterly follow-up visits. After statistical adjustments for non-genetic factors (sex and age), two unfavorable alleles (A*3601 and DRB1*0102) were independently associated with high VL in SPs (p<0.01) but not in SCs. In contrast, favorable HLA variants, mainly A*74, B*13, B*57 (or Cw*18), and one HLA-A and HLA-C combination (A*30+Cw*03), dominated in SCs; their independent associations with low VL were reflected in regression beta estimates that ranged from −0.47±0.23 to −0.92±0.32 log10 in SCs (p<0.05). Except for Cw*18, all favorable variants had diminishing or vanishing association with VL in SPs (p≤0.86).
Conclusions/Significance
Overall, each of the three HLA class I genes had at least one allele that might contribute to effective immune control, especially during the early course of HIV-1 infection. These observations can provide a useful framework for ongoing analyses of viral mutations induced by protective immune responses.
doi:10.1371/journal.pone.0009629
PMCID: PMC2835758  PMID: 20224785
15.  Human Leukocyte Antigen Class I Genotypes in Relation to Heterosexual HIV Type 1 Transmission within Discordant Couples1 
Differences in immune control of HIV-1 infection are often attributable to the highly variable HLA class I molecules that present viral epitopes to cytotoxic T-lymphocytes. In our immunogenetic analyses of 429 HIV-1 discordant Zambian couples (infected index partners paired with cohabiting seronegative partners), several HLA class I variants in index partners were associated with contrasting rates and incidence of HIV-1 transmission within a 12-year study period. In particular, A*3601 on the A*36-Cw*04-B*53 haplotype was the most unfavorable marker of HIV-1 transmission by index partners, while Cw*1801 (primarily on the A*30-Cw*18-B*57 haplotype) was the most favorable, irrespective of the direction of transmission (male to female or female to male) and other commonly recognized co-factors of infection, including age and genital ulcer/inflammation. The same HLA markers were further associated with contrasting viral load levels in index partners, but they had no clear impact on HIV-1 acquisition by the seronegative partners. Thus, HLA class I gene products not only mediate HIV-1 pathogenesis and evolution but also influence heterosexual HIV-1 transmission. {This is an author-produced version of a manuscript accepted for publication in The Journal of Immunology (The JI). The American Association of Immunologists, Inc. (AAI), publishers of The JI, holds the copyright to this manuscript. This manuscript has not been copyedited or subjected to editorial proofreading by The JI; hence it may differ from the final version published in The JI (online and in print). AAI (The JI) is not liable for errors or omissions in this author-produced version of the manuscript or in any version derived from it by the United States National Institutes of Health or any other third party. The final, citable version of record can be found at www.jimmunol.org}.
PMCID: PMC2570252  PMID: 18684953
AIDS; Comparative Immunology; Human; MHC
16.  Modified Kigali Combined Staging Predicts Risk of Mortality in HIV-Infected Adults in Lusaka, Zambia 
Abstract
We assessed the utility of the modified Kigali combined (MKC) staging system for predicting survival in HIV-infected Zambian adults in a prospective, longitudinal, open cohort. From 1995 to 2004, HIV-discordant couples (one HIV-infected partner and one HIV-negative partner) were recruited from couples' voluntary counseling and testing centers in Lusaka, Zambia and followed at 3-month intervals. MKC stage, which incorporates clinical stage with erythrocyte sedimentation rate (ESR), hematocrit, and body mass index (BMI), was determined at enrollment. Kaplan–Meier survival and Cox proportional hazard methods were used to calculate median survival and relative hazards. We enrolled 1479 HIV-discordant couples with a combined 7305 person-years of follow-up. Among HIV-infected participants over the 9-year study period, there were 333 confirmed deaths. The time to 50% mortality was 8.5 years with MKC stage 1 and 2 disease compared to 3.7 years with MKC stage 4 disease at enrollment. Survival rates at 3 years were 85% with MKC stage 1 and 2 disease, 74% with MKC stage 3 disease, and 51% with MKC stage 4 disease. A total of 275 HIV-negative partners seroconverted during follow-up. In comparison, survival rates at 3 years were 94% for HIV-negative participants and 92% for participants who seroconverted during follow-up. In multivariate analysis, MKC stage 4 disease (HR = 3.7, 95% CI = 2.7–5.0) remained a strong predictor of mortality. Incorporating ESR, hematocrit, and BMI with clinical staging is a powerful, low-cost tool to identify HIV-infected adults at high risk for mortality.
doi:10.1089/aid.2007.0297
PMCID: PMC2928550  PMID: 18593343

Results 1-16 (16)