Publications by authors named "William Kilembe"

87 Publications

Elevated levels of inflammatory plasma biomarkers are associated with risk of HIV infection.

Retrovirology 2021 03 17;18(1). Epub 2021 Mar 17.

Emory Vaccine Center at Yerkes National Primate Research Center, Atlanta, GA, USA.

Background: To determine if individuals, from HIV-1 serodiscordant couple cohorts from Rwanda and Zambia, who become HIV-positive have a distinct inflammatory biomarker profile compared to individuals who remain HIV-negative, we compared levels of biomarkers in plasma of HIV-negative individuals who either seroconverted (pre-infection) and became HIV-positive or remained HIV-negative (uninfected).

Results: We observed that individuals in the combined cohort, as well as those in the individual country cohorts, who later became HIV-1 infected had significantly higher baseline levels of multiple inflammatory cytokines/chemokines compared to individuals who remained HIV-negative. Genital inflammation/ulceration or schistosome infections were not associated with this elevated profile. Defined levels of ITAC and IL-7 were significant predictors of later HIV acquisition in ROC predictive analyses, whereas the classical Th1 and Th2 inflammatory cytokines such as IL-12 and interferon-γ or IL-4, IL-5 and Il-13 were not.

Conclusions: Overall, the data show a significant association between increased plasma biomarkers linked to inflammation and immune activation and HIV acquisition and suggests that pre-existing conditions that increase systemic biomarkers represent a factor for increased risk of HIV infection.
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http://dx.doi.org/10.1186/s12977-021-00552-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968240PMC
March 2021

HLA-associated preadaptation in HIV Vif is associated with higher set point viral load and faster CD4+ decline in Zambian transmission pairs.

AIDS 2021 07;35(8):1157-1165

Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia.

Objective S: We investigated the relationship between human leukocyte antigen (HLA)-associated preadaptation for the entire subtype C HIV-1 proteome of the transmitted founder virus and subsequent HIV-1 disease progression in a cohort of heterosexual linked transmission pairs in Zambia.

Design: An adaptation model was used to calculate an adaptation score for each virus-HLA combination in order to quantify the degree of preadaptation of the transmitted virus to the linked recipient's HLA alleles. These scores were then assessed for their relationship to viral load and longitudinal CD4+ decline in the recipient.

Methods: Viral RNA was extracted from the plasma of the donor partner and the linked recipient near the time of transmission, as well as longitudinally from the linked recipient. Viral adaptation scores were calculated for each individual and each protein in the subtype C HIV-1 proteome.

Results: The majority of HLA-associated sites were located in Gag, Pol and Nef; however, proportional to protein length, the accessory and regulatory proteins contained a relatively high proportion of HLA-associated sites. Over the course of infection, HLA-mediated immune adaptation increased for all proteins except Vpu and gp120. Preadaptation was positively associated with higher early set point viral load and faster CD4+ decline. When examined by protein, preadaptation in Pol and Vif were statistically significantly associated with these markers of disease progression.

Conclusion: Adaptation in Pol had the greatest impact on viral control. Despite containing a large proportion of HLA-associated sites, Vif was the only regulatory or accessory protein for which preadaptation significantly correlated with disease progression.
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http://dx.doi.org/10.1097/QAD.0000000000002868DOI Listing
July 2021

A Stronger Innate Immune Response During Hyperacute HIV-1 Infection is associated with ACUTE retroviral syndrome.

Clin Infect Dis 2021 Feb 15. Epub 2021 Feb 15.

KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya.

Background: Acute retroviral syndrome (ARS) is associated with HIV-1 subtype and disease progression, but the underlying immunopathological pathways are poorly understood. We aimed to elucidate associations between innate immune responses during hyperacute HIV-1 infection (hAHI) and ARS.

Methods: Plasma samples obtained from volunteers (≥18.0 years) before and during hAHI, defined as HIV-1 antibody negative and RNA or p24 antigen positive from Kenya, Rwanda, Uganda, Zambia and Sweden were analysed. Forty soluble innate immune markers were measured using multiplexed assays. Immune responses were differentiated into volunteers with stronger and comparatively weaker responses using principal component analysis. Presence or absence of ARS was defined based on eleven symptoms using latent class analysis. Logistic regression was used to determine associations between immune responses and ARS.

Results: Of 55 volunteers, 31 (56%) had ARS. Volunteers with stronger immune responses (n=36 [65%]) had increased odds of ARS which was independent of HIV-1 subtype, age, and risk group (adjusted odds ratio, 7.1 [95% CI: 1.7-28.8], p=0.003). IP-10 was fourteen-fold higher during hAHI, elevated in seven of the eleven symptoms, and independently associated with ARS. IP-10 threshold >466.0 pg/mL differentiated stronger immune responses with a sensitivity of 84.2% (95% CI: 60.4-96.6) and specificity of 100.0% (95% CI: 90.3-100.0).

Conclusions: A stronger innate immune response during hAHI was associated with ARS. Plasma IP-10 may be a candidate biomarker of stronger innate immunity. Our findings provide further insights on innate immune responses in regulating ARS and may inform the design of vaccine candidates harnessing innate immunity.
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http://dx.doi.org/10.1093/cid/ciab139DOI Listing
February 2021

Comprehensive epitope mapping using polyclonally expanded human CD8 T cells and a two-step ELISpot assay for testing large peptide libraries.

J Immunol Methods 2021 Apr 30;491:112970. Epub 2021 Jan 30.

Zambia Emory HIV Research Project, B22/737 Mwembelelo, Emmasdale, Lusaka, Zambia; Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road NE, Atlanta, GA 30329, USA. Electronic address:

The genetic diversity of circulating HIV-1 strains poses a major barrier to the design, development and evaluation of HIV-1 vaccines. The assessment of both vaccine- and natural infection-elicited T cell responses is commonly done with multivalent peptides that are designed to maximally capture the diversity of potential T cell epitopes (PTEs) observed in natural circulating sequences. However, depending on the sequence diversity of viral subtypes and number of the HIV immunogens under investigation, PTE estimates, including HLA-guided computational methods, can easily generate enormous peptide libraries. Evaluation of T cell epitope specificity using such extensive peptide libraries is usually limited by sample availability, even for high-throughput and robust epitope mapping techniques like ELISpot assays. Here we describe a novel, two-step protocol for in-vitro polyclonal expansion of CD8 T cells from a single vial of frozen PBMC, which facilitated the screening 441 HIV-1 Gag peptides for immune responses among 32 HIV-1 positive subjects and 40 HIV-1 negative subjects for peptide qualification. Using a pooled-peptide mapping strategy, epitopes were mapped in two sequential ELISpot assays; the first ELISpot screened 33 large peptide pools using CD8 T cells expanded for 7 days, while the second step tested pool-matrix peptides to identify individual peptides using CD8 T cells expanded for 10 days. This comprehensive epitope screening established the breadth and magnitude of HIV-1 Gag-specific CD8 T cells and further revealed the extent of immune responses to variable/polymorphic epitopes.
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http://dx.doi.org/10.1016/j.jim.2021.112970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008507PMC
April 2021

Loss to follow-up among female sex workers in Zambia: findings from a five-year HIV-incidence cohort.

Afr J AIDS Res 2020 Dec;19(4):296-303

Rwanda Zambia HIV Research Group, Emory University, School of Medicine, Atlanta, USA.

HIV-incidence studies are used to identify at-risk populations for HIV-prevention trials and interventions, but loss to follow-up (LTFU) can bias results if participants who remain differ from those who drop out. We investigated the incidence of and factors associated with LTFU among Zambian female sex workers (FSWs) in an HIV-incidence cohort from 2012 to 2017. Enrolled participants returned at month one, month three and quarterly thereafter. FSWs were considered LTFU if they missed six consecutive months, or if their last visit was six months before the study end date. Of 420 FSWs, 139 (33%) were LTFU at a rate of 15.7 per 100 person years. In multivariable analysis, LTFU was greater for FSWs who never used alcohol, began sex work above the age of consent, and had a lower volume of new clients. Our study appeared to retain FSWs in most need of HIV-prevention services offered at follow-up.
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http://dx.doi.org/10.2989/16085906.2020.1836005DOI Listing
December 2020

Cost-effectiveness of integrated HIV prevention and family planning services for Zambian couples.

AIDS 2020 09;34(11):1633-1642

Rwanda Zambia HIV Research Group, Department of Pathology & Laboratory Medicine, School of Medicine and Hubert Department of Global Health.

Objective: To present the incremental cost from the payer's perspective and effectiveness of couples' family planning counseling (CFPC) with long-acting reversible contraception (LARC) access integrated with couples' voluntary HIV counseling and testing (CVCT) in Zambia. This integrated program is evaluated incremental to existing individual HIV counseling and testing and family planning services.

Design: Implementation and modelling.

Setting: Fifty-five government health facilities in Zambia.

Subjects: Patients in government health facilities.

Intervention: Community health workers and personnel promoted and delivered integrated CVCT+CFPC from March 2013 to September 2015.

Main Outcome Measures: We report financial costs of actual expenditures during integrated program implementation and outcomes of CVCT+CFPC uptake and LARC uptake. We model primary outcomes of cost-per-: adult HIV infections averted by CVCT, unintended pregnancies averted by LARC, couple-years of protection against unintended pregnancy by LARC, and perinatal HIV infections averted by LARC. Costs and outcomes were discounted at 3% per year.

Results: Integrated program costs were $3 582 186 (2015 USD), 82 231 couples received CVCT+CFPC, and 56 409 women received LARC insertions. The program averted an estimated 7165 adult HIV infections at $384 per adult HIV infection averted over a 5-year time horizon. The program also averted 62 265 unintended pregnancies and was cost-saving for measures of cost-per-unintended pregnancy averted, cost-per-couple-year of protection against unintended pregnancy, and cost-per-perinatal HIV infection averted assuming 3 years of LARC use.

Conclusion: Our intervention was cost-savings for CFPC outcomes and CVCT was effective and affordable in Zambia. Integrated couples-focused HIV and family planning was feasible, affordable, and leveraged HIV and unintended pregnancy prevention.
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http://dx.doi.org/10.1097/QAD.0000000000002584DOI Listing
September 2020

African-led health research and capacity building- is it working?

BMC Public Health 2020 Jul 14;20(1):1104. Epub 2020 Jul 14.

Africa Health Research Institute, Durban, South Africa.

Background: Africa bears a disproportionately high burden of globally significant disease but has lagged in knowledge production to address its health challenges. In this contribution, we discuss the challenges and approaches to health research capacity strengthening in sub-Saharan Africa and propose that the recent shift to an African-led approach is the most optimal.

Methods And Findings: We introduce several capacity building approaches and recent achievements, explore why African-led research on the continent is a potentially paradigm-shifting and innovative approach, and discuss the advantages and challenges thereof. We reflect on the approaches used by the African Academy of Sciences (AAS)-funded Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE) consortium as an example of an effective African-led science and capacity building programme. We recommend the following as crucial components of future efforts: 1. Directly empowering African-based researchers, 2. Offering quality training and career development opportunities to large numbers of junior African scientists and support staff, and 3. Effective information exchange and collaboration. Furthermore, we argue that long-term investment from international donors and increasing funding commitments from African governments and philanthropies will be needed to realise a critical mass of local capacity and to create and sustain world-class research hubs that will be conducive to address Africa's intractable health challenges.

Conclusions: Our experiences so far suggest that African-led research has the potential to overcome the vicious cycle of brain-drain and may ultimately lead to improvement of health and science-led economic transformation of Africa into a prosperous continent.
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http://dx.doi.org/10.1186/s12889-020-08875-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359480PMC
July 2020

Cost-effectiveness of couples' voluntary HIV counselling and testing in six African countries: a modelling study guided by an HIV prevention cascade framework.

J Int AIDS Soc 2020 06;23 Suppl 3:e25522

Rwanda Zambia HIV Research Group, Department of Pathology & Laboratory Medicine, School of Medicine and Hubert Department of Global Health, Rollins School of Public Health, Laney Graduate School, Emory University, Atlanta, GA, USA.

Introduction: Couples' voluntary HIV counselling and testing (CVCT) is a high-impact HIV prevention intervention in Rwanda and Zambia. Our objective was to model the cost-per-HIV infection averted by CVCT in six African countries guided by an HIV prevention cascade framework. The HIV prevention cascade as yet to be applied to evaluating CVCT effectiveness or cost-effectiveness.

Methods: We defined a priority population for CVCT in Africa as heterosexual adults in stable couples. Based on our previous experience nationalizing CVCT in Rwanda and scaling-up CVCT in 73 clinics in Zambia, we estimated HIV prevention cascade domains of motivation for use, access and effectiveness of CVCT as model parameters. Costs-per-couple tested were also estimated based on our previous studies. We used these parameters as well as country-specific inputs to model the impact of CVCT over a five-year time horizon in a previously developed and tested deterministic compartmental model. We consider six countries across Africa with varied HIV epidemics (South Africa, Zimbabwe, Kenya, Tanzania, Ivory Coast and Sierra Leone). Outcomes of interest were the proportion of HIV infections averted by CVCT, nationwide CVCT implementation costs and costs-per-HIV infection averted by CVCT. We applied 3%/year discounting to costs and outcomes. Univariate and Monte Carlo multivariate sensitivity analyses were conducted.

Results: We estimated that CVCT could avert between 54% (Sierra Leone) and 62% (South Africa) of adult HIV infections. Average costs-per-HIV infection averted were lowest in Zimbabwe ($550) and highest in South Africa ($1272). Nationwide implementations would cost between 7% (Kenya) and 21% (Ivory Coast) of a country's President's Emergency Plan for AIDS Relief (PEPFAR) budget over five years. In sensitivity analyses, model outputs were most sensitive to estimates of cost-per-couple tested; the proportion of adults in heterosexual couples and HIV prevention cascade domains of CVCT motivation and access.

Conclusions: Our model indicates that nationalized CVCT could prevent over half of adult HIV infections for 7% to 21% of the modelled countries' five-year PEPFAR budgets. While other studies have indicated that CVCT motivation is high given locally relevant promotional and educational efforts, without required indicators, targets and dedicated budgets, access remains low.
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http://dx.doi.org/10.1002/jia2.25522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325504PMC
June 2020

A Population-Specific Optimized GeneXpert Pooling Algorithm for Chlamydia trachomatis and Neisseria gonorrhoeae To Reduce Cost of Molecular Sexually Transmitted Infection Screening in Resource-Limited Settings.

J Clin Microbiol 2020 08 24;58(9). Epub 2020 Aug 24.

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.

The sexually transmitted infections (STIs) chlamydia (CT) and gonorrhea (NG) are often asymptomatic in women and undetected by syndromic management, leading to complications such as pelvic inflammatory disease, infertility, and ectopic pregnancy. Molecular testing, such as the GeneXpert CT/NG assay, is highly sensitive, but cost restraints preclude implementation of these technologies in resource-limited settings. Pooled testing is one strategy to reduce the cost per sample, but the extent of savings depends on disease prevalence. The current study describes a pooling strategy based on identification of sociodemographic and laboratory factors associated with CT/NG prevalence in a high-risk cohort of Zambian female sex workers and single mothers conducted from 2016 to 2019. Factors associated with testing positive for CT/NG via logistic regression modeling included city, younger age, lower education, long-acting reversible contraception usage, infection, bacterial vaginosis, and incident syphilis infection. Based on these factors, the study population was stratified into high-, intermediate-, and low-prevalence subgroups and tested accordingly-individually, pools of 3, or pools of 4, respectively. The cost per sample was reduced from $18 to as low as $9.43 in the low-prevalence subgroup. The checklist tool and pooling approach described can be used in a variety of treatment algorithms to lower the cost per sample and increase access to molecular STI screening. This is particularly valuable in resource-limited settings to detect and treat asymptomatic CT/NG infections missed by traditional syndromic management.
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http://dx.doi.org/10.1128/JCM.00176-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448664PMC
August 2020

HIV-1 variants are archived throughout infection and persist in the reservoir.

PLoS Pathog 2020 06 3;16(6):e1008378. Epub 2020 Jun 3.

Emory Vaccine Center, Emory University, Atlanta, Georgia, United States of America.

The HIV-1 reservoir consists of latently infected cells that persist despite antiretroviral therapy (ART). Elucidating the proviral genetic composition of the reservoir, particularly in the context of pre-therapy viral diversity, is therefore important to understanding reservoir formation and the persistence of latently infected cells. Here we investigate reservoir proviral variants from 13 Zambian acutely-infected individuals with additional pre-therapy sampling for a unique comparison to the ART-naïve quasispecies. We identified complete transmitted/founder (TF) viruses from seroconversion plasma samples, and additionally amplified and sequenced HIV-1 from plasma obtained one year post-infection and just prior to ART initiation. While the majority of proviral variants in the reservoir were most closely related to viral variants from the latest pre-therapy time point, we also identified reservoir proviral variants dating to or near the time of infection, and to intermediate time points between infection and treatment initiation. Reservoir proviral variants differing by five or fewer nucleotide changes from the TF virus persisted during treatment in five individuals, including proviral variants that exactly matched the TF in two individuals, one of whom had remained ART-naïve for more than six years. Proviral variants during treatment were significantly less divergent from the TF virus than plasma variants present at the last ART-naïve time point. These findings indicate that reservoir proviral variants are archived throughout infection, recapitulating much of the viral diversity that arises throughout untreated HIV-1 infection, and strategies to target and reduce the reservoir must therefore permit for the clearance of proviruses encompassing this extensive diversity.
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http://dx.doi.org/10.1371/journal.ppat.1008378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295247PMC
June 2020

Better Viral Control despite Higher CD4 T Cell Activation during Acute HIV-1 Infection in Zambian Women Is Linked to the Sex Hormone Estradiol.

J Virol 2020 07 30;94(16). Epub 2020 Jul 30.

Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA

The influence of biological sex on disease progression in HIV-1-infected individuals has been focused on the chronic stage of infection, but little is known about how sex differences influence acute HIV-1 infection. We observed profound differences in viral load and CD4 T cell activation from the earliest time points in men and women in a Zambian heterosexual acute infection cohort. Women exhibited a >2-fold higher rate of CD4 T cell loss despite significantly lower viral loads (VL) than men. The importance of studying acute infection was highlighted by the observation that very early in infection, women exhibited significantly higher levels of CD4 T cell activation, a difference that was lost over the first 3 years of infection as activation in men increased. In women, activation of CD4 T cells in the acute phase was significantly correlated with plasma levels of 17β-estradiol (E2). However, unlike in men, higher CD4 T cell activation in women was not associated with higher VL. In contrast, a higher E2 level in early infection was associated with lower early and set-point VL in women. We attribute this to an inhibitory effect of estradiol on virus replication, which we were able to observe with relevant transmitted/founder viruses Thus, estradiol plays a key role in defining major differences between men and women during early HIV-1 infection by contributing to both viral control and CD4 T cell loss, an effect that extends into the chronic phase of the disease. Previous studies have identified sex-specific differences during chronic HIV-1 infection, but little is known about sex differences in the acute phase, or how disparities in the initial response to the virus may affect disease. We demonstrate that restriction of viral load in women begins during acute infection and is maintained into chronic infection. Despite this, women exhibit more rapid CD4 T cell loss than men. These profound differences are influenced by 17β-estradiol, which contributes both to T cell activation and to reduced viral replication. Thus, we conclude that estradiol plays a key role in shaping responses to early HIV-1 infection that influence the chronic phase of disease.
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http://dx.doi.org/10.1128/JVI.00758-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394904PMC
July 2020

Fertility intentions and long-acting reversible contraceptive use among HIV-negative single mothers in Zambia.

Am J Obstet Gynecol 2020 04 14;222(4S):S917.e1-S917.e15. Epub 2020 Jan 14.

Rwanda Zambia Emory HIV Research Group, Department of Pathology, Emory University School of Medicine, Atlanta, GA.

Background: Integrating family planning interventions with HIV studies in developing countries has been shown to prevent mother-to-child HIV transmission and simultaneously reduce HIV and unintended pregnancy in high-risk populations. As part of a prospective cohort study on HIV incidence and risk factors in Zambian women having unprotected sex, we also offered family planning counseling and immediate access to long-acting reversible contraceptives. Although long-acting reversible contraceptives are the most effective form of contraception, many Zambian women are limited to oral or injectable methods because of a lack of knowledge or method availability. This project offers to single mothers who are enrolled in a cohort study information about and access to long-acting reversible contraceptives at enrollment and at each follow-up visit.

Objective: This study evaluates how fertility intentions affect long-acting reversible contraceptive use in HIV-negative single mothers in Zambia. Our primary outcome was long-acting reversible contraceptive use throughout the study participation. We also estimated rates of long-acting reversible contraceptive uptake and discontinuation. We specifically studied single mothers because they are at high risk for unintended pregnancy, which can have significant negative ramifications on their financial, social, and psychologic circumstances.

Study Design: From 2012-2017, Zambia Emory HIV Research Project recruited 521 HIV-negative single mothers ages 18-45 years from government clinics in Lusaka and Ndola, Zambia's 2 largest cities. Participants were followed every 3 months for up to 5 years. At each visit, we discussed fertility goals and contraceptive options and offered a long-acting reversible method to any woman who was not pregnant or who already was using a long-acting reversible or permanent contraceptive method. Data were collected on demographic factors, sexual behavior, and reproductive history. Multivariable logistic regression was used to model baseline fertility intentions with long-acting reversible contraceptive use.

Results: We enrolled 518 women; 57 women did not return for any follow-up visits. There was a significant increase in long-acting reversible contraceptive use during the study. At baseline, 93 of 518 women (18%) were using a long-acting reversible method, and 151 of 461 women (33%) used a long-acting reversible method at the end of follow-up period (P<.0001). Four women chose an intrauterine device, and 91 women chose an implant for their first uptake event. After we adjusted the data for other confounders, we found that women in Ndola who did not desire any more children were more likely to use a long-acting reversible contraceptive (adjusted prevalence ratio, 2.02; 95% confidence interval, 1.88-3.42). During follow up, 37 of 183 long-acting reversible contraceptive users (20%) discontinued their method; women who desired future children at baseline were more likely to discontinue earlier (P=.016).

Conclusion: This study demonstrates that integrated family planning services can increase long-acting reversible contraceptive use successfully among Zambian single mothers, who are a vulnerable population that disproportionately is affected by unintended pregnancy. A steady increase in use over time confirms the importance of repeated messaging about these unfamiliar methods. Thus, it is imperative that family planning interventions target single mothers in developing countries to promote effective contraceptive use.
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http://dx.doi.org/10.1016/j.ajog.2019.12.269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138749PMC
April 2020

Factors associated with alcohol use before sex among HIV-negative female sex workers in Zambia.

Int J STD AIDS 2020 02 16;31(2):119-126. Epub 2020 Jan 16.

Rwanda Zambia HIV Research Group, Pathology & Laboratory Medicine, School of Medicine, Emory University, Atlanta, GA, USA.

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http://dx.doi.org/10.1177/0956462419886159DOI Listing
February 2020

A couple-focused, integrated unplanned pregnancy and HIV prevention program in urban and rural Zambia.

Am J Obstet Gynecol 2020 04 13;222(4S):S915.e1-S915.e10. Epub 2020 Jan 13.

Rwanda Zambia HIV Research Group, the Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, GA.

Background: Zambia's total fertility rate (5 births per woman) and adult HIV prevalence (11.5%) are among the highest in the world, with heterosexual couples being the most affected group. Jointly counseling and testing couples for HIV has reduced up to 58% of new HIV infections in Zambian clinics. Married women using contraceptives in Zambia have a high (20%) unmet need for family planning and low (8.6%) uptake of cost-effective long-acting reversible contraceptives. We present an integrated counseling, testing, and family-planning program to prevent HIV and unplanned pregnancy in Zambia.

Objective: The objective of this study was to integrate effective HIV prevention and family-planning services for Zambian couples.

Study Design: A 3 year program (2013-2016) progressively integrated the promotion and provision of couples' voluntary HIV counseling and testing and long-acting reversible contraceptives. The program was based in 55 urban and 215 rural government clinics across 33 districts. In the first year, a couples' family-planning counseling training program was developed and combined with existing couples HIV counseling training materials. To avoid congestion during routine clinic hours, joint counseling services were initially provided on weekends, while nurses were trained in intrauterine device and hormonal implant insertion and removal during weekday family-planning services. Demand was created through mutual referral between weekend and weekday programs and by clinic staff, community health workers, and satisfied family-planning clients. When the bulk of integrated service training was completed, the program transitioned services to routine weekday clinic hours, ensuring access to same-day services. Performance indicators included number of staff trained, clients served, integrated service referrals, HIV infections averted, and unplanned pregnancies averted.

Results: A stepwise approach trained high-performing service providers to be trainers and used high-volume clinics for practicum training of the next generation. In total, 1201 (391 urban, 810 rural) counselors were trained and served 120,535 urban and 87,676 rural couples. In urban clinics, 236 nurses inserted 65,619 long-acting reversible contraceptives, while in rural clinics, 243 nurses inserted 35,703 implants and intrauterine devices. The program prevented an estimated 12,869 urban and 8279 rural adult HIV infections, and 98,626 unintended urban pregnancies. In the final year, the proportion of clients receiving joint counseling services on weekdays rose from 11% to 89%, with many referred from within clinics including HIV testing and treatment services (32%), outpatient department (31%), family planning (16%), and infant vaccination (15%). The largest group of clients requesting long-acting reversible contraceptives (45%) did so after joint fertility goal-based counseling, confirming the high impact of this couple-focused demand creation approach. Remaining family-planning clients responded to referrals from clinic nurses (34%), satisfied implant/intrauterine device users (13%), or community health workers (8%).

Conclusion: Integrated HIV and unplanned pregnancy prevention can be implemented in low-resource public sector facilities. Combination services offered to couples mutually leverage HIV prevention and unplanned pregnancy prevention. The addition of long-acting reversible contraceptives is an important complement to the method mix available in government clinics. Demand creation in the clinic and in the community must be coordinated with a growing supply of well-trained providers.
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http://dx.doi.org/10.1016/j.ajog.2020.01.007DOI Listing
April 2020

Protective HLA alleles are associated with reduced LPS levels in acute HIV infection with implications for immune activation and pathogenesis.

PLoS Pathog 2019 08 26;15(8):e1007981. Epub 2019 Aug 26.

Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.

Despite extensive research on the mechanisms of HLA-mediated immune control of HIV-1 pathogenesis, it is clear that much remains to be discovered, as exemplified by protective HLA alleles like HLA-B*81 which are associated with profound protection from CD4+ T cell decline without robust control of early plasma viremia. Here, we report on additional HLA class I (B*1401, B*57, B*5801, as well as B*81), and HLA class II (DQB1*02 and DRB1*15) alleles that display discordant virological and immunological phenotypes in a Zambian early infection cohort. HLA class I alleles of this nature were also associated with enhanced immune responses to conserved epitopes in Gag. Furthermore, these HLA class I alleles were associated with reduced levels of lipopolysaccharide (LPS) in the plasma during acute infection. Elevated LPS levels measured early in infection predicted accelerated CD4+ T cell decline, as well as immune activation and exhaustion. Taken together, these data suggest novel mechanisms for HLA-mediated immune control of HIV-1 pathogenesis that do not necessarily involve significant control of early viremia and point to microbial translocation as a direct driver of HIV-1 pathogenesis rather than simply a consequence.
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http://dx.doi.org/10.1371/journal.ppat.1007981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730937PMC
August 2019

Hormonal Contraception and Vaginal Infections Among Couples Who Are Human Immunodeficiency Virus Serodiscordant in Lusaka, Zambia.

Obstet Gynecol 2019 09;134(3):573-580

Department of Gynecology and Obstetrics, Emory University, School of Medicine, the Rwanda Zambia HIV Research Group, Department of Pathology & Laboratory Medicine, School of Medicine and Hubert Department of Global Health, Rollins School of Public Health, Emory University, and the Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia; the Department of Epidemiology, Ryals School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama; and the Department of Gynecology and Obstetrics, School of Medicine, University of Zambia, and the Ministry of Community Development, Mother and Child Health, Lusaka, Zambia.

Objective: To examine the relationship between hormonal contraception and vaginal infections with bacterial vaginosis, vaginal candidiasis, or trichomoniasis.

Methods: Couples who were human immunodeficiency virus (HIV) serodiscordant in Zambia were enrolled in a longitudinal cohort study. From 1994 to 2002, both partners were seen quarterly and received physical exams including genital examinations. Separate rates for three outcome infections of interest (bacterial vaginosis, vaginal candidiasis, and trichomoniasis) were calculated. Bivariate associations between baseline and time-varying covariates and outcome infections of interest were evaluated using unadjusted Anderson-Gill survival models. Adjusted hazard ratios (aHRs) were generated using multivariable Anderson-Gill survival models that included demographic and clinical factors associated with both hormonal contraceptive use and each infection of interest.

Results: There were 1,558 cases of bacterial vaginosis, 1,529 cases of vaginal candidiasis, and 574 cases of trichomoniasis over 2,143 person-years of observation. Depot medroxyprogesterone acetate (DMPA) users had significantly lower rates of trichomoniasis and bacterial vaginosis. In adjusted models, DMPA was protective for bacterial vaginosis (aHR=0.72; 95% CI 0.54-0.95), candidiasis (aHR 0.75, 95% CI 0.57-1.00) and trichomoniasis (aHR=0.43, 95% CI 0.25-0.74). Oral contraceptive pills were protective for candidiasis (aHR=0.79, 95% CI 0.65-0.97).

Conclusion: We confirm that DMPA use was associated with reduced rates of the three most common causes of vaginitis, and oral contraceptive pill use was associated with reduced rates of candidiasis among women in couples who were HIV discordant.
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http://dx.doi.org/10.1097/AOG.0000000000003404DOI Listing
September 2019

Rapid and Focused Maturation of a VRC01-Class HIV Broadly Neutralizing Antibody Lineage Involves Both Binding and Accommodation of the N276-Glycan.

Immunity 2019 07;51(1):141-154.e6

International AIDS Vaccine Initiative Neutralizing Antibody Center, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative, New York, NY 10004, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address:

The VH1-2 restricted VRC01-class of antibodies targeting the HIV envelope CD4 binding site are a major focus of HIV vaccine strategies. However, a detailed analysis of VRC01-class antibody development has been limited by the rare nature of these responses during natural infection and the lack of longitudinal sampling of such responses. To inform vaccine strategies, we mapped the development of a VRC01-class antibody lineage (PCIN63) in the subtype C infected IAVI Protocol C neutralizer PC063. PCIN63 monoclonal antibodies had the hallmark VRC01-class features and demonstrated neutralization breadth similar to the prototype VRC01 antibody, but were 2- to 3-fold less mutated. Maturation occurred rapidly within ∼24 months of emergence of the lineage and somatic hypermutations accumulated at key contact residues. This longitudinal study of broadly neutralizing VRC01-class antibody lineage reveals early binding to the N276-glycan during affinity maturation, which may have implications for vaccine design.
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http://dx.doi.org/10.1016/j.immuni.2019.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642152PMC
July 2019

Client-Initiated Violence Against Zambian Female Sex Workers: Prevalence and Associations With Behavior, Environment, and Sexual History.

J Interpers Violence 2019 Jul 3:886260519860083. Epub 2019 Jul 3.

3 Rwanda Zambia HIV Research Group, Emory University, Pathology & Laboratory Medicine, School of Medicine, Atlanta, GA, United States.

Violence against women is a known risk factor for HIV and affects female sex workers (FSW) in sub-Saharan Africa. Little is known about the magnitude and determinants of violence against FSW in Zambia, where HIV and gender-based violence prevalence are high. We conducted a cross-sectional study, using multivariable logistic regression, to determine the prevalence and correlates of client-initiated physical violence among 419 FSW in Lusaka and Ndola. The prevalence of client-initiated physical violence was 39%. The odds of violence were higher for FSW who: lived in Lusaka, recruited clients from the street, serviced clients in the clients' homes, had a physically forced sexual debut, and had a higher client volume. Our results call for safer working spaces for FSW and violence prevention interventions for their male clients.
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http://dx.doi.org/10.1177/0886260519860083DOI Listing
July 2019

Sustained virological response and drug resistance among female sex workers living with HIV on antiretroviral therapy in Kampala, Uganda: a cross-sectional study.

Sex Transm Infect 2019 09 2;95(6):405-411. Epub 2019 Jul 2.

MRC/UVRI and LSHTM Uganda Research Unit, Kampala, Uganda.

Objectives: We assessed the prevalence and risk factors associated with virological failure among female sex workers living with HIV on antiretroviral therapy (ART) in Kampala, Uganda.

Methods: We conducted a cross-sectional study between January 2015 and December 2016 using routinely collected data at a research clinic providing services to women at high risk of STIs including HIV. Plasma samples were tested for viral load from HIV-seropositive women aged ≥18 years who had been on ART for at least 6 months and had received adherence counselling. Samples from women with virological failure (≥1000 copies/mL) were tested for HIV drug resistance by population-based sequencing. We used logistic regression to identify factors associated with virological failure.

Results: Of 584 women, 432 (74%) with a mean age of 32 (SD 6.5) were assessed, and 38 (9%) were found to have virological failure. HIV resistance testing was available for 78% (28/38), of whom 82.1% (23/28) had at least one major drug resistance mutation (DRM), most frequently M184V (70%, 16/23) and K103N (65%, 15/23). In multivariable analysis, virological failure was associated with participant age 18-24 (adjusted OR (aOR)=5.3, 95% CI 1.6 to 17.9), self-reported ART non-adherence (aOR=2.6, 95% CI 1.2 to 5.8) and baseline CD4+ T-cell count ≤350 cells/mm (aOR=3.1, 95% CI 1.4 to 7.0).

Conclusions: A relatively low prevalence of virological failure but high rate of DRM was found in this population at high risk of transmission. Younger age, self-reported ART non-adherence and low CD4+ T-cell count on ART initiation were associated with increased risk of virological failure.
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http://dx.doi.org/10.1136/sextrans-2018-053854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824617PMC
September 2019

Reduced frequency of HIV superinfection in a high-risk cohort in Zambia.

Virology 2019 09 15;535:11-19. Epub 2019 Jun 15.

Emory Vaccine Center, Emory University, Atlanta, GA, USA; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA. Electronic address:

Rates of HIV-1 superinfection, re-infection with a genetically distinct virus despite HIV-1 specific immune responses, vary in different risk populations. We previously found the rates of superinfection were similar to primary HIV infection (PHI) in a Zambian heterosexual transmission cohort. Here, we conduct a similar analysis of 47 HIV-positive Zambians from an acute infection cohort with more frequent follow-up, all infected by non-spousal partners. We identified only one case of superinfection in the first two years, significantly fewer than in our previous study, which was likely due to increased counseling during acute infection and an overall population-wide decline in factors associated with HIV transmission. The predominant virus detected after superinfection was a recombinant of the transmitted founder (TF) and the superinfecting strain. The superinfected individual mounted a neutralizing antibody response to the primary TF virus, which remained TF-specific over time and even after superinfection, did not neutralize the superinfecting variant.
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http://dx.doi.org/10.1016/j.virol.2019.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179746PMC
September 2019

Single Mothers and Female Sex Workers in Zambia Have Similar Risk Profiles.

AIDS Res Hum Retroviruses 2019 09 30;35(9):814-825. Epub 2019 Jul 30.

Rwanda Zambia HIV Research Group, Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, Georgia.

The aim of the study was to compare reproductive health and high-risk behaviors in female sex workers (FSWs) and single mothers (SMs) in Zambia's two largest cities, Lusaka and Ndola. FSWs were invited from known community hot spots, and sexually active HIV- SMs were referred from infant vaccination services for free and anonymous screening and treatment for HIV and other sexually transmitted infections (STIs) and long acting reversible contraception. A subset completed an interviewer-administered survey. From 2012 to 2016, 1,893 women (1,377 FSWs and 516 HIV- SMs) responded to referrals. HIV prevalence was 50% in Lusaka and 33% in Ndola FSWs. Positive syphilis serology (rapid plasmin reagin) was found in 29%-31% of HIV+ FSWs and 9%-12% of HIV- FSWs and SMs. Trichomonas was more common in Ndola (11%-12%), compared with Lusaka (3%-7%). Antiretroviral therapy (ART) use among HIV+ FSWs was 9%-15%. In all groups, consistent condom use (8%-11%) and modern contraceptive use (35%-65%) were low. Low literacy and reported coercion at first sexual intercourse were common in both FSWs and SMs, as was alcohol use during sex among FSWs. Zambian FSWs and SMs have low condom use and high HIV/STI and unplanned pregnancy risk. Many FSWs and half of SMs are ≥25 years of age, and thus too old for HIV prevention services targeting "adolescent girls and young women" (aged 15-24). Tailored and targeted reproductive health services are needed to reduce HIV, STI, and unplanned pregnancy in these vulnerable women.
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http://dx.doi.org/10.1089/AID.2019.0013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735314PMC
September 2019

Control of the HIV-1 Load Varies by Viral Subtype in a Large Cohort of African Adults With Incident HIV-1 Infection.

J Infect Dis 2019 07;220(3):432-441

International AIDS Vaccine Initiative Human Immunology Laboratory, London, United Kingdom.

Few human immunodeficiency virus (HIV)-infected persons can maintain low viral levels without therapeutic intervention. We evaluate predictors of spontaneous control of the viral load (hereafter, "viral control") in a prospective cohort of African adults shortly after HIV infection. Viral control was defined as ≥2 consecutively measured viral loads (VLs) of ≤10 000 copies/mL after the estimated date of infection, followed by at least 4 subsequent measurements for which the VL in at least 75% was ≤10 000 copies/mL in the absence of ART. Multivariable logistic regression characterized predictors of viral control. Of 590 eligible volunteers, 107 (18.1%) experienced viral control, of whom 25 (4.2%) maintained a VL of 51-2000 copies/mL, and 5 (0.8%) sustained a VL of ≤50 copies/mL. The median ART-free follow-up time was 3.3 years (range, 0.3-9.7 years). Factors independently associated with control were HIV-1 subtype A (reference, subtype C; adjusted odds ratio [aOR], 2.1 [95% confidence interval {CI}, 1.3-3.5]), female sex (reference, male sex; aOR, 1.8 [95% CI, 1.1-2.8]), and having HLA class I variant allele B*57 (reference, not having this allele; aOR, 1.9 [95% CI, 1.0-3.6]) in a multivariable model that also controlled for age at the time of infection and baseline CD4+ T-cell count. We observed strong associations between infecting HIV-1 subtype, HLA type, and sex on viral control in this cohort. HIV-1 subtype is important to consider when testing and designing new therapeutic and prevention technologies, including vaccines.
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http://dx.doi.org/10.1093/infdis/jiz127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603968PMC
July 2019

VH1-69 Utilizing Antibodies Are Capable of Mediating Non-neutralizing Fc-Mediated Effector Functions Against the Transmitted/Founder gp120.

Front Immunol 2018 15;9:3163. Epub 2019 Jan 15.

Yerkes National Primate Research Center, Emory University, Atlanta, GA, United States.

Multiple antibody effector functions arise in HIV-1 infection that could be harnessed to protect against infection or clear the persistent reservoir. Here, we have investigated the genetic and functional memory B cell and antibody landscape present during early infection in six individuals infected with either subtype A, C, or an A/C recombinant HIV-1. These individuals demonstrated varying levels of plasma autologous neutralization (nAb) against the transmitted/founder envelope (T/F Env) pseudovirus and non-neutralizing Fc-mediated effector function (nnFc) antibody-dependent cell-mediated cytotoxicity (ADCC) against the T/F Env gp120 protein at ~7 months after infection. Genetic analysis of the immunoglobulin heavy (VH) and light (VL) chain variable domain gene segments from 352 autologous T/F Env gp120-specific single B cells recovered at this same 7-month time-point revealed an over-representation of the VH1-69 germline in five of six individuals. A defining feature of the VH1-69 utilizing gp120-specific antibodies was their significantly more hydrophobic complementarity-determining region-2 (CDRH2) regions compared to other VH CDRH2 sequences from each individual. While none of the VH1-69 antibodies possessed strong neutralizing activity against virions pseudotyped with the autologous T/F Env, almost a third were capable of mediating high ADCC activity, as assayed by intracellular granzyme B activity in CEM.NKr.CCR5 target cells coated with autologous T/F Env gp120. High ADCC mediating VH1-69 antibodies exhibited shorter complementarity-determining region-3 (CDRH3) lengths and a more neutral isoelectric point than antibodies lacking this function. In the individual that developed the highest autologous ADCC responses, the high granzyme B producing antibodies bound to surface expressed envelope in the absence of CD4 and were not enhanced by the addition of soluble CD4. Overall, VH1-69 utilizing antibodies are commonly induced against gp120 in diverse HIV-1 infections and a subset of these antibodies can mediate ADCC functions, serving as a bridge between the innate and adaptive immune response to HIV-1.
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http://dx.doi.org/10.3389/fimmu.2018.03163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341001PMC
October 2019

Schistosomiasis is associated with incident HIV transmission and death in Zambia.

PLoS Negl Trop Dis 2018 12 13;12(12):e0006902. Epub 2018 Dec 13.

Rwanda Zambia HIV Research Group, Department of Pathology & Laboratory Medicine, School of Medicine and Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America.

Background: We examined relationships between schistosome infection, HIV transmission or acquisition, and all-cause death.

Methods: We retrospectively tested baseline sera from a heterosexual HIV-discordant couple cohort in Lusaka, Zambia with follow-up from 1994-2012 in a nested case-control design. Schistosome-specific antibody levels were measured by ELISA. Associations between baseline antibody response to schistosome antigens and incident HIV transmission, acquisition, and all-cause death stratified by gender and HIV status were assessed. In a subset of HIV- women and HIV+ men, we performed immunoblots to evaluate associations between Schistosoma haematobium or Schistosoma mansoni infection history and HIV incidence.

Results: Of 2,145 individuals, 59% had positive baseline schistosome-specific antibody responses. In HIV+ women and men, baseline schistosome-specific antibodies were associated with HIV transmission to partners (adjusted hazard ratio [aHR] = 1.8, p<0.005 and aHR = 1.4, p<0.05, respectively) and death in HIV+ women (aHR = 2.2, p<0.001). In 250 HIV- women, presence of S. haematobium-specific antibodies was associated with increased risk of HIV acquisition (aHR = 1.4, p<0.05).

Conclusion: Schistosome infections were associated with increased transmission of HIV from both sexes, acquisition of HIV in women, and increased progression to death in HIV+ women. Establishing effective prevention and treatment strategies for schistosomiasis, including in urban adults, may reduce HIV incidence and death in HIV+ persons living in endemic areas.
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http://dx.doi.org/10.1371/journal.pntd.0006902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292564PMC
December 2018

HIV testing and counselling couples together for affordable HIV prevention in Africa.

Int J Epidemiol 2019 02;48(1):217-227

Rwanda Zambia HIV Research Group, Department of Pathology and Laboratory Medicine, School of Medicine and Hubert Department of Global Health, Rollins School of Public Health, Laney Graduate School.

Background: The impact and cost-effectiveness of couples' voluntary HIV counselling and testing (CVCT) has not been quantified in real-world settings. We quantify cost-per-HIV-infection averted by CVCT in Zambia from the donor's perspective.

Methods: From 2010 to 2016, CVCT was established in 73 Zambian government clinics. The cost-per-HIV-infection averted (CHIA) of CVCT was calculated using observed expenditures and effectiveness over longitudinal follow-up. These observed measures parameterized hypothetical 5-year nationwide implementations of: 'CVCT'; 'treatment-as-prevention (TasP) for discordant couples' identified by CVCT; and 'population TasP' for all HIV+ cohabiting persons identified by individual testing.

Results: In all, 207 428 couples were tested (US $52/couple). Among discordant couples in which HIV+ partners self-reported antiretroviral therapy (ART), HIV incidence was 8.5/100 person-years before and 1.8/100 person-years after CVCT (79% reduction). Corresponding reductions for non-ART-using discordant and concordant negative couples were 63% and 47%, respectively. CVCT averted an estimated 58% of new infections at US $659 CHIA. In nationwide implementation models, CVCT would prevent 17 times the number of infections vs 'TasP for discordant couples' at 86% of the cost, and nine times the infections vs 'population TasP' at 28% of the cost.

Conclusions: CVCT is a cost-effective, feasible prevention strategy in Zambia. We demonstrate the novel, added effectiveness of providing CVCT to ART users, for whom ART use alone only partially mitigated transmission risk. Our results indicate a major policy shift (supporting development of CVCT indicators, budgets and targets) and have clinical implications (suggesting promotion of CVCT in ART clinics as a high-impact prevention strategy).
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http://dx.doi.org/10.1093/ije/dyy203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380312PMC
February 2019

Fc-gamma receptor IIA and IIIA variants in two African cohorts: Lack of consistent impact on heterosexual HIV acquisition, viral control, and disease progression.

Virology 2018 12 1;525:132-142. Epub 2018 Oct 1.

Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, United States; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, United States. Electronic address:

Human Fc-gamma receptors (FcγRs) FcγRIIA and FcγRIIIA contain amino acid variants with both high and low affinities for IgG that modulate antibody-mediated effector functions. Recent HIV vaccine trials suggested that these FcγR variants can influence susceptibility to HIV infection, which prompted us to fully assess the role of FcγR variants on HIV acquisition, viral control, and disease progression in two longitudinal heterosexual transmission cohorts with HIV subtypes A and C as the major circulating viruses. For 836 participants, molecular genotyping resolved genetic variations encoding the FcγRIIA (131 H/R) and FcγRIIIA (158 V/F) single nucleotide polymorphisms. Kaplan-Meier curves, Cox proportional hazards models, and linear regression models did not reveal any clear or consistent FcγR association with time to HIV acquisition, viral load in early infection, or extent of CD4 + T-cell decline over time after infection. Overall, previous epidemiological findings on FcγR variants and vaccine efficacy are not readily applicable to heterosexual HIV transmission.
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http://dx.doi.org/10.1016/j.virol.2018.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343481PMC
December 2018

HIV transmission in discordant couples in Africa in the context of antiretroviral therapy availability.

AIDS 2018 07;32(12):1613-1623

Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.

Objective: The study aims to understand the basis of continued HIV-1 transmission in Zambian and Rwandan HIV-1-discordant couples in the context of antiretroviral therapy (ART).

Design: We identified nine Zambian and seven Rwandan acutely infected, epidemiologically-linked couples from government couples' voluntary counseling and testing (CVCT) clinics where transmitting partners reported being on ART near the time of transmission.

Methods: We quantified viral load and plasma antiretroviral drug concentrations near the time of transmission and used these as surrogate measures for adherence. We also sequenced the polymerase gene from both donor and recipient partners to determine the presence of drug resistance mutations (DRMs).

Results: In Zambia, all transmitting partners had detectable viral loads, and 8/9 were not on therapeutic antiretroviral regimens. In the remaining couple, despite being on a therapeutic regimen, DRMs were present and transmitted. In Rwanda, although six of seven transmitting partners had detectable viral loads, therapeutic levels of antiretroviral drugs were detected in four of seven, but were accompanied by DRMs. In the remaining three couples, either no antiretrovirals or subtherapeutic regimens were detected.

Conclusions: A reduction of ART effectiveness in nontrial settings was associated with lack of antiretrovirals in plasma and detectable viral load, and also drug resistance. In Zambia, where CVCT is not widely implemented, inconsistent adherence was high in couples unaware of their HIV discordance. In Rwanda, where CVCT is deployed country-wide, virologic failure was associated with drug resistance and subsequent transmission. Together, these findings suggest that increasing ART availability in resource-limited settings without risk reduction strategies that promote adherence may not be sufficient to control the HIV epidemic in the post-ART era.
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http://dx.doi.org/10.1097/QAD.0000000000001871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211178PMC
July 2018

Prediction of extended high viremia among newly HIV-1-infected persons in sub-Saharan Africa.

PLoS One 2018 3;13(4):e0192785. Epub 2018 Apr 3.

Kenya Medical Research Institute, Kilifi, Kenya.

Objective: Prompt identification of newly HIV-infected persons, particularly those who are most at risk of extended high viremia (EHV), allows important clinical and transmission prevention benefits. We sought to determine whether EHV could be predicted during early HIV infection (EHI) from clinical, demographic, and laboratory indicators in a large HIV-1 incidence study in Africa.

Design: Adults acquiring HIV-1 infection were enrolled in an EHI study assessing acute retroviral syndrome (ARS) symptoms and viral dynamics.

Methods: Estimated date of infection (EDI) was based on a positive plasma viral load or p24 antigen test prior to seroconversion, or the mid-point between negative and positive serological tests. EHV was defined as mean untreated viral load ≥5 log10 copies/ml 130-330 days post-EDI. We used logistic regression to develop risk score algorithms for predicting EHV based on sex, age, number of ARS symptoms, and CD4 and viral load at diagnosis.

Results: Models based on the full set of five predictors had excellent performance both in the full population (c-statistic = 0.80) and when confined to persons with each of three HIV-1 subtypes (c-statistic = 0.80-0.83 within subtypes A, C, and D). Reduced models containing only 2-4 predictors performed similarly. In a risk score algorithm based on the final full-population model, predictor scores were one for male sex and enrollment CD4<350 cells/mm3, and two for having enrollment viral load >4.9 log10 copies/ml. With a risk score cut-point of two, this algorithm was 85% sensitive (95% CI: 76%-91%) and 61% specific (55%-68%) in predicting EHV.

Conclusions: Simple risk score algorithms can reliably identify persons with EHI in sub-Saharan Africa who are likely to sustain high viral loads if treatment is delayed. These algorithms may be useful for prioritizing intensified efforts around care linkage and retention, treatment initiation, adherence support, and partner services to optimize clinical and prevention outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192785PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882095PMC
July 2018
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