HIV transmission dynamics: Infectivity, sexual partnership patterns, and the role of early infection

Although remarkable progress has been made in the diagnosis, treatment, and prevention of HIV, a cure is unavailable and many of the most promising prevention interventions have failed. At this critical juncture in the epidemic, there is a necessity for improved understanding of the fundamental drivers of the epidemic, as well as an urgent need for innovative interventions against HIV. This dissertation focuses on two of these fundamental drivers - the heterosexual infectivity of HIV-1 and the details of sexual partnership patterns - as well as the power of interventions initiated during the highly infectious period of early HIV infection (EHI). We conducted a systematic review and meta-analysis of the heterosexual infectivity of HIV-1, defined as the per-contact probability of HIV-1 transmission in a single heterosexual contact between an infected and a susceptible individual. Infectivity estimates were extremely heterogeneous, ranging from zero transmissions after more than 100 penile-vaginal contacts in some sero-discordant couples to one transmission for every 3.1 episodes of heterosexual anal intercourse. Several co-factors were associated with increased infectivity. Infectivity differences (95% confidence intervals), expressed as number of transmissions per 1000 contacts, were 8 (0-16) comparing uncircumcised to circumcised male susceptibles, 6 (3-9) comparing susceptible individuals with and without GUD, 2 (1-3) comparing late-stage to mid-stage index cases, and 3 (0-5) comparing early-stage to mid-stage index cases. We also analyzed recent sexual partnership patterns in a sexually transmitted infections (STI) clinic in Lilongwe, Malawi. We found that multiple sexual partnerships were uncommon (14%), and partnerships were long on average (mean=858 days). Among those reporting multiple recent partners, patterns ranged from long-term concurrency (mean overlap=246 days) to narrowly spaced consecutive partnerships (mean gap=21 days), presenting a substantial risk for efficient HIV transmission. Finally, we conducted a mathematical modeling study to determine the contribution of EHI to epidemic spread in Lilongwe, Malawi. Our analyses suggest that 38.4% (95% CI: 18.6%-57.5%) of ongoing HIV transmissions in Lilongwe can be attributed to EHI index cases, and that interventions targeting the entire duration of infection will be needed to have a significant, lasting effect on the epidemic

Gender asymmetry in concurrent partnerships and HIV prevalence

The structure of the sexual network of a population plays an essential role in the transmission of HIV. Concurrent partnerships, i.e. partnerships that overlap in time, are important in determining this network structure. Men and women may differ in their concurrent behavior, e.g. in the case of polygyny where women are monogamous while men may have concurrent partnerships. Polygyny has been shown empirically to be negatively associated with HIV prevalence, but the epidemiological impacts of other forms of gender-asymmetric concurrency have not been formally explored. Here we investigate how gender asymmetry in concurrency, including polygyny, can affect the disease dynamics. We use a model for a dynamic network where individuals may have concurrent partners. The maximum possible number of simultaneous partnerships can differ for men and women, e.g. in the case of polygyny. We control for mean partnership duration, mean lifetime number of partners, mean degree, and sexually active lifespan. We assess the effects of gender asymmetry in concurrency on two epidemic phase quantities (R0 and the contribution of the acute HIV stage to R0) and on the endemic HIV prevalence. We find that gender asymmetry in concurrent partnerships is associated with lower levels of all three epidemiological quantities, especially in the polygynous case. This effect on disease transmission can be attributed to changes in network structure, where increasing asymmetry leads to decreasing network connectivity

Repeat Human Immunodeficiency Virus Testing by Transmission Risk Group and Rurality of Residence in North Carolina

Background Understanding of repeat human immunodeficiency virus (HIV) testing (RHT) is limited and the impact of rural residence as a potential barrier to RHT is unknown. Rural populations are of particular interest in the Southeastern United States because of their disproportionate HIV burden. Methods We used HIV surveillance data from publicly funded HIV testing sites in North Carolina to assess repeat testing by transmission risk group and residential rurality in a retrospective cohort study. Linear binomial regression models were used to estimate adjusted, 1-year cumulative incidences and cumulative incidence differences comparing RHT within transmission risk populations by level of rurality. Results In our total study population of 600,613 persons, 19,275 (3.2%) and 9567 (1.6%) self-identified as men who have sex with men (MSM) and persons who inject drugs (PWID), respectively. A small minority, 13,723 (2.3%) resided in rural ZIP codes. Men who have sex with men were most likely to repeat test (unadjusted, 1-year cumulative incidence after an initial negative test, 16.4%) compared with PWID (13.2%) and persons who did not identify as either MSM or PWID (13.6%). The greatest effect of rurality was within PWID; the adjusted, 1-year cumulative incidence of RHT was 6.4 (95% confidence interval, 1.4-11.4) percentage points higher among metropolitan versus rural PWID. Conclusions One-year cumulative incidence of RHT was low among all clients of publicly funded HIV testing sites in North Carolina, including MSM and PWID for whom annual testing is recommended. Our findings suggest a need for public health efforts to increase access to and support for RHT, particularly among rural PWID

Chlamydia Prevalence Trends among Women and Men Entering the National Job Training Program from 1990 Through 2012

Background Evaluating chlamydia prevalence trends from sentinel surveillance is important for understanding population disease burden over time. However, prevalence trend estimates from surveillance data may be misleading if they do not account for changes in risk profiles of individuals who are screened (case mix) and changing performance of the screening tests used. Methods We analyzed chlamydia screening data from a sentinel surveillance population of 389,555 young women (1990-2012) and 303,699 young men (2003-2012) entering the US National Job Training Program. This period follows the introduction of national chlamydia screening programs designed to prevent transmission and reduce population disease burden. After ruling out bias due to case mix, we used an expectation-maximization-based maximum likelihood approach to account for measurement error from changing screening tests, and generated minimally biased long-term chlamydia prevalence trend estimates among youth and young adults in this sentinel surveillance population. Results Adjusted chlamydia prevalence among women was high throughout the study period, but fell from 20% in 1990 to 12% in 2003, and remained between 12% and 14% through 2012. Adjusted prevalence among men was steady throughout the study period at approximately 7%. For both women and men, adjusted prevalence was highest among Black and American Indian youth and young adults, and in the Southern and Midwestern regions of the United States throughout the study period. Conclusions Our minimally biased trend estimates provide support for an initial decrease in chlamydia prevalence among women soon after the introduction of national chlamydia screening programs. Constant chlamydia prevalence in more recent years suggests that screening may not be sufficient to further reduce chlamydia prevalence among high-risk youth and young adults

Modeling viral and drug kinetics: Hepatitis C virus treatment with pegylated interferon alfa-2b

Administration of peginterferon alfa-2b plus ribavirin results in an early hepatitis C virus (HCV) RNA decay followed by an increase as the drug concentration declines between doses. Upon administration of the next dose 1 week later, the same pattern is observed. We have incorporated pharmacokinetic/pharmacodynamic analysis into a model of viral dynamics to describe the effect that changes in drug concentration and effectiveness can have on viral levels. To illustrate the relationship between pharmacokinetics and viral dynamics, we fit the model to data from four HCV/human immunodeficiency virus co-infected patients, and obtained good agreement with the measured serum HCV RNA levels. We were able to account for the observed increases in HCV RNA, and estimate virion and drug half-lives that are in agreement with previous reports. Models incorporating pharmacokinetics are needed to correctly interpret viral load changes and estimate drug effectiveness in treatment protocols using peginterferon alfa-2b

HIV-1 treatment as prevention: the good, the bad, and the challenges

This work focuses on the use of antiretroviral agents to prevent the sexual transmission of HIV-1

Rethinking the heterosexual infectivity of HIV-1: a systematic review and meta-analysis

Studies of cumulative HIV incidence suggest that co-factors such as genital ulcer disease (GUD), HIV disease stage, and circumcision influence HIV transmission; however, the heterosexual infectivity of HIV-1 is commonly cited as a fixed value (∼0·001, or 1 transmission per thousand contacts). We sought to estimate transmission co-factor effects on the heterosexual infectivity of HIV-1 and to quantify the extent to which study methods have affected infectivity estimates

Fertility Intentions and Clinical Care Attendance Among Women Living with HIV in South Africa

Poor HIV care retention impedes optimal treatment outcomes in persons living with HIV. Women trying to become pregnant may be motivated by periconception horizontal and vertical transmission concerns and thus more likely to attend HIV care visits than women not trying to conceive. We estimated the effect of fertility intentions on HIV care attendance over 12 months among non-pregnant, HIV-positive women aged 18–35 years who were on or initiating antiretroviral therapy in Johannesburg, South Africa. The percentage of women attending an HIV care visit decreased from 93.4% in the first quarter to 82.8% in the fourth quarter. Fertility intentions were not strongly associated with care attendance in this cohort of reproductive-aged women; however, attendance declined over time irrespective of childbearing plans. These findings suggest a need for reinforced efforts to support care engagement and risk reduction, including safer conception practices for women wishing to conceive

Depression, ART Adherence, and Receipt of Case Management Services by Adults with HIV in North Carolina, Medical Monitoring Project, 2009–2013

Depression among persons with HIV is associated with antiretroviral therapy (ART) interruption and discontinuation, virological failure, and poor clinical and survival outcomes. Case management services can address needs for emotional counseling and other supportive services to facilitate HIV care engagement. Using 2009–2013 North Carolina Medical Monitoring Project data from 910 persons engaged in HIV care, we estimated associations of case management utilization with “probable current depression” and with 100% ART dose adherence. After weighting, 53.2% of patients reported receiving case management, 21.7% reported depression, and 87.0% reported ART adherence. Depression prevalence was higher among those reporting case management (24.9%) than among other patients (17.6%) (p < 0.01). Case management was associated with depression among patients living above the poverty level [adjusted prevalence ratio (aPR), 2.05; 95% confidence interval (CI) 1.25–3.36], and not among other patients (aPR, 1.01; 95% CI 0.72–1.43). Receipt of case management was not associated with ART adherence (aPR, 1.00; 95% CI 0.95–1.05). Our analysis indicates a need for more effective depression treatment, even among persons receiving case management services. Self-reported ART adherence was high overall, though lower among persons experiencing depression (unadjusted prevalence ratio, 0.92; 95% CI 0.86–0.99). Optimal HIV clinical and prevention outcomes require addressing psychological wellbeing, monitoring of ART adherence, and effective case management services

Community viral load as a measure for assessment of HIV treatment as prevention

Community viral load (CVL), an aggregation of individual viral loads of HIV-infected persons within a defined community, has been proposed as a useful metric for monitoring HIV treatment uptake and quantifying its impact on transmission. The first publications regarding CVL appeared in 2009 and the metric was subsequently incorporated into the United States National HIV/AIDS Strategy. Although CVL is intuitively appealing, it has several theoretical limitations and biases that require further evaluation. These limitations and biases can be categorized in four areas related to: 1) selection and measurement issues in calculating CVL among HIV-infected persons, 2) the importance of HIV prevalence in determining the potential for ongoing HIV transmission, 3) interpretation of CVL and its impact on ongoing HIV transmission in a community, and 4) the ecological fallacy (ecological bias). These potential issues deserve careful assessment as CVL is being considered as a public health metric to assess the impact of HIV care on prevention