Estimating HIV Incident Diagnoses Among Men Who Have Sex With Men Eligible for Pre-exposure Prophylaxis but Not Taking It: Protocol and Feasibility Assessment of Data Sources and Methods.

BACKGROUND: HIV incidence estimates are published each year for all Ending the HIV Epidemic (EHE) counties, but they are not stratified by the demographic variables highly associated with risk of infection. Regularly updated estimates of HIV incident diagnoses available at local levels are required to monitor the epidemic in the United States over time and could contribute to background incidence rate estimates for alternative clinical trial designs for new HIV prevention products. OBJECTIVE: We describe methods using existing, robust data sources within areas in the United States to reliably estimate longitudinal HIV incident diagnoses stratified by race and age categories among men who have sex with other men (MSM) eligible for pre-exposure prophylaxis (PrEP) but not taking it. METHODS: This is a secondary analysis of existing data sources to develop new estimates of incident HIV diagnoses in MSM. We reviewed past methods used to estimate incident diagnoses and explored opportunities to improve these estimates. We will use existing surveillance data sources and population sizes of HIV PrEP-eligible MSM estimated from population-based data sources (eg, US Census data and pharmaceutical prescription databases) to develop metropolitan statistical area-level estimates of new HIV diagnoses among PrEP-eligible MSM. Required parameters are number of new diagnoses among MSM, estimates of MSM with an indication for PrEP, and prevalent PrEP use including median duration of use; these parameters will be stratified by jurisdiction and age group or race or ethnicity. Preliminary outputs will be available in 2023, and updated estimates will be produced annually thereafter. RESULTS: Data to parameterize new HIV diagnoses among PrEP-eligible MSM are available with varying levels of public availability and timeliness. In early 2023, the most recent available data on new HIV diagnoses were from the 2020 HIV surveillance report, which reports 30,689 new HIV infections in 2020, and 24,724 of them occurred in an MSA with a population of ≥500,000. Updated estimates for PrEP coverage based on commercial pharmacy claims data through February 2023 will be generated. The rate of new HIV diagnoses among MSM can be estimated from new diagnoses within each demographic group (numerator) and the total person-time at risk of diagnosis for each group (denominator) by metropolitan statistical area and year. To estimate time at risk, the person-time of individuals on PrEP or person-time after incident HIV infection but before diagnosis should be removed from stratified population size estimates of the total number of person-years with indications for PrEP. CONCLUSIONS: Reliable, serial, cross-sectional estimates for rates of new HIV diagnoses for MSM with PrEP indications can serve as benchmark community estimates of failures of HIV prevention and opportunities to improve services and will support public health epidemic monitoring and alternative clinical trial designs. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/42267.

Serologic Follow-up of Middle East Respiratory Syndrome Coronavirus Cases and Contacts-Abu Dhabi, United Arab Emirates.

Background: Although there is evidence of person-to-person transmission of Middle East respiratory syndrome coronavirus (MERS-CoV) in household and healthcare settings, more data are needed to describe and better understand the risk factors and transmission routes in both settings, as well as the extent to which disease severity affects transmission. Methods: A seroepidemiological investigation was conducted among MERS-CoV case patients (cases) and their household contacts to investigate transmission risk in Abu Dhabi, United Arab Emirates. Cases diagnosed between 1 January 2013 and 9 May 2014 and their household contacts were approached for enrollment. Demographic, clinical, and exposure history data were collected. Sera were screened by MERS-CoV nucleocapsid protein enzyme-linked immunosorbent assay and indirect immunofluorescence, with results confirmed by microneutralization assay. Results: Thirty-one of 34 (91%) case patients were asymptomatic or mildly symptomatic and did not require oxygen during hospitalization. MERS-CoV antibodies were detected in 13 of 24 (54%) case patients with available sera, including 1 severely symptomatic, 9 mildly symptomatic, and 3 asymptomatic case patients. No serologic evidence of MERS-CoV transmission was found among 105 household contacts with available sera. Conclusions: Transmission of MERS-CoV was not documented in this investigation of mostly asymptomatic and mildly symptomatic cases and their household contacts. These results have implications for clinical management of cases and formulation of isolation policies to reduce the risk of transmission.

Reactive School Closure During Increased Influenza-Like Illness (ILI) Activity in Western Kentucky, 2013: A Field Evaluation of Effect on ILI Incidence and Economic and Social Consequences for Families.

Background. School closures are an important mitigation strategy during influenza pandemic: if implemented early in a local outbreak, they can slow the disease spread in the surrounding community. During seasonal influenza epidemics, school closures may occur reactively, after the disease is already widespread in the community. Such reactive closures are often too late to reduce influenza transmission. However, they can provide data to determine under which circumstances they might be effective in reducing influenza-like illness (ILI) transmission. Methods. We conducted a household survey in a school district in Kentucky. District A closed after high student absenteeism due to influenza-like illness (ILI), whereas adjacent Districts B and C remained open. We collected data on self-reported ILI among household members in these 3 districts 2 weeks before the District A closure, during closure, and 2 weeks after reopening, and we evaluated economic and social consequences of school closure on student households in District A. The difference-in-differences method was applied to compare changes in ILI rates from before to after closure between districts. Results. Estimated average daily ILI rate decreased less in District A than in District B or C for the entire sample and when stratified by age groups (0-5 years old, 6-18 years old, and above 18 years old). Twenty-five percent of District A households reported ≥1 closure-related economic or social difficulty. Conclusions. Closing schools after a widespread ILI activity in District A did not reduce ILI transmission but caused difficulties for some households.

Prevalence of Strongyloides stercoralis antibodies among a rural Appalachian population--Kentucky, 2013.

We investigated whether Strongyloides infection remains endemic in rural Kentucky's Appalachian regions; 7 of 378 (1.9%) participants tested positive for Strongyloides antibodies. We identified no statistically significant association between a positive test and travel to a known endemic country (P = 0.58), indicating that transmission in rural Kentucky might be ongoing.

Immune activation markers in peripartum women in Botswana: association with feeding strategy and maternal morbidity.

Hormone levels shift the immune state in HIV-uninfected pregnant and breastfeeding women away from Th1 responses and toward regulation to permit fetal tolerance. Limited data exist on inflammation during pregnancy or postpartum in HIV-infected women, though certain inflammatory markers are associated with adverse health outcomes among HIV-infected persons. We measured hsCRP, D-dimer, IFN-γ, IL-6, IL-10 and TNF-α at 34 weeks gestation and six months postpartum in HIV-infected women from the Botswana Mashi PMTCT trial who were randomized to breastfeeding or formula-feeding. Differences in inflammatory markers between gestation and postpartum periods, and by randomized feeding method, were estimated using generalized estimating equations, adjusting for baseline plasma HIV-1 viral load, CD4 count, calendar time, and antiretroviral treatment status. Additionally, we studied the association between marker concentrations at six months postpartum and major adverse clinical events over the following 4.5 years, using case-cohort sampling and adjusted Cox proportional hazards models. In 86 breastfeeding and 75 formula-feeding women, hsCRP and D-dimer decreased significantly between 34 weeks gestation and six months postpartum, while IFN-γ increased. There was no significant association between inflammatory marker change and randomized feeding method after adjusting for multiple comparisons and removing outliers. In univariate analysis, TNF-α, D-dimer, and IFN-γ concentrations at six months postpartum were significant predictors of subsequent clinical events, and TNF-α remained significant in multivariate analysis (HR = 4.16, p = 0.001). In young HIV-infected women in Botswana inflammatory marker concentrations did not differ significantly between women who breast- vs. formula-fed. However, postpartum TNF-α level was predictive of subsequent adverse clinical event.

Short communication: HIV type 1 subtype C variants transmitted through the bottleneck of breastfeeding are sensitive to new generation broadly neutralizing antibodies directed against quaternary and CD4-binding site epitopes.

Mother-to-child transmission of HIV-1 subtype C can occur in utero, intrapartum, or via breast milk exposure. While not well understood, there are putative differences in the mechanisms involved with the distinct routes of vertical HIV transmission. Here, we address the question of whether specific viral characteristics are common to variants transmitted through breastfeeding that may facilitate evasion of innate or adaptive immune responses. We amplified the envelope gene (env) from the plasma of six infants during acute infection who were infected with HIV-1 subtype C through breastfeeding, and from three available matched maternal samples. We sequenced the full-length env genes in these subjects revealing heterogeneous viral populations in the mothers and homogeneous populations in the infants. In five infants, the viral population arose from a single variant, while two variants were detected in the remaining infant. Infant env sequences had fewer N-linked glycosylation sites and shorter sequences than those of the available matched maternal samples. Though the small size of the study precluded our ability to test statistical significance, these results are consistent with selection for virus with shorter variable loops and fewer glycosylation sites during transmission of HIV-1 subtype C in other settings. Transmitted envs were resistant to neutralization by antibodies 2G12 and 2F5, but were generally sensitive to the more broadly neutralizing PG9, PG16, and VRC01, indicating that this new generation of broadly neutralizing monoclonal antibodies could be efficacious in passive immunization strategies.

The future of HIV prevention.

In the decades since the emergence of HIV, numerous approaches to prevent transmission have been tested with varying degrees of success. Because a highly effective vaccine will not be available within the next decade, it is increasingly clear that preventing new HIV infections will require successful implementation of promising behavioral and biomedical interventions in combination. These prevention packages must be sufficiently flexible to include a variety of evidence-based interventions that serve each dynamic population they target, particularly those who are most vulnerable. To optimize the impact of combination intervention packages, well-designed implementation science studies are vital. Efficacy in a clinical trial does not necessarily translate to effectiveness at the population-level, and prioritized research studies should investigate programmatic implementation and operations scale-up and new methods to monitor and evaluate these processes both for organization and cost-effectiveness. With an estimated 2.7 million people becoming newly infected with HIV in 2010, the prevention of HIV remains an urgent global health priority. Since the emergence of HIV/AIDS more than 30 years ago, the evidence base for HIV prevention has expanded and evolved. Here we explore the status of evidence-based HIV prevention, describing both the continuing challenges and the emerging opportunities to reduce HIV incidence.

The genetic bottleneck in vertical transmission of subtype C HIV-1 is not driven by selection of especially neutralization-resistant virus from the maternal viral population.

Subtype C human immunodeficiency virus type 1 (HIV-1C) continues to cause the majority of new cases of mother-to-child transmission (MTCT), and yet there are limited data on HIV-1C transmission. We amplified env from plasma RNA for 19 HIV-1C MTCT pairs, 10 transmitting in utero (IU) and 9 transmitting intrapartum (IP). There was a strong genetic bottleneck between all mother-infant pairs, with a majority of transmission events involving the transmission of a single virus. env genes of viruses transmitted to infants IP, but not IU, encoded Env proteins that were shorter and had fewer putative N-linked glycosylation sites in the V1-V5 region than matched maternal sequences. Viruses pseudotyped with env clones representative of each maternal and infant population were tested for neutralization sensitivity. The 50% inhibitory concentration of autologous serum was similar against both transmitted (infant) and nontransmitted (maternal) viruses in a paired analysis. Mother and infant Env proteins were also similar in sensitivity to soluble CD4, to a panel of monoclonal antibodies, and to heterologous HIV-1C sera. In addition, there was no difference in the breadth or potency of neutralizing antibodies between sera from 50 nontransmitting and 23 IU and 23 IP transmitting HIV-1C-infected women against four Env proteins from heterologous viruses. Thus, while a strong genetic bottleneck was detected during MCTC, with viruses of shorter and fewer glycosylation sites in env present in IP transmission, our data do not support this bottleneck being driven by selective resistance to antibodies.

The molecular epidemiology of HIV-1 envelope diversity during HIV-1 subtype C vertical transmission in Malawian mother-infant pairs.

OBJECTIVES: To study the relationship between HIV-1 subtype C genetic diversity and mother-to-child transmission and to determine if transmission of HIV-1 V1/V2 env variants occurs stochastically. DESIGN: Case-case-control study of Malawian mother-infant pairs consisting of 32 nontransmitting women, 25 intrauterine transmitters, and 23 intrapartum transmitters in Blantyre, Malawi. METHODS: A heteroduplex tracking assay against the highly variable HIV-1 env V1/V2 region was used to characterize the relationship between HIV-1 diversity and mother-to-child transmission. The relative abundance of the maternal env variants was quantified and categorized as transmitted or nontransmitted based on the env variants detected in the infant plasma. The V1/V2 region was sequenced from two mother-infant pairs and a phylogenetic tree was built. RESULTS: No relationship was found between transmission and overall maternal env diversity. Infants had less diverse HIV-1 populations than their mothers, and intrauterine-infected infants had fewer V1/V2 variants and were more likely to harbor a homogeneous V1/V2 population than infants infected intrapartum. V1/V2 sequences cloned from two mother-infant transmission pairs support multiple env variant transmission when multiple variants are detected, rather than single variant transmission followed by diversification. Almost 50% of the HIV-infected infants contained V1/V2 env variants that were not detected in maternal plasma samples. Finally transmission of env variants was not related to their abundance in maternal blood. CONCLUSION: These data suggest that the predominant mechanism(s) of HIV-1 subtype C mother-to-child transmission differs by the timing of transmission and is unlikely to be explained by a simple stochastic model.