Rising prevalence of non-B HIV-1 subtypes in North Carolina and evidence for local onward transmission.

HIV-1 diversity is increasing in North American and European cohorts which may have public health implications. However, little is known about non-B subtype diversity in the southern United States, despite the region being the epicenter of the nation's epidemic. We characterized HIV-1 diversity and transmission clusters to identify the extent to which non-B strains are transmitted locally. We conducted cross-sectional analyses of HIV-1 partial pol sequences collected from 1997 to 2014 from adults accessing routine clinical care in North Carolina (NC). Subtypes were evaluated using COMET and phylogenetic analysis. Putative transmission clusters were identified using maximum-likelihood trees. Clusters involving non-B strains were confirmed and their dates of origin were estimated using Bayesian phylogenetics. Data were combined with demographic information collected at the time of sample collection and country of origin for a subset of patients. Among 24,972 sequences from 15,246 persons, the non-B subtype prevalence increased from 0% to 3.46% over the study period. Of 325 persons with non-B subtypes, diversity was high with over 15 pure subtypes and recombinants; subtype C (28.9%) and CRF02_AG (24.0%) were most common. While identification of transmission clusters was lower for persons with non-B versus B subtypes, several local transmission clusters (≥3 persons) involving non-B subtypes were identified and all were presumably due to heterosexual transmission. Prevalence of non-B subtype diversity remains low in NC but a statistically significant rise was identified over time which likely reflects multiple importation. However, the combined phylogenetic clustering analysis reveals evidence for local onward transmission. Detection of these non-B clusters suggests heterosexual transmission and may guide diagnostic and prevention interventions

Selection Bias Due to Loss to Follow Up in Cohort Studies

Selection bias due to loss to follow up represents a threat to the internal validity of estimates derived from cohort studies. Over the last fifteen years, stratification-based techniques as well as methods such as inverse probability-of-censoring weighted estimation have been more prominently discussed and offered as a means to correct for selection bias. However, unlike correcting for confounding bias using inverse weighting, uptake of inverse probability-of-censoring weighted estimation as well as competing methods has been limited in the applied epidemiologic literature. To motivate greater use of inverse probability-of-censoring weighted estimation and competing methods, we use causal diagrams to describe the sources of selection bias in cohort studies employing a time-to-event framework when the quantity of interest is an absolute measure (e.g. absolute risk, survival function) or relative effect measure (e.g., risk difference, risk ratio). We highlight that whether a given estimate obtained from standard methods is potentially subject to selection bias depends on the causal diagram and the measure. We first broadly describe inverse probability-of-censoring weighted estimation and then give a simple example to demonstrate in detail how inverse probability-of-censoring weighted estimation mitigates selection bias and describe challenges to estimation. We then modify complex, real-world data from the University of North Carolina Center for AIDS Research HIV clinical cohort study and estimate the absolute and relative change in the occurrence of death with and without inverse probability-of-censoring weighted correction using the modified University of North Carolina data. We provide SAS code to aid with implementation of inverse probability-of-censoring weighted techniques

Outpatient Treatment of SARS-CoV-2 Infection to Prevent COVID-19 Progression

As of March 2021, COVID-19 has caused more than 123 million infections, and almost 3 million deaths worldwide. Dramatic advances have been made in vaccine development and non-pharmaceutical interventions to stop the spread of infection. But treatments to stop the progression of disease are limited. A wide variety of "repurposed" drugs explored for treatment of COVID-19 have had little or no benefit. More recently, intravenous monoclonal antibody (mAb) combinations have been authorized by the US FDA for emergency use (EUA) for outpatients with mild to moderate COVID-19 including some active against emerging SARS-COV-2 variants of concern (VOC). Easier to administer therapeutics including intramuscular and subcutaneous mAbs and oral antivirals are in clinical trials. Reliable, safe, effective COVID-19 treatment for early infection in the outpatient setting is of urgent and critical importance. Availability of such treatment should lead to reduced progression of COVID-19

Recent cancer incidence trends in an observational clinical cohort of HIV-infected patients in the US, 2000 to 2011

Abstract Background In HIV-infected populations in developed countries, the most recent published cancer incidence trend analyses are only updated through 2008. We assessed changes in the distribution of cancer types and incidence trends among HIV-infected patients in North Carolina up until 2011. Methods We linked the University of North Carolina Center for AIDS Research HIV Clinical Cohort, an observational clinical cohort of 3141 HIV-infected patients, with the North Carolina Cancer registry. Cancer incidence rates were estimated across calendar years from 2000 to 2011. The distribution of cancer types was described. Incidence trends were assessed with linear regression. Results Across 15,022 person-years of follow-up, 202 cancers were identified (incidence rate per 100,000 person-years [IR]: 1345; 95% confidence interval [CI]: 1166, 1544). The majority of cancers were virus-related (61%), including Kaposi sarcoma (N = 32) (IR: 213; 95%CI: 146, 301), non-Hodgkin lymphoma (N = 34) (IR: 226; 95%CI: 157, 316), and anal cancer (N = 16) (IR: 107; 95%CI: 61, 173). Non-Hodgkin lymphoma was observed to decrease from 2000 to 2011 (decline of 15 cases per 100,000 person-years per calendar year, 95%CI: -27, -3). No other changes in incidence or changes in incidence trends were observed for other cancers (all P > 0.20). Conclusions We observed a substantial burden of a variety of cancers in this population in the last decade. Kaposi sarcoma and non-Hodgkin lymphoma were consistently two of the greatest contributors to cancer burden across calendar time. Cancer rates appeared stable across calendar years, except for non-Hodgkin lymphoma, which appeared to decrease throughout the study period

Pre-Exposure Prophylaxis and Antiretroviral Resistance: HIV Prevention at a Cost?

Pre-exposure prophylaxis (PrEP), the use of antiretrovirals (ARVs) by human immunodeficiency virus (HIV)–uninfected individuals to prevent acquisition of the virus during high-risk sexual encounters, enjoyed its first 2 major successes with the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 and the Pre-Exposure Prophylaxis Initiative (iPrEx). These successes were buoyed by additional positive results from the TDF2 and Partners PrEP trials. Although no seroconverters in either arm of CAPRISA developed resistance to tenofovir, 2 participants in iPrEx with undetected, seronegative acute HIV infection were randomized to receive daily oral tenofovir-emtricitabine and resistance to emtricitabine was later discovered in both men. A similar case in the TDF2 study resulted in resistance to both ARVs. These cases prompted us to examine existing literature on the nature of resistance mutations elicited by ARVs used for PrEP. Here, we discuss the impact of signature mutations selected by PrEP, how rapidly these emerge with daily ARV exposure, and the individual-level and public health consequences of ARV resistance

Diversity and Tropism of HIV-1 Rebound Virus Populations in Plasma Level After Treatment Discontinuation

Human immunodeficiency virus–infected people discontinuing therapy experience a rebound in the virus level (hereafter, “rebound virus”) from a persistent reservoir. We examined 10 samples from patients in AIDS Clinical Trials Group study A5068 with rebound virus, using single-genome amplification and Primer ID deep sequencing, to assess env genetic diversity of the virus population. Most rebound-virus populations showed significant diversity. All env examined required high levels of CD4 for entry, consistent with selection of replication in CD4+ T cells. These results indicate that most people discontinuing therapy release a diverse population of virus and that this released virus has entry features of virus selected for replication in CD4+ T cells, rather than in myeloid cells