Person:

Boswell, Stephen L.

Human immunodeficiency virus type 1 (HIV-1) genomes often carry one or more mutations associated with drug resistance upon transmission into a therapy-naïve individual. We assessed the prevalence and clinical significance of transmitted drug resistance (TDR) in chronically-infected therapy-naïve patients enrolled in a multi-center cohort in North America. Pre-therapy clinical significance was quantified by plasma viral load (pVL) and CD4+ cell count (CD4) at baseline. Naïve bulk sequences of HIV-1 protease and reverse transcriptase (RT) were screened for resistance mutations as defined by the World Health Organization surveillance list. The overall prevalence of TDR was 14.2%. We used a Bayesian network to identify co-transmission of TDR mutations in clusters associated with specific drugs or drug classes. Aggregate effects of mutations by drug class were estimated by fitting linear models of pVL and CD4 on weighted sums over TDR mutations according to the Stanford HIV Database algorithm. Transmitted resistance to both classes of reverse transcriptase inhibitors was significantly associated with lower CD4, but had opposing effects on pVL. In contrast, position-specific analyses of TDR mutations revealed substantial effects on CD4 and pVL at several residue positions that were being masked in the aggregate analyses, and significant interaction effects as well. Residue positions in RT with predominant effects on CD4 or pVL (D67 and M184) were re-evaluated in causal models using an inverse probability-weighting scheme to address the problem of confounding by other mutations and demographic or risk factors. We found that causal effect estimates of mutations M184V/I ((-1.7log_{10})pVL) and D67N/G (-2.1(\sqrt[3]{CD4})) and ((+0.4log_{10}) pVL) were compensated by K103N/S and K219Q/E/N/R. As TDR becomes an increasing dilemma in this modern era of highly-active antiretroviral therapy, these results have immediate significance for the clinical management of HIV-1 infections and our understanding of the ongoing adaptation of HIV-1 to human populations.

Abstract We determined risk of virologic failure (VF) in individuals initiating tenofovir/emtricitabine/efavirenz as single versus multiple tablet regimens (MTR). We found no significant difference in the risk of VF, though did observe a trend toward more VF and M184 V mutations among persons initiating MTR. Temporal trends in care may have confounded results.

Abstract Background: The reasons why bacterial sexually transmitted infections (BSTIs) are increasing in US men who have sex with men (MSM) have not been fully characterized. Methods: An open cohort of MSM accessing medical care at a Boston community health center was used to assess secular trends in BSTI diagnoses. Frequency of infection and the estimated population size were used to calculate diagnosis rates. Poisson models were fit for multivariable analyses. Results: Between 2005 and 2015, 19 232 men had at least 1 clinic visit. Most (72.4%) were white; 6.0% were black, and 6.1% were Latino. Almost half had documented self-report of identifying as gay (42.6%) or bisexual (3.2%). Most had private health insurance (61.7%); 5.4% had Medicare, 4.6% had Medicaid, and 8.4% reported no insurance. Between 2005 and 2015, BSTI diagnoses increased more than 8-fold. In 2015, of 1319 men who were diagnosed with at least 1 BSTI; 291 were diagnosed with syphilis, 554 with gonorrhea (51.4% rectal, 31.0% urogenital), and 679 with chlamydia (69.1% rectal, 34.3% urogenital). In 2015, 22.7% of BSTIs were diagnosed among HIV-infected patients (15.4% of the clinic population), and 32.8% of BSTIs were diagnosed among HIV-uninfected patients using pre-exposure prophylaxis (PrEP; 10.1% of all men in care). In multivariable analyses, age 18 to 24 years, being HIV-infected, using PrEP, being nonwhite, or reporting Medicaid or not reporting having private insurance or Medicare were independently associated with being diagnosed with a new BSTI. Conclusions: Over the past decade, BSTI diagnosis rates increased in HIV-infected and uninfected MSM, with disproportionate increases in PrEP users, racial and ethnic minority MSM, those aged 25 to 34 years, and those without stable health insurance, warranting focused education, screening, and accessible services for these key subpopulations.