William C . Mathews | University of California, San Diego (original) (raw)

Thesis Chapters by William C . Mathews

M.A. Thesis, 2014

The public health principle of harm reduction as applied to heroin addiction includes both needle... more The public health principle of harm reduction as applied to heroin addiction includes both needle and syringe programs (NSPs) and opiate substitution therapy. This work examines the moral valuation of NSPs from three bioethical perspectives: secular, Roman Catholic, and Orthodox Christian. While some argue that Orthodox Christian bioethics is incommensurable with non-Orthodox bioethics, not all agree regarding this proposition. Orthodox Christian bioethics includes perspectives of relevance to the moral valuation of NSPs. Among these are: (1) the distinction between voluntary and involuntary sin; (2) the Church as a spiritual hospital rather than a tribunal; (3) patristic guidance in situations of moral conflict; and (4) the principle of oikonomia. While informal Orthodox Christian treatments of harm reduction and NSPs have been negative, this work argues for a broader bioethical discourse within the Orthodox Church and its bioethical community.

Papers by William C . Mathews

Journal of the International AIDS Society, 2020

Introduction: Weight gain following antiretroviral therapy (ART) initiation is common, potentiall... more Introduction: Weight gain following antiretroviral therapy (ART) initiation is common, potentially predisposing some persons with HIV (PWH) to cardio-metabolic disease. We assessed relationships between ART drug class and weight change among treatment-na€ ıve PWH initiating ART in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). Methods: Adult, treatment-na€ ıve PWH in NA-ACCORD initiating integrase strand transfer inhibitor (INSTI), protease inhibitor (PI) or non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based ART on/after 1 January 2007 were followed through 31 December 2016. Multivariate linear mixed effects models estimated weight up to five years after ART initiation, adjusting for age, sex, race, cohort site, HIV acquisition mode, treatment year, and baseline weight, plasma HIV-1 RNA level and CD4 + cell count. Due to shorter follow-up for PWH receiving newer INSTI drugs, weights for specific INSTIs were estimated at two years. Secondary analyses using logistic regression and all covariates from primary analyses assessed factors associated with >10% weight gain at two and five years. Results: Among 22,972 participants, 87% were male, and 41% were white. 49% started NNRTI-, 31% started PI-and 20% started INSTI-based regimens (1624 raltegravir (RAL), 2085 elvitegravir (EVG) and 929 dolutegravir (DTG)). PWH starting INSTI-based regimens had mean estimated five-year weight change of +5.9kg, compared to +3.7kg for NNRTI and +5.5kg for PI. Among PWH starting INSTI drugs, mean estimated two-year weight change was +7.2kg for DTG, +5.8kg for RAL and +4.1kg for EVG. Women, persons with lower baseline CD4 + cell counts, and those initiating INSTI-based regimens had higher odds of >10% body weight increase at two years (adjusted odds ratio = 1.37, 95% confidence interval: 1.20 to 1.56 vs. NNRTI). Conclusions: PWH initiating INSTI-based regimens gained, on average, more weight compared to NNRTI-based regimens. This phenomenon may reflect heterogeneous effects of ART agents on body weight regulation that require further exploration.

BMC Medicine, 2019

Background: Persons with human immunodeficiency virus (HIV) have higher risks for myocardial infa... more Background: Persons with human immunodeficiency virus (HIV) have higher risks for myocardial infarction (MI) than the general population. This is driven in part by higher type 2 MI (T2MI, due to coronary supply-demand mismatch) rates among persons with HIV (PWH). In the general population, T2MI has higher mortality than type 1 MI (T1MI, spontaneous and generally due to plaque rupture and thrombosis). PWH have a greater burden of comorbidities and may therefore have an even greater excess risk for complication and death in the setting of T2MI. However, mortality patterns after T1MI and T2MI in HIV are unknown. Methods: We analyzed mortality after MI among PWH enrolled in the multicenter, US-based Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort (N = 28,186). Incident MIs occurring between January 1, 1996, and December 31, 2014, were centrally adjudicated and classified as T1MI or T2MI. We first compared mortality following T1MI vs. T2MI among PWH. Cox survival analyses and Bayesian model averaging were then used to evaluate pre-MI covariates associated with mortality following T1MI and T2MI. Results: Among the 596 out of 28,186 PWH who experienced MI (2.1%; 293 T1MI and 303 T2MI), mortality rates were significantly greater after T2MI (22.2/100 person-years; 1-, 3-, and 5-year mortality 39%, 52%, and 62%) than T1MI (8.2/100 person-years; 1-, 3-, and 5-year mortality 15%, 22%, and 30%). Significant mortality predictors after T1MI were higher HIV viral load, renal dysfunction, and older age. Significant predictors of mortality after T2MI were low body-mass index (BMI) and detectable HIV viral load. Conclusions: Mortality is high following MI for PWH and substantially greater after T2MI than T1MI. Predictors of death after MI differed by type of MI, reinforcing the different clinical scenarios associated with each MI type and the importance of considering MI types separately.

AIDS Care, 2019

Low perceived social support (SS) negatively impacts health outcomes. We developed a measure of p... more Low perceived social support (SS) negatively impacts health outcomes. We developed a measure of perceived SS for use in HIV care. We sought and categorized legacy items, selecting strongest items within categories. We elicited SS concepts from patients in English/Spanish, coded transcripts to match item pool content, and developed new items for salient unrepresented content. In focus groups, patients prioritized highly-matched items. We conducted cognitive interviews on highpriority items, and validity testing on final items against two legacy measures. From interviews (n = 32), we matched the following concepts: sense of belonging/inclusion; communication; emotional support; feeling accepted by others as a person; companionship; and practical support. We identified a new concept: support from friends/family in remaining healthy. Focus groups (n = 23) prioritized emotional support, communication, and support to remain healthy. Cognitive interviews (n = 30) found items were well-understood. The final 8-item measure performed well with patients (n = 708), with good construct validity. We used an Item Response Theory program to create a 3-item Short Form version of the measure, which captures 96% of patients indicating low social support. We developed the Multifactoral Assessment of Perceived Social Support (MAPSS) and Short Form (MAPSS-SF); brief, clinically relevant, sufficiently unidimensional measures of SS for use in HIV care.

JAIDS Journal of Acquired Immune Deficiency Syndromes, 2019

Objective-Bilirubin is an antioxidant that may suppress lipid oxidation. Elevated bilirubin is as... more Objective-Bilirubin is an antioxidant that may suppress lipid oxidation. Elevated bilirubin is associated with decreased cardiovascular events in HIV-uninfected populations. We examined these associations in people living with HIV (PLWH). Methods-Potential myocardial infarctions (MI) and strokes were centrally adjudicated. We examined MI types: Type 1 MI (T1MI) from atherosclerotic plaque instability and Type 2 MI (T2MI) in the setting of oxygen demand/supply mismatch such as sepsis. We used multivariable Cox regression analyses to determine associations between total bilirubin levels and outcomes adjusting for traditional and HIV-specific risk factors. To minimize confounding by hepatobiliary disease we conducted analyses limited to bilirubin values<2.1 mg/dl; among those with Fibrosis-4 values<3.25; and among everyone. We repeated analyses stratified by hepatitis C status and time-updated atazanavir use. Results-Among 25,816 PLWH, there were 392 T1MI and 356 T2MI during follow-up. Adjusted hazard ratios (HR) for the association of higher bilirubin levels with T1MI were not significant. Higher bilirubin levels were associated with T2MI. In contrast, among PLWH on atazanavir, higher bilirubin levels were associated with fewer T2MI (HR 0.56:0.33-1.00). Higher Presented in part at the 18 th International Workshop on Comorbidities and Adverse Drug Reactions in HIV, New York

Journal of acquired immune deficiency syndromes (1999), Jan 19, 2018

Substance use is linked with poor outcomes among people living with HIV (PLWH) and is associated ... more Substance use is linked with poor outcomes among people living with HIV (PLWH) and is associated with mental health disorders. This analysis examines the impact of decreasing substance use, even without abstinence, on depressive symptoms among PLWH. Data are from PLWH enrolled in the Centers for AIDS Research Network of Integrated Clinical Sites (CNICS) cohort. Participants completed longitudinal assessments of substance use (modified ASSIST) and depressive symptoms (PHQ-9). Changes in substance use frequency were categorized as abstinence, reduced use, and non-decreasing use. Adjusted linear mixed models with time-updated change in substance use frequency and depressive symptom scores were used to examine associations between changes in the use of individual substances and depressive symptoms. Analyses were repeated using joint longitudinal survival models to examine associations with a high (PHQ-9≥10) score. Among 9,905 PLWH, 728 used cocaine/crack, 1,016 used amphetamine-type sub...

Epidemiology (Cambridge, Mass.), Jan 28, 2018

People living with human immunodeficiency virus (HIV) are at risk of increased myocardial infarct... more People living with human immunodeficiency virus (HIV) are at risk of increased myocardial infarction (MI). Cumulative HIV viral load (VL) has been proposed as a better measure of HIV inflammation than other measures of VL, like baseline VL, but its associations with MI are not known. The multi-site Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort includes clinical data and centrally adjudicated MI with distinction between atheroembolic MI (type 1) and MI related to supply-demand mismatch (type 2). We examined CNICS participants who were not on antiretroviral therapy (ART) at enrollment. Cumulative VL (copy-days of virus) from 6 months after enrollment was estimated with a time-weighted sum using the trapezoidal rule. We modeled associations of cumulative and baseline VL with MI by type using marginal structural Cox models. We contrasted the 75% percentile of the VL distribution with the 25% percentile. Among 11,324 participants, 218 MIs occurred betwee...

AIDS research and human retroviruses, Jan 21, 2018

The Universal Myocardial infarction (MI) definition divides MIs into different types. Type 1 MIs ... more The Universal Myocardial infarction (MI) definition divides MIs into different types. Type 1 MIs (T1MI) result spontaneously from atherosclerotic plaque instability. Type 2 MIs (T2MI) are due to secondary causes of myocardial oxygen demand/supply mismatch such as occurs with sepsis. T2MI are much more common among those with HIV than in the general population. T1MI and T2MI have different mechanisms, risk factors, and potential treatments suggesting that they should be distinguished to achieve a better scientific understanding of MIs in HIV. We sought to determine whether MI type could be accurately predicted by patient characteristics without adjudication in HIV-infected individuals. We developed a statistical model to predict T2MI versus T1MI using adjudicated events from six sites utilizing demographic characteristics, traditional cardiovascular, and HIV-related risk factors. Validation was assessed in a seventh site via mean calibration, and discrimination level was assessed by ...

AIDS (London, England), Jan 28, 2018

To evaluate the real world durability of contemporary ART for treatment-naïve people living with ... more To evaluate the real world durability of contemporary ART for treatment-naïve people living with HIV (PLWH). A retrospective follow-up study in a multisite cohort. This study of the CNICS (CFAR Network of Integrated Clinical Systems) cohort integrates data from eight Center for AIDS Research (CFARs). PLWH initiating ART between 2007 and 2014 were included. Durability was defined as time from the initiation until discontinuation/modification using Kaplan-Meier survival curves. Cox Proportional Hazards measured associations with various sociodemographic and clinical characteristics. Among 5373 PLWH, the initial regimen was modified in 2285 (43%) patients. Efavirenz/emtricitabine/tenofovir (n = 2173, 40%) was the most commonly prescribed initial ART regimen; elvitegravir/cobicistat/emtricitabine/tenofovir became more common after 2012. Median durability for all regimens was 48.6 months. There were statistically significant differences in median durability for NNRTI, InSTI, and protease...

AIDS (London, England), Jan 20, 2018

With combination-antiretroviral therapy, HIV-infected individuals live longer with an elevated bu... more With combination-antiretroviral therapy, HIV-infected individuals live longer with an elevated burden of cancer. Given the high prevalence of smoking among HIV-infected populations, we examined the risk of incident cancers attributable to ever smoking cigarettes. Observational cohort of HIV-infected participants with 270 136 person-years of follow-up in the North American AIDS Cohort Collaboration on Research and Design consortium. Among 52 441 participants, 2306 were diagnosed with cancer during 2000-2015. Estimated hazard ratios and population-attributable fractions (PAF) associated with ever cigarette smoking for all cancers combined, smoking-related cancers, and cancers that were not attributed to smoking. People with cancer were more frequently ever smokers (79%) compared with people without cancer (73%). Adjusting for demographic and clinical factors, cigarette smoking was associated with increased risk of cancer overall [hazard ratios = 1.33 (95% confidence interval: 1.18-1.4...

Journal of acquired immune deficiency syndromes (1999), Jan 6, 2018

There is persistent confusion as to whether abacavir (ABC) increases the risk for myocardial infa... more There is persistent confusion as to whether abacavir (ABC) increases the risk for myocardial infarction (MI), and whether such risk differs by Type 1 (T1MI) or 2 (T2MI) MI in adults with HIV. Incident MIs in NA-ACCORD participants were identified from 2001 to 2013. Discrete time marginal structural models addressed channeling biases and time-dependent confounding to estimate crude (HR) and adjusted hazard ratios (aHR) and 95% confidence intervals; analyses were performed for T1MI and T2MI separately. A sensitivity analysis evaluated whether Framingham Risk Score (FRS) modified the effect of ABC on MI occurrence. 8,265 adults who initiated antiretroviral therapy contributed 29,077 person-years and 123 MI events (65 T1MI, 58 T2MI). Median follow-up time was 2.9 (interquartile range 1.4, 5.1) years. ABC initiators were more likely to have a history of IDU, hepatitis C virus infection, hypertension, diabetes, impaired kidney function, hyperlipidemia, low (<200 cells/mm3) CD4 counts, ...

Antiviral therapy, Jan 9, 2018

Efavirenz has been a mainstay of antiretroviral therapy (ART) for over 15 years in the US. Its as... more Efavirenz has been a mainstay of antiretroviral therapy (ART) for over 15 years in the US. Its association with neuropsychiatric side effects may influence clinical prescribing and management. We included HIV-infected adults enrolled in care at 7 sites across the US, who initiated combination ART between 1999 and 2015. We examined the proportion initiating and continuing on efavirenz, overall and by mental health status. Log binomial and Cox models were used to estimate associations between mental health, clinical, and sociodemographic characteristics and initiating or switching from efavirenz as first line ART. Of the 8,230 participants included, 3,710 (45%) initiated efavirenz. In multivariable analyses, prior mono or dual ART, ART initiation after 2006, being female, intravenous drug use, antidepressant prescription, previous mental health diagnosis and baseline CD4 >350 were inversely associated with initiating efavirenz. Participants initiating efavirenz had a faster time to...

PloS one, 2017

Prompt initiation of combination antiretroviral therapy (ART) is important to reduce comorbidity ... more Prompt initiation of combination antiretroviral therapy (ART) is important to reduce comorbidity and mortality among people living with HIV, especially for those with a low CD4 cell count. However there is evidence that not everyone receives prompt initiation of ART after enrolling into HIV care. The current study investigated factors associated with failure to initiate ART within two years of entering into care among those with a CD4 count at or below 350 cells/mm3. The sample included 4,907 ART-naive patients with a CD4 count at or below 350 cells/mm3 enrolled between January 1, 2003 and December 31, 2012 at any of eight clinical sites in the Center for AIDS Research Network of Integrated Clinical Systems (CNICS). The two-year risk of delayed ART initiation was estimated using a log-binomial regression model with stabilized inverse probability of censoring weights for those lost to follow-up. Adjusting for other factors, an earlier enrollment date was the sole demographic characte...

PloS one, 2017

Youth have residual thymic tissue and potentially greater capacity for immune reconstitution than... more Youth have residual thymic tissue and potentially greater capacity for immune reconstitution than adults after initiation of combination antiretroviral therapy (cART). However, youth face behavioral and psychosocial challenges that may make them more likely than adults to delay ART initiation and less likely to attain similar CD4 outcomes after initiating cART. This study compared CD4 outcomes over time following cART initiation between ART-naïve non-perinatally HIV-infected (nPHIV) youth (13-24 years-old) and adults (≥25-44 years-old). Retrospective analysis of ART-naïve nPHIV individuals 13-44 years-old, who initiated their first cART between 2008 and 2011 at clinical sites in the HIV Research Network. A linear mixed model was used to assess the association between CD4 levels after cART initiation and age (13-24, 25-34, 35-44 years), accounting for random variation within participants and between sites, and adjusting for key variables including gender, race/ethnicity, viral load, ...

AIDS and behavior, Jan 11, 2017

Hazardous alcohol use is associated with detrimental health outcomes among persons living with HI... more Hazardous alcohol use is associated with detrimental health outcomes among persons living with HIV (PLWH). We examined the prevalence and factors associated with hazardous alcohol use in the current era using several hazardous drinking definitions and binge drinking defined as ≥5 drinks for men versus ≥4 for women. We included 8567 PLWH from 7 U.S. sites from 2013 to 2015. Current hazardous alcohol use was reported by 27% and 34% reported binge drinking. In adjusted analyses, current and past cocaine/crack (odd ratio [OR] 4.1:3.3-5.1, p < 0.001 and OR 1.3:1.1-1.5, p < 0.001 respectively), marijuana (OR 2.5:2.2-2.9, p < 0.001 and OR 1.4:1.2-1.6, p < 0.001), and cigarette use (OR 1.4:1.2-1.6, p < 0.001 and OR 1.3:1.2-1.5, p < 0.001) were associated with increased hazardous alcohol use. The prevalence of hazardous alcohol use remains high in the current era, particularly among younger men. Routine screening and targeted interventions for hazardous alcohol use, potenti...

The lancet. HIV, Jun 11, 2017

Clinical guidelines vary with respect to the optimal monitoring frequency of HIV-positive individ... more Clinical guidelines vary with respect to the optimal monitoring frequency of HIV-positive individuals. We compared dynamic monitoring strategies based on time-varying CD4 cell counts in virologically suppressed HIV-positive individuals. In this observational study, we used data from prospective studies of HIV-positive individuals in Europe (France, Greece, the Netherlands, Spain, Switzerland, and the UK) and North and South America (Brazil, Canada, and the USA) in The HIV-CAUSAL Collaboration and The Centers for AIDS Research Network of Integrated Clinical Systems. We compared three monitoring strategies that differ in the threshold used to measure CD4 cell count and HIV RNA viral load every 3-6 months (when below the threshold) or every 9-12 months (when above the threshold). The strategies were defined by the threshold CD4 counts of 200 cells per μL, 350 cells per μL, and 500 cells per μL. Using inverse probability weighting to adjust for baseline and time-varying confounders, we ...

AIDS research and human retroviruses, Jan 16, 2017

To examine associations between lipohypertrophy and lipoatrophy and illicit drug use, smoking, an... more To examine associations between lipohypertrophy and lipoatrophy and illicit drug use, smoking, and at-risk alcohol use among a large diverse cohort of persons living with HIV (PLWH) in clinical care. 7,931 PLWH at 6 sites across the US completed 21,279 clinical assessments including lipohypertrophy and lipoatrophy, drug/alcohol use, physical activity level, and smoking. Lipohypertrophy and lipoatrophy were measured using the FRAM body morphology instrument and associations were assessed with generalized estimating equations. Lipohypertrophy (33% mild, 4% moderate-to-severe) and lipoatrophy (20% mild, 3% moderate-to-severe) were common. Older age, male sex, and higher current CD4 count were associated with more severe lipohypertrophy (p values <0.001-0.03). Prior methamphetamine or marijuana use, and prior and current cocaine use, were associated with more severe lipohypertrophy (p values <0.001-0.009). Older age, detectable viral load and low current CD4 cell counts were assoc...

JAMA cardiology, Jan 21, 2016

Persons with human immunodeficiency virus (HIV) that is treated with antiretroviral therapy have ... more Persons with human immunodeficiency virus (HIV) that is treated with antiretroviral therapy have improved longevity but face an elevated risk of myocardial infarction (MI) due to common MI risk factors and HIV-specific factors. Despite these elevated MI rates, optimal methods to predict MI risks for HIV-infected persons remain unclear. To determine the extent to which existing and de novo estimation tools predict MI in a multicenter HIV cohort with rigorous MI adjudication. We evaluated the performance of standard of care and 2 new data-derived MI risk estimation models in 5 Centers for AIDS Research Network of Integrated Clinical Systems sites across the United States where a multicenter clinical prospective cohort of 19 829 HIV-infected adults received care in inpatient and outpatient settings since 1995. The new risk estimation models were validated in a separate cohort from the derivation cohort. Traditional cardiovascular risk factors, HIV viral load, CD4 lymphocyte count, stat...

JAMA cardiology, Jan 4, 2017

The Second Universal Definition of Myocardial Infarction (MI) divides MIs into different types. T... more The Second Universal Definition of Myocardial Infarction (MI) divides MIs into different types. Type 1 MIs result spontaneously from instability of atherosclerotic plaque, whereas type 2 MIs occur in the setting of a mismatch between oxygen demand and supply, as with severe hypotension. Type 2 MIs are uncommon in the general population, but their frequency in human immunodeficiency virus (HIV)-infected individuals is unknown. To characterize MIs, including type; identify causes of type 2 MIs; and compare demographic and clinical characteristics among HIV-infected individuals with type 1 vs type 2 MIs. This longitudinal study identified potential MIs among patients with HIV receiving clinical care at 6 US sites from January 1, 1996, to March 1, 2014, using diagnoses and cardiac biomarkers recorded in the centralized data repository. Sites assembled deidentified packets, including physician notes and electrocardiograms, procedures, and clinical laboratory tests. Two physician experts ...

Journal of acquired immune deficiency syndromes (1999), Jan 19, 2016

We examined factors associated with selection of initial antiretroviral regimen in the CNICS coho... more We examined factors associated with selection of initial antiretroviral regimen in the CNICS cohort. Patients initiating antiretroviral therapy (ART) between July 2009 and Dec 2012 were classified as receiving an NNRTI, boosted-PI, or raltegravir-based regimen. Among 873 patients initiating ART, 488 regimens contained an NNRTI, 319 a boosted-PI, and 66 raltegravir. Patients with depression and women were less likely to receive an NNRTI, while those with underlying cardiovascular disease, liver disease, and those co-infected with hepatitis C were more likely to receive raltegravir. Those with baseline viral load > 100,000 c/ml and those with substance use were more likely to receive a boosted PI. Thus, in the 'real world' ARV regimen choices appear to take into account adverse effects and patient baseline characteristics. Factors that impact initial regimen selection will likely become more heterogeneous over time as more choices for HIV therapy become available.

M.A. Thesis, 2014

Journal of the International AIDS Society, 2020

BMC Medicine, 2019

AIDS Care, 2019

JAIDS Journal of Acquired Immune Deficiency Syndromes, 2019

Journal of acquired immune deficiency syndromes (1999), Jan 19, 2018

Epidemiology (Cambridge, Mass.), Jan 28, 2018

AIDS research and human retroviruses, Jan 21, 2018

AIDS (London, England), Jan 28, 2018

AIDS (London, England), Jan 20, 2018

Journal of acquired immune deficiency syndromes (1999), Jan 6, 2018

Antiviral therapy, Jan 9, 2018

PloS one, 2017

AIDS and behavior, Jan 11, 2017

The lancet. HIV, Jun 11, 2017

AIDS research and human retroviruses, Jan 16, 2017

JAMA cardiology, Jan 21, 2016

JAMA cardiology, Jan 4, 2017

Journal of acquired immune deficiency syndromes (1999), Jan 19, 2016

PLOS ONE, 2016

Objective To describe disparities along the depression treatment cascade, from indication for ant... more Objective To describe disparities along the depression treatment cascade, from indication for antidepressant treatment to effective treatment, in HIV-infected individuals by gender and race/ ethnicity.