Showing papers by "Joseph J. Eron published in 2016"

Antiretroviral Therapy for the Prevention of HIV-1 Transmission

Abstract: BackgroundAn interim analysis of data from the HIV Prevention Trials Network (HPTN) 052 trial showed that antiretroviral therapy (ART) prevented more than 96% of genetically linked infections caused by human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. ART was then offered to all patients with HIV-1 infection (index participants). The study included more than 5 years of follow-up to assess the durability of such therapy for the prevention of HIV-1 transmission. MethodsWe randomly assigned 1763 index participants to receive either early or delayed ART. In the early-ART group, 886 participants started therapy at enrollment (CD4+ count, 350 to 550 cells per cubic millimeter). In the delayed-ART group, 877 participants started therapy after two consecutive CD4+ counts fell below 250 cells per cubic millimeter or if an illness indicative of the acquired immunodeficiency syndrome (i.e., an AIDS-defining illness) developed. The primary study end point was the diagnosis of genetically linked H...

Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society–USA Panel

Abstract: Importance New data and therapeutic options warrant updated recommendations for the use of antiretroviral drugs (ARVs) to treat or to prevent HIV infection in adults. Objective To provide updated recommendations for the use of antiretroviral therapy in adults (aged ≥18 years) with established HIV infection, including when to start treatment, initial regimens, and changing regimens, along with recommendations for using ARVs for preventing HIV among those at risk, including preexposure and postexposure prophylaxis. Evidence Review A panel of experts in HIV research and patient care convened by the International Antiviral Society–USA reviewed data published in peer-reviewed journals, presented by regulatory agencies, or presented as conference abstracts at peer-reviewed scientific conferences since the 2014 report, for new data or evidence that would change previous recommendations or their ratings. Comprehensive literature searches were conducted in the PubMed and EMBASE databases through April 2016. Recommendations were by consensus, and each recommendation was rated by strength and quality of the evidence. Findings Newer data support the widely accepted recommendation that antiretroviral therapy should be started in all individuals with HIV infection with detectable viremia regardless of CD4 cell count. Recommended optimal initial regimens for most patients are 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus an integrase strand transfer inhibitor (InSTI). Other effective regimens include nonnucleoside reverse transcriptase inhibitors or boosted protease inhibitors with 2 NRTIs. Recommendations for special populations and in the settings of opportunistic infections and concomitant conditions are provided. Reasons for switching therapy include convenience, tolerability, simplification, anticipation of potential new drug interactions, pregnancy or plans for pregnancy, elimination of food restrictions, virologic failure, or drug toxicities. Laboratory assessments are recommended before treatment, and monitoring during treatment is recommended to assess response, adverse effects, and adherence. Approaches are recommended to improve linkage to and retention in care are provided. Daily tenofovir disoproxil fumarate/emtricitabine is recommended for use as preexposure prophylaxis to prevent HIV infection in persons at high risk. When indicated, postexposure prophylaxis should be started as soon as possible after exposure. Conclusions and Relevance Antiretroviral agents remain the cornerstone of HIV treatment and prevention. All HIV-infected individuals with detectable plasma virus should receive treatment with recommended initial regimens consisting of an InSTI plus 2 NRTIs. Preexposure prophylaxis should be considered as part of an HIV prevention strategy for at-risk individuals. When used effectively, currently available ARVs can sustain HIV suppression and can prevent new HIV infection. With these treatment regimens, survival rates among HIV-infected adults who are retained in care can approach those of uninfected adults.

Selection Bias Due to Loss to Follow Up in Cohort Studies.

Abstract: Selection bias due to loss to follow up represents a threat to the internal validity of estimates derived from cohort studies. Over the past 15 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.

Rising Obesity Prevalence and Weight Gain Among Adults Starting Antiretroviral Therapy in the United States and Canada.

Abstract: The proportion of overweight and obese adults in the United States and Canada has increased over the past decade, but temporal trends in body mass index (BMI) and weight gain on antiretroviral therapy (ART) among HIV-infected adults have not been well characterized. We conducted a cohort study comparing HIV-infected adults in the North America AIDS Cohort Collaboration on Research and Design (NA-ACCORD) to United States National Health and Nutrition Examination Survey (NHANES) controls matched by sex, race, and age over the period 1998 to 2010. Multivariable linear regression assessed the relationship between BMI and year of ART initiation, adjusting for sex, race, age, and baseline CD4(+) count. Temporal trends in weight on ART were assessed using a generalized least-squares model further adjusted for HIV-1 RNA and first ART regimen class. A total of 14,084 patients from 17 cohorts contributed data; 83% were male, 57% were nonwhite, and the median age was 40 years. Median BMI at ART initiation increased from 23.8 to 24.8 kg/m(2) between 1998 and 2010 in NA-ACCORD, but the percentage of those obese (BMI ≥30 kg/m(2)) at ART initiation increased from 9% to 18%. After 3 years of ART, 22% of individuals with a normal BMI (18.5-24.9 kg/m(2)) at baseline had become overweight (BMI 25.0-29.9 kg/m(2)), and 18% of those overweight at baseline had become obese. HIV-infected white women had a higher BMI after 3 years of ART as compared to age-matched white women in NHANES (p = 0.02), while no difference in BMI after 3 years of ART was observed for HIV-infected men or non-white women compared to controls. The high prevalence of obesity we observed among ART-exposed HIV-infected adults in North America may contribute to health complications in the future.

Macrophages sustain HIV replication in vivo independently of T cells

Abstract: Macrophages have long been considered to contribute to HIV infection of the CNS; however, a recent study has contradicted this early work and suggests that myeloid cells are not an in vivo source of virus production. Here, we addressed the role of macrophages in HIV infection by first analyzing monocytes isolated from viremic patients and patients undergoing antiretroviral treatment. We were unable to find viral DNA or viral outgrowth in monocytes isolated from peripheral blood. To determine whether tissue macrophages are productively infected, we used 3 different but complementary humanized mouse models. Two of these models (bone marrow/liver/thymus [BLT] mice and T cell–only mice [ToM]) have been previously described, and the third model was generated by reconstituting immunodeficient mice with human CD34+ hematopoietic stem cells that were devoid of human T cells (myeloid-only mice [MoM]) to specifically evaluate HIV replication in this population. Using MoM, we demonstrated that macrophages can sustain HIV replication in the absence of T cells; HIV-infected macrophages are distributed in various tissues including the brain; replication-competent virus can be rescued ex vivo from infected macrophages; and infected macrophages can establish de novo infection. Together, these results demonstrate that macrophages represent a genuine target for HIV infection in vivo that can sustain and transmit infection.

HIV-1 Protease, Reverse Transcriptase, and Integrase Variation.

Abstract: HIV-1 protease (PR), reverse transcriptase (RT), and integrase (IN) variability presents a challenge to laboratories performing genotypic resistance testing. This challenge will grow with increased sequencing of samples enriched for proviral DNA such as dried blood spots and increased use of next-generation sequencing (NGS) to detect low-abundance HIV-1 variants. We analyzed PR and RT sequences from >100,000 individuals and IN sequences from >10,000 individuals to characterize variation at each amino acid position, identify mutations indicating APOBEC-mediated G-to-A editing, and identify mutations resulting from selective drug pressure. Forty-seven percent of PR, 37% of RT, and 34% of IN positions had one or more amino acid variants with a prevalence of ≥1%. Seventy percent of PR, 60% of RT, and 60% of IN positions had one or more variants with a prevalence of ≥0.1%. Overall 201 PR, 636 RT, and 346 IN variants had a prevalence of ≥0.1%. The median intersubtype prevalence ratios were 2.9-, 2.1-, and 1.9-fold for these PR, RT, and IN variants, respectively. Only 5.0% of PR, 3.7% of RT, and 2.0% of IN variants had a median intersubtype prevalence ratio of ≥10-fold. Variants at lower prevalences were more likely to differ biochemically and to be part of an electrophoretic mixture compared to high-prevalence variants. There were 209 mutations indicative of APOBEC-mediated G-to-A editing and 326 mutations nonpolymorphic treatment selected. Identification of viruses with a high number of APOBEC-associated mutations will facilitate the quality control of dried blood spot sequencing. Identifying sequences with a high proportion of rare mutations will facilitate the quality control of NGS. IMPORTANCE Most antiretroviral drugs target three HIV-1 proteins: PR, RT, and IN. These proteins are highly variable: many different amino acids can be present at the same position in viruses from different individuals. Some of the amino acid variants cause drug resistance and occur mainly in individuals receiving antiretroviral drugs. Some variants result from a human cellular defense mechanism called APOBEC-mediated hypermutation. Many variants result from naturally occurring mutation. Some variants may represent technical artifacts. We studied PR and RT sequences from >100,000 individuals and IN sequences from >10,000 individuals to quantify variation at each amino acid position in these three HIV-1 proteins. We performed analyses to determine which amino acid variants resulted from antiretroviral drug selection pressure, APOBEC-mediated editing, and naturally occurring variation. Our results provide information essential to clinical, research, and public health laboratories performing genotypic resistance testing by sequencing HIV-1 PR, RT, and IN.

HIV Infection, Immunosuppression, and Age at Diagnosis of Non-AIDS-Defining Cancers.

Abstract: Background It is unclear whether immunosuppression leads to younger ages at cancer diagnosis among people living with human immunodeficiency virus (PLWH). A previous study found that most cancers are not diagnosed at a younger age in people with AIDS, with the exception of anal and lung cancers. This study extends prior work to include all PLWH and examines associations between AIDS, CD4 count, and age at cancer diagnosis. Methods We compared the median age at cancer diagnosis between PLWH in the North American AIDS Cohort Collaboration on Research and Design and the general population using data from the Surveillance, Epidemiology and End Results Program. We used statistical weights to adjust for population differences. We also compared median age at cancer diagnosis by AIDS status and CD4 count. Results After adjusting for population differences, younger ages at diagnosis (P < .05) were observed for PLWH compared with the general population for lung (difference in medians = 4 years), anal (difference = 4), oral cavity/pharynx (difference = 2), and kidney cancers (difference = 2) and myeloma (difference = 4). Among PLWH, having an AIDS-defining event was associated with a younger age at myeloma diagnosis (difference = 4; P = .01), and CD4 count <200 cells/µL (vs ≥500) was associated with a younger age at lung cancer diagnosis (difference = 4; P = .006). Conclusions Among PLWH, most cancers are not diagnosed at younger ages. However, this study strengthens evidence that lung cancer, anal cancer, and myeloma are diagnosed at modestly younger ages, and also shows younger ages at diagnosis of oral cavity/pharynx and kidney cancers, possibly reflecting accelerated cancer progression, etiologic heterogeneity, or risk factor exposure in PLWH.

The effect of antiretroviral therapy on all-cause mortality, generalized to persons diagnosed with HIV in the USA, 2009–11

Abstract: Background Although antiretroviral therapy (ART) is known to be protective against HIV-related mortality, the expected magnitude of effect is unclear because existing estimates of the effect of ART may not directly generalize to recently HIV-diagnosed persons. Methods In this study, we estimated 5-year mortality risks for immediate versus no ART initiation among patients (n = 12,547) in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) using the complement of adjusted Kaplan-Meier survival functions. We subsequently standardized estimates to persons diagnosed with HIV in the USA between 2009 and 2011, who were enumerated using national surveillance data. Results The 5-year mortality, had all patients in the CNICS immediately initiated ART, was 10.6% [95% confidence interval (CI): 9.3%, 11.9%] compared with 28.3% (95% CI: 19.1%, 37.5%) had ART initiation been delayed at least 5 years. The 5-year mortality risk difference due to ART among patients in the CNICS was -17.7% (95% CI: -27.0%, -8.4%). Based on methods for generalizing an estimate from a study sample to a different target population, the expected risk difference due to ART initiation among recently HIV-diagnosed persons in the USA was -19.1% (95% CI: -30.5%, -7.8%). Conclusions Immediate ART initiation substantially lowers mortality among persons in the CNICS and this benefit is expected to be similar among persons recently diagnosed with HIV in the USA. We demonstrate a method by which concerns about generalizability can be addressed and evaluated quantitatively.

Poorly Controlled HIV Infection: An Independent Risk Factor for Liver Fibrosis.

Abstract: BACKGROUND Liver disease is a major cause of mortality among HIV-infected persons. There is limited information about the extent to which HIV disease severity impacts liver disease progression. METHODS We determined the incidence and predictors of advanced hepatic fibrosis measured by the Fibrosis-4 index (≥3.25) in a large diverse population of HIV-infected patients without significant liver disease at baseline (Fibrosis-4 score <1.45) in care between January 2000 and March 2014. We used Cox proportional hazards analysis to examine factors associated with progression to Fibrosis-4 score ≥3.25. RESULTS Among 14,198 HIV-infected patients, hepatitis C virus (HCV) coinfection [adjusted hazard ratio (aHR) 1.9, 95% confidence interval (CI): 1.6 to 2.1], hepatitis B virus coinfection (aHR 1.5, 95% CI: 1.2 to 1.8), alcohol-use disorder (aHR 1.4, 95% CI: 1.2 to 1.6), and diabetes (aHR 1.9, 95% CI: 1.6 to 2.3) were associated with progression to advanced fibrosis in multivariable analysis. In addition, patients at each lower level of time-varying CD4 cell count had a significantly greater risk of progression, with ∼7-fold higher risk in those with CD4 <100 cells per cubic millimeter (aHR 6.9, 95% CI: 5.8 to 8.3) compared with CD4 ≥500 cells per cubic millimeter. An increasing gradient of risk was also observed among patients with higher time-varying HIV viral load (VL), with the greatest risk noted with VL ≥100,000 copies per milliliter (aHR 2.6, 95% CI: 2.2 to 3.1) compared with VL <500 copies per milliliter. CONCLUSIONS Lower CD4 cell count and higher HIV VL were significantly associated with progression to advanced hepatic fibrosis in a dose-dependent manner, independent of the risk associated with traditional factors: hepatitis C virus or hepatitis B virus coinfection, alcohol, and diabetes. Our findings suggest that early treatment of HIV infection could mitigate liver disease.

Using observational data to emulate a randomized trial of dynamic treatment-switching strategies: an application to antiretroviral therapy

Abstract: Background: When a clinical treatment fails or shows suboptimal results, the question of when to switch to another treatment arises. Treatment switching strategies are often dynamic because the time of switching depends on the evolution of an individual’s time-varying covariates. Dynamic strategies can be directly compared in randomized trials. For example, HIV-infected individuals receiving antiretroviral therapy could be randomized to switching therapy within 90 days of HIV-1 RNA crossing above a threshold of either 400 copies/ml (tight-control strategy) or 1000 copies/ml (loose-control strategy). Methods: We review an approach to emulate a randomized trial of dynamic switching strategies using observational data from the Antiretroviral Therapy Cohort Collaboration, the Centers for AIDS Research Network of Integrated Clinical Systems and the HIV-CAUSAL Collaboration. We estimated the comparative effect of tight-control vs. loose-control strategies on death and AIDS or death via inverse-probability weighting. Results: Of 43 803 individuals who initiated an eligible antiretroviral therapy regimen in 2002 or later, 2001 met the baseline inclusion criteria for the mortality analysis and 1641 for the AIDS or death analysis. There were 21 deaths and 33 AIDS or death events in the tight-control group, and 28 deaths and 41 AIDS or death events in the loose-control group. Compared with tight control, the adjusted hazard ratios (95% confidence interval) for loose control were 1.10 (0.73, 1.66) for death, and 1.04 (0.86, 1.27) for AIDS or death. Conclusions: Although our effective sample sizes were small and our estimates imprecise, the described methodological approach can serve as an example for future analyses.

Continued Slow Decay of the Residual Plasma Viremia Level in HIV-1-Infected Adults Receiving Long-term Antiretroviral Therapy.

Abstract: UNLABELLED We measured plasma human immunodeficiency virus type 1 (HIV-1) RNA levels by means of single-copy assay in 334 participants receiving virologically suppressive antiretroviral therapy (ART). A residual viremia load of ≥1 copy/mL after 4 years of ART was predicted by a higher pre-ART HIV-1 RNA level, higher CD8(+) T-cell count during treatment, and a lower ratio of CD4+ T cells to CD8+ T cells during treatment but not by initial ART regimen. In a longitudinal subset of 64 individuals, continued decay of the plasma HIV-1 RNA level was observed, with an average annual decrease of 6% and an estimated half-life of 11.5 years. In contrast to prior reports, the persistent viremia level continues to slowly decline during years 4-12 of suppressive ART. CLINICAL TRIALS REGISTRATION NCT00001137.

Hypertension Among HIV-infected Patients in Clinical Care, 1996-2013.

Abstract: BACKGROUND Persons infected with human immunodeficiency virus (HIV) are at higher risk for major cardiovascular disease (CVD) events than uninfected persons. Understanding the epidemiology of major traditional CVD risk determinants, particularly hypertension, in this population is needed. METHODS The study population included HIV-infected patients participating in the UNC CFAR HIV Clinical Cohort from 1996 to 2013. Annual incidence rates of hypertension were calculated. Multivariable Poisson models were fit to identify factors associated with incident hypertension. RESULTS 3141 patients contributed 21 956 person-years (PY) of follow-up. Overall, 57% patients were black, 28% were women, and the median age was 35 years. Hypertension age-standardized incidence rates increased from 1.68 cases per 100 PYs in 1996 to 5.35 cases per 100 PYs in 2013 (P < .001). In adjusted analyses, hypertension rates were higher among obese patients (incidence rate ratio [IRR] 1.70, 95% confidence interval [CI], 1.43-2.02), and those with diabetes mellitus (IRR 1.44, 95% CI, 1.14-1.83) and renal insufficiency (IRR 1.36, 95% CI, 1.16-1.61), but lower among patients with a CD4 nadir of ≥500 cells/mm(3) (IRR 0.73, 95% CI, .53-1.01). CONCLUSIONS The incidence of hypertension increased from 1996 to 2013, alongside increases in traditional hypertension risk determinants. Notably, HIV-related immunosuppression and ongoing viral replication may contribute to an increased hypertension risk. Aggressive CVD risk factor management, early HIV diagnosis, linkage to care, antiretroviral therapy initiation, and durable viral suppression, will be important components of a comprehensive primary CVD prevention strategy in HIV-infected persons.

Impact of Health Insurance, ADAP, and Income on HIV Viral Suppression Among US Women in the Women's Interagency HIV Study, 2006-2009.

Abstract: Background: Implementation of the Affordable Care Act motivates assessment of health insurance and supplementary programs, such as the AIDS Drug Assistance Program (ADAP) on health outcomes of HIV-infected people in the United States. We assessed the effects of health insurance, ADAP, and income on HIV viral load suppression. Methods: We used existing cohort data from the HIV-infected participants of the Women's Interagency HIV Study. Cox proportional hazards models were used to estimate the time from 2006 to unsuppressed HIV viral load (>200 copies/mL) among those with Medicaid, private, Medicare, or other public insurance, and no insurance, stratified by the use of ADAP. Results: In 2006, 65% of women had Medicaid, 18% had private insurance, 3% had Medicare or other public insurance, and 14% reported no health insurance. ADAP coverage was reported by 284 women (20%); 56% of uninsured participants reported ADAP coverage. After accounting for study site, age, race, lowest observed CD4, and previous health insurance, the hazard ratio (HR) for unsuppressed viral load among those privately insured without ADAP, compared with those on Medicaid without ADAP (referent group), was 0.61 (95% CI: 0.48 to 0.77). Among the uninsured, those with ADAP had a lower relative hazard of unsuppressed viral load compared with the referent group (HR, 95% CI: 0.49, 0.28 to 0.85) than those without ADAP (HR, 95% CI: 1.00, 0.63 to 1.57). Conclusions: Although women with private insurance are most likely to be virally suppressed, ADAP also contributes to viral load suppression. Continued support of this program may be especially critical for states that have not expanded Medicaid.

Changes in Clinical Context for Kaposi's Sarcoma and Non-Hodgkin Lymphoma Among People With HIV Infection in the United States

Abstract: PurposeThe biology of HIV-associated cancers may differ depending on immunologic and virologic context during development. Therefore, an understanding of the burden of Kaposi's sarcoma (KS) and non-Hodgkin lymphoma (NHL) relative to antiretroviral therapy (ART), virologic suppression, and CD4 count is important.Patients and MethodsKS and NHL diagnoses during 1996 to 2011 were identified among patients with HIV infection in eight clinical cohorts in the United States. Among patients in routine HIV clinical care, the proportion of cases in categories of ART use, HIV RNA, and CD4 count at diagnosis were described across calendar time. Person-time and incidence rates were calculated for each category.ResultsWe identified 466 patients with KS and 258 with NHL. In recent years, KS was more frequently diagnosed after ART initiation (55% in 1996 to 2001 v 76% in 2007 to 2011; P-trend = .02). The proportion of patients with NHL who received ART was higher but stable over time (83% overall; P-trend = .81). An incre...

When to Monitor CD4 Cell Count and HIV RNA to Reduce Mortality and AIDS-Defining Illness in Virologically Suppressed HIV-Positive Persons on Antiretroviral Therapy in High-Income Countries: A Prospective Observational Study.

Abstract: OBJECTIVE To illustrate an approach to compare CD4 cell count and HIV-RNA monitoring strategies in HIV-positive individuals on antiretroviral therapy (ART). DESIGN Prospective studies of HIV-positive individuals in Europe and the USA in the HIV-CAUSAL Collaboration and The Center for AIDS Research Network of Integrated Clinical Systems. METHODS Antiretroviral-naive individuals who initiated ART and became virologically suppressed within 12 months were followed from the date of suppression. We compared 3 CD4 cell count and HIV-RNA monitoring strategies: once every (1) 3 ± 1 months, (2) 6 ± 1 months, and (3) 9-12 ± 1 months. We used inverse-probability weighted models to compare these strategies with respect to clinical, immunologic, and virologic outcomes. RESULTS In 39,029 eligible individuals, there were 265 deaths and 690 AIDS-defining illnesses or deaths. Compared with the 3-month strategy, the mortality hazard ratios (95% CIs) were 0.86 (0.42 to 1.78) for the 6 months and 0.82 (0.46 to 1.47) for the 9-12 month strategy. The respective 18-month risk ratios (95% CIs) of virologic failure (RNA >200) were 0.74 (0.46 to 1.19) and 2.35 (1.56 to 3.54) and 18-month mean CD4 differences (95% CIs) were -5.3 (-18.6 to 7.9) and -31.7 (-52.0 to -11.3). The estimates for the 2-year risk of AIDS-defining illness or death were similar across strategies. CONCLUSIONS Our findings suggest that monitoring frequency of virologically suppressed individuals can be decreased from every 3 months to every 6, 9, or 12 months with respect to clinical outcomes. Because effects of different monitoring strategies could take years to materialize, longer follow-up is needed to fully evaluate this question.

Ten Years of Screening and Testing for Acute HIV Infection in North Carolina.

Abstract: OBJECTIVE To describe demographic and behavioral characteristics of persons with acute HIV infection (AHI) over time. METHODS We conducted a retrospective assessment of AHI identified through the Screening and Tracing Active Transmission (STAT) program from 2003 to 2012 in North Carolina (NC). AHI was identified using pooled nucleic acid amplification for antibody negative samples and individual HIV-1 RNA for antibody indeterminate samples. The STAT program provides rapid notification and evaluation. We compared STAT-collected demographic and risk characteristics with all persons requesting tests and all non-AHI diagnoses from the NC State Laboratory of Public Health. RESULTS The STAT Program identified 236 AHI cases representing 3.4% (95% confidence interval: 3.0% to 3.9%) of all HIV diagnoses. AHI cases were similar to those diagnosed during established HIV. On pretest risk-assessments, AHI cases were predominately black (69.1%), male (80.1%), young (46.8% < 25 years), and men who have sex with men (MSM) (51.7%). Per postdiagnosis interviews, the median age decreased from 35 (interquartile range 25-42) to 27 (interquartile range 22-37) years, and the proportion <25 years increased from 23.8% to 45.2% (trend P = 0.04) between 2003 and 2012. AHI men were more likely to report MSM risk post-diagnosis than on pretest risk-assessments (64%-82.9%; P < 0.0001). Post-diagnosis report of MSM risk in men with AHI increased from 71.4% to 96.2%. CONCLUSIONS In NC, 3.4% of individuals diagnosed with HIV infection have AHI. AHI screening provides a real-time source of incidence trends, improves the diagnostic yield of HIV testing, and offers an opportunity to limit onward transmission.

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

Abstract: 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

Neurocognition with maraviroc compared with tenofovir in HIV

Abstract: Objective The objective was to determine whether maraviroc (MVC) has unique neurocognitive benefits in the context of initial antiretroviral therapy (ART). Design Randomized, double-blind, placebo-controlled, 48-week trial. Setting Participants were enrolled in US AIDS Clinical Trials Group clinical trial sites. Participants Total 262 ART-naive, chemokine coreceptor 5 tropic HIV, and HIV RNA greater than 1000 copies/ml participants were randomized, 230 participants completed the study. Intervention Participants received MVC 150 mg or tenofovir disoproxil fumarate (TDF) 300 mg on a background of ritonavir-boosted darunavir and emtricitabine. Main outcome measure(s) The neuropsychological battery of 15 tests done at baseline, week 24 and week 48 assessed seven domains, and were standardized into z-scores then converted into deficit scores and a global deficit score. The 48-week changes from baseline in the neuropsychological scores and the global deficit score were compared by Wilcoxon or Kruskal-Wallis test between arms, and among baseline impairment groups [classified as normal, mild (2 deficit scores ≥1) and moderate (2 deficit scores ≥2)]. It was hypothesized that the MVC arm would have improved neuropsychological performance over TDF. Results In this double-blind, randomized, placebo-controlled trial, there were no differences in neuropsychological performance between MVC and TDF. Those with moderate neuropsychological impairment at baseline experienced greater ART-mediated neuropsychological improvement than those with mild or no neuropsychological impairment. Conclusion Improvement in neurocognitive functioning was greater with more baseline impairment but was comparable with MVC or TDF.

Increased Cortical Cerebral Blood Flow in Asymptomatic Human Immunodeficiency Virus-Infected Subjects

Abstract: Background Human immunodeficiency virus (HIV)-infected individuals are at high risk for ischemic stroke. To investigate the physiological basis for this risk, we used magnetic resonance imaging (MRI) to measure oxygen extraction fraction (OEF) and cerebral blood flow (CBF) in treatment-naive asymptomatic HIV-infected subjects and controls. Methods In treatment-naive asymptomatic HIV-infected subjects and age-, gender-, and race-matched controls, OEF was measured by MRI asymmetric spin–echo echo-planar imaging sequences and CBF was measured by MRI pseudocontinuous arterial spin labeling. Results Twenty-six treatment-naive HIV-infected subjects and 27 age-, gender-, race-matched controls participated. Whole-brain, gray matter (GM), and white matter OEF were not different between the groups (all P > .70). Unexpectedly, HIV-infected subjects had significantly higher CBF in cortical GM (72.9 ± 16.2 mL/100 g/min versus 63.9 ± 9.9 mL/100 g/min; P = .01) but not in subcortical GM ( P = .25). Conclusions The observed increase in cortical GM CBF in treatment-naive HIV-infected subjects is unexpected, contrary to CBF decreases reported in HIV-infected subjects on treatment, and may represent an initial increase in metabolic activity due to an HIV-mediated inflammation.

Simultaneous vs Sequential Initiation of Therapy With Indinavir, Zidovudine, and Lamivudine for HIV-1 Infection

Abstract: CONTEXT Combination antiretroviral therapy can markedly suppress human immunodeficiency virus (HIV) replication but the duration of HIV suppression varies among patients. OBJECTIVE To compare the antiretroviral effect of a 3-drug regimen started simultaneously or sequentially in patients with HIV infection. DESIGN A multicenter, randomized, double-blind study, modified after at least 24 weeks of blinded therapy to provide open-label 3-drug therapy with follow-up through 100 weeks. SETTING Four clinical research units PATIENTS Ninety-seven patients with HIV infection who had taken zidovudine for at least 6 months with serum HIV RNA level of at least 20000 copies/mL and CD4 cell count of 0.05 to 0.40 x 10(9)/L. INTERVENTIONS Patients were initially randomized to receive 1 of 3 antiretroviral regimens: indinavir, 800 mg every 8 hours; zidovudine, 200 mg every 8 hours and lamivudine, 150 mg every 12 hours; or all 3 drugs. After at least 24 weeks of blinded therapy, all patients received open-label 3-drug therapy. MAIN OUTCOME MEASURES Antiretroviral activity was assessed by changes in HIV RNA level and CD4 cell count from baseline. Data through 100 weeks were summarized. RESULTS Simultaneous initiation of indinavir, zidovudine, and lamivudine suppressed HIV RNA in 78% (25/32) of contributing patients to less than 500 copies/mL and increased CD4 cell count to a median of 0.209 x 10(9)/L above baseline at 100 weeks. When these 3 drugs were initiated sequentially, only 30% to 45% of contributing patients (10 of 33 in the zidovudine-lamivudine group and 13 of 29 in the indinavir group, respectively) had a sustained reduction in HIV RNA to less than 500 copies/mL, and median CD4 cell count increased to 0.101 to 0.163 x 10(9)/L above baseline at 100 weeks. CONCLUSIONS A 3-drug combination of indinavir, zidovudine, and lamivudine started simultaneously has durable antiretroviral activity for at least 2 years. Sequential initiation of the same 3 drugs is much less effective.

Differential CD4+ cell count increase and CD4+ :CD8+ ratio normalization with maraviroc compared with tenofovir

Abstract: Objective Studies exploring the immunologic effects of maraviroc (MVC) have produced mixed results; hence, it remains unclear whether MVC has unique immunologic effects in comparison with other antiretroviral drugs. We sought to determine whether MVC has differential effects compared with tenofovir disoproxil fumarate (TDF) during initial antiretroviral therapy. Design Prospective study in AIDS Clinical Trials Group A5303, a double-blind, placebo-controlled trial (N = 262) of MVC vs. TDF, each combined with boosted darunavir and emtricitabine. Methods A total of 31 cellular and soluble biomarkers were assayed at weeks 0 and 48. Polychromatic flow cytometry was performed on cryopreserved peripheral blood mononuclear cells. Soluble markers were assayed in plasma using ELISA kits. Analyses were as treated. Results Analyses included 230 participants (119 in MVC arm and 111 in TDF arm). Over 48 weeks of treatment, no significant differences were detected in declines in markers of inflammation and activation with MVC vs. TDF. A greater CD4 T-cell count increase (median +234 vs. +188 cells/μl, P = 0.036), a smaller CD8 T-cell count decrease (-6 vs. -109 cells/μl, P = 0.008), and a smaller CD4 : CD8 ratio increase (0.26 vs. 0.39, P = 0.003) occurred with MVC. Among participants with a baseline CD4 : CD8 ratio less than 1, a smaller proportion of MVC group normalized to a ratio greater than 1 at week 48 (15 and 36%, P Conclusion MVC resulted in less improvement in the CD4 : CD8 ratio driven by greater increase in CD4 cell count but smaller decline in CD8 cell count. Changes in soluble or cellular biomarkers of inflammation and immune activation were not different between MVC and TDF.

Fixed-dose combination emtricitabine/tenofovir/efavirenz initiated during acute HIV infection; 96-week efficacy and durability.

Abstract: Background:Updated guidelines recommend immediate antiretroviral treatment (ART) during acute HIV infection (AHI), but efficacy data on regimens during AHI are limited.Methods:We provide final data on a prospective, single-arm 96-week open-label study of once-daily emtricitabine/tenofovir/efavirenz

Predicting resistance as indicator for need to switch from first-line antiretroviral therapy among patients with elevated viral loads: development of a risk score algorithm

Abstract: In resource-limited settings, where resistance testing is unavailable, confirmatory testing for patients with high viral loads (VL) delays antiretroviral therapy (ART) switches for persons with resistance. We developed a risk score algorithm to predict need for ART change by identifying resistance among persons with persistently elevated VL. We analyzed data from a Phase IV open-label trial. Using logistic regression, we identified demographic and clinical characteristics predictive of need for ART change among participants with VLs ≥1000 copies/ml, and assigned model-derived scores to predictors. We designed three models, including only variables accessible in resource-limited settings. Among 290 participants with at least one VL ≥1000 copies/ml, 51 % (148/290) resuppressed and did not have resistance testing; among those who did not resuppress and had resistance testing, 47 % (67/142) did not have resistance and 53 % (75/142) had resistance (ART change needed for 25.9 % (75/290)). Need for ART change was directly associated with higher baseline VL and higher VL at time of elevated measure, and inversely associated with treatment duration. Other predictors included body mass index and adherence. Area under receiver operating characteristic curves ranged from 0.794 to 0.817. At a risk score ≥9, sensitivity was 14.7–28.0 % and specificity was 96.7–98.6 %. Our model performed reasonably well and may be a tool to quickly transition persons in need of ART change to more effective regimens when resistance testing is unavailable. Use of this algorithm may result in public health benefits and health system savings through reduced transmissions of resistant virus and costs on laboratory investigations.