Overview of the US National HIV Strategy and Ending the HIV Epidemic Initiative.

The US National HIV/AIDS Strategy (NHAS) is a comprehensive plan that outlines specific goals for Ending the HIV Epidemic in the United States (EHE) by 2025. The strategy also provides specific strategies to prevent new HIV infections and improve health outcomes for people with HIV. The EHE is a companion document which focuses on achieving the goals of the NHAS in specific US jurisdictions where the HIV epidemic is concentrated. This article provides an overview of the NHAS and EHE and provides examples of programs and strategies that can be used to end the HIV epidemic in the United States.

Case Report: Reversal of Integrase Inhibitor- and Tenofovir Alafenamide-Related Weight Gain After Switching Back to Efavirenz/Emtricitabine/Tenofovir DF.

We report a case of substantial weight gain in a virologically suppressed patient with HIV after changing his antiretroviral therapy from efavirenz/emtricitabine/tenofovir DF to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide with subsequent rapid weight loss upon switching back. The role of antiretrovirals in weight gain and loss and patient- and HIV-specific factors are discussed.

Efficacy, pharmacokinetics and neurocognitive performance of dual, NRTI-sparing antiretroviral therapy in acute HIV-infection.

OBJECTIVES: The aim of this study was to evaluate penetration of antiretrovirals into compartments and efficacy of a dual, NRTI-sparing regimen in acute HIV infection (AHI). DESIGN: Single-arm, open-label pilot study of participants with AHI initiating ritonavir-boosted darunavir 800 mg once daily and etravirine 400 mg once daily or 200 mg twice daily within 30 days of AHI diagnosis. METHODS: Efficacy was defined as HIV RNA less than 200 copies/ml by week 24. Optional sub-studies included pharmacokinetics analysis from genital fluids (weeks 0-4, 12, 48), cerebrospinal fluid (CSF) (weeks 2-4, 24 and 48) and endoscopic biopsies (weeks 4-12 and 36-48). Neuropsychological performance was assessed at weeks 0, 24 and 48. RESULTS: Fifteen AHI participants were enrolled. Twelve (80%) participants achieved HIV RNA less than 200 copies/ml by week 24. Among 12 participants retained through week 48, nine (75%) remained suppressed to less than 50 copies/ml. The median time from ART initiation to suppression less than 200 and less than 50 copies/ml was 59 and 86 days, respectively. The penetration ratios for etravirine and darunavir in gut associated lymphoid tissue were 19.2 and 3.05, respectively. Most AHI participants achieving viral suppression experienced neurocognitive improvement. Of the three participants without overall improvement in neurocognitive functioning as measured by impairment ratings (more than two tests below 1 SD), two had virologic failure. CONCLUSION: NRTI-sparing ART started during AHI resulted in rapid viral suppression similar to NRTI-based regimens. More novel and compact two-drug treatments for AHI should be considered. Early institution of ART during AHI appears to improve overall neurocognitive function and may reduce the risk of subsequent neurocognitive impairment. CLINICALTRIALS.GOV:: NCT00855413.

Canary in the Coal Mine? Transmitted Mutations Conferring Resistance to All Integrase Strand Transfer Inhibitors in a Treatment-Naive Patient.

Transmitted drug resistance to the integrase strand transfer inhibitor (INSTI) class of antiretrovirals is very rare. We present a case of a treatment-naive female patient with human immunodeficiency virus harboring resistance to all INSTIs, including bictegravir and dolutegravir.

Acute HIV Infection and CD4/CD8 Ratio Normalization After Antiretroviral Therapy Initiation.

BACKGROUND: We estimated the effect of initiating virologically suppressive antiretroviral therapy (ART) during acute HIV infection versus chronic HIV infection (AHI vs. CHI) on CD4/CD8 ratio normalization. SETTING: A prospective clinical cohort study. METHODS: We included patients initiating ART with AHI and CHI between 2000 and 2015 and compared time from ART initiation to the first normal CD4/CD8 ratio (defined as CD4/CD8 ≥1) using Kaplan-Meier curves and multivariable Cox proportional hazards models. Patient time was censored at virologic failure, lost to follow-up, or death. We also characterized CD4, CD8, and CD4/CD8 trajectories over the first 3 years of ART. RESULTS: The 1198 patients were 27% female and 60% African American, with a median age of 37 years (interquartile range 28-47) at ART initiation. The 83 AHI patients were more likely male, younger, and of white race, than CHI patients. After 2 years of suppressive ART, 70% of AHI patients achieved a normal CD4/CD8 ratio, compared to 6%-38% of CHI patients, with greater likelihood of normalization at higher baseline CD4 counts. Time to normalization was shortest among AHI patients, followed by CHI patients with higher baseline CD4. The adjusted hazard ratio for time to normalization for AHI patients compared to CHI patients with baseline CD4 >350 was 4.33 (95% CI: 3.16 to 5.93). Higher baseline CD4/CD8 ratio was also associated with time to normalization (adjusted hazard ratio 1.54; 1.46, 1.63, per 0.1 increase in ratio). CONCLUSIONS: Initiating ART during AHI at higher baseline CD4 cell counts and CD4/CD8 ratios was associated with shorter time to CD4/CD8 ratio normalization.

Immunogenicity of AGS-004 Dendritic Cell Therapy in Patients Treated During Acute HIV Infection.

AGS-004 consists of matured autologous dendritic cells co-electroporated with in vitro transcribed RNA encoding autologous HIV antigens. In an open-label, single arm sub-study of AGS-004-003, AGS-004 was administered monthly to suppressed participants who started antiretroviral therapy (ART) during acute HIV infection. HIV-1 specific T cell responses were measured by multicolor flow cytometry after 3-4 doses. The frequency of resting CD4+ T-cell infection (RCI) was measured by quantitative viral outgrowth assay. Participants demonstrating increased immune response postvaccination were eligible for analytic treatment interruption (ATI). AGS-004 induced a positive immune response defined as ≥2-fold increase from baseline in the number of multifunctional HIV-1 specific CD28+/CD45RA- CD8+ effector/memory cytoxic T-lymphocytes (CTLs) in all six participants. All participants underwent ATI with rebound viremia at a median of 29 days. Immune correlates between time to viral rebound and the induction of effector CTLs were determined. Baseline RCI was low in most participants (0.043-0.767 IUPM). One participant had a >2-fold decrease (0.179-0.067 infectious units per million [IUPM]) in RCI at week 10. One participant with the lowest RCI had the longest ATI. AGS-004 dendritic cell administration increased multifunctional HIV-specific CD28+/CD45RA- CD8+ memory T cell responses in all participants, but did not permit sustained ART interruption. However, greater expansion of CD28-/CCR7-/CD45RA- CD8+ effector T cell responses correlated with a longer time to viral rebound. AGS-004 may be a useful tool to augment immune responses in the setting of latency reversal and eradication strategies.

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

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 initiated during AHI. The primary endpoint was the proportion of responders with HIV RNA less than 200 copies/ml by week 24. We examined time to viral suppression, retention, and CD8 cell activation through week 96 in relation to baseline characteristics. RESULTS: Between January 2005 and December 2011, 92 AHI participants enrolled. Most participants (78%) were men who have sex with men (MSM), and 42% were young MSM (18-25 years of age). Two participants withdrew leaving 90 patients for analysis. Eighty-one (90%) remained on therapy and achieved viral suppression to less than 200 copies/ml by week 24, and 71 (79%) to less than 50 copies/ml at week 48. The median time from ART initiation to suppression less than 200 copies/ml was 65 days (range 7-523) and to less than 50 copies/ml was 105 days (range 14-523). The frequency of immune activation declined from a median of 67% to 16% through week 96. Retention on study was maintained in 92% of participants at week 48 and in 83% through week 96. Among 75 participants retained through week 96, 92% were suppressed to less than 50 copies/ml. Among 39 young MSM, 79% completed a week 96 visit and 67% were suppressed at week 96. CONCLUSION: ART during AHI resulted in rapid and sustained viral suppression with high rates of retention in care and on ART in this cohort including a large proportion of young MSM.

The Development of an HIV Training Program for Nurse Practitioners.

Responding to a national need for a new workforce of HIV care providers as the first generation of providers decrease their practices or retire, the Duke University School of Nursing, with funding from the Health Resources and Services Administration, developed and implemented a program to train nurse practitioners (NP) to assume the full spectrum of primary care services needed by people living with HIV infection and various co-morbidities. The 12-credit program includes course work in HIV-related epidemiology; pathogenesis; psychosocial, political, ethical, and legal issues; and pharmacology and clinical management. Students complete 392 hours of HIV-specific clinical practice in addition to clinical hours required of all NP students. The program is the only distance-based program of its kind in the United States. Online didactic instruction is complemented by campus-based sessions with interprofessional faculty. We describe the 5 overarching goals that frame the program, and challenges and progress toward achieving those goals.

Incident sexually transmitted infection as a biomarker for high-risk sexual behavior after diagnosis of acute HIV.

BACKGROUND: Sexually transmitted infection (STI) diagnosis after diagnosis of acute HIV infection (AHI) indicates ongoing high-risk sexual behavior and possible risk of HIV transmission. We assessed predictors of STI acquisition and the effect of time since care entry on STI incidence in patients with AHI in care and receiving consistent risk-reduction messaging. METHODS: Data on incident gonorrhea, chlamydia, trichomoniasis, primary/secondary syphilis, demographic, and clinical risk factors were abstracted from medical charts for patients diagnosed as having AHI and engaged in care. Poisson regression models using generalized estimating equations were fit to estimate incidence rates (IRs), IR ratios, and robust 95% confidence intervals. RESULTS: Among 185 patients with AHI, 26 (14%) were diagnosed as having at least 1 incident STI over 709.4 person-years; 46 STIs were diagnosed during follow-up (IR, 6.8/100 person-years). The median time from HIV care entry to first STI diagnosis was 609 days (range, 168-1681 days). Men who have sex with men (P = 0.03), a shorter time between presentation to medical care and AHI diagnosis (P = 0.06), and STI diagnosis before AHI diagnosis (P = 0.0003) were predictors of incident STI. Sexually transmitted infection IR greater than 1 year after entering care was double that of patients in care 1 year or less (IR ratio, 2.0; 95% confidence interval, 0.8-4.9). HIV viral load was above the limits of detection within 1 month of 11 STI diagnoses in 6 patients (23.1%) (median, 15,898 copies/mL; range, 244-152,000 copies/mL). CONCLUSIONS: Despite regular HIV care, STI incidence was high among this primarily young, men who have sex with men AHI cohort. Early antiretroviral initiation may decrease HIV transmission given ongoing risk behaviors despite risk-reduction messaging.

Antiretroviral therapy initiated during acute HIV infection fails to prevent persistent T-cell activation.

Initiation of antiretroviral therapy during acute HIV-1 infection may prevent persistent immune activation. We analyzed longitudinal CD38+HLA-DR+ CD8+ T-cell percentages in 31 acutely infected individuals who started early (median 43 days since infection) and successful antiretroviral therapy, and maintained viral suppression through 96 weeks. Pretherapy a median of 72.6% CD8+ T cells were CD38+HLA-DR+, and although this decreased to 15.6% by 96 weeks, it remained substantially higher than seronegative controls (median 8.9%, P = 0.008). Shorter time to suppression predicted lower activation at 96 weeks. These results support the hypothesis that very early events in HIV-1 pathogenesis may result in prolonged immune dysfunction.

Acute HIV-1 infection in the Southeastern United States: a cohort study.

In 1998 a collaboration between Duke University and the University of North Carolina, Chapel Hill (UNC) was founded to enhance identification of persons with acute HIV-1 infection (AHI). The Duke-UNC AHI Research Consortium Cohort consists of patients ≥18 years old with a positive nucleic acid amplification test (NAAT) and either a negative enzyme immunoassay (EIA) test or a positive EIA with a negative/indeterminate Western blot. Patients were referred to the cohort from acute care settings and state-funded HIV testing sites that use NAAT testing on pooled HIV-1 antibody-negative samples. Between 1998 and 2010, 155 patients with AHI were enrolled: 81 (52%) African-Americans, 63 (41%) white, non-Hispanics, 137 (88%) males, 108 (70%) men who have sex with men (MSM), and 18 (12%) females. The median age was 27 years (IQR 22-38). Most (n=138/155) reported symptoms with a median duration of 17.5 days. The median nadir CD4 count was 408 cells/mm(3) (IQR 289-563); the median observed peak HIV-1 level was 726,859 copies/ml (IQR 167,585-3,565,728). The emergency department was the most frequent site of initial presentation (n=55/152; 3 missing data). AHI diagnosis was made at time of first contact in 62/137 (45%; 18 missing data) patients. This prospectively enrolled cohort is the largest group of patients with AHI reported from the Southeastern United States. The demographics reflect the epidemic of this geographic area with a high proportion of African-Americans, including young black MSM. Highlighting the challenges of diagnosing AHI, less than half of the patients were diagnosed at the first healthcare visit. Women made up a small proportion despite increasing numbers in our clinics.

CD4+CD8+ T cells represent a significant portion of the anti-HIV T cell response to acute HIV infection.

Previous studies have revealed that HIV-infected individuals possess circulating CD4(+)CD8(+) double-positive (DP) T cells specific for HIV Ags. In the present study, we analyzed the proliferation and functional profile of circulating DP T cells from 30 acutely HIV-infected individuals and 10 chronically HIV-infected viral controllers. The acutely infected group had DP T cells that showed more proliferative capability and multifunctionality than did both their CD4(+) and CD8(+) T cells. DP T cells were found to exhibit greater proliferation and higher multifunctionality compared with CD4 T cells in the viral controller group. The DP T cell response represented 16% of the total anti-HIV proliferative response and >70% of the anti-HIV multifunctional response in the acutely infected subjects. Proliferating DP T cells of the acutely infected subjects responded to all HIV Ag pools with equal magnitude. Conversely, the multifunctional response was focused on the pool representing Nef, Rev, Tat, VPR, and VPU. Meanwhile, the controllers' DP T cells focused on Gag and the Nef, Rev, Tat, VPR, and VPU pool for both their proliferative and multifunctional responses. Finally, we show that the presence of proliferating DP T cells following all HIV Ag stimulations is well correlated with proliferating CD4 T cells whereas multifunctionality appears to be largely independent of multifunctionality in other T cell compartments. Therefore, DP T cells represent a highly reactive cell population during acute HIV infection, which responds independently from the traditional T cell compartments.

Disability and home hazards and safety practices in US households.

BACKGROUND: Individuals with disabilities have an elevated risk of residential injury. However, the prevalence of home hazards and safety practices among households where an individual with a disability resides is unknown. METHODS: This study examined patterns of home hazards and safety practices among 1003 households across the United States in 2002. RESULTS: Households with at least 1 resident with a disability had a lower prevalence of household hazards than those without a resident with a disability, including living in a 2-story dwelling (34.6% vs 50.7%) and having stairs inside the home (48.1% vs 58.4%). They were more likely to implement fall prevention strategies, such as handrails or grab bars in the bathroom (40.4% vs 21.8%) and mats or nonskid strips in the tub or shower (71.7% vs 61.5%). CONCLUSION: There is room for improvement in safety practices among households where an individual with a disability resides.

Efficacy of NNRTI-based antiretroviral therapy initiated during acute HIV infection.

OBJECTIVE: Characterize responses to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral treatment (ART) initiated during acute HIV infection (AHI). DESIGN: This was a prospective, single-arm evaluation of once-daily, co-formulated emtricitabine/tenofovir/efavirenz initiated during AHI. METHODS: The primary endpoint is the proportion of responders with HIV RNA less than 200 copies/ml by week 24. We examined time to viral suppression and CD8 cell activation in relation to baseline participant characteristics. We compared time to viral suppression and viral dynamics using linear mixed-effects models between acutely infected participants and chronically infected controls. RESULTS: Between January 2005 and May 2009, 61 AHI participants were enrolled. Of participants whose enrollment date allowed 24 and 48 weeks of follow-up, 47 of 51 (92%) achieved viral suppression to less than 200 copies/ml by week 24, and 35 of 41 (85.4%) to less than 50 copies/ml by week 48. The median time from ART initiation to suppression below 50 copies/ml was 93 days (range 14-337). Higher HIV RNA levels at ART initiation (P = 0.02), but not time from estimated date of infection to ART initiation (P = 0.86), were associated with longer time to viral suppression. The median baseline frequency of activated CD8+CD38+HLA-DR+ T cells was 67% (range 40-95), and was not significantly associated with longer time to viral load suppression (P = 0.15). Viremia declined to less than 50 copies/ml more rapidly in AHI than chronically infected participants. Mixed-model analysis demonstrated similar phase I HIV RNA decay rates between acute and chronically infected participants, and more rapid viral decline in acutely infected participants in phase II. CONCLUSION: Once-daily emtricitabine/tenofovir/efavirenz initiated during AHI achieves rapid and sustained HIV suppression during this highly infectious period.

Risk and protective factors for fires, burns, and carbon monoxide poisoning in U.S. households.

BACKGROUND: More needs to be known about the prevalence of risk and protective factors for fires, burns, and carbon monoxide poisoning in U.S. households. METHODS: A random-digit-dial survey was conducted about home safety with 1003 respondents representing households in the continental United States. Descriptive statistics assess the prevalence of risk and protective factors for fires, burns, and carbon monoxide overall, and by demographic characteristics, household structure, region, and residential tenure. The data were weighted to adjust for nonresponse and to reflect the U.S. population. RESULTS: Although most respondents reported having a smoke alarm (97%), and 80% reported having one on each level of their home, <20% reported checking the alarm at least every 3 months. Seventy-one percent reported having a fire extinguisher, 29% had a carbon monoxide detector, and 51% of those living with at least one other person had a fire escape plan. Few could report the temperature of their hot water at the tap (9%), or the setting on the hot water heater (25%). Only 6% had an antiscald device. CONCLUSIONS: Results suggest that there is much room for improvement regarding adoption of measures to prevent fires, burns, and carbon monoxide poisoning. Further investigations of the efficacy of carbon monoxide detectors, fire extinguishers, and escape plans, as well as effectiveness studies of fire and burn-prevention efforts are needed.

The association of handgun ownership and storage practices with safety consciousness.

BACKGROUND: As with other injury prevention practices, education about safe firearm storage is recommended to prevent injuries to children. OBJECTIVE: To assess whether parents who are safety conscious in other respects also practice firearm safety. METHODS: Data come from responses to a baseline survey administered as part of an intervention study. Participants were consenting adults who brought a child into an emergency department. These analyses were restricted to those parents who had young children (<7 years) and who kept a firearm in their house. A safety consciousness score was developed; participants earned a point for each of 7 home and car safety behaviors they reported practicing. The relationship between safety consciousness with handgun ownership and firearm storage practices was assessed with Wilcoxon-Mann-Whitney test. RESULTS: Of the 221 participants, most reported that they keep poisonous substances out of children's reach (92%), always keep children restrained when in cars (90%), have the telephone number for a poison control center (82%), change smoke alarm batteries annually (73%), keep electrical outlets capped (72%), and keep their tap water temperature at 120 degrees F (49 degrees C) or less (65%). Only 22% reported checking smoke alarm batteries monthly. The median safety score was 4 (mean [SD], 3.99 [1.4]). Fifty-six percent said there was a handgun in their home, 27% reported an unlocked gun, 20% reported a loaded gun, and 7% reported a loaded and unlocked gun. Results were not consistent with safety consciousness being associated with safe firearm storage practices or the absence of a handgun. CONCLUSION: Compliance with safety practices may not be associated with safe firearm storage.