Twice-Daily Dolutegravir Based Antiretroviral Therapy with One Month of Daily Rifapentine and Isoniazid (1HP) for TB Prevention.

BACKGROUND: One month of daily rifapentine + isoniazid (1HP) is an effective, ultrashort option for TB prevention in people with HIV (PWH). However, rifapentine may decrease antiretroviral drug concentrations and increase the risk of virologic failure. ACTG A5372 evaluated the effect of 1HP on the pharmacokinetics of twice daily dolutegravir. METHODS: A5372 was a multicenter, pharmacokinetic study in PWH (≥18 years) already on dolutegravir-containing antiretroviral therapy with HIV RNA < 50 copies/mL. Participants received daily rifapentine/isoniazid (600mg/300mg) for 28 days as part of 1HP. Dolutegravir was increased to 50mg twice daily during 1HP and intensive pharmacokinetic sampling was performed on day 0 (before 1HP) and on the final day of 1HP treatment. RESULTS: Thirty-two participants (41% female; 66% Black/African; median (Q1, Q3) age 42 (34, 49) years) were included in the pharmacokinetic analysis. Thirty-one of 32 had HIV RNA levels <50 copies/mL at the end of 1HP dosing. One participant had an HIV RNA of 160 copies/mL at day 28, with HIV RNA <50 copies/mL upon repeat testing on day 42. The median (Q1, Q3) dolutegravir trough concentration was 1751 ng/mL (1195, 2542) on day 0 vs. 1987ng/mL (1331, 2278) on day 28 (day 28:day 0 GMR 1.05, [90% CI 0.93-1.2]; p = 0.43). No serious adverse events were reported. CONCLUSION: Dolutegravir trough concentrations with 50mg twice daily dosing during 1HP treatment were greater than those with standard dose dolutegravir once daily without 1HP. These pharmacokinetic, virologic, and safety data provide support for twice daily dolutegravir use in combination with 1HP for TB prevention.

Extended Analysis of HIV Infection in Cisgender Men and Transgender Women Who Have Sex with Men Receiving Injectable Cabotegravir for HIV Prevention: HPTN 083.

HPTN 083 demonstrated that injectable cabotegravir (CAB) was superior to oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) for HIV prevention in cisgender men and transgender women who have sex with men. We previously analyzed 58 infections in the blinded phase of HPTN 083 (16 in the CAB arm and 42 in the TDF-FTC arm). This report describes 52 additional infections that occurred up to 1 year after study unblinding (18 in the CAB arm and 34 in the TDF-FTC arm). Retrospective testing included HIV testing, viral load testing, quantification of study drug concentrations, and drug resistance testing. The new CAB arm infections included 7 with CAB administration within 6 months of the first HIV-positive visit (2 with on-time injections, 3 with ≥1 delayed injection, and 2 who restarted CAB) and 11 with no recent CAB administration. Three cases had integrase strand transfer inhibitor (INSTI) resistance (2 with on-time injections and 1 who restarted CAB). Among 34 CAB infections analyzed to date, diagnosis delays and INSTI resistance were significantly more common in infections with CAB administration within 6 months of the first HIV-positive visit. This report further characterizes HIV infections in persons receiving CAB preexposure prophylaxis and helps define the impact of CAB on the detection of infection and the emergence of INSTI resistance.

Novel Criteria for Diagnosing Acute and Early Human Immunodeficiency Virus Infection in a Multinational Study of Early Antiretroviral Therapy Initiation.

BACKGROUND: Antiretroviral therapy (ART) initiation during acute and early human immunodeficiency virus infection (AEHI) limits HIV reservoir formation and may facilitate post-ART control but is logistically challenging. We evaluated the performance of AEHI diagnostic criteria from a prospective study of early ART initiation. METHODS: AIDS Clinical Trials Group A 5354 enrolled adults at 30 sites in the Americas, Africa, and Asia who met any 1 of 6 criteria based on combinations of results of HIV RNA, HIV antibody, Western blot or Geenius assay, and/or the signal-to-cutoff (S/CO) ratio of the ARCHITECT HIV Ag/Ab Combo or GS HIV Combo Ag/Ab EIA. HIV status and Fiebig stage were confirmed by centralized testing. RESULTS: From 2017 through 2019, 195 participants were enrolled with median age of 27 years (interquartile range, 23-39). Thirty (15.4%) were female. ART was started by 171 (87.7%) on the day of enrollment and 24 (12.3%) the next day. AEHI was confirmed in 188 (96.4%) participants after centralized testing, 4 (2.0%) participants were found to have chronic infection, and 3 (1.5%) found not to have HIV discontinued ART and were withdrawn. Retrospectively, a nonreactive or indeterminate HIV antibody on the Geenius assay combined with ARCHITECT S/CO ≥10 correctly identified 99 of 122 (81.2%) Fiebig II-IV AEHI cases with no false-positive results. CONCLUSIONS: Novel AEHI criteria that incorporate ARCHITECT S/CO facilitated rapid and efficient ART initiation without waiting for an HIV RNA result. These criteria may facilitate AEHI diagnosis, staging, and immediate ART initiation in future research studies and clinical practice. CLINICAL TRIALS REGISTRATION: NCT02859558.

Effect of Canakinumab vs Placebo on Survival Without Invasive Mechanical Ventilation in Patients Hospitalized With Severe COVID-19: A Randomized Clinical Trial.

Importance: Effective treatments for patients with severe COVID-19 are needed. Objective: To evaluate the efficacy of canakinumab, an anti-interleukin-1ß antibody, in patients hospitalized with severe COVID-19. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled phase 3 trial was conducted at 39 hospitals in Europe and the United States. A total of 454 hospitalized patients with COVID-19 pneumonia, hypoxia (not requiring invasive mechanical ventilation [IMV]), and systemic hyperinflammation defined by increased blood concentrations of C-reactive protein or ferritin were enrolled between April 30 and August 17, 2020, with the last assessment of the primary end point on September 22, 2020. Intervention: Patients were randomly assigned 1:1 to receive a single intravenous infusion of canakinumab (450 mg for body weight of 40-<60 kg, 600 mg for 60-80 kg, and 750 mg for >80 kg; n = 227) or placebo (n = 227). Main Outcomes and Measures: The primary outcome was survival without IMV from day 3 to day 29. Secondary outcomes were COVID-19-related mortality, measurements of biomarkers of systemic hyperinflammation, and safety evaluations. Results: Among 454 patients who were randomized (median age, 59 years; 187 women [41.2%]), 417 (91.9%) completed day 29 of the trial. Between days 3 and 29, 198 of 223 patients (88.8%) survived without requiring IMV in the canakinumab group and 191 of 223 (85.7%) in the placebo group, with a rate difference of 3.1% (95% CI, -3.1% to 9.3%) and an odds ratio of 1.39 (95% CI, 0.76 to 2.54; P = .29). COVID-19-related mortality occurred in 11 of 223 patients (4.9%) in the canakinumab group vs 16 of 222 (7.2%) in the placebo group, with a rate difference of -2.3% (95% CI, -6.7% to 2.2%) and an odds ratio of 0.67 (95% CI, 0.30 to 1.50). Serious adverse events were observed in 36 of 225 patients (16%) treated with canakinumab vs 46 of 223 (20.6%) who received placebo. Conclusions and Relevance: Among patients hospitalized with severe COVID-19, treatment with canakinumab, compared with placebo, did not significantly increase the likelihood of survival without IMV at day 29. Trial Registration: ClinicalTrials.gov Identifier: NCT04362813.

Physical Function Impairment and Frailty in Middle-Aged People Living With Human Immunodeficiency Virus in the REPRIEVE Trial Ancillary Study PREPARE.

BACKGROUND: People with human immunodeficiency virus (PWH) are at risk for accelerated development of physical function impairment and frailty; both associated with increased risk of falls, hospitalizations, and death. Identifying factors associated with physical function impairment and frailty can help target interventions. METHODS: The REPRIEVE trial enrolled participants 40-75 years of age, receiving stable antiretroviral therapy with CD4+ T-cell count >100 cells/mm3, and with low to moderate cardiovascular disease risk. We conducted a cross-sectional analysis of those concurrently enrolled in the ancillary study PREPARE at enrollment. RESULTS: Among the 266 participants, the median age was 51 years; 81% were male, and 45% were black, and 28% had hypertension. Body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) was 25 to <30 in 38% and ≥30 in 30%, 33% had a high waist circumference, 89% were physically inactive, 37% (95% confidence interval, 31%, 43%) had physical function impairment (Short Physical Performance Battery score ≤10), and 6% (4%, 9%) were frail and 42% prefrail. In the adjusted analyses, older age, black race, greater BMI, and physical inactivity were associated with physical function impairment; depression and hypertension were associated with frailty or prefrailty. CONCLUSIONS: Physical function impairment was common among middle-aged PWH; greater BMI and physical inactivity are important modifiable factors that may prevent further decline in physical function with aging. CLINICAL TRIALS REGISTRATION: NCT02344290.

HIV Care Initiation: A Teachable Moment for Smoking Cessation?

Introduction: Tobacco use among persons living with HIV represents an important risk factor for poor treatment outcomes, morbidity, and mortality. Thus, efforts designed to inform the development of appropriate smoking cessation programs for this population remains a public health priority. To address this need, a study was conducted to longitudinally assess the relationship between intention to quit smoking and cessation over the 12-month period following initiation of HIV care. Methods: Patients initiating HIV care at a large inner city safety net clinic were enrolled (n = 378) in a 12-month prospective study. Audio computer-assisted self-interviews were conducted at baseline, and at 3, 6, 9, and 12 months post-enrollment, and HIV-related clinical data were collected from participants' electronic medical records. Variables of interest included intention to quit smoking, 7-day point prevalence smoking abstinence (biochemically verified), and stage of HIV. Data were collected in Houston, Texas from 2009 to 2015. Results: The sample was 75% male and 62% Black. Findings indicated that intention to quit smoking increased between baseline and 3 months, and subsequently trended downward from 3 to 12 months. Results from linear and generalized linear mixed models indicated that participants with advanced HIV disease (vs. not advanced) reported significantly (p < .05) higher intention to quit smoking at 3, 6, and 12 months post-study enrollment. A similar though nonsignificant pattern was observed in the smoking abstinence outcome. Conclusions: HIV treatment initiation appears to be associated with increases in intention to quit smoking thus serves as a potential teachable moment for smoking cessation intervention. Implications: This study documents significant increases in intention to quit smoking in the 3-month period following HIV care initiation. Moreover, quit intention trended downward following the 3-month follow-up until the 12-month follow-up. In addition, a marked effect for HIV disease stage was observed, whereby participants with advanced HIV disease (vs. those without) experienced a greater increase in intention to quit. HIV treatment initiation appears to be associated with increases in intention to quit smoking, thus serves as a crucial teachable moment for smoking cessation intervention for people living with HIV.

Combination antiretroviral therapy improves cognitive performance and functional connectivity in treatment-naïve HIV-infected individuals.

Our study aimed to investigate the short-term effect of combination antiretroviral therapy (cART) on cognitive performance and functional and structural connectivity and their relationship to plasma levels of antiretroviral (ARV) drugs. Seventeen ARV treatment-naïve HIV-infected individuals (baseline mean CD4 cell count, 479 ± 48 cells/mm3) were age matched with 17 HIV-uninfected individuals. All subjects underwent a detailed neurocognitive and functional assessment and magnetic resonance imaging. HIV-infected subjects were scanned before starting cART and 12 weeks after initiation of treatment. Uninfected subjects were assessed once at baseline. Functional connectivity (FC) was assessed within the default mode network while structural connectivity was assessed by voxel-wise analysis using tract-based spatial statistics (TBSS) and probabilistic tractography within the DMN. Tenofovir and emtricitabine blood concentration were measured at week 12 of cART. Prior to cART, HIV-infected individuals had significantly lower cognitive performance than control subjects as measured by the total Z-score from the neuropsychological tests assessing six cognitive domains (p = 0.020). After 12 weeks of cART treatment, there remained only a weak cognitive difference between HIV-infected and HIV-uninfected subjects (p = 0.057). Mean FC was lower in HIV-infected individuals compared with those uninfected (p = 0.008), but FC differences became non-significant after treatment (p = 0.197). There were no differences in DTI metrics between HIV-infected and HIV-uninfected individuals using the TBSS approach and limited evidence of decreased structural connectivity within the DMN in HIV-infected individuals. Tenofovir and emtricitabine plasma concentrations did not correlate with either cognitive performance or imaging metrics. CONCLUSIONS: Twelve weeks of cART improves cognitive performance and functional connectivity in ARV treatment-naïve HIV-infected individuals with relatively preserved immune function. Longer periods of observation are necessary to assess whether this effect is maintained.

Treatment-Naïve HIV-Infected Patients Have Fewer Gut-Homing ß7 Memory CD4 T Cells than Healthy Controls.

OBJECTIVES: The integrin α4ß7 is the gut-homing receptor for lymphocytes. It also is an important co-receptor for human immunodeficiency virus (HIV) via glycoprotein (gp)120 binding. Depletion of gut cluster of differentiation (CD)4 T cells is linked to chronic inflammation in patients with HIV; however, measuring CD4 cells in the gut is invasive and not routine. As such, establishing a peripheral marker for CD4 depletion of the gut is needed. We hypothesized that α4ß7 CD4 T cells are depleted in the peripheral blood of treatment-naïve patients with HIV compared with healthy controls. METHODS: The study groups were treatment-naïve patients with HIV and uninfected controls. Subjects were included if they were 18 years or older with no history of opportunistic infections, active tuberculosis, or cancer. We collected peripheral blood and examined on whole blood using flow cytometry for the following cell surface markers: CD4, CD45RO, chemokine receptor type 5, C-X-C chemokine receptor type 4 (CXCR4), and the integrin ß7. We collected demographic information, including age, sex, and ethnicity, as well as viral load (VL) and CD4 count. Two-sample t tests and Fisher exact tests were used to compare the differences between the two groups. Spearman correlation coefficients were calculated between CD4 count and log10- VL and percentage of CD4+/CD45RO+/ß7+ and log10- VL in patients. RESULTS: Twenty-two subjects were enrolled in the study (12 patients with HIV and 10 controls). There were no differences in age or sex between the two groups. There were more Hispanics and fewer Asians in the group comprising patients with HIV compared with the control group (7 vs 2 and 0 vs 4, P = 0.05, respectively). Patients infected with HIV had significantly lower frequencies of CD4+/CD45RO+/ß7+ cells (median 12%, range 5-18 compared with uninfected controls: median 20%, range 11-26, P = 0.0007). There was a statistically significant difference in the percentage of CD4+/CD45RO+/C-X-C chemokine receptor type 4+ cells between patients (72%, range 60%-91%) compared with controls (79%, range 72%-94%, P = 0.04). The percentage of CD4+/CD45RO+/chemokine receptor type 5+ did not differ between the group of patients with HIV and the control groups (22%, range 11%-57% vs 27%, range 14%-31%; P = 0.8, respectively). There was no correlation between percentage of CD4+/CD45RO+/ß+ cells and log10- VL as measured by the Spearman correlation coefficient (r = 0.05, P = 0.88) in patients infected with HIV. CONCLUSIONS: Memory CD4 ß7+ cells are reduced significantly in the peripheral blood of untreated patients infected with HIV, which could be used as a noninvasive indicator of intestinal CD4 T cell loss and recovery. Further studies are needed to examine whether depletion of these CD4+/CD45RO+/ß7+ cells in the peripheral blood parallels depletion in the gut of treatment-naïve patients with HIV and whether levels return to control levels after treatment.

The role of pain in quitting among human immunodeficiency virus (HIV)-positive smokers enrolled in a smoking cessation trial.

BACKGROUND: Smoking rates among people living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS; PLWHA) are at least twice as high as rates in the general population. Consistent with the reciprocal model of pain and smoking, PLWHA with pain who smoke may use smoking as a means of coping with pain, thus presenting a potential barrier to quitting. The aim of this study is to better understand how pain relates to smoking cessation among 474 HIV-positive adults enrolled in a cell phone-delivered smoking cessation trial. METHODS: Participants were randomly assigned to usual care (cessation advice and self-help materials) or 11 sessions of cell phone-delivered smoking cessation treatment. Pain, as assessed by the Medical Outcomes Study-HIV Health Survey (MOS-HIV), and point prevalence abstinence were collected at the 3-month treatment end and at 6- and 12-month follow-ups. Self-reported abstinence was biochemically verified by expired carbon monoxide (CO) level of <7 ppm. RESULTS: Using multilevel modeling for binary outcome data, the authors examined the relationship between pain and abstinence, from treatment end through the 12-month follow-up. Consistent with the authors' hypothesis, less pain was associated with greater likelihood of 24-hour (ß = .01, t(651) = 2.53, P = .01) and 7-day (ß = .01, t(651) = 2.35, P = .02) point prevalence abstinence, controlling for age, gender, baseline pain, nicotine dependence, and treatment group. No pain × treatment group interaction was observed. CONCLUSIONS: These results can help us to better identify PLWHA at greater risk for relapse in smoking cessation treatment. Future research may examine the effectiveness of more comprehensive smoking cessation treatment that incorporates aspects of pain management for PLWHA who smoke and have high pain and symptom burden.

Evaluation of Xpert MTB/RIF Versus AFB Smear and Culture to Identify Pulmonary Tuberculosis in Patients With Suspected Tuberculosis From Low and Higher Prevalence Settings.

BACKGROUND: The Xpert MTB/RIF (Xpert) assay is a rapid nucleic acid amplification test widely used in settings of high tuberculosis prevalence to detect tuberculosis as well asrpoBmutations associated with rifampin resistance. Data are needed on the diagnostic performance of Xpert in lower-prevalence settings to inform appropriate use for both tuberculosis detection and the need for respiratory isolation. METHODS: Xpert was compared to 2 sputum samples, each evaluated with acid-fast bacilli (AFB) smear and mycobacterial culture using liquid and solid culture media, from participants with suspected pulmonary tuberculosis from the United States, Brazil, and South Africa. RESULTS: Of 992 participants enrolled with evaluable results, 22% had culture-confirmed tuberculosis. In 638 (64%) US participants, 1 Xpert result demonstrated sensitivity of 85.2% (96.7% in participants with AFB smear-positive [AFB(+)] sputum, 59.3% with AFB smear-negative [AFB(-)] sputum), specificity of 99.2%, negative predictive value (NPV) of 97.6%, and positive predictive value of 94.9%. Results did not differ between higher- and low-prevalence settings. A second Xpert assay increased overall sensitivity to 91.1% (100% if AFB(+), 71.4% if AFB(-)), with specificity of 98.9%. In US participants, a single negative Xpert result predicted the absence of AFB(+)/culture-positive tuberculosis with an NPV of 99.7%; NPV of 2 Xpert assays was 100%, suggesting a role in removing patients from airborne infection isolation. Xpert detected tuberculosis DNA and mutations associated with rifampin resistance in 5 of 7 participants with rifampin-resistant, culture-positive tuberculosis. Specificity for rifampin resistance was 99.5% and NPV was 98.9%. CONCLUSIONS: In the United States, Xpert testing performed comparably to 2 higher-tuberculosis-prevalence settings. These data support the use of Xpert in the initial evaluation of tuberculosis suspects and in algorithms assessing need for respiratory isolation.

The role of BMI change on smoking abstinence in a sample of HIV-infected smokers.

The prevalence of cigarette smoking among persons living with HIV/AIDS (PLWHA) is approximately 40%, significantly higher than that of the general population. Identifying predictors of successful smoking cessation for PLWHA is necessary to alleviate the morbidity and mortality associated with smoking in this population. Weight gain has been associated with smoking relapse in the general population, but has not been studied among PLWHA. Data from 474 PLWHA enrolled in a smoking cessation randomized clinical trial were analyzed to examine the effect of BMI change, from baseline to 3-month follow-up, on smoking outcomes using multiple logistic regression. The odds of 7-day smoking abstinence at 3-month follow-up were 4.22 (95% CI = 1.65, 10.82) times higher for participants classified as BMI decrease and 4.22 (95% CI = 1.62, 11.01) times higher for participants classified as BMI increase as compared to participants with a minimal increase or decrease in BMI. In this sample, both weight gain and loss following smoking cessation were significantly associated with abstinence at 3-month follow-up among HIV-infected smokers. Further research and a better understanding of predictors of abstinence will encourage more tailored interventions, with the potential to reduce morbidity and mortality.

Cervical cancer screening adherence among HIV-positive female smokers from a comprehensive HIV clinic.

HIV-positive women are at elevated risk for developing cervical cancer. While emerging research suggests that gynecologic health care is underutilized by HIV-positive women, factors associated with adherence to Pap testing, especially among HIV-positive female smokers are not well known. We utilized baseline data from a smoking cessation trial and electronic medical records to assess Pap smear screening prevalence and the associated characteristics among the HIV-positive female participants (n = 138). 46 % of the women had at least 1 Pap test in the year following study enrollment. Multiple logistic regression analysis indicated that younger age, African American race, hazardous drinking, increased number of cigarettes smoked per day, and smoking risk perception were associated with non-adherence to Pap smear screening. Cervical cancer screening was severely underutilized by women in this study. Findings underscore the importance of identifying predictors of non-adherence and addressing multiple risk factors and behavioral patterns among HIV-positive women who smoke.

Perceptions of barriers and facilitators to cervical cancer screening among low-income, HIV-infected women from an integrated HIV clinic.

Significantly elevated rates of cervical cancer and low rates of Papanicolaou (Pap) smear screening have been documented among HIV-infected women. However, little is known about women's perceptions of cervical cancer screening utilization. Hence, this study describes barriers and facilitators related to cervical cancer screening in a sample of HIV-infected women seeking care at an integrated HIV clinic in Houston, Texas. Using an inductive qualitative methodological approach, data were obtained from five focus group discussions with a total of 33, HIV-infected women. The majority of the study sample consisted of women who self-identified as Black (69.7%), and reported heterosexual contact as the mode of HIV acquisition (75.8%). Barriers to cervical cancer screening were described as pain and discomfort associated with receiving Pap smears and subsequent procedures; lack of awareness of cervical cancer as a preventable disease; limited transportation access; and systemic issues as it relates to scheduling gynecological appointments. Facilitators were described as awareness of HIV-infected women's increased risk of cervical cancer and strong provider-patient relationships. To address disparities in cervical cancer screening among low-income HIV-infected women, programs should capitalize on the identified facilitators and alleviate modifiable barriers using multilevel strategies.

The influence of HIV disease events/stages on smoking attitudes and behaviors: project STATE (Study of Tobacco Attitudes and Teachable Events).

BACKGROUND: Given the increase in life expectancy among HIV-positive individuals attributable to antiretroviral therapies, cigarette smoking now represents one of the most salient health risks confronting the HIV-positive population. Despite this risk, very few efforts to date have been made to target persons living with HIV for smoking cessation treatment, and no efforts have been made to explore the role of cognitions and HIV disease events/stages on smoking outcomes. The purpose of the study, Project STATE (Study of Tobacco Attitudes and Teachable Events), is to prospectively examine the relationship between HIV events/stages, perceived impact of HIV disease, attitudes about cigarette smoking, and smoking behaviors. METHODS/DESIGN: This study employs a prospective design. Patients are recruited at the time of their first physician visit at a large inner city HIV-clinic--Thomas Street Health Center (TSHC). Consenting participants then complete a baseline assessment. All participants are offered standard care smoking cessation treatment. Follow-up assessments are completed on four subsequent occasions: 3, 6, 9, and 12 months post-baseline. These follow-up assessments are scheduled to coincide with routine clinic appointments with their TSHC physicians. In addition, each participant is given a prepaid cell phone at the time of enrollment and asked to complete brief phone assessments weekly for the first three months of the study period. DISCUSSION: By evaluating events/stages of HIV disease as potential teaching moments for smoking cessation, findings from this study could be used to develop treatments tailored to an individual's stage of HIV disease. This study design will enable us to carefully track changes in smoking behavior over time, and to link these changes to both the course of HIV disease and/or to the participant's' perceived impact of HIV. By identifying optimal time points for intervention, the findings from this study will have the potential to maximize the efficiency and efficacy of cessation treatments delivered in resource-limited settings. In addition, the findings will be instrumental in identifying specific constructs that should be targeted for intervention and will provide a strong foundation for the development of future cessation interventions targeting smokers living with HIV/AIDS.

Antiviral potency of long-acting islatravir subdermal implant in SHIV-infected macaques.

Treatment nonadherence is a pressing issue in people living with HIV (PLWH), as they require lifelong therapy to maintain viral suppression. Poor adherence leads to antiretroviral (ARV) resistance, transmission to others, AIDS progression, and increased morbidity and mortality. Long-acting (LA) ARV therapy is a promising strategy to combat the clinical drawback of user-dependent dosing. Islatravir (ISL) is a promising candidate for HIV treatment given its long half-life and high potency. Here we show constant ISL release from a subdermal LA nanofluidic implant achieves viral load reduction in SHIV-infected macaques. Specifically, a mean delivery dosage of 0.21 ± 0.07 mg/kg/day yielded a mean viral load reduction of -2.30 ± 0.53 log10 copies/mL at week 2, compared to baseline. The antiviral potency of the ISL delivered from the nanofluidic implant was higher than oral ISL dosed either daily or weekly. At week 3, viral resistance to ISL emerged in 2 out of 8 macaques, attributable to M184V mutation, supporting the need of combining ISL with other ARV for HIV treatment. The ISL implant produced moderate reactivity in the surrounding tissue, indicating tolerability. Overall, we present the ISL subdermal implant as a promising approach for LA ARV treatment in PLWH.

Impact of antiretroviral therapy during acute or early HIV infection on virologic and immunologic outcomes: results from a multinational clinical trial.

OBJECTIVE: To assess how antiretroviral therapy (ART) initiation during acute or early HIV infection (AEHI) affects the viral reservoir and host immune responses. DESIGN: Single-arm trial of ART initiation during AEHI at 30 sites in the Americas, Africa, and Asia. METHODS: HIV DNA was measured at week 48 of ART in 5 million CD4 + T cells by sensitive qPCR assays targeting HIV gag and pol . Peripheral blood mononuclear cells were stimulated with potential HIV T cell epitope peptide pools consisting of env , gag , nef, and pol peptides and stained for expression of CD3, CD4, CD8, and intracellular cytokines/chemokines. RESULTS: From 2017 to 2019, 188 participants initiated ART during Fiebig stages I ( n  = 6), II ( n  = 43), III ( n  = 56), IV ( n  = 23), and V ( n  = 60). Median age was 27 years (interquartile range 23-38), 27 (14%) participants were female, and 180 (97%) cisgender. Among 154 virally suppressed participants at week 48, 100% had detectable HIV gag or pol DNA. Participants treated during Fiebig I had the lowest HIV DNA levels ( P  < 0.001). Week 48 HIV DNA mostly did not correlate with concurrent CD4 + or CD8 + T cell HIV-specific immune responses (rho range -0.11 to +0.19, all P  > 0.025). At week 48, the magnitude, but not polyfunctionality, of HIV-specific T cell responses was moderately reduced among participants who initiated ART earliest. CONCLUSION: Earlier ART initiation during AEHI reduced but did not eliminate the persistence of HIV-infected cells in blood. These findings explain the rapid viral rebound observed after ART cessation in early-treated individuals with undetectable HIV DNA by less sensitive methods.

Long-term outcomes of a cell phone-delivered intervention for smokers living with HIV/AIDS.

BACKGROUND: People living with human immunodeficiency virus (HIV)/AIDS (PLWHA) have a substantially higher prevalence of cigarette smoking compared to the general population. In addition, PLWHA are particularly susceptible to the adverse health effects of smoking. Our primary objective was to design and test the efficacy over 12 months of a smoking cessation intervention targeting PLWHA. METHODS: Participants were enrolled from an urban HIV clinic with a multiethnic and economically disadvantaged patient population. Participants received smoking cessation treatment either through usual care (UC) or counseling delivered by a cell phone intervention (CPI). The 7-day point prevalence abstinence was evaluated at 3, 6, and 12 months using logistic regression and generalized linear mixed models. RESULTS: We randomized 474 HIV-positive smokers to either the UC or CPI group. When evaluating the overall treatment effect (7-day abstinence outcomes from 3-, 6-, and 12-month follow-ups), participants in the CPI group were 2.41 times (P = .049) more likely to demonstrate abstinence compared to the UC group. The treatment effect was strongest at the 3-month follow-up (odds ratio = 4.3, P < .001), but diminished at 6 and 12 months (P > .05). CONCLUSIONS: Cell phone-delivered smoking cessation treatment has a positive impact on abstinence rates compared to a usual care approach. Future research should focus on strategies for sustaining the treatment effect in the long term.

Poly-tobacco use among HIV-positive smokers: implications for smoking cessation efforts.

INTRODUCTION: Poly-tobacco use is defined as cigarette and other tobacco consumption with either product used daily or nondaily. While concurrent use of different types of tobacco has been documented within the general population, less is known about poly-tobacco use among HIV-positive smokers and its impact on smoking cessation efforts. OBJECTIVE: To characterize the profile of poly-tobacco users (PTU) in a sample of HIV-positive smokers participating in a cessation program. METHODS: The study sample consisted of 474 HIV-positive smokers enrolled in a 2-group randomized controlled trial of cigarette smoking cessation comparing a cell phone-based intervention to usual care. Prevalence was determined, and risk factors for poly-tobacco use were evaluated using logistic regression. RESULTS: In this cohort of HIV-positive cigarette smokers, 21.6% of participants were PTU, with cigars (73.4%) the most common tobacco product consumed. Among PTU, 73.5% used other form(s) of tobacco some days, and 26.5% use them every day. Perceived discrimination and unemployment were significantly associated with poly-tobacco use after adjusting for other demographic, behavioral, and psychosocial factors. Analysis showed that participants in the cell phone group (vs. usual care) were more likely to report 24-hr abstinence, both among monocigarette users (16.6% vs. 6.3%, p < .001) and PTU (18.5% vs. 0%, p < .001). CONCLUSION: Poly-tobacco use prevalence among adult HIV-positive smokers was considerably higher than in the general population. Special attention must be placed on concurrent use of cigarettes and cigars among HIV-positive smokers. Because PTU are a unique population less likely to succeed in brief smoking cessation interventions, effective cessation programs are needed.

Changes in local tissue microenvironment in response to subcutaneous long-acting delivery of tenofovir alafenamide in rats and non-human primates.

Several implantable long-acting (LA) delivery systems have been developed for sustained subcutaneous administration of tenofovir alafenamide (TAF), a potent and effective nucleotide reverse transcriptase inhibitor used for HIV pre-exposure prophylaxis (PrEP). LA platforms aim to address the lack of adherence to oral regimens, which has impaired PrEP efficacy. Despite extensive investigations in this field, tissue response to sustained subcutaneous TAF delivery remains to be elucidated as contrasting preclinical results have been reported in the literature. To this end, here we studied the local foreign body response (FBR) to sustained subdermal delivery of three forms of TAF, namely TAF free base (TAFfb), TAF fumarate salt (TAFfs), and TAFfb with urocanic acid (TAF-UA). Sustained constant drug release was achieved via titanium-silicon carbide nanofluidic implants previously shown to be bioinert. The analysis was conducted in both Sprague-Dawley (SD) rats and rhesus macaques over 1.5 and 3 months, respectively. While visual observation did not reveal abnormal adverse tissue reaction at the implantation site, histopathology and Imaging Mass Cytometry (IMC) analyses exposed a local chronic inflammatory response to TAF. In rats, UA mitigated foreign body response to TAF in a concentration-dependent manner. This was not observed in macaques where TAFfb was better tolerated than TAFfs and TAF-UA. Notably, the level of FBR was tightly correlated with local TAF tissue concentration. Further, regardless of the degree of FBR, the fibrotic capsule (FC) surrounding the implants did not interfere with drug diffusion and systemic delivery, as evidenced by TAF PK results and fluorescence recovery after photobleaching (FRAP).

Ideal cardiovascular health, biomarkers, and coronary artery disease in persons with HIV.

OBJECTIVE: To investigate relationships between Life's Simple 7 (LS7), an assessment of cardiovascular health (CVH), and coronary plaque among people with HIV (PWH). DESIGN: Cross-sectional. METHODS: Coronary computed tomography angiography, immune/inflammatory biomarkers, and characterization of LS7 were collected among a subset of ART-treated PWH enrolled in REPRIEVE, a primary prevention trial. Analyses adjusted for cardiovascular disease risk (ASCVD score). RESULTS: Median age of the 735 participants was 51(±6) years, 16% female, and median (Q1-Q3) CVD risk was 4.5% (2.6-6.9). Forty percent had poor (≤2 ideal components), 51% had intermediate (three or four ideal components), and only 9% had ideal CVH (≥5). Coronary plaque was present in 357 (49%); 167 (23%) had one or more vulnerable plaque features, 293 (40%) had noncalcified plaque, and 242 (35%) had a coronary artery calcium score >0. All three phenotypes were increasingly more prevalent with poorer CVH and these relationships remained after adjusting for ASCVD risk. Poor CVH was associated with higher high-sensitivity C-reactive protein, oxidized low-density cholesterol, and interleukin-6. The relationship of LS7 to plaque remained after adjusting for these biomarkers. CONCLUSIONS: Among PWH, poor CVH as measured by LS7 was associated with coronary plaque presence, vulnerable features, and calcification. LS7 was also associated with selected biomarkers; adjustment for these and ASCVD score reduced but did not eliminate LS7's association with plaque, suggesting the possibility of additional protective mechanisms against atherogenesis and plaque remodeling. Clinical use of LS7 and further exploration of its relationships with coronary artery disease may enhance efforts to reduce cardiovascular morbidity and mortality in PWH. CLINICAL TRIALS REGISTRATION: NCT02344290.