Building an Infectious Disease Diversity, Equity, and Antiracism (ID2EA) Curriculum: A Single Center's Experience and Reflections.

In response to longstanding healthcare inequities unmasked by the Coronavirus Disease 2019 pandemic, the infectious diseases (ID) section at the Yale School of Medicine designed and implemented a pilot curriculum integrating Infectious Disease Diversity, Equity, and Antiracism (ID2EA) into ID educational training and measured program outcomes. We herein describe a mixed-methods assessment of section members on whether the ID2EA curriculum affected their beliefs and behaviors regarding racism and healthcare inequities. Participants rated the curriculum as useful (92% averaging across sessions) and effective in achieving stated learning objectives (89% averaging across sessions), including fostering understanding of how inequities and racism are linked to health disparities and identifying strategies to effectively deal with racism and inequities. Despite limitations in response rates and assessment of longer-term behavioral change, this work demonstrates that training in diversity, equity, and antiracism can be successfully integrated into ID physicians' educational activities and affect physicians' perspectives on these topics.

Prevalence and Correlates of Physical Inactivity Among Individuals with HIV During the First COVID-19 Wave: A Cross-sectional Survey.

Physical activity is associated with improved health outcomes among people with HIV (PWH). In the recent pandemic context, policies designed to mitigate COVID-19 transmission may result in an increase in sedentary lifestyle and decreased physical activity. In this study, we aimed to characterize self-reported physical activity and factors associated with physical inactivity during the first wave of the COVID-19 pandemic among a sample of PWH engaged in care. We also described whether psychological coping strategies measured by the Brief COPE differed based on physical activity levels. Among 260 surveyed PWH in two HIV clinics in the US Northeast, 28.5% (n = 74) met the criteria for being physically active according to the Centers for Disease Control and Prevention (CDC)'s physical activity guidelines. Receiving care in New Haven, CT, presence of a detectable HIV viral load, every day tobacco use, and unhealthy alcohol use were associated with physical inactivity. Problem-focused coping, emotion-focused coping, and avoidance-focused coping strategies were found to be protective against physical inactivity. In adjusted analysis, only problem-focused coping continued to be significantly associated with lower odds of reporting physical inactivity. Efforts are urgently needed to promote physical activity among PWH, including among those without problem-focused coping strategies.

RESUMEN: La actividad física se asocia con mejores resultados de salud entre las personas con VIH (PCV). En el contexto de la reciente pandemia, las políticas diseñadas para mitigar la transmisión de COVID-19 pueden resultar en un aumento del estilo de vida sedentario y una disminución de la actividad física. En este estudio, nuestro objetivo fue caracterizar la actividad física autoinformada y los factores asociados con la inactividad física durante la primera ola de la pandemia de COVID-19 entre una muestra de PCV dedicados a la atención. También describimos si las estrategias psicológicas de afrontamiento medidas por el Brief COPE diferían según los niveles de actividad física. Entre las 260 PCV encuestadas en dos clínicas de VIH en el noreste de EE. UU., el 28,5% (n = 74) cumplía con los criterios para ser físicamente activo de acuerdo con las pautas de actividad física del Centros para el Control y la Prevención de Enfermedades (CDC). Recibir atención en New Haven, CT, la presencia de una carga viral de VIH detectable, el consumo diario de tabaco, y el consumo insano de alcohol se asociaron con la inactividad física. Se encontró que el afrontamiento centrado en el problema, el afrontamiento centrado en la emoción, y las estrategias de afrontamiento centradas en la evitación, protegen contra la inactividad física. En el análisis ajustado, solo el afrontamiento centrado en el problema siguió estando significativamente asociado con menores probabilidades de informar sobre la inactividad física. Se necesitan esfuerzos urgentes para promover la actividad física entre las PCV, incluso entre aquellas que no tienen estrategias de afrontamiento centradas en el problema.

Adherence Measured Using Electronic Dose Monitoring is Associated with Emergent Antiretroviral Resistance and Poor Outcomes in People with Human Immunodeficiency Virus/AIDS and Multidrug-Resistant Tuberculosis.

BACKGROUND: Medication adherence is known to challenge treatment of human immunodeficiency virus (HIV)/AIDS and multidrug-resistant tuberculosis (MDR-TB). We hypothesized that adherence using electronic dose monitoring (EDM) would identify an antiretroviral therapy (ART) adherence threshold for emergent ART resistance and predict treatment outcomes in patients with MDR-TB and HIV on ART and bedaquiline-containing TB regimens. METHODS: A prospective cohort of adults with MDR-TB and HIV on ART and initiating MDR-TB treatment with bedaquiline were enrolled at a public hospital in KwaZulu-Natal, South Africa (PRAXIS Study). Participants received separate EDM devices that measure adherence to bedaquiline and ART (nevirapine or lopinavir/ritonavir). Adherence was calculated cumulatively over 6 months. Participants were followed through completion of MDR-TB treatment. HIV genome sequencing was performed at baseline and 2 and 6 months on samples with HIV RNA ≥1000 copies/mL. RESULTS: From November 2016 through February 2018, 198 persons with MDR-TB and HIV were enrolled and followed (median, 17.2 months; interquartile range, 12.2-19.6). Eleven percent had baseline ART resistance mutations, and 7.5% developed emergent ART resistance at 6 months. ART adherence was independently associated with ART resistance and mortality. Modeling identified a significant (P < .001), linear association between ART adherence and emergent resistance, suggesting a strong association without a specific threshold. CONCLUSIONS: Our findings highlight the need for ART resistance testing, especially in patients with MDR-TB and HIV, which is currently not the standard of care in resource-limited settings. Despite short follow-up duration, reduced ART adherence was significantly associated with emergent resistance and increased mortality. CLINICAL TRIALS REGISTRATION: NCT03162107.

Qualitative assessment of anti-SARS-CoV-2 spike protein immunogenicity (QUASI) after COVID-19 vaccination in older people living with HIV.

OBJECTIVES: Effective and safe COVID-19 vaccines have been developed and have resulted in decreased incidence and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and can decrease secondary transmission. However, there are concerns about dampened immune responses to COVID-19 vaccination among immunocompromised patients, including people living with HIV (PLWH), which may blunt the vaccine's efficacy and durability of protection. This study aimed to assess the qualitative SARS-CoV-2 vaccine immunogenicity among PLWH after vaccination. METHODS: We conducted targeted COVID-19 vaccination (all received BNT162b2 vaccine) of PLWH (aged ≥ 55 years per state guidelines) at Yale New Haven Health System and established a longitudinal survey to assess their qualitative antibody responses at 3 weeks after the first vaccination (and prior to receipt of the second dose of the COVID-19 vaccine) (visit 1) and at 2-3 weeks after the second vaccination (visit 2) but excluded patients with prior COVID-19 infection. Our goal was to assess vaccine-induced immunity in the population we studied. Qualitative immunogenicity testing was performed using Healgen COVID-19 anti-Spike IgG/IgM rapid testing. Poisson regression with robust standard errors was used to determine factors associated with a positive IgG response. RESULTS: At visit 1, 45 of 78 subjects (57.7%) tested positive for SARS-CoV-2 anti-Spike IgG after the first dose of COVID-19 vaccine. Thirty-nine subjects returned for visit 2. Of these, 38 had positive IgG (97.5%), including 20 of 21 subjects (95.2%) with an initial negative anti-Spike IgG. Our bivariate analysis suggested that participants on an antiretroviral regimen containing integrase strand transfer inhibitors [relative risk (RR) = 1.81, 95% confidence interval (CI): 0.92-3.56, p = 0.085] were more likely to seroconvert after the first dose of the COVID-19 vaccine, while those with a CD4 count < 500 cells/µL (RR = 0.59, 95% CI: 0.33-1.05, p = 0.071), and those diagnosed with cancer or another immunosuppressive condition (RR = 0.49, 95% CI: 0.18-1.28, p = 0.15) may have been less likely to seroconvert after the first dose of the COVID-19 vaccine. The direction of these associations was similar in the multivariate model, although none of these findings reached statistical significance (RRintegrase inhibitor  = 1.71, 95% CI: 0.90-3.25, p = 0.10; RRCD4 count  = 0.68, 95% CI: 0.39-1.19, p = 0.18; RRcancer or another immunosuppressive condition  = 0.50, 95% CI: 0.19-1.33, p = 0.16). With regard to immunogenicity, we were able to record very high rates of new seroconversion following the second dose of the COVID-19 vaccine. CONCLUSIONS: Our study suggests that completing a two-dose series of BNT162b2 vaccine is critical for PLWH given suboptimal seroconversion rates after the first dose and subsequent improved seroconversion rates after the second dose.

Experiences with Telemedicine for HIV Care During the COVID-19 Pandemic: A Mixed-Methods Study.

To characterize perspectives and experiences with telemedicine during the COVID-19 pandemic, we conducted a mixed-methods study in two HIV clinics in the US Northeast. Among surveyed patients with HIV (PWH) who had a telemedicine appointment (n = 205), 42.4% perceived telemedicine visits as useful during the pandemic. PWH and clinical staff identified benefits of telemedicine: (1) ability to engage and re-engage patients in care; (2) perceived patient-centeredness and flexibility; (3) opportunity to engage family and multidisciplinary care team members; and (4) opportunity to enhance telemedicine use proficiency through practice and support. Identified barriers included: (1) technical challenges; (2) privacy concerns; (3) loss of routine clinical experiences and interactions; (4) limited objective patient remote monitoring; and (5) reimbursement concerns. Efforts to optimize telemedicine for HIV care should consider strategies to improve technology support for PWH, flexible options to access care, additional platforms to allow patient remote monitoring, and appropriate billing and reimbursement methods.

RESUMEN: Para caracterizar las perspectivas sobre y las experiencias con la telemedicina durante la pandemia de COVID-19, realizamos un estudio de métodos mixtos en dos clínicas de VIH en el noreste de los Estados Unidos. Entre los pacientes con VIH (PWH) encuestados que tuvieron una cita de telemedicina (n = 205), el 42.4% percibió las visitas de telemedicina como útiles durante la pandemia. Los PWH y el personal clínico identificaron como beneficios de la telemedicina: 1) la capacidad para involucrar y reinvolucrar a los pacientes en el cuidado; 2) el cuidado centrado en el paciente y flexibilidad percibidos; 3) la oportunidad de involucrar a la familia y miembros del equipo de cuidado multidisciplinario; y 4) la oportunidad de mejorar la capacidad para usar la telemedicina a través de la práctica y el apoyo. Las barreras identificadas incluyeron: 1) retos tecnológicos; 2) preocupaciones sobre la privacidad; 3) falta de experiencias e interacciones clínicas de rutina; 4) limitada monitorización remota objetiva del paciente; y 5) preocupaciones sobre los reembolsos. Los esfuerzos para optimizar la telemedicina para el cuidado del VIH deben considerar estrategias para mejorar el soporte tecnológico para los PWH, opciones flexibles para acceder a el cuidado, plataformas adicionales que permitan el monitoreo remoto del paciente, y métodos apropiados de facturación y reembolso.

Long-term quantitative assessment of anti-SARS-CoV-2 spike protein immunogenicity (QUASI) after COVID-19 vaccination in older people living with HIV (PWH).

BACKGROUND: The durability of immune responses to COVID-19 vaccines among older people living with HIV (PWH) is clinically important. METHODS: We aimed to assess vaccine-induced humoral immunity and durability in older PWH (≥ 55 years, n = 26) over 6 months (post-initial BNT162b2 series). A secondary and exploratory objective was to assess T-cell response and BNT162b2 booster reactogenicity, respectively. Our Visit 1 (3 weeks post-initial BNT162b2 dose) SARS-CoV-2 humoral immunity results are previously reported; these subjects were recruited for Visit 2 [2 weeks (+ 1 week window) post-second vaccination] and Visit 3 [6 months (± 2 week window) post-initial vaccination] in a single-center longitudinal observational study. Twelve participants had paired Visit 2/3 SARS-CoV-2 Anti-Spike IgG data. At Visit 3, SARS-CoV-2 Anti-Spike IgG testing occurred, and 5 subjects underwent T-cell immune response evaluation. Thereafter, subjects were offered BNT162b2 booster (concurrent day outside our study) per US FDA/CDC guidance; reactogenicity was assessed. The primary study outcome was presence of detectable Visit 3 SARS-CoV-2 Anti-Spike-1-RBD IgG levels. Secondary and exploratory outcomes were T-cell immune response and BNT162b2 booster reactogenicity, respectively. Wilcoxon signed-rank tests analyzed median SARS-CoV-2 Anti-Spike IgG 6-month trends. RESULTS: At Visit 3, 26 subjects underwent primary analysis with demographics noted: Median age 61 years; male n = 16 (62%), female n = 10 (38%); Black n = 13 (50%), White n = 13 (50%). Most subjects (n = 20, 77%) had suppressed HIV viremia on antiretroviral therapy, majority (n = 24, 92%) with CD4 > 200 cells/µL. At Visit 3, 26/26 (100%) had detectable Anti-Spike-1-RBD (≥ 0.8 U/mL). Among 12 subjects presenting to Visit 2/3, median SARS-CoV-2 Anti-Spike 1-RBD was 2087 U/mL at Visit 2, falling to 581.5 U/mL at Visit 3 (p = 0.0923), with a median 3.305-fold decrease over 6 months. Among subjects (n = 5) with 6-month T-cell responses measured, all had detectable cytokine-secreting anti-spike CD4 responses; 3 had detectable CD4 + Activation induced marker (AIM) + cells. Two had detectable cytokine-secreting CD8 responses, but all had positive CD8 + AIM + cells. CONCLUSIONS: Among older PWH, SARS-CoV-2 Anti-Spike IgG and virus-specific T-cell responses are present 6 months post-primary BNT162b2 vaccination, and although waning, suggest retention of some degree of long-term protective immunity.

Electronic Dose Monitoring Identifies a High-Risk Subpopulation in the Treatment of Drug-resistant Tuberculosis and Human Immunodeficiency Virus.

BACKGROUND: In generalized drug-resistant tuberculosis (DR-TB) human immunodeficiency virus (HIV) epidemics, identifying subpopulations at high risk for treatment failure and loss to care is critically important to improve treatment outcomes and prevent amplification of drug resistance. We hypothesized that an electronic dose-monitoring (EDM) device could empirically identify adherence-challenged patients and that a mixed-methods approach would characterize treatment challenges. METHODS: A prospective study of patients with DR-TB HIV on antiretroviral therapy (ART) initiating bedaquiline-containing regimens in KwaZulu-Natal, South Africa. Separate EDM devices measured adherence for bedaquiline and ART. Patients with low adherence (<85%) to both bedaquiline and ART were identified as high risk for poor outcomes. Baseline survey, study visit notes, and focus group discussions characterized treatment challenges. RESULTS: From December 2016-February 2018, 32 of 198 (16%) enrolled patients with DR-TB HIV were identified as dual-adherence challenged. In a multivariate model including baseline characteristics, only receiving a disability grant was significantly associated with dual nonadherence at 6 months. Mixed-methods identified treatment barriers including alcohol abuse, family conflicts, and mental health issues. Compared with adherent patients, dual-adherence-challenged patients struggled to prioritize treatment and lacked support, and dual-adherence-challenged patients experienced higher rates of detectable HIV viral load and mortality than more adherent patients. CONCLUSIONS: EDM empirically identified a subpopulation of patients with DR-TB HIV with dual-adherence challenges early in treatment. Mixed-methods revealed intense psychosocial, behavioral, and structural barriers to care in this subpopulation. Our data support developing differential, patient-centered, adherence support interventions focused on psychosocial and structural challenges for subpopulations of at-risk DR-TB HIV patients.

Confronting Another Pandemic: Lessons from HIV can Inform Our COVID-19 Response.

The novel coronavirus 2019 illness (COVID-19) has completely transformed and uprooted lives across the globe. While different diseases, there are critical observations and lessons to be learned from the ongoing HIV epidemic to inform our response to COVID-19. We reflect on how this relates to (1) testing, including contact tracing; (2) health system redesign; (3) telehealth; (4) health disparities; (5) political denial, with inadequate and uncoordinated governmental response; (6) occupational exposure; and (7) complex reactions among healthcare providers. Decades of experiences with HIV provide an important framework for moving forward as we combat COVID-19.

Reducing Loss to Follow-Up with Tele-audiology Diagnostic Evaluations.

BACKGROUND: Infants who do not pass their newborn hearing screen require diagnostic follow-up visits but often face access barriers such as travel distance and shortage of pediatric audiologists. Telemedicine (tele-audiology) is a potential solution to provide diagnostic hearing evaluations for families of infants facing access barriers. We determined the feasibility and impact of a tele-audiology program that provided comprehensive diagnostic evaluations to a region with a high lost to follow-up rate among newborns who did not pass their newborn hearing screen. MATERIALS AND METHODS: We evaluated the tele-audiology program using parent and provider surveys to determine the perception of quality and satisfaction of care. We also compared the lost to follow-up rate of the tele-audiology program with the loss to follow-up in the region before the implementation of the program. RESULTS: Twenty-two infants who did not pass their newborn hearing screen were referred to the tele-audiology program for diagnostic evaluation. Among these infants, 59.1% were diagnosed with some form of hearing loss. The mean quality score rated by both parents and providers on the telemedicine interaction was over 6.5 on a 7-point Likert scale. All parents rated the importance of tele-audiology as 7 (extremely important) for their family, whereas the provider rated the mean importance as 6.4 (95% confidence interval, 5.9, 6.9) on a 7-point Likert scale. Almost all parents actively participated or were engaged during history taking and counseling and were comfortable in discussing their child's hearing status remotely over telemedicine. All infants completed their diagnostic evaluation with no loss to follow-up compared with 22% loss to follow-up in the region before the implementation of the program. CONCLUSIONS: Tele-audiology is a feasible solution that reduces the loss to follow-up among infants who do not pass their newborn hearing screen and have access barriers to qualified audiologists for diagnostic evaluations.

Minimal diversity of drug-resistant Mycobacterium tuberculosis strains, South Africa.

Multidrug- (MDR) and extensively drug-resistant tuberculosis (XDR TB) are commonly associated with Beijing strains. However, in KwaZulu-Natal, South Africa, which has among the highest incidence and mortality for MDR and XDR TB, data suggest that non-Beijing strains are driving the epidemic. We conducted a retrospective study to characterize the strain prevalence among drug-susceptible, MDR, and XDR TB cases and determine associations between strain type and survival. Among 297 isolates from 2005-2006, 49 spoligotype patterns were found. Predominant strains were Beijing (ST1) among drug-susceptible isolates (27%), S/Quebec (ST34) in MDR TB (34%) and LAM4/KZN (ST60) in XDR TB (89%). More than 90% of patients were HIV co-infected. MDR TB and XDR TB were independently associated with mortality, but TB strain type was not. We conclude that, although Beijing strain was common among drug-susceptible TB, other strains predominated among MDR TB and XDR TB cases. Drug-resistance was a stronger predictor of survival than strain type.

Integration of antiretroviral therapy with tuberculosis treatment.

BACKGROUND: We previously reported that integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, the timing for the initiation of ART during tuberculosis treatment remains unresolved. METHODS: We conducted a three-group, open-label, randomized, controlled trial in South Africa involving 642 ambulatory patients, all with tuberculosis (confirmed by a positive sputum smear for acid-fast bacilli), human immunodeficiency virus infection, and a CD4+ T-cell count of less than 500 per cubic millimeter. Findings in the earlier-ART group (ART initiated within 4 weeks after the start of tuberculosis treatment, 214 patients) and later-ART group (ART initiated during the first 4 weeks of the continuation phase of tuberculosis treatment, 215 patients) are presented here. RESULTS: At baseline, the median CD4+ T-cell count was 150 per cubic millimeter, and the median viral load was 161,000 copies per milliliter, with no significant differences between the two groups. The incidence rate of the acquired immunodeficiency syndrome (AIDS) or death was 6.9 cases per 100 person-years in the earlier-ART group (18 cases) as compared with 7.8 per 100 person-years in the later-ART group (19 cases) (incidence-rate ratio, 0.89; 95% confidence interval [CI], 0.44 to 1.79; P=0.73). However, among patients with CD4+ T-cell counts of less than 50 per cubic millimeter, the incidence rates of AIDS or death were 8.5 and 26.3 cases per 100 person-years, respectively (incidence-rate ratio, 0.32; 95% CI, 0.07 to 1.13; P=0.06). The incidence rates of the immune reconstitution inflammatory syndrome (IRIS) were 20.1 and 7.7 cases per 100 person-years, respectively (incidence-rate ratio, 2.62; 95% CI, 1.48 to 4.82; P<0.001). Adverse events requiring a switching of antiretroviral drugs occurred in 10 patients in the earlier-ART group and 1 patient in the later-ART group (P=0.006). CONCLUSIONS: Early initiation of ART in patients with CD4+ T-cell counts of less than 50 per cubic millimeter increased AIDS-free survival. Deferral of the initiation of ART to the first 4 weeks of the continuation phase of tuberculosis therapy in those with higher CD4+ T-cell counts reduced the risks of IRIS and other adverse events related to ART without increasing the risk of AIDS or death. (Funded by the U.S. President's Emergency Plan for AIDS Relief and others; SAPIT ClinicalTrials.gov number, NCT00398996.).

Intensified specimen collection to improve tuberculosis diagnosis in children from Rural South Africa, an observational study.

BACKGROUND: In drug-resistant TB settings, specimen collection is critical for drug-susceptibility testing (DST). This observational study included multiple specimen types collected from pediatric TB suspects with the aim to determine diagnostic yield and inform clinical practice in children with drug-resistant and drug-susceptible TB. METHODS: From 03/2009-07/2010, TB suspects aged ≥6 months and ≤12 years were recruited among outpatient and inpatient settings. Subjects were new TB suspects or had persistent symptoms despite ≥2 months of TB treatment. The protocol included collection of a single blood and urine specimen, a single sputum induction and, if inpatients and <5 years of age, collection of 3 gastric aspirates (GA). Samples were cultured on solid and/or liquid media. DST was by 1% proportion method. RESULTS: Among 118 children with possible, probable or confirmed TB, the mean age was 4.9 years [SD 3.2] and 64 (62%) of those tested were HIV-positive. Eight (7%) subjects were culture-positive from at least one specimen; yield did not differ by HIV status or TB treatment history. Among those with positive cultures, 7/8 (88%) were from induced sputum, 5/6 (83%) from GA, 3/8 (38%) from blood, and 3/7 (43%) from urine. In subjects with both induced sputum and GA collection, sputum provided one additional case compared to GA. Multidrug resistant (MDR)-TB was detected by urine culture alone in one child >5 years old. Pan-resistant extensively drug resistant (XDR)-TB was identified by cultures from all sites in one subject. CONCLUSIONS: TB was cultured from HIV-positive and -negative children, and allowed for identification of MDR and XDR-TB cases. Urine and induced sputum each provided an additional TB diagnosis and, when compared to GA, may be considered a less invasive, same-day method of specimen collection for childhood TB suspects. This study illustrates the continued challenges and limitations of available strategies for pediatric TB diagnostics.

Nosocomial transmission of extensively drug-resistant tuberculosis in a rural hospital in South Africa.

BACKGROUND: Extensively drug-resistant tuberculosis (XDR-tuberculosis) is a global public health threat, but few data exist elucidating factors driving this epidemic. The initial XDR-tuberculosis report from South Africa suggested transmission is an important factor, but detailed epidemiologic and molecular analyses were not available for further characterization. METHODS: We performed a retrospective, observational study among XDR-tuberculosis patients to identify hospital-associated epidemiologic links. We used spoligotyping, IS6110-based restriction fragment-length polymorphism analysis, and sequencing of resistance-determining regions to identify clusters. Social network analysis was used to construct transmission networks among genotypically clustered patients. RESULTS: Among 148 XDR-tuberculosis patients, 98% were infected with human immunodeficiency virus (HIV), and 59% had smear-positive tuberculosis. Nearly all (93%) were hospitalized while infectious with XDR-tuberculosis (median duration, 15 days; interquartile range: 10-25 days). Genotyping identified a predominant cluster comprising 96% of isolates. Epidemiologic links were identified for 82% of patients; social network analysis demonstrated multiple generations of transmission across a highly interconnected network. CONCLUSIONS: The XDR-tuberculosis epidemic in Tugela Ferry, South Africa, has been highly clonal. However, the epidemic is not the result of a point-source outbreak; rather, a high degree of interconnectedness allowed multiple generations of nosocomial transmission. Similar to the outbreaks of multidrug-resistant tuberculosis in the 1990s, poor infection control, delayed diagnosis, and a high HIV prevalence facilitated transmission. Important lessons from those outbreaks must be applied to stem further expansion of this epidemic.

Differentiated service delivery framework for people with multidrug-resistant tuberculosis and HIV co-infection.

INTRODUCTION: For people living with HIV/AIDS, care is commonly delivered through Differentiated Service Delivery (DSD). Although people with multidrug-resistant tuberculosis (MDR-TB) and HIV/AIDS experience severe treatment associated challenges, there is no DSD model to support their treatment. In this study, we defined patterns of medication adherence and characterized longitudinal barriers to inform development of an MDR-TB/HIV DSD framework. METHODS: Adults with MDR-TB and HIV initiating bedaquiline (BDQ) and receiving antiretroviral therapy (ART) in KwaZulu-Natal, South Africa, were enrolled and followed through the end of MDR-TB treatment. Electronic dose monitoring devices (EDM) measured BDQ and ART adherence. Longitudinal focus groups were conducted and transcripts analyzed thematically to describe discrete treatment stage-specific and cross-cutting treatment challenges. RESULTS: 283 participants were enrolled and followed through treatment completion (median 17.8 months [IQR 16.5-20.2]). Thirteen focus groups were conducted. Most participants (82.7%, 234/283) maintained high adherence (mean BDQ adherence 95.3%; mean ART adherence 85.5%), but an adherence-challenged subpopulation with <85% cumulative adherence (17.3%, 49/283) had significant declines in mean weekly BDQ adherence from 94.9% to 39.9% (p<0.0001) and mean weekly ART adherence from 83.9% to 26.6% (p<0.0001) over 6 months. Psychosocial, behavioral, and structural obstacles identified in qualitative data were associated with adherence deficits in discrete treatment stages, and identified potential stage specific interventions. CONCLUSION: A DSD framework for MDR-TB/HIV should intensify support for adherence-challenged subpopulations, provide multi-modal support for adherence across the treatment course and account for psychosocial, behavioral, and structural challenges linked to discrete treatment stages.

Investigation of the interactions between methadone and elvitegravir-cobicistat in subjects receiving chronic methadone maintenance.

Interactions between HIV and opioid dependence therapies are known to occur. We sought to determine if such interactions occurred between methadone and elvitegravir boosted with cobicistat (EVG/COBI). We performed a within-subject open-label pharmacokinetic and pharmacodynamic study of 11 HIV-seronegative subjects stabilized on at least 2 weeks of methadone. Subjects underwent baseline and steady-state evaluation of the effect of elvitegravir 150 mg once a day (QD) boosted with 150 mg QD of cobicistat (EVG/COBI) on methadone pharmacokinetic parameters. Safety and pharmacodynamics were monitored throughout the study. Compared to baseline values, the R-methadone mean area under the concentration-time curve to the end of the dosing period (AUCtau) (5,550 versus 6,210 h · ng/ml) and mean maximum concentration of drug in serum (Cmax) (316 versus 337 ng/ml) did not significantly increase in the presence of EVG/COBI. Compared to baseline values, the S-methadone mean AUCtau (7,040 versus 7,540 h · ng/ml) and mean Cmax (446 versus 452 ng/ml) did not significantly increase in the presence of EVG/COBI. The AUCtau, Cmax, and Ctau of elvitegravir and cobicistat did not significantly differ from those of historical controls. Opioid withdrawal or overdose was not observed among subjects in this study. The addition of EVG/COBI to stabilized patients receiving methadone did not affect methadone pharmacokinetics and pharmacodynamics. These two agents can be safely coadministered.

Timing of initiation of antiretroviral drugs during tuberculosis therapy.

BACKGROUND: The rates of death are high among patients with coinfection with tuberculosis and the human immunodeficiency virus (HIV). The optimal timing for the initiation of antiretroviral therapy in relation to tuberculosis therapy remains controversial. METHODS: In an open-label, randomized, controlled trial in Durban, South Africa, we assigned 642 patients with both tuberculosis and HIV infection to start antiretroviral therapy either during tuberculosis therapy (in two integrated-therapy groups) or after the completion of such treatment (in one sequential-therapy group). The diagnosis of tuberculosis was based on a positive sputum smear for acid-fast bacilli. Only patients with HIV infection and a CD4+ cell count of less than 500 per cubic millimeter were included. All patients received standard tuberculosis therapy, prophylaxis with trimethoprim-sulfamethoxazole, and a once-daily antiretroviral regimen of didanosine, lamivudine, and efavirenz. The primary end point was death from any cause. RESULTS: This analysis compares data from the sequential-therapy group and the combined integrated-therapy groups up to September 1, 2008, when the data and safety monitoring committee recommended that all patients receive integrated antiretroviral therapy. There was a reduction in the rate of death among the 429 patients in the combined integrated-therapy groups (5.4 deaths per 100 person-years, or 25 deaths), as compared with the 213 patients in the sequential-therapy group (12.1 per 100 person-years, or 27 deaths); a relative reduction of 56% (hazard ratio in the combined integrated-therapy groups, 0.44; 95% confidence interval, 0.25 to 0.79; P=0.003). Mortality was lower in the combined integrated-therapy groups in all CD4+ count strata. Rates of adverse events during follow-up were similar in the two study groups. CONCLUSIONS: The initiation of antiretroviral therapy during tuberculosis therapy significantly improved survival and provides further impetus for the integration of tuberculosis and HIV services. (ClinicalTrials.gov number, NCT00398996.)

Transmission of tuberculosis in resource-limited settings.

Unrecognized transmission is a major contributor to ongoing TB epidemics in high-burden, resource-constrained settings. Limitations in diagnosis, treatment, and infection control in health-care and community settings allow for continued transmission of drug-sensitive and drug-resistant TB, particularly in regions of high HIV prevalence. Health-care facilities are common sites of TB transmission. Improved implementation of infection control practices appropriate for the local setting and in combination, has been associated with reduced transmission. Community settings account for the majority of TB transmission and deserve increased focus. Strengthening and intensifying existing high-yield strategies, including household contact tracing, can reduce onward TB transmission. Recent studies documenting high transmission risk community sites and strategies for community-based intensive case finding hold promise for feasible, effective transmission reduction. Infection control in community settings has been neglected and requires urgent attention. Developing and implementing improved strategies for decreasing transmission to children, within prisons and of drug-resistant TB are needed.

Natural ventilation reduces high TB transmission risk in traditional homes in rural KwaZulu-Natal, South Africa.

BACKGROUND: Transmission of drug susceptible and drug resistant TB occurs in health care facilities, and community and households settings, particularly in highly prevalent TB and HIV areas. There is a paucity of data regarding factors that may affect TB transmission risk in household settings. We evaluated air exchange and the impact of natural ventilation on estimated TB transmission risk in traditional Zulu homes in rural South Africa. METHODS: We utilized a carbon dioxide decay technique to measure ventilation in air changes per hour (ACH). We evaluated predominant home types to determine factors affecting ACH and used the Wells-Riley equation to estimate TB transmission risk. RESULTS: Two hundred eighteen ventilation measurements were taken in 24 traditional homes. All had low ventilation at baseline when windows were closed (mean ACH = 3, SD = 3.0), with estimated TB transmission risk of 55.4% over a ten hour period of exposure to an infectious TB patient. There was significant improvement with opening windows and door, reaching a mean ACH of 20 (SD = 13.1, p < 0.0001) resulting in significant decrease in estimated TB transmission risk to 9.6% (p < 0.0001). Multivariate analysis identified factors predicting ACH, including ventilation conditions (windows/doors open) and window to volume ratio. Expanding ventilation increased the odds of achieving ≥12 ACH by 60-fold. CONCLUSIONS: There is high estimated risk of TB transmission in traditional homes of infectious TB patients in rural South Africa. Improving natural ventilation may decrease household TB transmission risk and, combined with other strategies, may enhance TB control efforts.