Adherence to tuberculosis preventive therapy measured by urine metabolite testing among people with HIV.

OBJECTIVES: Tuberculosis preventive therapy for people living with HIV is effective, widely recommended, and increasingly prescribed, but completion rates are less than ideal, and adherence is not typically monitored. We sought to quantify adherence to isoniazid preventive therapy using a urine metabolite assay. DESIGN: Two cross-sectional surveys. SETTING: Rio de Janeiro, Brazil, 2008-2009; and Northwest Province, South Africa, 2018-2019. PARTICIPANTS: Two hundred and three Brazilian and 93 South African patients attending HIV clinics with active prescriptions for isoniazid preventive therapy MAIN OUTCOME MEASURES:: Self-reported isoniazid adherence, paired with semiquantitative measurement of urine isoniazid metabolites. RESULTS: By self-report, 90% of patients [95% confidence interval (CI) 86-93%] reported having taken a dose of isoniazid on the day of enrollment or the preceding day, and 91% (95% CI 87-94%) reported missing an average of one dose or fewer per week. By urine testing, only 65% (95% CI 59-70%) of all patients, and 69% (95% CI 63-74%) of those who reported having taken isoniazid on the current or preceding day, had detectable urine metabolites (expected in 95% of patients at 24 h). Longer time since starting preventive therapy was independently associated with a negative urine test for isoniazid metabolites (adjusted prevalence ratio 1.11 per month of isoniazid, 95% CI 1.05-1.18). CONCLUSION: Adherence to isoniazid preventive therapy among patients with HIV in Brazil and South Africa is inadequate, is overestimated by self-report, and declines with time on treatment. Shorter regimens for TB preventive therapy may improve adherence and completion, but adherence support for all patients may be necessary.

A Phase 2 Randomized Trial of a Rifapentine plus Moxifloxacin-Based Regimen for Treatment of Pulmonary Tuberculosis.

BACKGROUND: The combination of rifapentine and moxifloxacin administered daily with other anti-tuberculosis drugs is highly active in mouse models of tuberculosis chemotherapy. The objective of this phase 2 clinical trial was to determine the bactericidal activity, safety, and tolerability of a regimen comprised of rifapentine, moxifloxacin, isoniazid, and pyrazinamide administered daily during the first 8 weeks of pulmonary tuberculosis treatment. METHODS: Adults with sputum smear-positive pulmonary tuberculosis were randomized to receive either rifapentine (approximately 7.5 mg/kg) plus moxifloxacin (investigational arm), or rifampin (approximately 10 mg/kg) plus ethambutol (control) daily for 8 weeks, along with isoniazid and pyrazinamide. The primary endpoint was sputum culture status at completion of 8 weeks of treatment. RESULTS: 121 participants (56% of accrual target) were enrolled. At completion of 8 weeks of treatment, negative cultures using Löwenstein-Jensen (LJ) medium occurred in 47/60 (78%) participants in the investigational arm vs. 43/51 (84%, p = 0.47) in the control arm; negative cultures using liquid medium occurred in 37/47 (79%) in the investigational arm vs. 27/41 (66%, p = 0.23) in the control arm. Time to stable culture conversion was shorter for the investigational arm vs. the control arm using liquid culture medium (p = 0.03), but there was no difference using LJ medium. Median rifapentine area under the concentration-time curve (AUC0-24) was 313 mcg*h/mL, similar to recent studies of rifapentine dosed at 450-600 mg daily. Median moxifloxacin AUC0-24 was 28.0 mcg*h/mL, much lower than in trials where rifapentine was given only intermittently with moxifloxacin. The proportion of participants discontinuing assigned treatment for reasons other than microbiological ineligibility was higher in the investigational arm vs. the control arm (11/62 [18%] vs. 3/59 [5%], p = 0.04) although the proportions of grade 3 or higher adverse events were similar (5/62 [8%] in the investigational arm vs. 6/59 [10%, p = 0.76] in the control arm). CONCLUSION: For intensive phase daily tuberculosis treatment in combination with isoniazid and pyrazinamide, a regimen containing moxifloxacin plus low dose rifapentine was at least as bactericidal as the control regimen containing ethambutol plus standard dose rifampin. TRIAL REGISTRATION: www.ClinicalTrials.gov NCT00728507.

Yield of close contact tracing using two different programmatic approaches from tuberculosis index cases: a retrospective quasi-experimental study.

BACKGROUND: Being a contact of a pulmonary tuberculosis (TB) case is a risk factor for active and latent TB. The objective of this study is to determine the contact tracing yield using two different programmatic definitions of close contact in the city of Rio de Janeiro, Brazil. METHODS: This is a retrospective quasi-experimental study. Data were obtained by reviewing the medical records from TB index cases and their close contacts admitted to the Outpatient TB Clinic of the Institute of Thoracic Diseases, University of Rio de Janeiro. From January 2001 to December 2004, a close contact was defined as an individual who shared an enclosed space with a TB index case for a total period of ≥ 100 hours, whereas from January 2005 to December 2008 the definition of close contact was changed to an individual who shared an enclosed space with a TB index case ≥ 4 hours a week. The primary outcome of this study was newly diagnosed pulmonary TB cases and the secondary outcome was the prevalence of latent TB infection (LTBI) among close contacts during both periods. RESULTS: From 2001-2004, 810 close contacts from 257 index cases were evaluated and the prevalence of active TB and LTBI were 2% (16/810) and 62% (496/794), respectively. From 2005-2008, 1,310 close contacts from 369 index cases were identified and the prevalence of active TB and LTBI were 2.7% (35/1,310) and 69% (877/1,275), respectively. There was not a statically significant difference in the detection of active TB (p = 0.3) between the 2 time periods, but the detection of LTBI was significant higher (p = 0.003). The number needed to screen (contacts/new cases) decreased from 50 to 37 and the number need to contact trace (index cases/new cases) decreased from 16 to 10 from 2001-2004 to 2005-2008. CONCLUSION: In conclusion, the findings of this study suggest that the less conservative definition of TB close contacts (sharing space ≥ 4 h/week) can be a helpful tool for increasing the rate of diagnosis for newly active pulmonary TB cases and for the detection of LTBI among contacts of active pulmonary TB cases.

Understanding and retention of trial-related information among participants in a clinical trial after completing the informed consent process.

BACKGROUND METHODS: for assessing the level of understanding of trial-related information during the informed consent (IC) process in developing countries are lacking. PURPOSE: To assess the understanding and retention of trial-related information presented in the IC process by administering an informed consent assessment instrument (ICAI) to participants in a clinical trial for a new tuberculosis (TB) regimen being conducted in Rio de Janeiro (Brazil). Methods The format of the ICAI was based on the language and structure of the United States National Cancer Institute's IC comprehension checklist. The ICAI was designed to assess points of the RioMAR study IC process that addressed the principles of research ethics requested by Brazilian Regulatory Authority: autonomy, beneficence, non-maleficence, and justice. Briefly, (1) Is the respondent participating in a clinical trial? (2) Are two different treatments being evaluated? (3) Is the treatment arm chosen by chance? (4) Is an HIV test required? (5) Are liver function tests required? (6) Can participants leave the study at any time? (7) Are the risks and benefits of taking part in the study clear? (8) May pregnant women participate in the study? (9) Can one of the study drugs reduce the effectiveness of contraceptives? (10) Are patients paid to participate in the study? The ICAI was applied at two time points: immediately after enrollment in the clinical trial and 2 months later. RESULTS: A total of 61 patients who enrolled in the RioMAR study participated in this study. The percentage of correct answers to all questions was 82% at the time of the first ICAI; 31 participants (51%) did not recall that an HIV test was required (question 4) and 43 (70%) did not know that they could leave the study (question 6). Other individual questions were answered correctly by at least 76% of participants. There was no association between incorrect answers and age, gender, monthly family income, neighborhood, or level of education (p > 0.07). When the responses to the first and the second ICAI questions were compared, 15% or more of participants had conflicting answers to 5 of the 10 questions. LIMITATIONS: The ICAI uses dichotomous responses, leading to a 50% chance of guessing the correct answers. Two questions were asked only of women. Finally, only 6 of the 10 questions on the current version of the ICAI apply to most trials; others are trial-specific. CONCLUSIONS: The ICAI may be adapted to an individual trial and may prove to be a useful tool following a consent discussion to identify issues not fully understood by the research participants, thus prompting study staff to re-explain topics, possibly in a more elementary manner.

Effect of improved tuberculosis screening and isoniazid preventive therapy on incidence of tuberculosis and death in patients with HIV in clinics in Rio de Janeiro, Brazil: a stepped wedge, cluster-randomised trial.

BACKGROUND: Preventive therapy for tuberculosis in patients with HIV is effective, but it has not been widely implemented in moderate or high-burden settings. We assessed the effect of widespread use of isoniazid preventive therapy on rates of tuberculosis and death in people with HIV in Brazil. METHODS: We did a stepped wedge, cluster-randomised trial with patients actively enrolled in 29 HIV clinics in Rio de Janeiro. Clinic staff were trained in tuberculosis screening, use of tuberculin skin tests, and use of isoniazid preventive therapy. Clinics were randomly allocated a date to begin the intervention period, with two clinics beginning the intervention every 2 months starting from Sept 1, 2005. The primary outcome was tuberculosis incidence alone or combined with death in the control versus intervention periods until Aug 31, 2009. This trial is registered at ClinicalTrials.gov, number NCT00107887. RESULTS: Of 17,413 patients in the cohort, 12,816 were eligible for the intervention. Overall, there were 475 tuberculosis cases and 838 deaths. The intervention increased the rate of patients receiving skin tests from 19 per 100 person-years to 59 per 100 person-years, and from 36 per 100 person-years to 144 per 100 person-years for those eligible for isoniazid preventive therapy. In the control period, 221 cases of tuberculosis were diagnosed (1.31 per 100 person-years) compared with 254 (1.10 per 100 person-years) in the intervention period (unadjusted hazard ratio [HR] 0.87; 95% CI 0.69-1.10). Rates of tuberculosis incidence or death were 3.64 and 3.04 per 100 person-years, respectively (0.76; 95% CI 0.66-0.87). When adjusted for age, sex, entry CD4 count, and use of antiretroviral therapy, the HR for tuberculosis was 0.73 (95% CI 0.54-0.99) and for tuberculosis or death was 0.69 (0.57-0.83). INTERPRETATION: Operational training aimed at increasing tuberculosis screening, provision of tuberculin skin tests, and use of isoniazid preventive therapy in Brazilian HIV clinics significantly reduced incident tuberculosis and death. Thus, scale-up of preventive therapy for HIV-infected patients in settings of moderate tuberculosis incidence is achievable and should be widely implemented in Brazil and elsewhere. FUNDING: Bill & Melinda Gates Foundation and the National Institutes of Health.

Patient-nominated, community-based HIV treatment supporters: patient perspectives, feasibility, challenges, and factors for success in HIV-infected South African adults.

This study aimed to characterize the experience of having a treatment supporter among HIV-infected South African patients enrolled in a randomized controlled trial that compared the efficacy of patient-nominated treatment supporters administering partial directly observed antiretroviral therapy (DOT-ART) versus self-administered ART (Self-ART). Results of the parent study showed no virologic or sustained immunologic differences between groups, but revealed a significant survival benefit among the DOT-ART group. One hypothesis is that this survival benefit may be explained by differences in the training and involvement of the treatment supporters between groups. In the current study, results from a semi-structured exit interview of 172 participants indicate that most participants in both arms maintained a positive, satisfying relationship with a single supporter, typically family member or friend. Most patients (82.6%) perceived supporters as helpful with medication adherence, with no significant difference between groups (p=0.752). Additionally, supporters provided emotional, instrumental, and material support. DOT-ART patients were more likely than Self-ART patients to report that their supporter helped to decrease drug or alcohol use (p=0.03). Patients identified supporter trustworthiness, availability, good communication and reciprocity of support as factors beneficial to a successful relationship. These results suggest: (1) Patient-nominated peers are feasible candidates for ART supporters in this resource-constrained setting; (2) In addition to assistance with medications, treatment supporters have the capacity to promote healthy behaviors and provide other types of support, which may contribute to improved outcomes, particularly with enhanced training; (3) Trustworthiness, availability, good communication, and reciprocity are key factors in a successful patient-supporter relationship.

Impact of immune reconstitution inflammatory syndrome on antiretroviral therapy adherence.

OBJECTIVE: We determined the impact of immune reconstitution inflammatory syndrome (IRIS) on antiretroviral therapy (ART) adherence in a cohort of 274 human immunodeficiency virus (HIV)-infected South African adults initiating ART. METHODS: We carried out a secondary analysis of data from a randomized controlled trial of partially supervised ART in Cape Town, South Africa. Monthly pill count adherence, viral suppression (HIV viral load < 50 c/mL), and IRIS events were documented. Poisson regression was used to identify variables associated with ART adherence below the median in the first 6 months of ART. RESULTS: We enrolled 274 patients: 58% women, median age 34 years, median CD4 count 98 cells/µL, 46% World Health Organization clinical stage IV, and 40% on treatment for tuberculosis (TB). IRIS and TB-IRIS developed in 8.4% and 6.6% of patients, respectively. The median cumulative adherence at 6 months for those with an IRIS event vs no IRIS was 95.5% vs 98.2% (P = 0.04). Although not statistically significant, patients developing IRIS had a lower 6-month viral load suppression than those without IRIS (68% vs 80%, P = 0.32). ART adherence below the median of 98% was independently associated with alcohol abuse (relative risk [RR] 1.5; 95% confidence interval [CI] 1.2-1.9; P = 0.003) and IRIS events (RR 1.7; 95% CI 1.2-2.2; P = 0.001). CONCLUSION: Although IRIS events were associated with slightly lower adherence rates, overall adherence to ART remained high in this study population. Concerns about IRIS should not deter clinicians from early ART initiation.

The implementation of isoniazid preventive therapy in HIV clinics: the experience from the TB/HIV in Rio (THRio) study.

OBJECTIVE: The TB/HIV in Rio (THRio) study was launched in September 2005 to assess the impact of integrated tuberculosis (TB) and HIV treatment strategies in 29 HIV clinics in Rio de Janeiro, Brazil. DESIGN: THRio is a cluster-randomized trial (CRT) to determine whether routine screening for and treatment of latent TB in HIV clinic patients with access to antiretroviral therapy will reduce TB incidence at the clinic level. THRio is part of the Consortium to Respond Effectively to AIDS/TB Epidemic that is implementing research studies to assess the impact of bold, new public health paradigms for controlling the AIDS/TB epidemic. METHODS: Twenty-nine public primary HIV clinics were randomly assigned a date to begin implementing TB screening procedures and provision of isoniazid preventive therapy (IPT) for TB/HIV coinfected patients. Final analysis of the CRT is expected in 2011. RESULTS: Starting at date of tuberculin skin test (TST)/IPT implementation at each clinic through August 2010, 1670 HIV-infected patients initiated IPT, of which 215 are still receiving treatment. Of the remaining 1455 patients, 1230 (85%) completed therapy and only 20 (1.2%) patients initiating IPT reported adverse reactions leading to discontinuation of therapy. IPT completion was higher among HIV-infected patients receiving HAART (87%) than those not yet receiving HAART (79%, P < 0.01). Times to TST and IPT have markedly decreased postintervention, but remain considerably long. The richness of the THRio database has resulted in several analyses of this expansive cohort of HIV-infected patients that are reviewed here. CONCLUSIONS: The national implementation of TST and IPT for HIV-positive patients in Brazil has been invigorated partly due to THRio's baseline results. Expanded use of IPT in HIV patients in Rio de Janeiro is achievable with high adherence and low adverse events, although this effort requires a package of activities including training, advocacy and reorganization of services.

Randomized controlled trial of trained patient-nominated treatment supporters providing partial directly observed antiretroviral therapy.

BACKGROUND: Directly observed therapy (DOT) for antiretroviral therapy (ART) may improve adherence, but there are limited data on its clinical effectiveness. METHODS: Adult patients initiating ART in a public clinic in Cape Town, South Africa, were randomized to treatment-supporter DOT-ART or self-administered ART. DOT-ART patients and supporters received baseline and follow-up training and monitoring. The primary endpoints were the proportions of patients with HIV viral load less than 400 copies/ml and change in CD4 cell counts at 12 and 24 months. RESULTS: Two hundred and seventy-four patients enrolled (137 in each arm) and baseline characteristics were similar for both arms. The study was stopped early for futility by an independent Data and Safety Monitoring Board. In an intention-to-treat analysis, the proportions of patients with viral load less than 400 copies/ml at 12 months were 72.8% in the DOT-ART arm and 68.4% in the Self-ART arm (P = 0.42). DOT-ART patients had greater median CD4 cell count (cells/microl) increases at 6 months [148 (IQR 84-222) vs. 111 (IQR 44-196) P = 0.02] but similar results at all other time-points. Survival was significantly better in the DOT-ART arm (9 deaths, 6.6%) than in the Self-ART arm (20 deaths, 14.6%; log-rank P = 0.02). In Cox regression analysis, mortality was independently associated with study arm [DOT vs. self-ART; HR 0.38, 95% confidence interval (CI) 0.17-0.86]. CONCLUSION: DOT-ART showed no effect on virologic outcomes but was associated with greater CD4 cell count increases at 6-month follow-up. Survival was significantly better for DOT-ART compared to Self-ART, but this was not explained by improved virologic or immunologic outcomes.

Point-of-care Arkansas method for measuring adherence to treatment with isoniazid.

We evaluated the accuracy of a point-of-care test designed to measure adherence to isoniazid (INH) preventive therapy in a hospital setting in Rio de Janeiro, Brazil. Patients on treatment with daily INH and patients not receiving INH were included. Sensitivity and specificity of the test were 84%/98% at the first minute, and 95%/98% at the fifth minute, respectively. Among smokers, sensitivity and specificity was reduced (80%/89% at the fifth minute, respectively), but only 17% smoked. This test accurately detected INH metabolites 24h following directly observed INH intake, though sensitivity and specificity may be compromised by tobacco smoke exposure.

Moxifloxacin versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, controlled phase II trial.

BACKGROUND: New treatments are needed to shorten the time required to cure tuberculosis and to treat drug-resistant strains. The fluoroquinolone moxifloxacin is a promising new agent that might have additive activity to existing antituberculosis agents. We assessed the activity and safety of moxifloxacin in the initial stage of tuberculosis treatment. METHODS: We undertook a phase II, double-blind, randomised controlled trial of a regimen that included moxifloxacin in adults with sputum smear-positive tuberculosis at one hospital in Rio de Janeiro, Brazil. 170 participants received isoniazid, rifampicin, and pyrazinamide at standard doses and were assigned by permuted block randomisation to receive either moxifloxacin (400 mg) with an ethambutol placebo (n=85) or ethambutol (15-20 mg/kg) plus moxifloxacin placebo (n=85) 5 days per week for 8 weeks. The primary endpoint was the proportion of patients whose sputum culture had converted to negative by week 8. Analysis was by modified intention to treat (ITT); patients whose baseline cultures were negative, contaminated, or contained drug-resistant Mycobacterium tuberculosis were excluded from the analysis. Additionally, all missing 8-week results were deemed treatment failures. This study is registered with ClinicalTrials.gov, number NCT00082173. FINDINGS: 74 patients assigned to the moxifloxacin group and 72 in the ethambutol group were included in the modified ITT population. 125 patients had 8-week data (moxifloxacin n=64, ethambutol n=61); the main reason for absence of data was culture contamination. At 8 weeks, culture conversion to negative had occurred in 59 (80%) of 74 patients in the moxifloxacin group compared with 45 (63%) of 72 in the ethambutol group (difference 17.2%, 95% CI 2.8-31.7; p=0.03). There were 16 adverse events (eight in each group) in 12 patients. Only one event was judged related to study drug (grade 3 cutaneous reaction in the ethambutol group). INTERPRETATION: Moxifloxacin improved culture conversion in the initial phase of tuberculosis treatment. Trials to assess whether moxifloxacin can be used to shorten the duration of tuberculosis treatment are justified.

T-SPOT.TB responses during treatment of pulmonary tuberculosis.

BACKGROUND: Immune responses to Mycobacterium tuberculosis antigens could serve as surrogate markers of treatment response. METHODS: Using the T-SPOT.TB assay and frozen peripheral blood mononuclear cells, we enumerated ESAT-6- and CFP-10-specific IFN-gamma-producing T cells over time in pulmonary TB patients receiving directly observed treatment. T cell responses (measured as "spot forming cells" or "SFCs") were assessed prior to treatment and at 16 and 24 weeks of treatment. RESULTS: 58 patients were evaluated, of whom 57 were HIV seronegative. Mean (SD) ESAT-6, CFP-10, and summed RD1 specific SFCs declined from 42.7 (72.7), 41.2 (66.4), and 83.8 (105.7) at baseline to 23.3 (39.4, p = 0.01), 23.2 (29.4, p = 0.18), and 46.5 (59.5, p = 0.02) at completion of 24 weeks of treatment, respectively. Only 10% of individuals with a baseline reactive test reverted to negative at treatment week 24. For the group that was culture positive at completion of 8 weeks of treatment compared to the culture negative group, the incidence rate ratio (IRR) of ESAT-6, CFP-10, and summed RD1 specific SFC counts were, respectively, 2.23 (p = 0.048), 1.51 (p = 0.20), and 1.83 (p = 0.047). Patients with cavitary disease had mean ESAT-6 specific SFC counts that were higher than those without cavitary disease (IRR 2.08, p = 0.034). CONCLUSION: IFN-gamma-producing RD1-specific T cells, as measured in the T-SPOT.TB assay, may be directly related to bacterial load in patients undergoing treatment for pulmonary TB. However, high inter-subject variability in quantitative results coupled with failure of reversion to negative of qualitative results in most subjects at treatment completion may limit the utility of this assay as a surrogate marker for treatment efficacy.

The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in HIV-infected patients in Rio de Janeiro, Brazil.

BACKGROUND: Tuberculosis is a common complication and leading cause of death in HIV infection. Antiretroviral therapy (ART) lowers the risk of tuberculosis, but may not be sufficient to control HIV-related tuberculosis. Isoniazid preventive therapy (IPT) reduces tuberculosis incidence significantly, but is not widely used. METHODS: We analysed tuberculosis incidence in 11 026 HIV-infected patients receiving medical care at 29 public clinics in Rio de Janeiro, Brazil, between 1 September 2003 and 1 September 2005. Data were collected through a retrospective medical record review. We determined rates of tuberculosis in patients who received neither ART nor IPT, only ART, only IPT, or both ART and IPT. RESULTS: The overall tuberculosis incidence was 2.28 cases/100 person-years (PY) [95% confidence interval (CI) 2.06-2.52]. Among patients who received neither ART nor IPT, incidence was 4.01/100 PY. Patients who received ART had an incidence of 1.90/100 PY (95% CI 1.66-2.17) and those treated with IPT had a rate of 1.27/100 PY (95% CI 0.41-2.95). The incidence among patients who received ART and IPT was 0.80/100 PY (95% CI 0.38-1.47). Multivariate Cox proportional hazards modeling revealed a 76% reduction in tuberculosis risk among patients receiving both ART and IPT (adjusted relative hazard 0.24; P < 0.001) after adjusting for age, previous tuberculosis diagnosis, and CD4 cell counts at baseline. CONCLUSION: The use of both IPT and ART in HIV-infected patients is associated with significantly reduced tuberculosis incidence. In conjunction with expanded access to ART, the wider use of IPT in patients with HIV will improve tuberculosis control in high burden areas.

Treatment supporter to improve adherence to antiretroviral therapy in HIV-infected South African adults. A qualitative study.

Little is known about the patient characteristics, social support networks, and relationship factors associated with excellent adherence in resource-limited settings, even though these can be important clues that inform the identification of targets and the approaches of individual- and community-based antiretroviral therapy adherence interventions. In this study, we aimed to understand how patient-selected treatment supports might affect antiretroviral treatment outcomes and to identify key components of support, including the social and material resources necessary for promoting high adherence in South Africa. Data were collected from the proceedings of 2 focus groups with 6 HIV-infected adults each and from 7 in-depth interviews with health care providers in the Western Cape Province of South Africa. The patients and health care workers identified individuals-usually a mother, daughter, sister, brother, or partner-who were confidantes and had moral authority with them. These individuals command respect, and patients allow them to influence health-related decision making, both of which are necessary if they are to be effective treatment supporters. Barriers to adherence identified by study participants include alcohol abuse, stigma related to disclosure of HIV status, and lack of financial resources and food. These are critically important challenges to address if high adherence is to be achieved in this setting. In addition, our results suggest that interventions tailored to treatment supporter characteristics and relationship factors may be effective in influencing patients' antiretroviral therapy adherence.