Chelsea Morroni

Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome

Objective:Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a frequent complication of antiretroviral therapy in resource-limited countries. We aimed to assess whether a 4-week course of prednisone would reduce morbidity in patients with paradoxical TB-IRIS without excess adverse events. Design:A randomized, double-blind, placebo-controlled trial of prednisone (1.5 mg/kg per day for 2 weeks then 0.75 mg/kg per day for 2 weeks). Patients with immediately life-threatening TB-IRIS manifestations were excluded. Methods:The primary combined endpoint was days of hospitalization and outpatient therapeutic procedures, which were counted as one hospital day. Results:One hundred and ten participants were enrolled (55 to each arm). The primary combined endpoint was more frequent in the placebo than the prednisone arm {median hospital days 3 [interquartile range (IQR) 0–9] and 0 (IQR 0–3), respectively; P = 0.04}. There were significantly greater improvements in symptoms, Karnofsky score, and quality of life (MOS-HIV) in the prednisone vs. the placebo arm at 2 and 4 weeks, but not at later time points. Chest radiographs improved significantly more in the prednisone arm at weeks 2 (P = 0.002) and 4 (P = 0.02). Infections on study medication occurred in more participants in prednisone than in placebo arm (27 vs. 17, respectively; P = 0.05), but there was no difference in severe infections (2 vs. 4, respectively; P = 0.40). Isolates from 10 participants were found to be resistant to rifampicin after enrolment. Conclusion:Prednisone reduced the need for hospitalization and therapeutic procedures and hastened improvements in symptoms, performance, and quality of life. It is important to investigate for drug-resistant tuberculosis and other causes for deterioration before administering glucocorticoids.

Neurologic Manifestations of Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome: A Case Series

BACKGROUND Paradoxical neurologic tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a potentially life-threatening condition that occurs within 3 months after starting combination antiretroviral therapy (ART). The reports in the published literature are anecdotal, and the prevalence and outcomes of neurologic TB-IRIS are unknown. METHODS We prospectively assessed patients with suspected TB-IRIS from June 2005 through October 2007 at our hospital in Cape Town, South Africa. We defined paradoxical TB-IRIS and paradoxical neurologic TB-IRIS with use of consensus clinical case definitions. We collected data on tuberculosis diagnosis, ART, details of TB-IRIS diagnosis, other opportunistic infections, corticosteroid use, and outcome. RESULTS We reviewed 279 patients with suspected TB-IRIS, 54 (19%) of whom had suspected neurologic TB-IRIS, and 225 (81%) of whom had suspected non-neurologic TB-IRIS. Paradoxical TB-IRIS was diagnosed in 190 patients; 23 (12%) of these 190 patients had neurologic TB-IRIS (95% confidence interval, 7%-17%). Eight had meningitis, 7 had tuberculoma, 5 had both tuberculoma and meningitis, and 3 had radiculomyelopathy. Twenty (87%) of the 23 patients with neurologic TB-IRIS required hospital admission (median duration, 12 days; interquartile range, 6-24 days), and 21 (91%) received corticosteroids (median duration, 58 days; interquartile range, 29-86 days). Outcomes 6 months after the initial assessment for neurologic deterioration were as follows: 16 (70%) of the patients were alive (10 of these patients had documented full physical and mental recovery), 3 (13%) were dead, and 4 (17%) were lost to follow-up. CONCLUSIONS Paradoxical neurologic TB-IRIS accounts for 12% of paradoxical TB-IRIS cases. Neurologic TB-IRIS causes considerable short-term morbidity but has reasonable long-term outcomes. Further research is needed to devise optimal diagnostic and management strategies for patients with tuberculosis who experience neurologic deterioration after starting ART.

Initiation of oral contraceptives using a quick start compared with a conventional start: a randomized controlled trial.

OBJECTIVE: To estimate whether young women taking the first pill on the day of prescription had higher continuation rates and lower pregnancy rates than women who waited until menses to start the oral contraceptive pill (OCP). METHODS: We recruited 1,716 women aged younger than 25 years seeking to initiate the oral contraceptive at three publicly funded family planning clinics, and randomly assigned them to conventional initiation of the pill (conventional start) or immediate, directly observed ingestion of the first pill (quick start) during the clinic visit. Women underwent follow-up interviews at 3 and 6 months. RESULTS: Sixty percent of participants discontinued the pill, and 8% became pregnant during follow-up. Women who took the first pill in the clinic were more likely to continue to the second OCP pack (odds ratio 1.5, 95% confidence interval 1.0–2.1.); however, the Quick Start approach did not improve OCP continuation rates at 3 and 6 months. Those assigned to Quick Start were slightly less likely to become pregnant within 6 months from the time they started the pill (hazard ratio 0.90, 95% confidence interval 0.64—1.25). Eighty-one percent of women rated the Quick Start approach as acceptable or preferable to waiting. Rates of serious adverse events were low and similar in the two groups. CONCLUSION: Protocols that require a woman to wait until the next menses to start hormonal contraceptives are an obstacle to contraceptive initiation. Directly observed, immediate initiation of the pill improves short-term continuation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00068848 LEVEL OF EVIDENCE: I

Novel Relationship between Tuberculosis Immune Reconstitution Inflammatory Syndrome and Antitubercular Drug Resistance

BACKGROUND Tuberculosis (TB) immune reconstitution inflammatory syndrome (IRIS) is emerging as an important early complication of combination antiretroviral therapy in patients with TB in developing countries. The differential diagnosis of TB IRIS includes deterioration caused by other human immunodeficiency virus-related morbidities and drug-resistant TB. METHODS We prospectively evaluated consecutive patients with suspected TB IRIS from February 2005 through July 2006 at a community-based secondary hospital in Cape Town, South Africa, by means of clinical case definitions for TB IRIS. Specimens were sent for TB culture and susceptibility testing, and a rapid test (FASTplaque-Response) was performed to expedite determination of rifampin susceptibility. RESULTS One hundred patients with suspected TB IRIS were evaluated, 26 of whom were being retreated for TB. IRIS symptoms developed a median of 14 days (interquartile range, 7-25 days) after the initiation of combination antiretroviral therapy. In 7 patients, an alternative opportunistic disease was diagnosed. Rifampin-resistant TB was present in 13 patients, 9 of whom received a diagnosis after study entry (7 of 9 had multidrug-resistant TB). Undiagnosed rifampin-resistant TB was thus present in 10.1% of patients (95% confidence interval, 3.9%-16.4%) who presented with TB IRIS, once those with alternative diagnoses and TB with known rifampin resistance were excluded. In the remaining 80 patients, TB IRIS without rifampin resistance was the final diagnosis. CONCLUSIONS TB IRIS that is clinically indistinguishable from TB IRIS that occurs in the context of drug-susceptible disease may occur in patients with undiagnosed multidrug-resistant TB. Antitubercular drug resistance should be excluded in all cases of suspected TB IRIS, and corticosteroids should be used with caution for patients with presumed TB IRIS until the result of drug-susceptibility testing is known.

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/μl) 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.

Clinical, Immunological, and Epidemiological Importance of Antituberculosis T Cell Responses in HIV-Infected Africans

BACKGROUND Human immunodeficiency virus (HIV)-associated tuberculosis is a major cause of mortality in Africa. The assay of T cell interferon- gamma released in response to antigens of greater specificity than purified protein derivative is a useful improvement over the Mantoux tuberculin skin test, but few studies have evaluated interferon-gamma secretion in HIV-infected individuals. METHODS Mycobacterium tuberculosis antigen-specific interferon-gamma secretion was assessed by whole blood assay and enzyme-linked immunospot, which were compared with the Mantoux tuberculin skin test in HIV-infected and HIV-uninfected individuals without active tuberculosis and HIV-infected patients with pulmonary tuberculosis in Khayelitsha, South Africa. RESULTS The skin test and whole blood assay responses to purified protein derivative in HIV-positive subjects were decreased, compared with responses in HIV-negative subjects (P < .001). By contrast, the responses to M. tuberculosis antigens (early secreted antigenic target 6, culture filtrate protein 10, TB10.3, and alpha-crystallin 2) were less affected, indicating a high prevalence of latent tuberculosis (approximately 80%) in both HIV-negative and HIV-positive subject groups. Whole blood assay responses did not differ between the HIV-positive subjects without tuberculosis and HIV-positive subjects with tuberculosis, but the enzyme-linked immunospot method response to early secreted antigenic target 6 and culture filtrate protein 10 was higher in the group of HIV-infected subjects with tuberculosis (P < or = .04), although this group had lower CD4+ cell counts. A ratio of the combined enzyme-linked immunospot method response divided by the CD4+ cell count of > 1.0 had 88% sensitivity and 80% specificity for active pulmonary tuberculosis in HIV-infected individuals. CONCLUSIONS Interferon-gamma release appears to be less impaired than skin testing by HIV coinfection. The novel potential to relate the enzyme-linked immunospot method and CD4+ cell count to assist diagnosis of active tuberculosis in patients with HIV infection is important and deserves further evaluation.

Patient and provider delay in tuberculosis suspects from communities with a high HIV prevalence in South Africa: A cross-sectional study

BackgroundDelay in the diagnosis of tuberculosis (TB) results in excess morbidity and mortality, particularly among HIV-infected individuals. This study was conducted at a secondary level hospital serving communities with a high HIV prevalence in Cape Town, South Africa. The aim was to describe patient and provider delay in the diagnosis of TB in patients with suspected TB requiring admission, and to determine the risk factors for this delay and the consequences.MethodsA cross-sectional study was conducted. Patients admitted who were TB suspects were interviewed using a structured questionnaire to assess history of their symptoms and health seeking behaviour. Data regarding TB diagnosis and outcome were obtained from the medical records. Bivariate associations were described using students T-tests (for means), chi-square tests (for proportions), and Wilcoxon rank-sum tests (for medians). Linear regression models were used for multivariate analysis.ResultsOne hundred twenty-five (125) patients were interviewed. In 104 TB was diagnosed and these were included in the analysis. Seventy of 83 (84%) tested were HIV-infected. Provider delay (median = 30 days, interquartile range (IQR) = 10.3–60) was double that of patient delay (median = 14 days, IQR = 7–30). Patients had a median of 3 contacts with formal health care services before referral. Factors independently associated with longer patient delay were male gender, cough and first health care visit being to public sector clinic (compared with private general practitioner). Patient delay ≥ 14 days was associated with increased need for transfer to a TB hospital. Provider delay ≥ 30 days was associated with increased mortality.ConclusionDelay in TB diagnosis was more attributable to provider than patient delay, and provider delay was associated with increased mortality. Interventions to expedite TB diagnosis in primary care need to be developed and evaluated in this setting.

Bleeding patterns after immediate initiation of an oral compared with a vaginal hormonal contraceptive.

Objective: This study compared 84-day bleeding patterns after immediate initiation of a triphasic oral contraceptive with a 25-&mgr;g daily dose of ethinyl estradiol (E2) compared with the contraceptive vaginal ring, which has a 15-&mgr;g daily dose of ethinyl E2. Methods: This was an open-label controlled trial. We randomly assigned 201 women to immediate start of a contraceptive pill or immediate start of the ring in a 1:1 allocation ratio. Our primary outcome was difference in mean bleeding–spotting days per woman according to treatment assignment. Secondary outcomes were differences in World Health Organization—defined menstrual indices, differences in perceived bleeding changes, and differences in bleeding according to cycle day at the start of method. Results: The mean bleeding–spotting days in the 84-day reference period for all subjects was 19.2 days (17.0 days for ring users and 21.4 days for pill users, mean difference 4.4 days). Using the World Health Organization menstrual indices, the ring users experienced fewer days or episodes of bleeding–spotting and shorter intervals. Among ring users, no baseline characteristics were associated with bleeding outcomes. Older nulliparous pill users, however, reported more bleeding–spotting days. Significantly more ring users reported a decrease in duration of bleeding compared with pill users (P < .01). We found no significant differences in bleeding patterns based on analysis of cycle day at study enrollment. Conclusion: Our study shows advantageous bleeding patterns for subjects using the contraceptive vaginal ring. It also confirms our previous findings that immediate start of hormonal contraception is an acceptable alternative to waiting for menses. Level of Evidence: II-1

Corticosteroid-modulated immune activation in the tuberculosis immune reconstitution inflammatory syndrome.

RATIONALE HIV-tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an immunopathological reaction to mycobacterial antigens induced by antiretroviral therapy. Prednisone reduces morbidity in TB-IRIS, but the mechanisms are unclear. OBJECTIVES To determine the effect of prednisone on the inflammatory response in TB-IRIS (antigen-specific effector T cells, cytokines, and chemokines). METHODS Blood was taken from participants in a randomized placebo-controlled trial of prednisone for TB-IRIS, at 0, 2, and 4 weeks. Participants received prednisone at a dosage of 1.5 mg/kg/day for 2 weeks followed by 0.75 mg/kg/day for 2 weeks, or placebo at identical dosages. MEASUREMENTS AND MAIN RESULTS Analyses included IFN-γ enzyme-linked immunospot (ELISPOT), reverse transcription-polymerase chain reaction on peripheral blood mononuclear cells after restimulation with heat-killed Mycobacterium tuberculosis, Luminex multiplex cytokine analysis of corresponding tissue culture supernatants, and Luminex multiplex cytokine analysis of serum. Fifty-eight participants with TB-IRIS (31 receiving prednisone, 27 receiving placebo) were included. In serum, significant decreases in IL-6, IL-10, IL-12 p40, tumor necrosis factor-α, IFN-γ, and IFN-γ-induced protein-10 concentrations during prednisone, but not placebo, treatment were observed. No differences in ELISPOT responses comparing prednisone and placebo groups were shown in response to ESAT-6 (early secreted antigen target-6), Acr1, Acr2, 38-kD antigen, or heat-killed H37Rv M. tuberculosis. Purified protein derivative ELISPOT responses increased over 4 weeks in the prednisone group and decreased in the placebo group (P = 0.007). CONCLUSIONS The beneficial effects of prednisone in TB-IRIS appear to be mediated via suppression of predominantly proinflammatory cytokine responses of innate immune origin, not via a reduction of the numbers of antigen-specific T cells in peripheral blood.

Missed opportunities to address reproductive health care needs among HIV-infected women in antiretroviral therapy programmes

Objectives  To investigate the delivery of reproductive health care services in an antiretroviral therapy (ART) programme in Cape Town, South Africa.