The immune reconstitution inflammatory syndrome after antiretroviral therapy initiation in patients with tuberculosis: findings from the SAPiT trial.

BACKGROUND: Concerns about the immune reconstitution inflammatory syndrome (IRIS) remain a barrier to antiretroviral therapy (ART) initiation during antituberculosis treatment in co-infected patients. OBJECTIVE: To assess IRIS incidence, severity, and outcomes relative to the timing of ART initiation in patients with HIV-related tuberculosis. DESIGN: Randomized, open-label clinical trial. (ClinicalTrials.gov registration number: NCT00398996) SETTING: An outpatient clinic in Durban, South Africa. PATIENTS: 642 patients co-infected with HIV and tuberculosis. MEASUREMENTS: In a secondary analysis of the SAPiT (Starting Antiretroviral Therapy at Three Points in Tuberculosis) trial, IRIS was assessed in patients randomly assigned to initiate ART within 4 weeks of tuberculosis treatment initiation (early integrated treatment group), within 4 weeks of completion of the intensive phase of tuberculosis treatment (late integrated treatment group), or within 4 weeks after tuberculosis therapy completion (sequential treatment group). The syndrome was defined as new-onset or worsening symptoms, signs, or radiographic manifestations temporally related to treatment initiation, accompanied by a treatment response. Severity of IRIS, hospitalization, and time to resolution were monitored. RESULTS: Incidence of IRIS was 19.5 (n = 43), 7.5 (n = 18), and 8.1 (n = 19) per 100 person-years in the early integrated, late integrated, and sequential treatment groups, respectively. Among patients with a baseline CD4+ count less than 0.050 × 109 cells/L, IRIS incidence was 45.5, 9.7, and 19.7 per 100 person-years in the early integrated, late integrated, and sequential treatment groups, respectively. Incidence of IRIS was higher in the early integrated treatment group than in the late integrated (incidence rate ratio, 2.6 [95% CI, 1.5 to 4.8]; P < 0.001) or sequential (incidence rate ratio, 2.4 [CI, 1.4 to 4.4]; P < 0.001) treatment groups. More severe IRIS cases occurred in the early integrated treatment group than in the other 2 groups (35% vs. 19%; P = 0.179), and patients in the early integrated treatment group had significantly higher hospitalization rates (42% vs. 14%; P = 0.007) and longer time to resolution (70.5 vs. 29.0 days; P = 0.001) than patients in the other 2 groups. LIMITATIONS: It was not possible to assess IRIS in more patients in the sequential treatment group (n = 74) than in the late integrated (n = 50) and early integrated (n = 32) treatment groups because of loss to follow-up, withdrawal, or death within 6 months of scheduled ART initiation. This study did not assess IRIS risk in nonambulatory patients or in those with extrapulmonary and smear-negative tuberculosis. CONCLUSION: Initiation of ART in early stages of tuberculosis treatment resulted in significantly higher IRIS rates, longer time to resolution, and more severe cases of IRIS requiring hospitalization. These findings are particularly relevant to patients initiating ART with a CD4+ count less than 0.050 × 109 cells/L, given the increased survival benefit of early ART initiation in this group. PRIMARY FUNDING SOURCE: Comprehensive International Program of Research on AIDS.

HIV-Associated Tuberculosis.

The intersecting HIV and Tuberculosis epidemics in countries with a high disease burden of both infections pose many challenges and opportunities. For patients infected with HIV in high TB burden countries, the diagnosis of TB, ARV drug choices in treating HIV-TB coinfected patients, when to initiate ARV treatment in relation to TB treatment, managing immune reconstitution, minimising risk of getting infected with TB and/or managing recurrent TB, minimizing airborne transmission, and infection control are key issues. In addition, given the disproportionate burden of HIV in women in these settings, sexual reproductive health issues and particular high mortality rates associated with TB during pregnancy are important. The scaleup and resource allocation to access antiretroviral treatment in these high HIV and TB settings provide a unique opportunity to strengthen both services and impact positively in meeting Millennium Development Goal 6.

High incidence of hospital admissions with multidrug-resistant and extensively drug-resistant tuberculosis among South African health care workers.

BACKGROUND: Nosocomial transmission has been described in extensively drug-resistant tuberculosis (XDR-TB) and HIV co-infected patients in South Africa. However, little is known about the rates of drug-resistant tuberculosis among health care workers in countries with high tuberculosis and HIV burden. OBJECTIVE: To estimate rates of multidrug-resistant tuberculosis (MDR-TB) and XDR-TB hospitalizations among health care workers in KwaZulu-Natal, South Africa. DESIGN: Retrospective study of patients with drug-resistant tuberculosis who were admitted from 2003 to 2008 for the initiation of drug-resistant tuberculosis therapy. SETTING: A public tuberculosis referral hospital in KwaZulu-Natal, South Africa. PARTICIPANTS: 231 health care workers and 4151 non-health care workers admitted for initiation of MDR-TB or XDR-TB treatment. MEASUREMENTS: Hospital admission rates and hospital admission incidence rate ratios. RESULTS: Estimated incidence of MDR-TB hospitalization was 64.8 per 100,000 health care workers versus 11.9 per 100,000 non-health care workers (incidence rate ratio, 5.46 [95% CI, 4.75 to 6.28]). Estimated incidence of XDR-TB hospitalizations was 7.2 per 100,000 health care workers versus 1.1 per 100,000 non-health care workers (incidence rate ratio, 6.69 [CI, 4.38 to 10.20]). A higher percentage of health care workers than non-health care workers with MDR-TB or XDR-TB were women (78% vs. 47%; P < 0.001), and health care workers were less likely to report previous tuberculosis treatment (41% vs. 92%; P < 0.001). HIV infection did not differ between health care workers and non-health care workers (55% vs. 57%); however, among HIV-infected patients, a higher percentage of health care workers were receiving antiretroviral medications (63% vs. 47%; P < 0.001). LIMITATION: The study had an observational retrospective design, is subject to referral bias, and had no information on type of health care work or duration of occupational exposure to tuberculosis. CONCLUSION: Health care workers in this HIV-endemic area were substantially more likely to be hospitalized with either MDR-TB or XDR-TB than were non-health care workers. The increased risk may be explained by occupational exposure, underlining the urgent need for tuberculosis infection-control programs.

Recurrent tuberculosis among HIV-coinfected patients: a case series from KwaZulu-Natal.

BACKGROUND: Recurrent tuberculosis (TB) following TB treatment completion in HIV-infected individuals remains a major public health burden. We assessed the role of various risk factors in mediating the development of recurrent TB and subsequent resistance to antiretroviral therapy and anti-TB drugs. PATIENTS AND METHODS: We analyzed secondary demographic, clinical, and laboratory data from medical records of five HIV-infected TB patients enrolled between 2009 and 2014 in a prospective observational study investigating TB recurrence. Paired clinical isolates of Myco-bacterium tuberculosis were typed by IS6110 restriction fragment length polymorphism analysis to determine the mechanism of TB recurrence. Plasma samples were genotyped to determine acquisition of HIV drug resistance mutations on antiretroviral treatment (ART). RESULTS: All five patients were HIV-coinfected, with a previous history of TB infection and prior exposure to anti-TB treatment, and residual lung damage, and demonstrated poor treatment adherence - significant risk factors linked to the development of recurrent TB disease. Furthermore, three of the five patients had multiple episodes of drug-susceptible TB infection with subsequent drug-resistant TB infection. Genotyping of the initial and recurrent M. tuberculosis isolates demonstrated three cases of recurrent TB because of relapse and two because of reinfection. All five patients had no mutations at ART initiation; however, by the end of the study follow-up, all patients developed dual class resistance. CONCLUSION: This series demonstrates the complexity of recurrent TB in HIV coinfection. We highlight the challenges of managing coinfected patients and the increased propensity for the development of drug resistance. We report on the role of various risk factors mediating the development of resistance and subsequent clinical impact. This report underscores the need for structural clinical and adherence interventions for the management of complex treatment and dosing.

Turning the tide against tuberculosis.

Despite affecting men, women, and children for millennia, tuberculosis (TB) is the most neglected disease. In contrast, the global response to HIV has reached a defining moment. By uniting efforts, promptly integrating major scientific findings for both treatment and prevention, and scaling up services, the once inconceivable end to the HIV epidemic may no longer be an illusion. "The world has made defeating AIDS a top priority. This is a blessing. But TB remains ignored" - Nelson Mandela. While there is no doubt that revolutionary diagnostics and new and repurposed drugs have provided some hope in the fight against TB, it is evident that scientific advances on their own are inadequate to achieve the World Health Organization's ambitious goal to end TB by 2035. In this article, the consequences of a myopic and conventional biomedical approach to TB, which has ultimately permeated to the level of individual patient care, are highlighted.

High rates of tuberculosis in patients accessing HAART in rural South Africa.

BACKGROUND: The challenge of early tuberculosis (TB) infection among rural patients accessing highly active antiretroviral therapy (HAART) in a resource-limited setting with high HIV and TB burden has not been fully quantified. METHODS: This is a retrospective study nested within a prospective study of 969 patients consecutively initiated onto HAART at the CAPRISA AIDS Treatment programme in rural KwaZulu-Natal between January 2007 and December 2010. Patients were screened for clinical symptoms consistent with TB using a standardized checklist, and routine clinical investigations that included sputum microscopy and chest x-ray diagnosis. RESULTS: Of 969 HIV-infected patients initiated on HAART, 173 [17.9%; 95% confidence interval (CI): 15.5 to 20.4] had active TB at HAART initiation. TB incidence rates were 3-fold higher in the first 3 months (early incident TB) after HAART initiation [11.5/100 person-years (py); 95% CI: 7.1 to 17.5] compared with 4-24 months (late incident TB) post-HAART initiation (3.2/100 py; 95% CI: 2.2 to 4.5; incidence rate ratio: 3.6; 95% CI: 2.0 to 6.4; P < 0.001). Immune status of patients at HAART initiation did not impact TB incidence rates in patients with CD4 counts of <50 (5.3/100) and >200 (4.9/100 py; P = 0.81) cells per cubic millimeter. CD4 count gains achieved 12 months post-HAART initiation were significantly different in patients with early incident TB versus late incident TB; P = 0.03. CONCLUSIONS: Rural HIV treatment programmes in TB-endemic settings experience high rates of TB irrespective of immunologic status of patients at HAART initiation, or duration on HAART.

Co-enrollment in multiple HIV prevention trials - experiences from the CAPRISA 004 Tenofovir gel trial.

BACKGROUND: In settings where multiple HIV prevention trials are conducted in close proximity, trial participants may attempt to enroll in more than one trial simultaneously. Co-enrollment impacts on participant's safety and validity of trial results. We describe our experience, remedial action taken, inter-organizational collaboration and lessons learnt following the identification of co-enrolled participants. EXPERIENCES: Between February and April 2008, we identified 185 of the 398 enrolled participants as ineligible. In violation of the study protocol exclusion criteria, there was simultaneous enrollment in another HIV prevention trial (ineligible co-enrolled, n=135), and enrollment of women who had participated in a microbicide trial within the past 12 months (ineligible not co-enrolled, n=50). Following a complete audit of all enrolled participants, ineligible participants were discontinued via study exit visits from trial follow-up. Custom-designed education program on co-enrollment impacting on participants' safety and validity of the trial results was implemented. Shared electronic database between research units was established to enable verification of each volunteer's trial participation and to prevent future co-enrollments. LESSONS LEARNT: Interviews with ineligible enrolled women revealed that high-quality care, financial incentives, altruistic motives, preference for sex with gel, wanting to increase their likelihood of receiving active gel, perceived low risk of discovery and peer pressure are the reasons for their enrollment in the CAPRISA 004 trial. CONCLUSION: Instituting education programs based on the reasons reported by women for seeking enrollment in more than one trial and using a shared central database system to identify co-enrollments have effectively prevented further co-enrollments.