Severe adverse events during second-line tuberculosis treatment in the context of high HIV Co-infection in South Africa: a retrospective cohort study

Abstract

BackgroundAccording to the World Health Organization, South Africa ranks as one of the highest burden of TB, TB/HIV co-infection, and drug-resistant TB (DR-TB) countries. DR-TB treatment is complicated to administer and relies on the use of multiple toxic drugs, with potential for severe adverse drug reactions. We report the occurrence of adverse events (AEs) during a standardised DR-TB treatment regimen at two outpatient, decentralized, public-sector sites in Johannesburg, South Africa.MethodsWe reviewed medical records of the six-month intensive treatment phase for rifampicin-resistant (RR) TB patients registered May 2012 - December 2014. Patients contributed follow-up time until death, loss from treatment, censoring (6 months) or data extraction. A standardized regimen of kanamycin, moxifloxacin, ethionamide, terizidone, and pyrazinamide was used according to national guidelines. AEs were graded using the AIDS Clinical Trial Group scale. We present subhazard ratios from competing risk analysis for time to severe AE, accounting for mortality and loss from treatment.ResultsAcross the two sites, 578 eligible patient files were reviewed. 36.7 % were categorized as low weight (≤50 kg) at DR-TB initiation. 76.0 % had no history of TB treatment prior to the current episode of RR TB. 26.8 % were diagnosed with RR TB while hospitalized, indicating poor clinical condition. 82.5 % of patients were also HIV positive, of whom 43.8 % were on ART prior to RR TB treatment and 32.1 % initiated ART with or after RR TB treatment. Median CD4 count was 114.5 (IQR: 45-246.5). Overall, 578 reports of AEs were captured for 204 patients (35.3 %) and 110 patients (19.0 %) had at least one severe AE reported. Patients with at least one AE experienced a median of 3 (IQR: 2-4) AEs per patient. HIV-positive patients with CD4 counts ≤100 cells/mm3 and those newly initiating ART were more likely to experience a severe AE (sHR: 2.76, 95 % CI: 1.30–5.84 and sHR: 3.07, 95 % CI: 1.46–6.46, respectively).ConclusionSevere AE are common during the first 6 months of RR TB treatment and HIV-positive patients newly initiating ART have the highest subdistribution hazard ratio for severe AE, accounting for the competing risks of death and loss from treatment.

Predictors of mortality among multidrug-resistant tuberculosis patients in central Ethiopia: a retrospective follow-up study

“…There is no comprehensive DST programme for first and second-line TB drugs in the Amhara Region; consequently, all patients are put on standardized regimens (i.e., constructed for the majority of patients) instead of tailored regimens based on susceptibility test results of individual patients which have been shown to achieve more successful outcomes [18]. Moreover, putting MDR-TB patients for more than 20 months on treatment would likely increase severe adverse events which can contribute additionally to the risk of death [19]. A recent study in our region showed the median time to commencement of treatment after a diagnosis of multidrug-resistant TB was 8 days [20] which falls short of international standards in developing countries, and so may play a role in the high death rate [21].…”

Unfavorable outcomes to second-line tuberculosis therapy among HIV-infected versus HIV-uninfected patients in sub-Saharan Africa: A systematic review and meta-analysis

“…Besides, patient-provider interactions were likely stronger for more patient empowerment and support during second-line TB therapy among HIV-infected patients compared with those HIV-uninfected [ 84 , 85 ]. More importantly, higher rates of severe adverse drug events and hospital readmissions due to the events during second-line TB treatment in HIV-infected patients than in those HIV-uninfected might reduce the rates of loss from treatment [ 86 , 87 ].…”

Potentially High Number of Ineffective Drugs with the Standard Shorter Course Regimen for Multidrug-Resistant Tuberculosis Treatment in Haiti

“…[20][21][22] Patients who are receiving concurrent treatment for HIV and MDR-TB are more likely to have adverse events, particularly if they have severe immunologic suppression. 23 Of particular concern for persons on both antiretroviral and antituberculous treatment is the risk of neuropathy, central nervous system side effects, and druginduced liver toxicity, which are reported for anti-TB medications such as isoniazid, as well as antiretroviral therapy agents. 24,25 The final safety data from the current STREAM trial of the shorter course have not yet been published; however, adverse event data from other shorter course studies demonstrate a high prevalence of adverse events, with 63% of patients reporting at least one adverse drug event among those receiving short-course regimen in Niger, with 20% reporting hearing impairment.…”