The influence of HIV status on single and multiple drug reactions to antituberculous therapy in Africa.

OBJECTIVE: To document the influence of HIV status on drug reactions occurring in patients on antituberculous therapy in Harare, Zimbabwe. DESIGN: Retrospective cohort study. SETTING: City of Harare Tuberculosis Unit. PATIENTS: Records of 906 patients with tuberculosis, of whom 162 reacted to antituberculous therapy, were analysed. RESULTS: Reactions to antituberculous drugs were more frequent in HIV-positive (98 out of 363) than in HIV-negative (64 out of 543; P less than 0.0001) patients. The most common drug reaction was cutaneous hypersensitivity, occurring in 139 patients, 89 (64%) of whom were HIV-positive. Thiacetazone was implicated in 115 (82.7%) of the 139 cutaneous reactions and streptomycin in 10 (7.2%). Almost all cutaneous reactions occurred within 8 weeks of beginning treatment. Severe cutaneous reactions occurred more often in HIV-positive patients (P less than 0.001) and the only two deaths occurred in this group. Reactions to multiple drugs occurred in 18 HIV-positive and three HIV-negative patients (P = 0.017). CONCLUSIONS: The use of thiacetazone and streptomycin in antituberculous drug regimens should be reassessed in those countries where coinfection with HIV and tuberculosis is common.

Risk factors for adverse drug reactions during thiacetazone treatment of pulmonary tuberculosis in human immunodeficiency virus infected adults.

SETTING: Prospective randomised clinical trial comparing the safety and efficacy of rifampicin- and thiacetazone-containing regimens in human immunodeficiency virus (HIV)-infected adults with pulmonary tuberculosis (TB) at the National Tuberculosis Treatment Centre, Kampala, Uganda. OBJECTIVE: To assess demographic, clinical and laboratory risk factors associated with toxicity during treatment with streptomycin, thiacetazone and isoniazid (STH) of HIV-1 infected adults with pulmonary TB. DESIGN: Nested case-control study of all subjects randomized to the STH treatment arm. Baseline demographic, clinical, microbiological, hematological and radiographic characteristics were compared between subjects who developed and those who did not develop adverse drug reactions (ADR). RESULTS: Of the 90 subjects randomized to STH, 13 developed ADR yielding an incidence rate of 19.6 events per 100 person years of observation (PYO). Eleven of the 13 ADR were cutaneous hypersensitivity reactions, including one fatal case of Stevens-Johnson syndrome. Eight of 13 patients who developed ADR were tuberculin anergic, compared to 12 of 77 patients who did not develop ADR (P < 0.001). An absolute lymphocyte count below 2000 cells/mm3 was also associated with ADR (P = 0.02). CONCLUSION: Initial anergy to tuberculin and lymphocytopenia, markers of advanced HIV infection and immunosuppression, were associated with increased risk for adverse drug reactions during STH chemotherapy.

Cutaneous reactions to thiacetazone in Zambia--implications for tuberculosis treatment strategies.

Tuberculosis in patients infected with human immunodeficiency virus (HIV) is a growing threat to public health in Africa. Thiacetazone, one of the continent's most widely used antituberculous agents, may lead to severe cutaneous reactions in the HIV infected individual. We describe the impact of this reaction on the tuberculosis (TB) control programme of a district hospital in Zambia in 1990, and examine the cost implications of changing the standard treatment regime. We carried out a retrospective survey of records of all patients beginning TB treatment in 1990, together with HIV test results and the cost of all treatments given. From this we derived estimates of costs of different regimes which are and could be used in TB control in Zambia. Severe reactions occurred in 18.7% of all HIV seropositive patients receiving thiacetazone, fatally so in 1.2% (odds ratio 16.6). The greatest part of the cost of the current regime is that attributable to the inpatient stay; we estimated that 29.4% of patients would be unable to receive drugs as out-patients but, even allowing for this, rifampicin-based regimes given to outpatients where possible would not cost more than the current strategy. We conclude that ethical and economic considerations support a change to rifampicin-based regimes in areas of Africa where HIV seroprevalence is high.

Pharmacokinetic evaluation of thiacetazone.

STUDY OBJECTIVE: To investigate the steady-state pharmacokinetics of thiacetazone (TB-1), which is active in vitro against Mycobacterium avium complex (MAC). DESIGN: Open-label phase I study. SETTING: Specialized referral hospital. PATIENTS: Twelve healthy men and women. INTERVENTIONS: Oral TB-1 150 mg/day was administered for 7 days, followed by blood and urine collection over 48 hours. MEASUREMENTS AND MAIN RESULTS: The serum concentration versus time curves of TB-1 showed sustained concentrations, with maximum values of 1.59 +/- 0.47 micrograms/ml, time to maximum 3.30 +/- 1.18 hours, and serum half-life of 15-16 hours. Less than 25% of TB-1 was recovered unchanged in the urine over 48 hours. Rashes occurred in two subjects at the end of the 7-day dosing period and resolved without progression or sequelae. CONCLUSIONS: Based on these data, we initiated a phase II study of TB-I in patients with pulmonary MAC infection who do not have the acquired immunodeficiency syndrome.

Multiforme skin lesions in Yekatit 12 Hospital, 1976-1994.

Because the number of cases of multiforme skin lesions encountered in the medical department of Yekatit 12 Hospital has increased in recent years, we conducted a retrospective study to identify the likely precipitating factors and the possible relationship of these with HIV infection. Forty-seven patients with Multiforme Skin Lesions (29 males, 18 females) were admitted between 1976 and January 1994, of whom 43 (92%) were admitted in the past 5 years. Most patients were aged 15-49 years. Thirty patients (64%) were discharged improved and 14 (30%) expired in hospital. The outcome of 3 patients are not known. The charts of only 16 patients could be retrieved for review. Fifteen of these (94%) gave a history of intake of streptomycin, isoniazed and thiacetazone prior to developing the skin manifestation. The anti-TB medications were discontinued initially; 14 patients were restarted on STM, INH and ethambutol without recurrence of the rash. All but 1 were discharged improved. HIV screening tests were done on 24 patients with multiforme skin lesion of whom 21 (88%) were seropositive. Our study suggested that the adverse effects of thiacetazone are increased in HIV associated tuberculous patients. We recommend that further studies be conducted in HIV seropositive and seronegative patients.

Life-threatening cutaneous reactions to thiacetazone-containing antituberculosis treatment in Kumasi, Ghana.

Antituberculosis treatment containing thiacetazone is associated with a high incidence of life-threatening cutaneous drug reactions in patients infected with the human immunodeficiency virus (HIV). In order to develop a local policy concerning the use of this drug, a study was undertaken to determine the incidence of such reactions in a total of 1063 Ghanaian adult patients treated for pulmonary tuberculosis (PTB) with thiacetazone-containing regimens. The incidence was retrospectively determined in 3 different treatment groups, comparing: (A) unselected use of thiacetazone; (B) exclusion of thiacetazone from all patients with positive HIV serology; (C) selective exclusion of thiacetazone from patients with clinical criteria suggesting HIV infection plus education of health workers and patients. Of the 408 patients in group A receiving thiacetazone, 9 (2.2%) developed life-threatening cutaneous reactions and 7 of these were HIV-positive. Overall, 6.8% of HIV-positive patients compared to 0.65% of HIV-negative patients developed severe reactions (P < 0.01; relative risk = 10.5). Six of the 9 patients with reactions died. All 379 patients in group B were screened for HIV antibodies and positive cases (23%) received a regimen in which thiacetazone was substituted by ethambutol. In contrast to Group A, only one HIV-negative patient (0.26%) developed a severe cutaneous reaction (P = 0.02). Among 276 patients in group C, thiacetazone was substituted with ethambutol only in those with clinical evidence of HIV infection (8%) and staff and patients were educated about early recognition of the side-effect. With this policy, these were no admissions with severe cutaneous reactions compared to 2.2% of those in group A (P = 0.01). In conclusion, a policy of selective use of thiacetazone in the treatment of PTB based on clinical criteria combined with patient and staff education was found to be a practical and cost-effective strategy combating severe cutaneous reactions to thiacetazone.

[Lyell syndrome in Senegal: responsibility of thiacetazone]. / Syndrome de Lyell au Sénégal: responsabilité de la thiacétazone.

INTRODUCTION: Toxic epidermal necrolysis is a severe disease often leading to death or to mucosal, particularly ocular, after effects. The principle drugs responsible are antibacterial sulfonamides, anti-epileptics, non-steroid anti-inflammatories, allopurinol and chlormezanone. We report a series of 38 cases of toxic epidermal necrolysis, observed in Dakar, imputable to thiacetazone and lethal in 60 percent of cases. PATIENTS AND METHODS: Our study was retrospective. Diagnosis of toxic epidermal necrolysis was made in patients presenting more than 30 p. 100 of the epidermis of their total body surface stripped off, multi-orificial mucosal damage and epidermal necrosis revealed on histological examination. Drug imputability was established on classical criteria. Treatment was composed of reanimation and antibiotics. RESULTS: Among the 38 cases of toxic epidermal necrolysis counted, 24 were imputable to thiacetazone. All the patients presented typical clinical features, confirmed histologically. Evolution was lethal in 60 p. 100 of cases. The causes of death were frequently hypovolemic shock during the first week and septic shock during the second. The deceased were generally aged over 50, had more than 50 p. 100 of total epidermis stripped off, presented evolving tuberculosis at the time of the accident and HIV infection at the AIDS stage. After effects were vaginal synechia and 2 cases of blindness. COMMENTS: Our series is exceptional in that a) the drug responsible: thiacetazone, an economic tuberculostatic of minor efficacy, was systematically introduced after 2 months of intensive treatment with 4 major anti-tuberculosis agents; b) the 60 percent mortality rate, two-fold greater that that usually observed. Other than the known elements of poor prognosis in our patients, the treatment conditions of this dermatological emergency explain this high rate of mortality.

[Skin toxicity of thiacetazone (TB1) at a hospital service in Dakar]. / Toxidermies au Thiacétazone (TB1) dans un service hospitalier à Dakar.

From 1980 to 1997 we had observed 50 cases of cutaneous side effects of thiacetazone. There were 25 cases of Steven-Jonhson syndrome, 23 cases of Lyell syndrome, a case of erythrodermia and a case of lichenoid toxidermia. The mortality was 40% with 16 cases of Lyell syndrome and 4 cases of Steven Johnson syndrome. Thiacetazone is a minor tuberculostatic drug used widely in the national program against tuberculosis. Our results confirm the seriousness of cutaneous side effects due to this drug. So like in other neighboring countries, we suggest to avoid use of this drug in Senegal.