Evaluation of an intensive intermittent-induction regimen and duration of short-course treatment for human immunodeficiency virus-related pulmonary tuberculosis. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) and the AIDS Clinical Trials Group (ACTG). A controlled trial of 3-month, 4-month, and 6-month regimens of chemotherapy for sputum-smear-negative pulmonary tuberculosis. Results at 5 years. Hong Kong Chest Service/Tuberculosis Research Centre, Madras/British Medical Research Council. [Daily ultrashort chemotherapy and intermittent short-term chemotherapy with 4 drugs of communicable pulmonary tuberculosis treated for the first time. Results of a cooperative multicenter study]. Treatment of pulmonary tuberculosis with short course chemotherapy in south India--5-year follow up. Staff training and ambulatory tuberculosis treatment outcomes: a cluster randomized controlled trial in South Africa. Shortest possible acceptable, effective ambulatory chemotherapy in pulmonary tuberculosis: preliminary report I. Does routine home visiting improve the return rate and outcome of DOTS patients who delay treatment? Long-term effect of preventive therapy for tuberculosis in a cohort of HIV-infected Zambian adults. [Compliance and tolerance of new antitubercular short-term chemopreventive regimens in childhood--a pilot project].
This study examined whether adding levofloxacin to a standard four-drug regimen improved the 8-week culture response and compared effectiveness of 9 versus 6 months of intermittent therapy for human immunodeficiency virus-related pansusceptible pulmonary tuberculosis. Patients were randomized to receive either four or five drugs, the fifth being levofloxacin. Patients who completed induction therapy were randomized to complete 9 versus 6 months of intermittent therapy with isoniazid and rifampin. In the randomized induction phase, 97.3% of patients in the four-drug group and 95.8% in the five-drug group had sputum culture conversion at 8 weeks (P = 1.00). In the continuation phase, one patient (2%) assigned to 9 months and two patients (3.9%) assigned to 6 months of therapy had treatment failure/relapse (P = 1.00). In conclusion, this study showed that levofloxacin added no benefit to a highly effective, largely intermittent, four-drug induction regimen. Both 9 and 6 months of intermittent therapy were associated with low treatment failure/relapse rates. Of 1,710 Chinese patients with radiologically active pulmonary tuberculosis but with sputum negative for acid-fast bacilli on four or more initial microscopic examinations who were studied for 5 yr, 592 (35%) had one or more initial sputum cultures positive for Mycobacterium tuberculosis. These 592 patients were randomly allocated to receive streptomycin, isoniazid, rifampin, and pyrazinamide daily for 4 months or 3 times a week for either 4 or 6 months. The remaining 1,118 patients with all their initial cultures negative were randomly allocated to receive the same four drugs daily for 3 months or 3 times a week for either 3 or 4 months. There were no bacteriologic failures during chemotherapy, and the relapse rates for the 4-month regimens during the 5 yr were 2% in 293 patients with drug-susceptible cultures initially (95% confidence limits, 1 to 5%); 8% in 59 patients with cultures resistant to isoniazid, streptomycin, or both drugs, but susceptible to rifampin initially; and 4% in 325 patients with all their cultures negative initially (95% confidence limits, 1 to 7%). The combined relapse rate for the 3-month regimens was 7% in 709 patients with all their cultures negative initially (95% confidence limits, 5 to 9%). In Hong Kong, 4 months of chemotherapy is now used routinely in the treatment of patients with smear-negative pulmonary tuberculosis, whether their initial sputum cultures are positive or negative. Three short-course regimens, all comprising isoniazide (H), rifampicine (R), streptomycine (S) and pyrazinamide (Z), are compared in a randomized prospective cooperative clinical trial. The drugs are given daily in a 3-month regimen (3-HRSZ), twice a week in a 6-month regimen (6-HRSZ2), and in a further two-phase 6-month regimen the 4 drugs are administered 3 times a week for the first 3 months followed by the administration of HSZ twice a week (without R) for further 3 months (3-HRSZ3/3-HSZ2). The number of patients admitted to study is 80, 144 and 139 respectively. The 3-month regimen has been stopped because of a high rate of relapses. 17 p.c. of the patients admitted have to be excluded from analysis for various reasons, out of these 5.8 p.c. because of adverse reactions. Two thirds of the patients had heavily positive sputum cultures at the start. 300 patients completed therapy. At the end of therapy cultures were negative in 94 p.c., 100 p.c. and 99 p.c. respectively. The rate of bacteriological relapses is 19 p.c. in 3-HRSZ, 9 p.c. in 3-HRSZ3/3-HSZ2 and 3 p.c. in 6-HRSZ2, during a follow-up period of 3-4 years after completing therapy. The acceptability was good in all treatment groups. Adverse reactions like "flu" were rarely observed. Increased blood urea was common but in general without clinical symptoms. Elevation of ALAT and ASAT was relatively frequent but mostly transient and without clinical importance. The results served as basis for the new "Recommendation for Treatment of Tuberculosis" and are interpreted with regard to practical consequences and possibilities for further rationalisation of treatment. A controlled clinical trial of three short-course chemotherapy regimens was undertaken in patients with newly diagnosed bacteriologically positive pulmonary tuberculosis. The patients were randomly allocated to receive one of three regimens: rifampicin, streptomycin, isoniazid and pyrazinamide daily for 2 months, followed by streptomycin, isoniazid and pyrazinamide twice weekly for 3 months (R/5) or for 5 months (R/7), or the same regimen as R/7 but without rifampicin (Z/7). A bacteriological relapse requiring retreatment occurred by 5 years in 7.1% of 126 R/5, 4.0% of 124 R/7 and 6.7% of 253 Z/7 patients with organisms initially sensitive to streptomycin and isoniazid; none of these differences is statistically significant. Of the 31 relapses, 16 occurred within 2 years of the completion of chemotherapy and the remaining 15 between 2 and 5 years. Among 65 patients with initial drug resistance to streptomycin or isoniazid or both, there were six bacteriological relapses requiring retreatment. To assess whether adding a training intervention for clinic staff to the usual DOTS strategy (the internationally recommended control strategy for tuberculosis (TB)) would affect the outcomes of TB treatment in primary care clinics with treatment success rates below 70%.
                A cluster randomized controlled trial was conducted from July 1996 to July 2000 in nurse-managed ambulatory primary care clinics in Cape Town, South Africa. Clinics with successful TB treatment completion rates of less than 70% and annual adult pulmonary TB loads of more than 40 patients per year were randomly assigned to either the intervention (n = 12) or control (n = 12) groups. All clinics completed follow-up. Treatment outcomes were measured in cohorts of adult, pulmonary TB patients before the intervention (n = 1200) and 9 months following the training (n = 1177). The intervention comprised an 18-hour experiential, participatory in-service training programme for clinic staff delivered by nurse facilitators and focusing on patient centredness, critical reflection on practice, and quality improvement. The main outcome measure was successful treatment, defined as patients who were cured and those who had completed tuberculosis treatment.
                The estimated effect of the intervention was an increase in successful treatment rates of 4.8% (95% confidence interval (CI): -5.5% to 15.2%) and in bacteriological cure rates of 10.4% (CI: -1.2% to 22%). A treatment effect of 10% was envisaged, based on the views of policy-makers on the minimum effect size for large-scale implementation.
                This is the first evidence from a randomized controlled trial on the effects of experiential, participatory training on TB outcomes in primary care facilities in a developing country. Such training did not appear to improve TB outcomes. However, the results were inconclusive and further studies are required. In two 4.5-month regimens and one 3-month regimen the four most potent antituberculous drugs (isoniazid, rifampin, pyrazinamide, and streptomycin) were given for the initial 3 months of chemotherapy. Acceptance by the patients was high, and bacillary sterilization was achieved in 96% of cases within 2 months. Addition of a fifth drug, ethionamide, during the initial 3 months was neither acceptable nor useful. No relapses were observed during a 12-month follow-up period after completion of the 4.5-month regimens. A relapse rate of 5% followed the 3-month regimen. The toxicity and side effects of antituberculous drugs were observed in 16% of patients during the initial 3-month period. In 3.4% of patients, toxicity necessitated cessation of treatment. In the remaining 13% of patients, adverse side effects could be managed without cessation of treatment. Even when patients were ambulatory and outpatient attendance was required for drug administration, the noncompliance rate was only approximately 10%. With the current over-all cost of drugs being limited to 100 United States dollars, the patients with moderately extensive disease must be treated for 100 days, or a maximum of 100 doses. Over a period of 6 months the effect of home visits on compliance with directly observed therapy, short course (DOTS), was studied on 480 new smear-positive tuberculosis patients who had delayed collecting their drugs on one occasion. Patients registered at 15 tuberculosis treatment centres in Baghdad, Iraq, were randomized to an intervention group (receiving home visits from trained personnel) or a control group. Home visits were highly effective in improving the return to treatment of patients who were late for treatment (231/240, 96.3%). The intervention group showed a higher treatment success rate (94.2% versus 76.7%), lower default rate (0.8% versus 10.0%) and higher smear conversion rate after the end of treatment (92.9% versus 75.0%) than controls. Home visiting by trained personnel significantly improves patient compliance with DOTS. To determine the long-term effect of preventive therapy (PT) for tuberculosis on the rates of tuberculosis, mortality and HIV progression.
                In a randomized controlled trial, 1053 HIV-positive Zambian adults received isoniazid (H) for 6 months, rifampicin plus pyrazinamide (RZ) for 3 months, or a placebo. CD4 percentage, neopterin, absolute lymphocyte count and haemoglobin were measured from enrolment (absolute CD4 cell counts from 12 months after enrolment). Because PT reduced the incidence of tuberculosis, eligible placebo subjects were offered H. Here, tuberculosis and mortality rates are compared in the three original arms (intention to treat) using data beyond the end of the trial (average follow-up 3 years; maximum 7 years).
                There were 102 cases of tuberculosis and 281 deaths (rates 3.6 and 9.0/100 person-years, respectively). There was no significant difference between the tuberculosis rates in the H and RZ groups at any time. The effect of H/RZ on tuberculosis diminished over time (P = 0.011) but the cumulative risk of tuberculosis in the first 2.5 years was significantly lower in the H/RZ group than the placebo group (rate ratio 0.55; 95% confidence interval 0.32-0.93; P = 0.028). There was no significant effect of PT on mortality or progression markers. Tuberculosis was associated with an increased mortality (adjusted rate ratio 1.96; 95% confidence interval 1.21-3.18; P = 0.006).
                Both PT regimens protect against tuberculosis for at least 2.5 years but appear to have no effect on HIV progression or mortality. These results may be used in cost-effectiveness models of PT. Efficacy of preventive chemotherapy in tuberculosis-infected children depends to a great extend on medical compliance and drug tolerability. Two new short-course chemoprevention-regimes of tuberculosis--four months Rifampin (A) and two months Rifampin plus Pyrazinamide (B)--were compared with the well established regimen of six months Isoniacid (C). 150 children (mean age 3.6 years with Tb conversion) were randomly allocated to these three regimens. 13 patients were non-compliant, in terms of interview, urinary INH-test strips, urine colour and prescription frequency: 7 in group C and 3 in group A and B, respectively. Adverse effects were observed in 5 patients: 3 in group C and 1 in group A and B. 1 child (group B) developed tuberculosis two years after stopping short course chemoprevention. Good compliance (94%) as well as neglectable risks of adverse effects (2%) justify further controlled studies to evaluate the efficacy of short course chemoprevention in childhood.
Longer periods of treatment (at least up to 6 months) result in higher success rates in patients with active TB, but the differences are small. Under field conditions, where adherence to treatment is a big problem, and shorter regimens might improve adherence, these differences may not be evident. A comparison of <6 months vs. 6 months of treatment under programme conditions would be needed to determine this.