Efficacy of a 6-month versus 9-month intermittent treatment regimen in HIV-infected patients with tuberculosis: a randomized clinical trial.
BACKGROUND
The outcome of fully intermittent thrice-weekly antituberculosis treatment of various durations in HIV-associated tuberculosis is unclear.


OBJECTIVE
To compare the efficacy of an intermittent 6-month regimen (Reg6M: 2EHRZ(3)/4HR(3) [ethambutol, 1,200 mg; isoniazid, 600 mg; rifampicin, 450 or 600 mg depending on body weight <60 or > or =60 kg; and pyrazinamide, 1,500 mg for 2 mo; followed by 4 mo of isoniazid and rifampicin at the same doses]) versus a 9-month regimen (Reg9M: 2EHRZ(3)/7HR(3)) in HIV/tuberculosis (TB).


METHODS
HIV-infected patients with newly diagnosed pulmonary or extrapulmonary TB were randomly assigned to Reg6M (n = 167) or Reg9M (n = 160) and monitored by determination of clinical, immunological, and bacteriological parameters for 36 months. Primary outcomes included favorable responses at the end of treatment and recurrences during follow-up, whereas the secondary outcome was death. Intent-to-treat and on-treatment analyses were performed. All patients were antiretroviral treatment-naive during treatment.


RESULTS
Of the patients, 70% had culture-positive pulmonary TB; the median viral load was 155,000 copies/ml and the CD4(+) cell count was 160 cells/mm(3). Favorable response to antituberculosis treatment was similar by intent to treat (Reg6M, 83% and Reg9M, 76%; P = not significant). Bacteriological recurrences occurred significantly more often in Reg6M than in Reg9M (15 vs. 7%; P < 0.05) although overall recurrences were not significantly different (Reg6M, 19% vs. Reg9M, 13%). By 36 months, 36% of patients undergoing Reg6M and 35% undergoing Reg9M had died, with no significant difference between regimens. All 19 patients who failed treatment developed acquired rifamycin resistance (ARR), the main risk factor being baseline isoniazid resistance.


CONCLUSIONS
Among antiretroviral treatment-naive HIV-infected patients with TB, a 9-month regimen resulted in a similar outcome at the end of treatment but a significantly lower bacteriological recurrence rate compared with a 6-month thrice-weekly regimen. ARR was high with these intermittent regimens and neither mortality nor ARR was altered by lengthening TB treatment. Clinical Trials Registry Information: ID# NCT00376012 registered at www.clinicaltrials.gov.
Swaminathan
Soumya
S
Tuberculosis Research Center, Indian Council of Medical Research, Chetput, Chennai, India. doctorsoumya@yahoo.com
Narendran
Gopalan
G
Venkatesan
Perumal
P
Iliayas
Sheik
S
Santhanakrishnan
Rameshkumar
R
Menon
Pradeep Aravindan
PA
Padmapriyadarsini
Chandrasekharan
C
Ramachandran
Ranjani
R
Chinnaiyan
Ponnuraja
P
Suhadev
Mohanarani
M
Sakthivel
Raja
R
Narayanan
Paranji R
PR
D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy* / Q000382:microbiology* / Q000821:virology; D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018791:CD4 Lymphocyte Count; D004334:Drug Administration Schedule; D024901:Drug Resistance, Multiple, Bacterial; D004359:Drug Therapy, Combination; D004977:Ethambutol / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000382:microbiology* / Q000821:virology; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D055118:Medication Adherence; D011718:Pyrazinamide / Q000008:administration & dosage / Q000009:adverse effects; D012293:Rifampin / Q000008:administration & dosage / Q000009:adverse effects; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology / Q000821:virology*; D019562:Viral Load / Q000187:drug effects
D000995:Antitubercular Agents; D011718:Pyrazinamide; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin