Early versus delayed initiation of highly active antiretroviral therapy for HIV-positive adults with newly diagnosed pulmonary tuberculosis (TB-HAART): a prospective, international, randomised, placebo-controlled trial.

BACKGROUND: WHO guidelines recommend early initiation of antiretroviral therapy (ART) irrespective of CD4 cell count for all patients with tuberculosis who also have HIV, but evidence supporting this approach is poor quality. We assessed the effect of timing of ART initiation on tuberculosis treatment outcomes for HIV-positive patients with CD4 counts of 220 cells per µL or more. METHODS: We did this randomised, placebo-controlled trial between Jan 1, 2008, and April 31, 2013 at 26 treatment centres in South Africa, Tanzania, Uganda, and Zambia. We enrolled HIV-positive patients with culture-confirmed tuberculosis who had tolerated 2 weeks of tuberculosis short course chemotherapy. Participants were randomly allocated (1:1) to early ART (starting after 2 weeks of tuberculosis treatment) or delayed ART (placebo, then starting ART at the end of 6 months of tuberculosis treatment). Randomisation was computer generated, with permuted blocks of size eight, and stratified by CD4 count (220-349 cells per µL vs ≥350 cells per µL). Patients and investigators were masked to treatment allocation until completion of 6-months' tuberculosis treatment, after which the study was open label. The primary endpoint was a composite of failure of tuberculosis treatment, tuberculosis recurrence, and death within 12 months of starting tuberculosis treatment in the modified intention-to-treat population. Secondary endpoints included mortality. The study is registered with controlled-trials.com (ISRCTN77861053). FINDINGS: We screened 13,588 patients and enrolled 1675: 834 assigned early ART, 841 delayed ART. The primary endpoint was reached by 65 (8·5%) of 767 patients in the early ART group versus 71 (9·2%) of 771 in the delayed ART group (relative risk [RR] 0·91, 95% CI 0·64-1·30; p=0·9). Of patients with a CD4 cell count of 220-349 cells per µL, 26 (7·9%) of 331 patients versus 33 (9·6%) of 342 reached the primary endpoint (RR 0·80, 95% CI 0·46-1·39; p=0·6). For those with 350 cells per µL or more, 39 (8·9%) of 436 versus 38 (8·9%) of 429 reached the primary endpoint (RR 1·01, 95% CI 0·63-1·62; p=0·4). Mortality did not differ significantly between treatment groups (RR 1·4, 95% CI 0·8-2·3; p=0·23). Grade 3 and 4 adverse events occurred in 149 (18%) of 834 patients assigned early ART versus 174 (21%) of 841 assigned delayed ART (p=0·37). 87 (10%) of 834 versus 84 (10%) of 841 had immune reconstitution inflammatory syndrome (p=0·56). INTERPRETATION: ART can be delayed until after completion of 6 months of tuberculosis treatment for HIV-positive patients with tuberculosis who have CD4 cell counts greater than 220 cells per µL. WHO guidelines should be updated accordingly. FUNDING: USAID, Zambia Ministry of Health, Tanzania Commission for Science and Technology, WHO-TDR.

Advances in the Diagnosis, Treatment and Control of HIV Associated Tuberculosis.

There has been an increase in the number of published tuberculosis/HIV (TB/HIV) research findings in recent times. The potential impact of these findings on routine care has informed this review which aims at discussing current concepts and practices underpinning TB/HIV care and control. Any HIV infected person with a cough of any duration is currently considered a TB suspect. Preliminary results also show that the diagnostic yield of same day sputum samples (front loading) is comparable to two-day samples. Laboratory diagnosis is shifting from Ziehl-Neelsen (ZN) smear microscopy and solid culture to fluorescent microscopy, molecular tests and liquid culture. Concomitant TB/HIV therapy improves survival and WHO has recommended ART for all TB/HIV patients. Unless CD4 cell counts are less than 50 cells/µl, ART can be deferred until end of intensive phase. Evidence of survival benefit at high CD4 cell counts is still lacking. New TB drugs and treatment shortening studies are underway but so far no new TB drugs has been added to the current arsenal and treatment duration still remains six months or more. WHO has recommended the 31s (intensified TB case finding, isoniazid prophylaxis and infection control) for TB/HIV control in addition to effective therapy, Antiretroviral therapy and TB vaccines. There has been immense progress in TB/HIV research, however optimal management of HIV-Infected TB patients, will require further research and appropriate translation of emerging evidence to policy and practice.

Advances in the diagnosis, treatment and control of HIV associated tuberculosis

There has been an increase in the number of published tuberculosis/HIV (TB/HIV) research findings in recent times. The potential impact of these findings on routine care has informed this review which aims at discussing current concepts and practices underpinning TB/HIV care and control. Any HIV infected person with a cough of any duration is currently considered a TB suspect. Preliminary results also show that the diagnostic yield of same day sputum samples(front loading) is comparable to two­day samples. Laboratory diagnosis is shifting from Ziehl­Neelsen (ZN) smear microscopy and solid culture to fluorescent microscopy, molecular tests and liquid culture. Concomitant TB/HIV therapy improves survival and WHO has recommended ART for all TB/HIV patients. Unless CD4 cell counts are less than 50 cells/µl, ART can be deferred until end of intensive phase. Evidence of survival benefit at high CD4 cell counts is still lacking. New TB drugs and treatment shortening studies are underway but so far no new TB drugs has been added to the current arsenal and treatment duration still remains six months or more. WHO has recommended the 3Is (intensified TB case finding, isoniazid prophylaxis and infection control) for TB/HIV control in addition to effective therapy, Antiretroviral therapy and TB vaccines. There has been immense progress in TB/HIV research, however optimal management of HIV­Infected TB patients, will require further research and appropriate translation of emerging evidence to policy and practice