Uncertainty about the optimum time to initiate antiretroviral therapy in HIV-positive patients with active tuberculosis (TB) could be answered by clinical trials currently recruiting, investigators report in a supplement to the November 1st edition of the Journal of Infectious Diseases. The studies are recruiting patients with different degrees of immune suppression who are ill with tuberculosis in resource-limited countries. However, recruitment to one study has already been terminated due to problems with funding and poor enrolment.
Although tuberculosis is the biggest single cause of death in HIV-positive people worldwide, some basic aspects of the management of the disease have still to be established.
Given the increasing prevalence of tuberculosis in countries hardest hit by HIV and expanding access to antiretroviral therapy it is becoming increasing urgent to understand the best way of treating the two infections.
Crucially, there is still uncertainty about the best time to start antiretroviral therapy in patients receiving treatment for active tuberculosis.
Although anti-HIV treatment can lead to the restoration of tuberculosis-specific immune responses, this restoration of immune function can results in a transient worsening of tuberculosis disease called an immune restoration inflammatory syndrome (IRIS). It has been reported in as many as a third of HIV-positive patients receiving concurrent tuberculosis and anti-HIV therapy.
Physicians therefore need to trade-off the risks of further HIV disease progression because of a weak immune system against the risks of an IRIS or interaction between anti-HIV and anti-tuberculosis drugs.
There are also concerns that taking anti-HIV drugs and tuberculosis therapy at the same time will impose additional adherence demands on patients and that the risk of treatment side-effects will be increased.
Although guidelines, such as those of the British HIV Association, exist regarding the initiation of antiretroviral therapy in patients taking tuberculosis treatment, there are no published randomised controlled trials examining the optimal timing of anti-HIV treatment after the commencement of tuberculosis therapy.
However, four studies have been designed to answer this key question.
The CAMELIA study
This is intended to see if patients who start antiretroviral therapy two weeks after commencing treatment for tuberculosis have better outcomes than those who wait two months after initiating tuberculosis therapy before commencing anti-HIV treatment.
Recruitment started in early 2006 and it is hoped to enrol 660 individuals who are aged over 18 years, have a CD4 cell count below 200 cells/mm3 and are naïve to both tuberculosis and HIV therapy. Patients will be recruited at sites in rural Cambodia.
The study’s primary outcome is the survival at the end of the trial. It is also hoped that the study will also answer questions regarding the safety of early initiation of HIV therapy, in terms of drug interactions and IRIS; adherence rates; predictive factors for survival and response to TB/HIV therapy.
The AACTG A5221 trial
This study is also recruiting patients coinfected with tuberculosis and HIV with CD4 cell counts of 200 cells/mm3 or less.
Enrolment started in September 2006 and it is planned to recruit 800 patients in eight resource-limited countries.
It is primarily designed to see if starting anti-HIV therapy approximately two weeks after treatment for tuberculosis is started reduces mortality compared to the later initiation of antiretroviral therapy. Data will also be collected on side-effects, drug interactions, IRIS, falls in viral load, increases in CD4 cell count and HIV drug resistance.
The START study
Recruitment to this study started in South Africa started in May 2006. It was planned to recruit 592 patients with CD4 cell counts above 50 cells/mm3 and was designed to compare outcomes in patients who received concurrent HIV and tuberculosis treatment and those who started anti-HIV therapy once they had completed tuberculosis treatment. However, the study was terminated early because of lack of funding and difficulty recruiting patients.
WHO/TDR study
This trial is “an evaluation of the early impact of HAART on TB treatment outcomes for patients coinfected with HIV.”
Recruitment started in March 2007 and it is intended to enrol 1,900 patients in four African countries.
Unlike the other studies, this trial will involve patients with higher CD4 cell counts in two categories – those above 200 cells/mm3, and those with counts above 350 cells/mm3 . Individuals will be randomised to receive either antiretroviral therapy or a placebo two weeks after starting tuberculosis treatment. The primary to be measured by the study is the failure of tuberculosis treatment or death after six months. Other outcomes to be assessed include drug interactions and the effects of different levels of immune suppression and ethnicity on drug absorption.
The authors of the report hope that “together, these trials will provide critical data needed to decide the best timing of HAART initiation in HIV-1-infected patients with clinical TB with different levels of immunosuppression.”
Because the studies are being conducted on different populations their findings “will be robust and not be ethnicity specific”, although they note that none of the studies are being conducted in Europe or North America.
They also suggest that studies need to be designed to assess the optimum time to initiate anti-HIV treatment in patients taking second-line tuberculosis treatment.
Blanc F-X et al. Treatment strategies for HIV-infected patients with tuberculosis: ongoing and planned clinical trials. J infect Dis 196: S46 – 51, 2007.