Minimising the gap between the start of TB treatment and the start of antiretroviral treatment had the biggest impact on death rates in people with very low CD4 counts, but made much less difference in patients with higher CD4 counts, observational cohort data from Rwanda show.
The findings, presented at the 41st Union World Conference on Lung Health in Berlin, also demonstrated a very similar reduction in the risk of death in patients treated early to that observed in the CAMELIA study, a randomised comparison of immediate versus delayed antiretroviral treatment in TB patients conducted in Cambodia.
The question of when to start antiretroviral treatment in people already receiving TB treatment has been the focus of considerable attention among researchers due to concerns about drug interactions between rifampicin and some antiretroviral drugs.
There has also been concern about the possible development of immune reconstitution inflammatory syndrome (IRIS) in people who have not cleared TB, and of a potential risk of death due to severe cases of IRIS.
For all these reasons there has been a tendency to delay the start of antiretroviral treatment until at least two months after starting TB treatment. Some physicians have preferred to delay antiretroviral treatment until after the completion of TB treatment, particularly in those with less advanced HIV disease and higher CD4 counts.
However, a large study in South Africa, the SAPIT trial, reported in 2008 that delaying antiretroviral treatment until after the completion of TB treatment was associated with a signficantly higher risk of death.
World Health Organization guidelines have subsequently been updated to recommend that antiretroviral treatment should be commenced in all HIV-positive patients receiving TB treatment, regardless of CD4 count.
What remains unclear is just how soon after starting TB treatment it is necessary to start antiretroviral therapy in order to minimise the risk of death.
The SAPIT study is continuing with a comparison of starting antiretroviral treatment no more than two months after TB treatment, or starting within two weeks of starting TB treatment.
A US AIDS Clinical Trials Group (ACTG) study, ACTG 5221, is also comparing the effects of initiating antiretroviral therapy either two or eight weeks after starting TB treatment.
A study conducted in Cambodia, the CAMELIA trial, recently reported that among a group of patients with very advanced HIV disease, starting antiretroviral treatment within two weeks of TB treatment was associated with a significantly reduced risk of death. Intriguingly, the reduction in risk became more pronounced over time, and was not confined to the early period of TB treatment.
However, the results of the CAMELIA study may not be applicable to all settings, or to patients with higher CD4 counts, so in advance of results from further studies, researchers from Harvard Medical School and Partners in Health used routinely collected observational data from Rwanda to examine whether a similar pattern held true in their cohort.
In particular, they wanted to examine whether the results of the CAMELIA study were generalisable to settings where it is not possible to carry out microbiological confirmation of TB (microbiologically confirmed TB was an entry criterion for the CAMELIA study).
Their study reviewed data from medical records of 308 patients with CD4 counts below 350 who had started TB treatment and subsequently started HIV treatment.
The researchers evaluated the two-year survival rate based on the delay between starting TB and HIV treatment regimens – 15, 30, 60 or 180 days.
They controlled for baseline confounding factors (CD4 count, age, gender, rural or urban care, inpatient or outpatient care), and for time-variant confounding factors (current CD4 count and hospitalisation).
In this population, only 17% of patients had smear-positive pulmonary TB. Twenty-five per cent had smear-negative pulmonary TB; the remainder had extrapulmonary TB.
The median interval between starting TB treatment and starting ART was 72 days. Starting antiretroviral treatment within 15 days of TB treatment had a significant protective effect compared with any greater delay only in those with baseline CD4 counts below 100.
When the investigators compared the survival probability according to baseline CD4 count in the Rwanda cohort among those who started ART no more than 15 days after beginning TB treatment, they found a very close fit with the survival probabilities observed in the CAMELIA study among patients with very low CD4 counts.
Starting ART by day 15 was associated with two-year survival probabilities of 0.82 [0.76 to 0.89] and 0.86 [0.80 to 0.92] in persons with baseline CD4 counts below 50 and 100 respectively in the Rwanda cohort.
In comparison, the two-year survival probability observed in the CAMELIA trial among those who initiated treatment within 15 days was 0.82 (0.78 to 0.86). In that study the median CD4 count of participants was 25 cells/mm3.
Although the authors of the study are careful not to overstate the significance of the findings, they point out that observational databases such as the Rwanda cohort have a valuable role to play in informing future practice, and in providing information that may be lacking in clinical trials.
“Failure to draw on the experience of national treatment programs may come at a formidable cost to clinicians, patients and their families as they await results from randomized trials,” the researchers warned.
Franke MF et al. Effectiveness of early antiretroviral initiation among HIV-infected adults with tuberculosis disease. 41st Union World Conference on Lung Health, late breaker session, Berlin, 2010.