Starting antiretroviral therapy (ART) in people with TB and advanced HIV disease two weeks after starting TB therapy, rather than waiting eight weeks, significantly improves survival according to the results of the CAMbodian Early vs Late Introduction of Antiretroviral drugs (or CAMELIA) study, presented on Thursday as a late breaker at the Eighteenth International AIDS Conference in Vienna.
The study randomised 661 participants with HIV and smear-positive TB to either an early-start arm or one starting HIV treatment after eight weeks. By the study’s conclusion, 59 patients had died in the early-start arm, compared to 90 in the late-start arm – a 34% difference. “The difference in mortality rate was highly significant,” said Dr Francois Blanc, who is lead investigator for the study.
At the same time, however, immune reconstitution inflammatory syndrome (IRIS) – which is frequently cited by clinicians as a reason to delay starting ART – was more common among people HIV treatment early (and even led to five deaths, compared to one IRIS-related death in the delayed treatment arm). However, this did not offset the survival benefit provided by earlier ART.
Notably, the survival benefit only emerged gradually over time and became significant well after ART had begun (ART appeared to be effective in both groups, with no significant differences between virological or CD4 response).
The study was conducted in people with very advanced HIV – the median CD4 cell count was 25mm3 at the time of study inclusion. Although it is not clear that early treatment would make as significant a difference in people with less advanced HIV, the study adds significant clinical evidence to the 2010 WHO recommendations to begin ART in TB patients “as soon as possible” after starting TB treatment – and will intensify calls for integration of TB/HIV services in countries with a high burden of co-infection.
In many settings, TB clinicians have wanted to delay ART until after TB treatment, or at least until after the intensive phase of treatment – which generally ends at eight weeks – because of concerns about high pill burdens, overlapping side-effects, drug interactions and IRIS. However, during this time, HIV progression may continue, perhaps even at an accelerated rate because of the TB infection, making it both more difficult to fight off TB and to ward off other HIV-related conditions.
A large proportion of people with HIV and TB die despite receiving standard TB treatment.
However, a growing body of data suggests that starting ART while still on TB treatment could improve outcomes.
For instance, almost two years ago, preliminary results of the SAPIT study found twice the number of deaths in participants in whom ART was delayed until after TB treatment was finished, compared to patients who got ART while still on TB treatment, either within the first four weeks of TB treatment, or within four weeks of concluding intensive TB treatment. The optimal time to start ART in people who have begun treatment for active TB remains unclear, so that study is continuing to compare those two 'integrated therapy' arms.
That study validated 2003 WHO guidelines, which recommended that ART be started in people with HIV who have begun TB treatment as soon as it is clear that TB treatment is tolerated (between two weeks and two months). The most recent version of the guidelines however, change the wording slightly: strongly recommending that TB treatment be started first, followed by ART as soon as possible afterwards (and within the first eight weeks). The guidelines note, however, that there was only evidence of "moderate quality" to support this recommendation.
The CAMELIA study
The CAMELIA study was conducted at five study sites in Cambodia by the French organisation Agence Nationale de Recherche sur la Sida et les hépatites virales (ANRS), and the US National Institute of Allergy and Infectious Diseases (the CIPRA trial), in partnership with the Cambodian Health Committee. It was designed as a superiority trial to determine the best time to start ART in people with advanced HIV disease (CD4 cell counts below 200) who had started TB treatment. Again, its two arms compared the introduction of later ART (eight weeks) vs early (two weeks). The primary endpoint was survival at the end of the trial (when the last participant completed 50 weeks of ART), with an intent-to-treat analysis.
All the participants received daily treatment with the standard TB regimen, with two months of intensive treatment (four drugs) followed by a continuation phase with rifampicin/isoniazid, and the same ART regimen (d4T/3TC/efavirenz). The first participant enrolled in January 2006 and the last one in May 2009, so the study has just been completed. The median duration of follow-up in the trial was 27 months.
The study enrolled 661 subjects, 332 randomised to early ART, 322 to late. Even though all subjects were smear-positive, some were not culture-positive. In fact, there were 38 subjects who were culture-negative, plus 12 with Nontuberculous mycobacteria (NTM) in the early treatment arm – compared to 31 culture-negative and four with NTM in the late arm.
Patient characteristics at baseline were similar. However, “these patients were extremely sick”, said Dr Blanc. The median CD4 cell count at inclusion was 25mm3, the median viral load was 5.6 log and the body mass index (BMI) was below 17, indicating severe wasting.
About 90% of the subjects had pulmonary disease. MDR-TB was rare, found in about 2% of the participants, and there was no difference between the arms. However, drug sensitivity tests were unavailable for about 68 patients.
After a follow-up time of 712.4 person-years, there were 59 deaths in the early arm, a mortality rate of 8.28 (95% confidence interval (CI) 6.42 to 10.69). In the late arm, after 653.7 days follow-up time, there were 90 deaths for a mortality rate of 13.77 (95% CI 11.20 to 16.93). There was a significant reduction in mortality in the early arm (p= 0.02). Only 12 patients (1.8%) were lost to follow-up, and fewer than 2% missed clinic visits.
Kaplan-Meier curves showed the survival over time. As noted earlier, the difference in survival between the two arms became more marked with time. At week 50, the survival probability was 86.1% (95% CI 81.8 to 89.4) in the early arm, vs 80.7% (95% CI 76.0 to 84.6) in the late arm (p= 0.07).
At week 100, the survival probability in the early arm was 82.6% (95% CI 78 to 86.4), but in the late arm it had dropped to 73% (95% CI 67.7 to 77.6) (p = 0.006). At week 150, survival was more or less stable in the early arm, but it continued to decline in the late arm.
In a multivariate analysis, several factors (apart from being assigned to the late arm) were associated with an increased risk of mortality, including BMI, low Karnosky scores, having both pulmonary and extra-pulmonary disease, and having an infection with a non-tuberculous mycobacterium (these do not necessarily respond to TB treatment – but notably, there were more of these in the early treatment arm).
Not surprisingly, having MDR-TB was highly associated with mortality with an adjusted hazard ratio of 8.02 (4.00 to 16.07), p <0.001.
“We also observed that IRIS was much more frequent in the early arm, nearly 2.5-fold in the early arm versus the late arm, but most of the time it was easy to manage. No patients received corticosteroids,” said Dr Blanc, adding that IRIS tended to emerge two to three weeks after ART started (in both arms). “We need to be prepared to face that and manage that,” he said.
The response to ART was quite impressive in both arms. At week 50, more than 95% had undetectable viral loads and this has remained constant over the course of the study (this however, must be an on-treatment analysis). Likewise, CD4 cells increased by a median of 114 cells over baseline, and have continued rising for participants with longer follow-up. Note, given that the median CD4 cell count at entry was 25, many patients would still be at risk of a number of HIV-related complications for quite some time despite beign on treatment, and would continue to require cotrimoxazole prophylaxis.
Another point Dr Blanc stressed was that “These patients were extremely adherent, despite their very poor condition at enrollment.”
Conclusion, discussion and implications
“We can speculate that initiating ART two weeks after the onset of TB treatment could potentially save 150,000 of the 450,000 annual HIV-TB related deaths,” Dr Blanc said in conclusion.
It’s not really clear that his calculation (a one-third reduction in death) was appropriately applied here, as many of the annual TB deaths in people with HIV probably occur in people not receiving treatment at all. But if everyone received appropriate and timely diagnosis and received TB treatment followed by ART two weeks afterwards, the survival benefit could be expected to be even greater. However, this would require far better integration of TB/HIV services than exists presently.
These data are rather new, and some questions still remain unanswered. For example, was there a faster time to TB culture conversion in people on early ART? Was there less weight loss?
It is interesting that ART didn’t seem to change the risk of early death and that the differences are powered by later events. It is also curious that simply starting ART a mere six weeks earlier, although – and, perhaps critically, while – the body was under assault from a catastrophic co-infection, produced a survival benefit that doesn’t seem to be explained by differences in virological or CD4 cell responses.
Many of these deaths would have occurred after the course of TB treatment was completed. Perhaps ART protects the body from TB’s constitutional effects or perhaps having active TB – even if it is successfully treated – significantly weakens people, making them more frail and susceptible to succumbing to other HIV-related conditions.
This may be a particular danger in very advanced HIV disease. As a member of the audience pointed out, it isn’t clear that you would see a similar survival benefit, or IRIS frequency, in people with higher CD4 cells.
Dr Kevin de Cock of the US Centers for Disease Control asked if would make more sense to treat both conditions at once? Dr Blanc pointed out that there are often very real operational challenges to starting HIV treatment earlier – such as the timing of getting a patient with TB tested for HIV and giving them their results.
“I think it is reasonable to have a two week delay: 72% of our patients did not know their status a month before going into the study,” said Dr Blanc.
But the results created quite a stir on the same day activists in a marched through the conference centre in a 'cough-in', carrying coffins and signs that said “No more people with HIV dying from TB”. In the question period and during a later session on TB and HIV co-infection, various experts discussed the implications of the findings.
“This is a wonderful study that complements the results of the SAPIT study. I want to point out that in the SAPIT study, the CD4 counts were substantially higher, and the rate of IRIS was about 12% in those who started ART on TB drugs and there was no mortality attributable to IRIS. So I think that the IRIS issue – not that it’s not important – but it should not be a barrier to initiating ART in people with HIV and TB,” said Jerry Friedland of Yale University
“It makes it very compelling now more than ever, to do the testing as well as initiate ART,” said Dr Wafaa El-Sadr of Columbia University and ICAP in a TB/HIV session just after the CAMELIA findings were presented. “I’m wondering whether we should reconceptualise the treatment of TB in patients with HIV, and frame it to them as 'ART is part of treating their TB' rather than presenting it as treating two diseases. I think there’s compelling need to change the way we are presenting ART to TB patients.”
View abstract and slides from this session on the official conference website.
Blanc FX et al. Significant enhancement in survival with early (2 weeks) vs. late (8 weeks) initiation of highly active antiretroviral treatment (HAART) in severely immunosuppressed HIV-infected adults with newly diagnosed tuberculosis. Eighteenth International AIDS Conference, Vienna, abstract THLBB106, 2010.