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 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 Xavier 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 was even associated with
five deaths, compared to one IRIS-associated death in the delayed treatment
arm). However, this did not offset the survival benefit provided by earlier ART.
Notably, the survival benefit emerged gradually over time and only 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.
Because of the potential importance of this study, after the publication
of the original version of this report on aidsmap, we queried
HATIP’s advisory panel and other experts to see what they think about the study
findings, and what the consequences may be for clinical practice. Their
responses are incorporated into this version of the article.
Background
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
remained unclear, however, 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 had smear-positive TB, 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
25 cells/mm3, 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.
Results
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.
Although there were six deaths associated with IRIS in the trial, Dr Stephen
Lawn of the Desmond Tutu HIV Centre told HATIP, “I think it can be a
tough call to distinguish deaths from TB IRIS vs deaths with TB
IRIS...and it is important to note that those with the highest risk of TB IRIS
are the ones with the highest pre-existing mortality risk. The number of TB IRIS
deaths reported in the early arm (approx 4.5%) is consistent with the systematic
analysis by Muller et al in Lancet Infect Dis 2010” (see references).
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, is 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. There was a non-significant difference in
median CD4 cell counts after week 102 (median 230 on early ART and 201 on late
ART at week 150). Note, given that the median CD4 cell count at entry was 25,
many patients were still at risk for a number of HIV-related complications for
quite some time despite being 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
“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 occur in people not receiving treatment at all. But if everyone with
advanced HIV disease received appropriate and timely diagnosis and received TB
treatment followed by ART two weeks afterwards, the survival benefit could
potentially be expected to be even greater. However, this would require far
better integration of TB/HIV services than exists presently.
Discussion
The study has only recently completed, so the analysis should be treated as
preliminary, and some questions still remain unanswered. For example, was there
a faster time to TB culture conversion in people on early ART?
“From the point of view of TB control programmes, they will be interested to
know whether early ART improves TB-specific treatment outcomes, ie. 6 months
after starting anti-TB treatment is the treatment success rate increased and the
case fatality lowered,” said Professor Anthony Harries, Senior Adviser to
International Union Against Tuberculosis and Lung Disease.
Another study also presented at AIDS2010 could have bearing on this question.
Dr Gabriel Chamie reported on the microbiologic, radiological and clinical
treatment outcomes in 223 coinfected Ugandans with CD4 cells above 350 who were
randomised to start ART 2-4 weeks after starting TB treatment versus those who
only were put on ART if their CD4 cells fell to below 250. To cut a long story
short - there were no TB treatment failures and no differences in culture
conversion or other responses per arm. Dr Chamie concluded that six months on
ART may have been too short a time to see differences in immunological responses
to m.TB. But if people whose immune systems are somewhat more intact can’t mount
these responses within six months, it might be even more difficult to get a
rapid TB-specific immune response people with a baseline CD4 cell counts
averaging around 25.
If ART doesn’t dramatically improve TB-specific treatment outcomes, the
survival benefit could be more associated with treating HIV. However, it is
curious that in CAMELIA, simply starting ART a mere six weeks earlier produced a
survival benefit that doesn’t seem to be explained by differences in virological
or CD4 cell responses between the arms.
CAMELIA’s results are in contrast to a study by Tavuka et al, which was presented at the 2nd South
African TB Conference and included over 1600 subjects and found no
significant difference in the risk of death if antiretroviral (ARV) treatment
was initiated within two months of beginning TB treatment or more than two
months after beginning TB treatment. About 10% of the subjects died in each arm.
Notably, this study involved people with higher CD4 cell counts and follow-up
was only until 12 months after initiating TB treatment.
Part of what is most interesting about the CAMELIA study, however, is that
ART didn’t so much prevent more early deaths as cumulative deaths over time.
From the Kaplan-Meier curves, while differences in survival emerge gradually
after the first few months of TB treatment, in the late ART arm, it appears as
though about half of the deaths occur after the time TB therapy would have been
completed, and about a third of the deaths occurred more than 50 weeks after
starting TB treatment. The difference between the two arms only becomes
significant at some point after 50 weeks.
“In SAPIT the mortality difference also opened out greatly after the
completion of TB treatment,” Mark Harrington of the Treatment Action Group told
HATIP. In fact, the survival difference in that study starts to become more
marked 10 to 12 months after TB treatment was initiated.
“It would be good to stratify death in those on early ART and later ART by
2-months of TB treatment, 6-months of TB treatment (ie at the end), 12-months –
the Kaplan Meier will show it but it may also be useful to look at these set
points in time,” said Professor Harries.
Another question is whether there were other clinical changes on ART that
might have been prognostic of better outcomes, such as, was there less weight
loss in those on early ART? One thing that both Tavuka et al and the CAMELIA
study noted was that low BMI was highly associated with poor survival. Prof
Harries has observed this as well.
“Our studies in Malawi showed that low BMI in TB patients was strongly
associated with early 1-month mortality (before ART) and I am not sure
theoretically that ART could fix this in time,” he told HATIP.
Perhaps early ART is primarily protecting against the greater constitutional
consequences of active TB in people with HIV. Even if TB is successfully
treated, without ART during active TB disease, people might end up more wasted,
weaker and frail — and more susceptible to succumbing to other infections and
HIV related conditions. This may be a particular danger in very advanced HIV
disease. As a member of the audience at the conference pointed out, it isn’t
clear that you would see a similar survival benefit, or IRIS frequency, in
people with higher CD4 cell counts.
Even so, the CAMELIA data seem to be a profound illustration that people with
advanced HIV need ART as soon as possible for their HIV disease.
During the conference, Dr Kevin de Cock of the US Centers for Disease Control
asked if it 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.
Implications
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, and in subsequent correspondence
with HATIP, various experts discussed the implications of the findings.
“I think that overall these data are very important and very credible. These
provide strong support for the 2010 WHO guidelines (which is very reassuring!)
and also entirely consistent with the Zolopa study in patients who
were also very immunocompromised but with non-TB illnesses. We clearly need
further data from other settings and at different CD4 counts but all the data
are pointing in the same direction,” Dr Lawn told HATIP, but he added:
“There is an important exception, though: when the OI is intra-cranial.
Immediate ART conferred no survival benefit among patients with TB meningitis in
Vietnam (2 weeks vs 2 months) (Torok et al ICAAC 2009). And immediate ART vs
>10 week delay was associated with much higher mortality in patients with
cryptococcal meningitis in Zimbabwe (Makadadzange et al CID 2010). When these
serious OIs involved vital structures within the confines of the cranium, then
the consequences of IRIS are likely to be far more severe. Thus, I think early
ART is good except for patients with CNS TB or crypto[coccal meningitis]. More
data are needed here,” he told HATIP.
Professor Di Gibb of the UK’s Medical Research Council also told HATIP she
believes “knowing more about how easy IRIS was to treat ...or might be if the
CD4 is higher…outside major centres would be important for programmes.”
“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 – it should not be a barrier to initiating ART in
people with HIV and TB,” said Gerry Friedland of Yale University, speaking at
the conference.
“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 a compelling need to change the way we
are presenting ART to TB patients.”
“If the statement “the earlier the better” cannot scientifically be made as
yet, but among experts we agree that it is highly probable, then common clinical
and public health sense and a patient’s perspective needs to be taken into
account as well,” Eric van Praag of Family Health International in Tanzania told
HATIP.
“If the patient is ambulant and pill load is understood and acceptable and
there is easy access to the TB/HIV clinic, and a home-based care programme is
guaranteed for follow-up of side effects/ IRIS, then we should advocate for a
start at 2 weeks. In situations where patients are not that stable clinically,
or have very low CD4 counts, or live far or isolated from the clinic, or are not
really ready as yet, we should be more prudent, manage other conditions, and
nutrition, and try linking up with home-based care or outreach. In other words,
we need to have room for individualisation of clinical management,” he
concluded.
Reference
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.
Müller M et al. Immune reconstitution inflammatory syndrome in patients
starting antiretroviral therapy for HIV infection: a systematic review and
meta-analysis. Lancet Infect Dis 2010 Apr;10(4):251-61.
Further information
View abstract and slides
from this session on the official conference website.