Molly Franke, Megan Murray, and colleagues report that early cART reduces
mortality among HIV-infected adults with tuberculosis and improves retention in
care, regardless of CD4 count.
Randomized clinical trials examining the optimal time to initiate combination
antiretroviral therapy (cART) in HIV-infected adults with sputum
smear-positive tuberculosis (TB) disease have demonstrated improved survival
among those who initiate cART earlier during TB treatment. Since these
trials incorporated rigorous diagnostic criteria, it is unclear whether
these results are generalizable to the vast majority of HIV-infected
patients with TB, for whom standard diagnostic tools are unavailable. We
aimed to examine whether early cART initiation improved survival among
HIV-infected adults who were diagnosed with TB in a clinical setting.
Methods and Findings
We retrospectively reviewed charts for 308 HIV-infected adults in Rwanda with
a CD4 count≤350 cells/µl and a TB diagnosis. We estimated the
effect of cART on survival using marginal structural models and simulated
2-y survival curves for the cohort under different cART strategies:start
cART 15, 30, 60, or 180 d after TB treatment or never start cART. We
conducted secondary analyses with composite endpoints of (1) death, default,
or lost to follow-up and (2) death, hospitalization, or serious
opportunistic infection. Early cART initiation led to a survival benefit
that was most marked for individuals with low CD4 counts. For individuals
with CD4 counts of 50 or 100 cells/µl, cART initiation at day 15
yielded 2-y survival probabilities of 0.82 (95% confidence interval:
[0.76, 0.89]) and 0.86 (95% confidence interval:
[0.80, 0.92]), respectively. These were significantly higher than
the probabilities computed under later start times. Results were similar for
the endpoint of death, hospitalization, or serious opportunistic infection.
cART initiation at day 15 versus later times was protective against death,
default, or loss to follow-up, regardless of CD4 count. As with any
observational study, the validity of these findings assumes that biases from
residual confounding by unmeasured factors and from model misspecification
Early cART reduced mortality among individuals with low CD4 counts and
improved retention in care, regardless of CD4 count.
Please see later in the article for the Editors' Summary
HIV infection has exacerbated the global tuberculosis (TB) epidemic,
especially in sub-Saharan Africa, in which in some countries, 70% of
people with TB are currently also HIV positive—a condition commonly
described as HIV/TB co-infection. The management of patients with HIV/TB
co-infection is a major public health concern.
There is relatively little good evidence on the best time to initiate
combination antiretroviral therapy (cART) in adults with HIV/TB
co-infection. Clinicians sometimes defer cART in individuals initiating TB
treatment because of concerns about complications (such as immune
reconstitution inflammatory syndrome) and the risk of reduced adherence if
patients have to remember to take two sets of pills. However, starting cART
later in those patients who are infected with both HIV and TB can result in
potentially avoidable deaths during therapy.
Why Was This Study Done?
Several randomized control trials (RCTs) have been carried out, and the
results of three of these studies suggest that, among individuals with
severe immune suppression, early initiation of cART (two to four weeks after
the start of TB treatment) leads to better survival than later ART
initiation (two to three months after the start of TB treatment). These
results were reported in abstract form, but the full papers have not yet
been published. One problem with RCTs is that they are carried out under
controlled conditions that might not represent well the conditions in varied
settings around the world. Therefore, observational studies that examine how
effective a treatment is in routine clinical conditions can provide
information that complements that obtained during clinical trials. In this
study, the researchers aimed to confirm the results from RCTs among a cohort
of adult patients with HIV/TB co-infection in Rwanda, diagnosed under
routine program conditions and using routinely collected clinical data. The
researchers also wanted to investigate whether early cART initiation reduced
the risk of other adverse outcomes, including treatment default and loss to
What Did the Researchers Do and Find?
The researchers retrospectively reviewed the charts and other program records
of 308 patients with HIV, who had CD4 counts≤350 cells/µl, were
aged 15 years or more, had never previously taken cART, and received their
first TB treatment at one of five cART sites (two urban, three rural) in
Rwanda between January 2004 and February 2007. Using this method, the
researchers collected baseline demographic and clinical variables and
relevant clinical follow-up data. They then used this data to estimate the
effect of cART on survival by using sophisticated statistical models that
calculated the effects of initiating cART at 15, 30, 60, or 180 d after the
start of TB treatment or not at all.
The researchers then conducted a further analysis to assess combined outcomes
of (1) death, default, lost to follow-up, and (2) death, hospitalization due
to any cause, or occurrence of severe opportunistic infections, such as
Kaposi's sarcoma. The researchers used the resulting multivariable
model to estimate survival probabilities for each individual, based on
his/her baseline characteristics.
The researchers found that when they set their model to first CD4 cell counts
of 50 and 100 cells/µl, and starting cART at day 15, mean survival
probabilities at two years were 0.82 and 0.86, respectively, statistically
significantly higher than the survival probabilities calculated for each of
the other treatment strategies, where cART was started later. They observed
a similar pattern for the combined outcome of death, hospitalization, or
serious opportunistic infection In addition, two-year outcomes for death or
lost to follow-up were also improved with early cART, regardless of CD4
count at treatment initiation.
What Do These Findings Mean?
These findings show that in a real world program setting, starting cART 15 d
after the start of TB treatment is more beneficial (measured by differences
in survival probabilities) among patients with HIV/TB co-infection who have
CD4 cell counts≤100 cells/µl than starting later. Early cART
initiation may also increase retention in care for all individuals with CD4
cell counts≤350 cells/µl.
As the outcomes of this modeling study are based on data from a retrospective
observational study, the biases associated with use of these data must be
carefully addressed. However, the results support the recommendation of cART
initiation after 15 d of TB treatment for patients with CD4 cell
counts≤100 cells/µl and can be used as an advocacy base for TB
treatment to be used as an opportunity to refer and retain HIV-infected
individuals in care, regardless of CD4 cell count.
Please access these Web sites via the online version of this summary at
Information is available on HIV/TB co-infection from the
World Health Organization, the
US Centers for Disease Control and Prevention, and the
International AIDS Society