People with HIV reduce their overall risk
of tuberculosis (TB) by starting antiretroviral therapy, an international team
of investigators report in the online edition of Clinical Infectious Diseases. Despite this, the risk of the disease
increased in the first three months of HIV treatment, especially for older
people and those with a low CD4 cell count. For severely immunosuppressed
people, the risk of TB remained increased in the longer term.
“Physicians should be aware of the
potentially increased risk of developing tuberculosis after cART [combination
antiretroviral therapy] initiation,” comment the investigators.
The study was conducted because of
uncertainty about the level of protection which starting HIV therapy provides
The immune restoration which accompanies
the initiation of antiretroviral treatment should offer protection against the
infection. However, it can also be associated with a short-term risk of what is
called immune reconstitution inflammatory syndrome (IRIS). This could be
because of the paradoxical worsening of previously treated TB, or the 'unmasking' of sub-clinical disease. The risk of IRIS is greatest during the
first three months of HIV therapy.
Investigators from Europe and the US
therefore designed a study involving approximately 65,000 people who received
HIV care between 1996 and 2007. All these participants were antiretroviral naive at
baseline. The overall risk of TB was compared between individuals who started
HIV therapy and those who did not. The risk of the disease was also calculated
according to the time since HIV therapy was started and also according to risk
factors such as CD4 cell count and age.
During a median of 28 months of follow-up,
a total of 712 patients were diagnosed with TB. This provided an overall
incidence of three cases per 100 person-years.
Overall, starting HIV therapy was
associated with a substantial reduction in the risk of TB (HR = 0.56; 95% CI,
0.44-0.72), leading the investigators to comment: “This study shows a reduction of 44% in tuberculosis incidence among HIV-positive individuals who start cART
in high income countries.”
However, incidence of TB differed according
to a number of HIV-related and demographic characteristics.
It was highest among people with a CD4
cell count below 50 cells/mm3 (8.4 cases per 100 person-years) and
lowest for those with a CD4 cell count above 500 cells/mm3 (2.1
cases per 100 person-years). This difference is explained by the much higher numerical incidence of TB at lower CD4 cell counts.
Incidence also differed according to HIV
risk group. It was lowest among gay and other men who have sex with men (one
case per 100 person-years), and highest in people who originated from
sub-Saharan Africa (7.7 cases per 100 person-years).This difference is explained by the population burden of latent TB infection and by higher infection rates in sub-Saharan Africa.
Incidence of the infection was lower in
younger people compared to older people (under 35 = 2.4 cases per 100 person-years vs over 50 = 4.8
cases per 100 person-years), due in part to a lower duration of potential exposure to TB among younger people,
“Impaired immunological responses to M. tuberculosis in people starting cART
at very low CD4 cell counts and those above 50 years of age warrant further
investigation,” comment the investigators.
Despite the overall reduction in the risk
of TB associated with HIV therapy, the investigators found that people starting treatment actually had an increased
risk of the disease during the first three months of treatment compared to
those who remained antiretroviral naive (HR = 1.36; 95% CI, 0.98-1.89).
HIV therapy lasting longer than three
months was associated with a 56% reduction in the risk of TB (HR = 0.44; 95%
“The epidemiological pattern suggests that
unmasking IRIS may be playing a role,” write the authors.
But even after three months of therapy,
people with a CD4 cell count below 50 cells/mm3 were still more
likely to develop TB than those who had not started antiretroviral
treatment (HR = 1.02; 95% CI, 0.44-2.36).
“These patients remain in a state of
relevant immunodeficiency in spite of cART for longer periods and are therefore
at higher risk of reactivating latent tuberculosis beyond 3 months after
starting cART,” suggest the investigators. “Further follow-up of these cohorts
will show whether the risk of tuberculosis does eventually drop with longer
exposure to cART.”
The role of IRIS in TB risk
was further suggested by the overall reduction in the incidence and risk of PCP
(Pneumocystis jirovecii pneumonia)
that accompanied the initiation of antiretroviral treatment in both the short
and long term.
The authors conclude: “For cART to be
useful in tuberculosis control, prompt HIV infection testing is needed so cART
can be started when clinically indicated rather than at advanced
immunodeficiency. Diagnosis and treatment of M. tuberculosis infection, as
national and international guidelines recommend, should be reinforced. Even in
countries with low tuberculosis transmission, intensified case finding remains