“The antenatal and prevention of mother-to-child
transmission programmes, which have really been the focus for a lot of the HIV
planning for women, are a key entry point for healthcare for women in general
and represent an opportunity to detect active and latent tuberculosis, and to
educate women about TB, particularly if they are HIV-infected because they
really are the greatest risk,” said Dr Gupta.
She also noted that research has shown women tend to have
less TB literacy compared to their male counterparts.
Indeed, a large national survey documented low awareness of
TB among women in Nigeria.
As many as 28.9% of the women in a survey said that they had never even heard
of TB (compared to 11.6% who were unaware of HIV). Looking over the demographic
data, implementers puzzled about how to reach these poor young rural women with
little education — the original plan had been to integrate a TB/HIV literacy
component into family planning services.
However, these particular women did
not commonly use those services. On the other hand roughly 30-40% of them had
accessed antenatal care — suggesting
that that would be the most logical place to focus their TB/HIV efforts and
reach this underserved population.19
have already been several studies introducing TB screening into antenatal
clinics but they used somewhat different screening approaches. Most have relied on symptom screens, but
others added or substituted tuberculin skin tests (TSTs) and some added chest
x-rays to identify TB suspects for further diagnostic work-up. However, the
role of shielded chest X-rays and tuberculin skin testing in this population
continues to be debated (and indeed continued to be debated later in the
symposium and conference (see below).20
In 2006, a programme in Soweto, South Africa
integrated TB screening into the post HIV test/counselling session at the
antenatal clinic.21 A nurse/lay counsellor was given a 7-minute
symptom screen to administer to the patients that looked specifically for cough
greater than 2 weeks as well as other signs and symptoms of TB. Symptomatic
women were then referred for further investigation. They screened 370 women and
identified TB symptoms in 120 (32%). Ultimately, eight women (2.2% of overall
group, 7% of symptomatic group) were diagnosed with active TB –each one was
Earlier in 2003, Nachega el al performed TB screening specifically
during the post-natal follow-up period in women living with HIV and their male
partners by performing tuberculin skin tests (TST)
to identify those who had been
exposed to TB.22 Participants were to return two or three days later to have
their reaction read. A positive result was defined as an induration (bump) over
>5mm, and these were sent for a complete diagnostic work up.
But there were
problems with this strategy. Out of 438 HIV-positive patients given a TST, 120
(27.4%) did not return for results. A little under half (157) of subjects who
returned for TST reading were TST-positive, but only about 120 of these came
back for the full diagnostic work-up (a loss of another 24%. Out of the 120 with an evaluable diagnostic
work-up, 13, or 11% had active TB (as they were TST-positive, the remaining 107
had latent TB infection (LTBi) — and thus were candidates for isoniazid
preventive therapy (IPT).
In addition to the loss to follow-up there are a couple of other
downsides to using TSTs as a screen. Tuberculin supplies require cold chain
management, which makes it difficult to implement in remote lower resourced
settings. In addition, people living with HIV are often anergic (fail to have a
immune reaction on the TST) but that doesn’t mean that they are not latently
infected and therefore at risk of developing active tuberculosis.
On the other
hand, TSTs do identify those most likely to benefit from IPT — which may be a
useful piece of treatment information for a person living with HIV in a high TB
burden setting, who is faced with the decision of whether to take continuous
IPT to prevent TB due to reinfection(see below). It might also conserve
laboratory capacity by reducing the number of specimens sent to the lab —
especially with such appalling losses during referral.
Nevertheless, a case
detection rate of 11% is exceptionally high, and if a way were found to retain
patients in care (perhaps by having a community healthcare worker make home
visits to read the TST), including access to TST in maternal-child health
services might prove useful.
Indeed, in India,
Dr Gupta performed a study that found a 1.4% prevalence of active TB among
women screened around the time of delivery in India, using either the WHO symptom
screen or TST.23
Grounder et al reported on a study in Soweto in which she
and her colleagues implemented TB symptom screening at six antenatal and
prevention of parent-to-child transmission clinics, with the specific objective
of getting as much of the diagnostic process done during the patient’s very
first antenatal visit — in a valiant effort to minimise the opportunities for
the patients to be lost to referral during the process. So the TB symptom
screen was actually performed during the HIV pre-test counselling session, and
if the symptom screen was positive, a sputum specimen was taken on the spot for
smear, culture, and drug sensitivity testing.
Including all the women, irrespective of HIV-status – they
found that 23% of the HIV-positive women had a positive symptom screen,
compared to 14% of the HIV negative women; and after the diagnostic workup they
identified 15 active TB cases out of a total of 3963 women, of whom 37% were HIV-positive.
Ten active TB cases were identified out of 1454 HIV positive women (0.6%;
688/100,000 persons/years) and five active TB cases were found among 2483
HIV-negative women (0.2%; 201/100,000 persons).24
WHO’s 4-symptom screen
Most of these studies used symptom screens that are now considered
old and out-dated since the introduction of the WHO 4 symptom screen to rule
out TB. Based on a meta-analysis including data on over 8,148
people living with HIV, Getahun et al identified four symptoms: any
current cough, fever, night sweats or weight loss which were only somewhat
sensitive for TB (78%) and poorly specific (50%) for TB, but the negative
predictive value (NPV) was quite high at 98% in a context of 5% TB prevalence
among people living with HIV (though the NPV falls to 90% if there is a 20% TB
In other words, it isn’t a very precise test for identifying TB cases, but a patient who does not have
any of the four symptoms is highly unlikely to have active TB, and could
be given IPT without having to worry about undertreating an active case of TB.
Of course, a few cases could slip through anyway, so WHO recommends
that the symptom screen be performed any time a person living with HIV has any
interaction with the health system, especially
if they are on IPT and come back to the clinic to collect the next month’s
supply of medicine. This reduces even further the likelihood that any
breakthrough active TB cases will undergo prolonged monotherapy — and TB cases
that are detected while on IPT, still respond well to standard treatment that includes
isoniazid (unless it is a case of transmitted drug resistance.
The symptom screen isn’t for everyone however. While the
meta-analysis included large numbers of women, it did not include small
children. WHO does not recommend its use for TB screening in children, in whom
symptoms and the natural history of the disease can be very different.
But what about pregnant women? Getahun et al make no
reference to them in their paper, and just like children, one cannot simply
assume that a meta-analysis based a general population can apply to a specific
and different population.
Fortuitously, Dr Gupta decided to evaluate the WHO symptom
screen retrospectively in their Indian cohort of 841 HIV-positive women around
the time of delivery (they had previously performed symptom screening and TST
screening at delivery, and women received a diagnostic workup if either was
positive. as part of their early symptom screening).
“We found similar findings to the meta-analysis in
non-pregnant populations [a negative predictive value of 99.3%] … no symptoms
for this population means that it’s going to be quite reasonable to consider IPT,”
said Dr Gupta.
The negative predictive value was slightly lower, 97.8% in women
with CD4 cell counts below 350. (Notably, the inclusion of TST in this study
increased the negative predictive value to 100% regardless of CD4 cell count).
Gupta believes the GeneXpert assay could be a “game-changer” given its high
sensitivity in both HIV-positive and HIV-negative individuals, in
smear-positive and smear negative case, and its potential to significantly
decrease in median time to case detection.
Dr Gupta described a paper that had been recently published
that proposes integrating GeneXpert into antenatal clinics — as a point-of-care
test, “where a woman who would be coming in for antenatal care would get
educated about HIV and TB and then get registered with the symptom screen. If
she’s symptom positive, she would then give a sputum sample for the GeneXpert,
and carry on based on the results of that test. Certainly these kinds of models
need to be tested – particularly in terms of cost-effectiveness. Whether such a
model would really prove to be feasible in such a setting remains to be
“I also believe that GeneXpert is fabulous, but its not
feasible to roll out at the level of where the antenatal clinic is, and it never
will be. Particularly if you look at the economic barriers, you have to
diagnose many many cases to make it cost-effective,” said Stacie Stender of
JHIPIEGO, who gave the next presention.
Indeed, GeneXpert is something like the iPAD of the TB
diagnostics world — everyone would like to have one on their desk. While HATIP
does believe GeneXpert to be a significant technological advance, an upcoming
issue will more closely investigate operational issues related to its
implementation and its likely clinical impact.
Latent TB, diagnosis
Dr Gupta next turned her attention to screening for latent
TB infection to identify those at highest risk of reactivation disease who are
most likely to benefit from IPT or other preventive treatments. However, the
challenges of implementing TST (the return visit to read it, operator
dependency and a degree of cross reactivity and false positivity) have held
this strategy back, which is something of a shame since it is inexpensive and
Alternatives such as the interferon gamma release assays
(IGRA) initially created a bit of excitement because they don’t require a
return visit, nor do they cross-react with the BCG vaccine (which complicated
the interpretation of TSTs in children). But they are expensive, require a
fresh blood sample and there are issues around cut-offs interpretation and
reproducibility. Another issue is that TSTs and IGRAs are often in
disagreement, and they appear to be measuring somewhat different things. For
instance, IGRAs could potentially be detecting an immune response that has
developed in someone exposed to TB, but who did not become latently infected,
and who may not be at risk of active disease.
“We’re not really
quite sure what that means, and how to interpret that,” said Dr Gupta.
IPT and other
The WHO ICF/IPT guidance recommends offering at least
six months of IPT in any adolescent or adult living with HIV who screens
negative on the WHO Symptom Screen, including, now, pregnant women. Dr Gupta
had some reservations about how widespread the implementation of IPT should be,
given that the prevalence of latent TB varies significantly from place to
Clearly in a population where at least 25-30% are known to
be latently infected, we’re likely to see a benefit of wide implementation of
IPT. But in other settings where there may be a low burden of latent
tuberculosis, there may be less benefit.
30% where antenatal HIV prevalence 5%
Sheriff BMC Infect Dis 2010
Nachega AIDS 2003
20% where antental HIV prevalence 2 – 3%
Gupta CID 2007
11% in HIV-positive women
Mofenson Arch Int Med 1995
But while it is helpful to have the WHO recommendation to
implement IPT in pregnant women — which could be particularly beneficial for
TST-positive women, Dr Gupta believes that a pregnant woman has a number of
things to consider when thinking about TB preventive options.
“When we think about maternal health, ART, administered to
women during pregnancy and beyond, clearly has a huge impact on reducing TB
incidence. But we need to understand some of the side-effects that potentially
can occur when we coadminister ART with IPT, and with cotrimoxazole — and if a
woman is hepatitis B surface Antigen positive (HBsAg+)— there may be issues about
safety to consider,” she said.
Many healthcare providers have raised concerns about hepatotoxicity
as one of the reasons not to necessarily implement IPT across the board in
“We know that hepatotoxicity is increased during the state
of pregnancy, by itself. Certainly some of the antiretrovirals are associated
with hepatotoxicity. And there are old data from the pre-HIV, pre-HAART era
suggesting that INH, at least during pregnancy, caused some hepatotoxicity,”
said Dr Gupta.
In fact, because of the concerns related to using IPT in
pregnant women, pregnancy has been an exclusion criteria for all IPT trials to
date. But Dr Gupta feels evidence on IPT
during pregnancy is needed to convince providers and programmes.
So the NIH-funded IMPAACT trials network will be conducting
a randomised trial, the TB Apprise trial (IMPAACT P1078) looking at the safety
and timing of IPT — should it be given early in pregnancy or should it be
deferred into the postpartum period? — to provide some additional evidence on
the risks and benefits of IPT in pregnant women, particularly in those taking
The study will randomise 950 pregnant HIV-infected women
living in countries with a high burden of TB/HIV to immediate vs. deferred (3
months postpartum) IPT. Many women will be on ART and IPT concurrently, and
between 2 – 10% are expected to have occult HBsAg+. The primary endpoints is
safety — effectiveness will be a secondary endpoint.
Adherence on IPT is commonly reported to be suboptimal — and
in settings where the risk of re-exposure is not high, there is a need for new
short TB preventive regimens to be evaluated. Recently, a regimen of weekly isoniazid
and rifapentine given for 12 weeks and was shown as efficacious as a nine-month
regimen of IPT in mostly HIV-negative individuals. Soon a very large AIDS
Clinical Trials Group Study will study the effectiveness of daily isoniazid
with rifapentine for 4 weeks in 3000 people living with HIV above 13 years of
age (participants are permitted an NNRTI-based ART regimen).
Naturally, there are no pharmacokinetic or safety data for
rifapentine in pregnancy.
“Clearly I think we
need to push to say we need to study these drugs in women – specifically
pregnant women - at the same time, so that we can have the data ready to
implement as soon as these big trials release results,” said Dr Gupta.