Given the importance of
the issue, HATIP asked our advisory panel and other TB/HIV experts the
Do you believe
in that earlier ART or immediate ART may still have a significant role for TB
prevention above and beyond treating at the 350 CD4 cell threshold?
What should be
done to reduce the risk of TB in PLHIV: (a) at higher CD4 cell counts? (b) on
other modalities to reduce the risk of TB in PLHIV?
Do you have
any other explanations for the HPTN 052 findings?
1. Do you
believe that earlier ART or immediate ART may still have significant a role for
TB prevention above the 350 CD4 cell threshold?
Harries, International Union against
Tuberculosis and Lung Disease: Yes, although I believe this TB preventive effect
of ART diminishes as the CD4 count increases. However, I believe one must
dissociate the public health strategy of placing HIV-infected people early on
ART from the individual practice of doing this. At the individual level, the TB
preventive effect may be modest – however, at the individual level you also
have to take into account the other benefits of early ART (reduced HIV
transmission to sexual partners and newborn children, treatment for Hepatitis B
and so on). At the population level, a strategy of early start of ART will
ensure many more people starting ART before catastrophically low CD4 counts
develop, and this also gets us away from the undoubted barrier in low-income
countries of trying to get CD4 count measurements done to determine eligibility
Annelies Van Rie, University of North Carolina School of Public Health: At this point in time,
I do not think we have good evidence to support ART > 350 for TB prevention.
We need to wait for results of the other ongoing trials.
Dr Halima Dawood,
Grey’s Hospital, Pietermaritzburg, South Africa: I
think this effect is limited by other factors: exposure to TB and the nature of
immune reconstitution, socio-economic factors and nutrition, for example.
Diane Havlir, University of California,
San Francisco: The 052
study is the primary new information to inform your questions. As you know this
study was a RCT, the gold standard, conducted in areas of high TB prevalence.
In an ITT analysis it showed that ART provides protection against AIDS/TB for
persons with CD4 up to 550. Of note, even with the fact that the follow-up was
relatively short because of the profound impact that ART had on HIV
transmission, the protection afforded by ART was impressive. Multiple cohort
studies summarised by Lawn, et al bolster these data and show that ART protects
TB is a leading killer of persons with HIV—the evidence
tells us that ART given to persons up to a threshold of CD4 550 prevents AIDS
and TB (including MDRTB) – policy and guidelines should incorporate this
evidence now. Of course implementing will be a challenge, but that should not
prevent policy from incorporating new evidence.
Professor Gavin Churchyard,
Aurum Institute for Health Research: “I still can’t explain why there
may be a differential effect on extrapulmonary TB, but I am not sure this was
an appropriate analysis strategy. The key message should remain that ART
reduces TB risk based on 052 and the observational data.”
Dr Annelies Van Rie: I agree with Diane
with respect to activism and engagement. There is lots of data to support early
initiation of ART and we should all advocate for that.
The issue to debate is whether we have sufficient data to use
prevention of TB as an argument for early ART (meaning ART above 350)? The best
data we have is the RCT HPTN 052, which is puzzling. EPTB was prevented,
pulmonary TB was not. This is an unexpected finding and hard to explain. I have
not yet read any clear hypothesis to explain this finding.
Some have stated that one could use the argument that ART is needed
because people with TB transmit, but people with EPTB are less infectious, so
to prevent transmission of TB, early ART would need to prevent pulmonary TB,
which, based on the only RCT data we have, it does not.
Some have raised the issue of mortality. Data suggest that people with
HIV and diagnosed TB who receive ART
do not have higher mortality rates than those who start ART and do not have TB.
The mortality rate of people with TB on ART is driven by undiagnosed TB, and among those treated for TB mortality is driven
by CD4 count. As such we see strong differences in mortality between major
studies of ART in people on TB treatment: SAPIT, STRIDE and CAMELIA. Mortality
in people with TB and high CD4 count (> 350) may not be substantially
different from HIV-negative individuals with TB, although the data are again
Wafaa El-Sadr, Columbia University and the International Center for AIDS Care
and Treatment Programs (ICAP): I agree with Diane that
HPTN 052 as a randomised clinical trial is the most rigorous source of
evidence. However, I have to say that the results of HPTN 052 are very
surprising and puzzling to me as they do NOT provide a strong support for the
value of early ART on prevention of TB.
Pulmonary TB is a much more common condition than
extrapulmonary TB as well as easier to diagnose. Thus, if the hypothesis is
that early ART prevents TB, then one would have been much more likely to see a
significant effect on pulmonary TB. The lack of such an effect on pulmonary TB
(similar number in both arms of HPTN 052) is very puzzling to me and is not
consistent with prior findings from observational data (which of course have
all the usual limitations and biases).
2. What should be done
to reduce the risk of TB in PLHIV at: (a) higher CD4 cell counts? (b) On ART?
I am a believer in early start of ART
not only to reduce the risk of TB but for the other reasons mentioned above. If
this early ART strategy is not adopted, it makes sense to give IPT but I would
only do this within the structure of a pre-ART clinic where the intervention
can be monitored. I am totally against giving it out as a free-for-all.
In relation to patients on ART there are three important issues here –
a) regular symptomatic screening for TB every time the person attends the
clinic with diagnostic action if the symptom screen is positive – in this way
active screening and diagnosis and treatment of those with TB; b) good
infection control, as the last thing we want is to expose persons on ART to
nosocomial TB transmission; c) consideration of IPT. For how long though is a
moot point; despite WHO recommending TDF with a phasing out of d4T, this will
be very difficult in the current economic climate and the interaction between
isoniazid and d4T is significant.
Dr Annelies van Rie: For patients on ART I
think there is a body of evidence for IPT, but I’m not convinced that there is
sufficient evidence for people stable on ART with higher CD4 counts. For
patients with higher CD4 cell counts I would definitely support IPT for those
not yet eligible for ART.
Dr Halima Dawood: For patients at higher CD4 cell counts, good TB control at a
population level. For patients on ART, ensuring adherence to ART and good
Dr Stephen Lawn: Viral load is a strong
independent risk factor for prevalent TB pre-ART. In a recent unpublished
analysis of long-term follow-up of the Gugulethu cohort (median 5 years), VL
>1000 on ART is an independent predictor of TB having adjusted for current
CD4. Thus I agree that unsuppressed virus is 'bad' with regards to TB risk.
3. Are there other modalities to reduce the risk of
TB in PLHIV?
Professor Anthony Harries: Of course we need to
consider IPT. I still think this will be a major challenge for a number of
reasons: a) Where are the structures to deliver this? b) The effect of IPT
comes for those who are TST-positive, and getting TST performed and the skin
test read in the routine setting is nearly impossible.
HATIP: The capacity to
perform TSTs of course varies by setting; and even those settings which can
provide TSTs can have difficulty getting patients to return to the health
facility to have their reactions measured. For this reason, WHO guidelines
state that TST are not required to provide IPT since it could serve as a barrier
to accessing treatment.
Dr Halima Dawood: "This issue needs to start with prevention of
HIV in addition to TB. Once a person is HIV infected, we need to ensure health
care is optimised to prevent TB and if TB disease occurs, we provide rapid
treatment and containment of disease, along with contact screening. I know it
may sound simplistic but we are not doing the basics optimally."
Dr Annelies van Rie: Investing in basic TB
control! We know that a lot of the sources of transmission of TB are HIV-negative
individuals with TB in the community and HIV-positive individuals in health care
settings, so good TB control with early diagnosis (intensified case finding)
and optimal treatment for all individuals with TB (HIV-positive and negative)
is essential. In addition, contact tracing at household level, coupled with HIV
testing (as done in Zambart [the ZAMSTAR study) is an intervention that could
identify people with TB earlier, as well as unknown HIV among contacts with TB
who would definitely benefit from IPT(and ART if CD4 < 350).
HATIP: Indeed, this ties in
well with a paper presented by Middelkoop et al at IAS that found that most of
the TB in people living with HIV in that peri-urban community near Cape Town
was recently acquired, and that the source/index case was most commonly an
HIV-negative individual — suggesting that it is in the vested interest of
people living with HIV to make certain ALL TB is detected, diagnosed and
4. Do you have any other explanations for the HPTN
Annelies Van Rie: I am also puzzled by the HPTN results. The only thing I can think of is
differential assessment practices by CD4 count. There was no standard operating
procedure for EPTB across sites for assessment of EPTB. If you are more
thorough in screening for EPTB in patents with low CD4 counts (a practice that
makes sense given the higher risk of EPTB in people with low CD4 count), then
you may find more EPTB in those in the delayed arm.
If all cases of EPTB were truly EPTB, then this would not matter, as
those who you do not diagnose would develop symptoms over time and be diagnosed
later (one would think). No information is given whether cases were confirmed
microbacteriologically, which is often the case for lymph node and especially
My hypothesis is that there was not differential assessment by arm, but
by CD4 count, which results in differential assessment by arm over time
So, if there was a bias in assessing for EPTB based on CD4
count (which differed over time between groups and was lower in the delayed
group) and patients were started on
treatment for non-bacteriologically confirmed EPTB and not all patients treated empirically actually had EPTB, then one could see this difference
without there truly being a difference in EPTB rates.
El-Sadr: Why an effect was noted only for extrapulmonary TB, I do not know.
But the absence of an effect on pulmonary TB (as indicated above) makes me
worried that the difference noted in extrapulmonary TB was due to chance or
ascertainment bias. In addition, my understanding is that none of the
extrapulmonary TB cases were microbiologically confirmed. So provider differences in their suspicion
level for extrapulmonary TB at the various sites could have influenced this
finding. It is also important to keep in mind that HPTN 052 was not a blinded
study and of course this can influence provider behavior, and ascertainment
practices. For example, were providers were more likely to think of
extrapulmonary TB in patients not on ART versus believing that those on ART (in
the early ART arm) were “protected” from TB?
The findings from HPTN 052 actually raise questions about
the findings shown in the observational studies in terms of effect of early
versus delayed ART on TB incidence.
While many of these studies were excellent, they suffer from inherent
and unavoidable limitations.
Dr. Stephen D. Lawn, London School
of Hygiene & Tropical Medicine & Desmond Tutu HIV Centre, Cape Town: Regarding HPTN 052. I
note the scepticism expressed by others regarding the TB end-point. I haven't
had chance to look at the study protocol in detail. My impression of the study
is that the HIV transmission end-point was very, very rigorously assessed. Well
done to them. I strongly suspect that the same rigour did not apply to the TB
end-point and that this was probably not standardised across the study sites.
HIV acquisition is extremely simple to assess regardless of the study setting;
TB is not. I think the takeaway message is that overall TB was reduced by early
ART. More detail from the investigators is needed to understand this better.
Anthony Harries: With regards to HPTN 052 we do not know enough from the
paper. If I combine PTB and EPTB then we have 16 TB cases in the early therapy
group with 1580 person-years of follow-up (which gives a TB rate of about 1%
per annum or 1,000 per 100,000 per year) and we have 32 cases in the delayed
therapy group with 1580 person-years of follow up (which gives a TB rate of
about 2% per annum or 2,000 per 100,000 per year). These are huge rates of TB! I think to
understand HPTN 052, we need more data on the TB side.