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INT J TUBERC LUNG DIS 13(8):927–935
© 2009 The Union
UNRESOLVED ISSUES
Isoniazid preventive therapy for people living with HIV:
public health challenges and implementation issues
N. Aït-Khaled, E. Alarcon, K. Bissell, F. Boillot, J. A. Caminero, C-Y. Chiang, P. Clevenbergh, R. Dlodlo,
D. A. Enarson, P. Enarson, O. Ferroussier, P. I. Fujiwara, A. D. Harries, E. Heldal, S. G. Hinderaker,
S. J. Kim, C. Lienhardt, H. L. Rieder, I. D. Rusen, A. Trébucq, A. Van Deun, N. Wilson
International Union Against Tuberculosis and Lung Disease, Paris, France
SUMMARY
Isoniazid preventive therapy (IPT) is recognised as an important component of collaborative tuberculosis (TB) and
human immunodeficiency virus (HIV) activities to reduce
the burden of TB in people living with HIV (PLHIV).
However, there has been little in the way of IPT implementation at country level. This failure has resulted in a
recent call to arms under the banner title of the ‘Three
I’s’ (infection control to prevent nosocomial transmission
of TB in health care settings, intensified TB case finding
and IPT). In this paper, we review the background of
IPT. We then discuss the important challenges of IPT in
PLHIV, namely responsibility and accountability for the
implementation, identification of latent TB infection,
exclusion of active TB and prevention of isoniazid resistance, length of treatment and duration of protective
efficacy. We also highlight several research questions
that currently remain unanswered. We finally offer practical suggestions about how to scale up IPT in the field,
including the need to integrate IPT into a package of
care for PLHIV, the setting up of operational projects
with the philosophy of ‘learning while doing’, the development of flow charts for eligibility for IPT, the development and implementation of care prior to antiretroviral
treatment, and finally issues around procurement, distribution, monitoring and evaluation. We support the implementation of IPT, but only if it is done in a safe and
structured way. There is a definite risk that ‘sloppy’ IPT
will be inefficient and, worse, could lead to the development of multidrug-resistant TB, and this must be avoided
at all costs.
K E Y W O R D S : tuberculosis; HIV/AIDS; isoniazid preventive therapy; drug resistance
HUMAN IMMUNODEFICIENCY VIRUS (HIV) infection, by targeting CD4 T-lymphocytes and reducing
cellular immune function, is the strongest recognised
risk factor for the development of tuberculosis (TB).
Not only does HIV increase the risk of reactivating
latent Mycobacterium tuberculosis,1 it also increases
the risk of rapid TB progression soon after infection
or reinfection with M. tuberculosis.2 This increased
risk of active TB is detectable as early as HIV seroconversion, and doubles by the end of the first year of
HIV infection.3 As the CD4 lymphocyte count declines, the risk of active TB further increases to reach
levels of between 15% and 20% per annum in patients
with CD4 cell counts of less than 200 cells/μl.4,5
In high prevalence areas, HIV has been the driving force behind the escalating TB epidemic. Despite
the implementation of functional DOTS programmes,
many high HIV prevalence countries in sub-Saharan
Africa have seen case notification rates increase 2- to
6-fold in the last two decades, prompting a call to
consider TB control activities that go beyond DOTS.6
One of these activities is preventive therapy for TB.
In 1998, based on several randomised placebo-
controlled trials,7,8 the World Health Organization
(WHO) and the joint United Nations Programme on
HIV and AIDS (UNAIDS) issued a policy statement
that recognised the effectiveness of TB preventive therapy in persons living with HIV (PLHIV), and recommended the use of targeted isoniazid preventive therapy (IPT) as part of the package of care for PLHIV.9
In 2004, the WHO produced an interim policy on TBHIV collaborative activities to reduce the joint burden of TB and HIV (Table).10 One of the important
policy recommendations is that national HIV/AIDS
programmes (NAPs) should provide IPT for PLHIV
on the condition that active TB has been safely excluded. This recommendation has also been included
in the new 10-year Global Plan to Stop TB (2006–
2015)11 and the Stop TB Strategy,12 and is regarded
as an important component of several collaborative
TB-HIV activities.
Despite these international policy statements, there
has been little IPT implementation at country level.
The target of the Global Plan to Stop TB was for IPT
to be offered to 1 200 000 PLHIV during 2006, yet
only 30 000 persons were reported to have undergone
Correspondence to: A D Harries, Old Inn Cottage, Colden Common, Vears Lane, Winchester SO21 1TQ, UK. Fax: (+33)
1 4329 9087. e-mail: [email protected]
[A version in French of this article is available from the Editorial Office in Paris and from the Union website www.theunion.org]
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The International Journal of Tuberculosis and Lung Disease
Table
Recommended collaborative TB-HIV activities
Establish the mechanism for collaboration
• Set up a co-ordinating body for TB-HIV activities effective at all
levels
• Conduct surveillance of HIV prevalence among tuberculosis
patients
• Carry out joint TB-HIV planning
• Conduct monitoring and evaluation
Reduce the burden of TB in people living with HIV/AIDS
• Establish intensified tuberculosis case-finding
• Introduce isoniazid preventive therapy
• Ensure tuberculosis infection control in health care and
congregate settings
Reduce the burden of HIV in TB patients
• Provide HIV testing and counselling
• Introduce HIV prevention methods
• Introduce cotrimoxazole (CTX) preventive therapy
• Ensure HIV/AIDS care and support
• Introduce antiretroviral therapy
Adapted from World Health Organization.10
preventive treatment.13 Moreover, 70% of these
PLHIV were in Botswana, the only country that has
tried to scale up IPT at national level and, worryingly,
more than 60% of these failed to complete a 6-month
course of treatment.13 The global failure to deliver
IPT to PLHIV resulted in a further recent call to arms
in April 2008, under the banner title of the ‘Three I’s’
(infection control to prevent nosocomial transmission of TB in health care settings, intensified TB case
finding and IPT).14
Why has the implementation of IPT in PLHIV been
almost non-existent to date, and is there anything we
can do to change this inertia? This article addresses
these issues and is divided into two sections. We first
discuss the important challenges and concerns of IPT
in PLHIV, namely 1) the uncertainty and confusion
about who takes responsibility for implementation of
IPT, 2) the identification of latent TB infection (LTBI)
and who should receive the intervention, 3) the exclusion of active TB and the potential for creating
drug resistance if isoniazid (INH) monotherapy is inadvertently given to patients with active TB, and 4) the
length of treatment and the duration of protective efficacy. Second, we offer suggestions about how to scale
up IPT practically and safely in the field.
CHALLENGES OF IMPLEMENTING IPT IN PLHIV
Responsibility for implementation of IPT
Since the WHO/UNAIDS policy statement on IPT was
released,9 there has been uncertainty about who takes
responsibility for the task of its implementation. Procurement and distribution of anti-tuberculosis drugs,
including INH, have always been the responsibility of
National TB Programmes (NTPs), and it therefore
seemed that this intervention should fall under the remit of the NTP. However, with ever-increasing numbers of TB patients being registered for treatment,
NTPs felt they simply did not, and do not, have the
capacity to undertake this additional and very specific task. NAPs, which focused for the first 20 years
of the epidemic on preventing HIV infection, initially
had no experience or structures available to deliver a
6-month course of treatment to prevent TB in thousands of PLHIV.
With the advent and scale-up of antiretroviral treatment (ART) in resource-poor countries following the
WHO’s ‘3 by 5’ initiative in 2003,15 NAPs have logically directed their attention and resources to providing this life-saving intervention for PLHIV, and this
has diverted attention away from TB preventive activities. In April 2008, the HIV Department of the
WHO took up the mantra of this initiative under the
banner of the Three I’s,14 and clearly stated that it is
the responsibility of NAPs to deliver this package to
PLHIV within the context of general health systems.
However, because of its limited implementation within
general health services, there is a lack of practical
knowledge about where or how to implement IPT in
the field. Despite the implementation as early as 1997
of several pilot projects for collaborative TB-HIV activities,16 including IPT administration, the lessons
learnt to date from field experiences remain insufficient to guide national-level introduction of IPT.
Identification of latent TB infection and determining
who receives IPT
IPT reduces the risk of active TB by 60–70% in PLHIV
who are infected with Mycobacterium tuberculosis
as determined by a positive tuberculin skin test (TST),
but it has no significant effect in PLHIV whose TST is
negative.7,8 This important and well-known fact creates an immediate difficulty. Performing, reading and
interpreting TSTs in the context of busy HIV clinics
is a challenge for both health staff and patients. The
response to an intradermal injection of tuberculin is
read 48–72 h later, requiring the patient to revisit
the clinic soon after the first appointment. The result
and its interpretation is complicated by false-positive
results occurring from previous BCG vaccination or
exposure to environmental mycobacteria, and falsenegative results from HIV immunosuppression, malnutrition and other serious concurrent illness.17 Furthermore, tuberculin is either lacking or in short supply
in many resource-limited countries, although this could
be rectified. Interferon-gamma release assays (IGRAs)
using ESAT-6 and/or CFP-10 antigens have recently
been proposed as a possible solution to some of the
problems encountered with the TST.17,18 They are
much more specific than the TST, particularly in BCGvaccinated populations, and only require a single visit
by the patient. However, like the TST, IGRAs cannot distinguish between active and latent TB, and, despite reports showing improved sensitivity, their performance in PLHIV needs further investigation, as
results vary according to CD4 cell counts.19 There are
also problems with high costs, and there is a need for
IPT for PLHIV
access to specific laboratory equipment and venous
blood samples.17,18 Current evidence and experience
do not support the use of IGRAs in routine practice
in settings with high LTBI and high HIV prevalence.
Given the difficulties related to the use of the TST
or IGRAs in the field, it has been argued that IPT
should be given to all PLHIV, without determining
the presence or absence of LTBI. A high annual risk
of infection of 4% in children living in Cape Town,
South Africa,20 and an estimated prevalence of LTBI
of nearly 90% in South African goldminers21 would
support this approach. However, such high rates of
infection are probably the exception rather than the
rule in most of sub-Saharan Africa. For example, the
annual risk of a child becoming infected with M. tuberculosis in Kenya and Tanzania is of the order of
1%.22,23 While the annual risk of infection in these
countries is likely to be higher among young adults, a
large proportion of this population will still be expected to have escaped infection, and some who had
become infected earlier in life will no longer be harbouring live bacilli. Is it then ethical or cost-effective to
provide an intervention for more than half of a target
population who would derive no benefit from it?
IPT is relatively inexpensive, and if it was a completely safe intervention the benefits at the population
level might outweigh the risks. However, INH may
cause hepatitis, which can be fatal. The estimated rate
of symptomatic INH-related hepatitis ranges from one
to three per 1000 individuals, with known risk factors
being increasing age, pre-existing liver disease, chronic
hepatitis C infection, concomitant use of other hepatotoxic medications such as ART non-nucleoside reverse
transcriptase inhibitors (for example, nevirapine) and
regular alcohol consumption.17 INH may also cause
peripheral neuropathy, which can be exacerbated by
concomitant use of stavudine, an ART nucleoside reverse transcriptase inhibitor, although the addition of
vitamin B6 (pyridoxine) may provide some protection. The dilemma of whether to provide IPT only to
PLHIV who have a positive TST or IGRA result or
to all PLHIV is one of the reasons for the current
state of inertia in this area. The best way forward has
yet to be found, and it may be context-specific.
Excluding active TB and preventing isoniazid
resistance
In early HIV disease, most individuals are asymptomatic and the probability of active TB is lower than in
more advanced stages of HIV infection. Nevertheless,
the risk of active TB is still far greater than that in the
general population.3–5 A study in Tanzania found that
5% of PLHIV with CD4 counts >200 cells/μl with
no symptoms, normal chest radiography and, in several cases, negative sputum smear microscopy, had
active TB as determined by positive sputum cultures.24
A high degree of subclinical TB has also been found
in Zimbabwe25 and South Africa.26 This emphasises
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the fact that, even in a population where TB diagnosis
would be expected to be relatively straightforward,
a single evaluation may fail to completely rule out
active TB.
A diagnosis of TB is even more difficult in late stage
HIV disease, especially with the tools that are generally available in resource-poor settings—namely, sputum smear microscopy for acid-fast bacilli and chest
radiography. HIV-infected patients often have a low
sputum bacillary load that decreases as CD4 counts
decline,27 and this compromises the sensitivity of smear
microscopy, resulting in more patients being diagnosed
with smear-negative pulmonary TB.28 In patients with
culture-confirmed pulmonary TB, chest radiographs
have been reported to be normal in 14% of patients
in one study,29 and normal or not consistent with TB
in 23% of patients in another study.30 Coupled with
poor quality films and lack of skilled radiographic interpretation in many resource-limited settings, these
difficulties can lead to the diagnosis of TB being completely overlooked. There may be great difficulty in
diagnosing disseminated TB which commonly masquerades as the ‘HIV wasting syndrome’.31 In the busy,
overcrowded clinics and the increasingly overburdened
laboratories of African hospitals, where technicians
spend ever shorter periods of time examining sputum
smears32 or compromise on the examination of additional specimens following a first negative result,33,34
it is easy to envisage symptomatic patients with active TB slipping through the ‘TB screening net’ and
inadvertently being started on IPT. It is also easy to
see that those who have started IPT may be continued on it despite the development of active TB.
Inadvertent use of INH monotherapy in individuals
with active TB may potentially result in the selection
of INH-resistant strains. Does this matter? Studies
conducted 20 years ago, before the advent of the HIV
epidemic, showed that patients with INH-resistant TB
responded just as well to standardised short-course
treatment as patients with susceptible TB, although
there was an increased risk of relapse.35 Consequently,
some experts continue to think that the development
of INH-resistant TB is not an important consideration. We disagree, and in the presence of HIV infection we would be concerned about the risk of creating multidrug-resistant TB (MDR-TB, M. tuberculosis
resistant to at least INH and rifampicin [RMP]). These
concerns are justified by recent analyses that suggest
high rates of treatment failure (8%) in patients with
initial single drug resistance compared with low failure rates of 0.9% in patients whose TB is susceptible
to all anti-tuberculosis drugs.36
In a patient with INH resistance on a standardised
regimen of 2-month RMP, INH, pyrazinamide (Z,
PZA) (and ethambutol [E, EMB]) followed by 4 months
of RMP and INH (2RHZ[E]/4RH), the 2-month initial
phase is de facto with two or three active drugs, one
of which, PZA, is reportedly inactive in the non-acid
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The International Journal of Tuberculosis and Lung Disease
environment of cavity linings containing the large numbers of bacilli from which resistant mutants might be
selected. The 4-month continuation phase is de facto
RMP monotherapy. Despite international and national
guidelines that RH in the continuation phase be given
as directly observed treatment (DOT) administered
by a health worker, our collective experience is that
this is rarely the case. Poor adherence to RMP monotherapy for 4 months is a definite risk for selection of
RMP-resistant strains. In addition, the absorption of
RMP in HIV-infected patients may be poor.37 In the
HIV-infected host, monoresistant RMP strains can develop and accumulate additional resistance to other
first- and second-line anti-tuberculosis medications.38
That rifamycin resistance emerges preferentially in
HIV-infected patients in the absence of INH activity
was clearly demonstrated in the US Public Health
Service rifapentine trial, in which INH was given in
too-widely spaced doses to remain efficacious.39
Recent systematic reviews, already mentioned earlier, have shown that initial resistance to a single drug,
such as INH, can lead to increased rates of failure, relapse and acquired drug resistance in newly treated
patients,36 and acquired MDR-TB will lead to high
failure rates in patients on retreatment regimens.40 This
is a road to be avoided at all costs. The crucial message is that IPT must not be given to any PLHIV who
may have active TB, and must be discontinued in any
PLHIV on IPT who develops symptoms and signs of
active TB. A systematic review assessing the effect of
IPT on the risk for INH-resistant TB reported a summary relative risk of 1.45 (95% confidence interval
0.85–2.47).41 Although this result did not reach statistical significance, an increased risk for INH-resistant
TB after IPT could not be excluded. At present, no
data from randomised controlled trials of IPT conclusively show an increased risk of INH resistance, but
if scale-up of IPT does proceed, this will be an important area to highlight for future research efforts.
Treatment of latent TB infection and duration
of protective efficacy
The WHO and UNAIDS policy statement on IPT is
that INH should be given to PLHIV as daily, selfadministered therapy for 6 months.9 The only trial ever
to have compared the durations of 3, 6 and 12 months
of IPT was the large trial of the International Union
Against Tuberculosis in Eastern Europe, in which
persons with fibrotic lung lesions were followed for
5 years.42 Among patients who were adherent and
completed treatment, a 12-month course of IPT resulted in a risk reduction of active TB of 93%, while
a 6-month course resulted in a risk reduction of 69%.
A secondary analysis of the Bethel preventive therapy
trial suggested that protection from IPT may be maximised with at least 9 months’ treatment, but that
treating beyond 12 months gives no added protection.43 While a 9-month course of IPT seems to be
optimal, a major limitation is that completion rates
are typically low, and for this reason a shorter regimen
of 6 months has been recommended as an alternative.17 Other, shorter combination regimens have been
assessed, such as RMP+PZA for 2 months,44 RMP+
INH for 3 months,45 and RMP for 4 months,46 but
they are not generally recommended due to unacceptable side effects, especially with RMP+PZA,17 lack
of evidence from controlled trials, or other reasons.
The two randomised trials in HIV-infected persons
in Africa looking at 6-month IPT versus 3 months of
various combinations of RMP, PZA and INH showed
that the duration of protection with 6-month IPT
lasted no longer than 2.5 years.47,48 Increasing the
duration of IPT may lead to longer-term protection;
the definitive answers to this question await publication of comparative trials that have taken place in
southern Africa. Long-term protection may also be adversely affected by the rate of transmission of M. tuberculosis in the community, which influences the risk
of re-infection. These are important questions that
deserve further investigation, particularly in high TB
burden areas.
PRACTICAL SUGGESTIONS FOR SCALING UP
IPT IN THE FIELD
Ensure IPT is an integral part of a package
of interventions for PLHIV
IPT as a stand-alone intervention is doomed to failure. For patients accessing HIV care prior to starting
ART, or for patients on ART, IPT has to be one of
several interventions that provide patient benefit and
keep the patient in structured care, such as cotrimoxazole preventive therapy (CPT), nutritional support
or family planning. It also has to be intimately linked
with the other key related activity of preventing TB
in PLHIV, namely regular intensified screening for
TB every time the patient attends the health facility
for care or treatment.
Set up operational projects in a variety
of routine settings
Despite numerous pilot projects and other field evaluations of IPT, we still do not know how best to implement this intervention. It is therefore wise to conduct operational research, i.e., a culture of ‘learning
by doing’. We suggest that operational projects be set
up within different routine settings that provide programmatic lessons for the preparation of national
coverage of IPT. Running these projects should not be
dependent on additional financial or human resource
support over and above what is usually provided.
However, these pilot projects need to be rigorously
monitored, preferably by an independent agency that
will need additional resources, paying particular attention to who is started on IPT, adherence to 6-month
therapy, stocks of INH, health staff training and super-
IPT for PLHIV
vision, recording and reporting, patient information,
creation of community awareness, etc. Again, these
should always be part of a package of interventions
designed to benefit PLHIV, and they should never be
stand-alone IPT projects.
Develop simple flow charts for eligibility for IPT
HIV testing is usually offered either from stand-alone
sites (usually offering client-initiated counselling and
testing to people who walk in off the street) or from
health care facilities (offering provider-initiated testing and counselling to people who are sick).49 From
both types of site, PLHIV must be referred to the appropriate centres where they can be assessed for eligibility for ART50,51 and eligibility for IPT.
Symptomatic patients with weight loss, fever, cough,
chest pain, shortness of breath and haemoptysis may
have active TB, as indeed may those with less overt
symptoms. For these patients, it is essential to carry out
TB-specific investigations such as sputum smear examination, chest radiography, sputum culture for M. tuberculosis (where this is available), and other investigations appropriate for suspected extra-pulmonary
disease (Figure 1). If these investigations indicate a
diagnosis of TB, then anti-tuberculosis treatment is
started and IPT is not given. If the investigations are
indeterminate, re-investigation is necessary at some
later stage and IPT is not given. If investigations are
normal, but the patient is still symptomatic, it would
be safer to avoid IPT. This can be deferred until such
time as the patient is asymptomatic, and then administration of IPT could be carefully considered.
Figure 1 Flow chart for IPT in HIV-infected patients with any
symptoms suggestive of tuberculosis. PTB = pulmonary tuberculosis; IPT = isoniazid preventive therapy; HIV = human
immunodeficiency virus.
931
In general, most patients who are eligible for ART
will not initially be suitable for IPT, as it is too difficult in busy clinics to confidently exclude TB at this
stage. However, once patients are stable and have become asymptomatic on ART, it will be possible to reevaluate and decide whether it is safe and worthwhile
to start IPT. Studies in South Africa have shown first
that rates of TB are significantly reduced in PLHIV
on ART compared with those not on ART,5 and second that the longer a patient is on effective ART, the
lower the annual risk of developing TB.52 However,
rates of TB still remain substantial in patients on ART
and are much higher than those observed in populations who are HIV-negative.53,54 The reasons for this
are unclear, but may relate to incomplete restoration
of TB-specific immune responses on ART, poor adherence to the medication, or high rates of nosocomial TB transmission occurring as a result of frequent
visits to health facilities to collect ART medication.
Data from Brazil suggest that ART and IPT together
may result in a highly significant synergistic decline in
risk of active TB,55 and thus it might be worthwhile
to consider adding IPT once the patient has stabilised
on ART. The patient on ART is in structured care, and
proper administration of 6 months of IPT could be
managed, even within the context of a busy clinic.
Asymptomatic PLHIV can be considered for IPT. A
few patients who are eligible for ART will be asymptomatic and will have started therapy based on CD4
lymphocyte criteria. Whether these patients and those
who are asymptomatic but not eligible for ART could
be safely started on IPT without any further investigations, or whether they should have prior screening
with sputum smears and/or chest radiography to rule
out subclinical TB is not known, and would be helped
by context-specific research studies. Some studies have
shown that it is useful and important to screen PLHIV
with a chest radiograph, with further investigation of
those with an abnormal picture,56,57 while others have
shown contrary results and concluded that a screening
chest radiograph is not necessary.58 The majority of
PLHIV who are asymptomatic and not eligible for
ART are currently failed by the system, as there are
generally no care or support structures available for
providing care and follow-up that include IPT. This
has to change, and the concept of ‘pre-ART care’ needs
to be championed.
Provide structured pre-antiretroviral care
and treatment
Pre-ART care needs to be set up appropriately within
various facilities that provide HIV testing and care,
with the design and functionality dependent upon infrastructure and available human resources. PLHIV in
WHO Clinical Stage 1 and 2 (who are not eligible for
ART unless CD4 cell counts are below the threshold
for starting ART) should be offered a package of care
and support that includes regular checks of clinical
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The International Journal of Tuberculosis and Lung Disease
Figure 2
Example of a care and treatment card for use in a pre-ART clinic.
status and CD4 lymphocyte count, the provision of
CPT in patients in whom it is indicated,59 nutritional
support, family planning, possibly insecticide-treated
bed nets for the prevention of malaria,60 and regular
intensified screening for TB and IPT. Patients with
symptoms need careful assessment, and if there is any
doubt about the presence or absence of TB, IPT should
be withheld.
How pre-ART care is best set up and managed
within the general health system is not currently known
and requires operational research. Ideally, any PLHIV
should be assessed for eligibility for ART, and for
those not eligible pre-ART care should be provided.
A package of interventions that includes regular clinical and CD4 count assessment would be of enormous
benefit and could avert the problem of many patients
accessing ART too late.
Procure, distribute and administer IPT in the simplest
possible way
The administration of IPT should be made as simple
as possible. Small pill bottles or blister packs could
be produced that each contain 30 tablets of INH
(300 mg), in the same way as special pill bottles have
been produced for ART61 and for CPT in Malawi.
These can be administered every 1 or 2 months, depending on the frequency of clinic visits. Procurement
orders and distribution can be made on the basis of
pill bottles or blister packs and, although this will be
slightly more expensive than ordering INH in tins of
1000 tablets, this considerably eases the work for staff.
NAPs will need to work closely with NTPs to develop
and adapt the supply chain management tools that
have been used over many years to ensure regular and
sufficient supplies of anti-tuberculosis drugs.
Monitor the package of care at pre-ART clinics and
ART clinics
In the pre-ART clinics, the monitoring and evaluation
of IPT should be integrated into pre-ART treatment
monitoring cards and a pre-ART treatment register.
These must be developed and piloted in the field, and,
based on collective experience gained over a year or
two, a generic, simple-to-use card and reporting system could be produced. An example of such a treatment card is shown in Figure 2. Simple quarterly reports could be generated that indicate the number of
patients enrolled in pre-ART clinics, the number assessed and treated for TB and the number started on
IPT, and, in one year’s time the number of patients
who started IPT in the quarter 12 months previously
who completed IPT. Pre-ART clinics need to work
out details of how to perform such monitoring and
recording. In a similar vein, in the ART clinics the
treatment and monitoring cards can incorporate columns to indicate monthly TB screening, diagnosis and
treatment of active TB and use of IPT.
CONCLUSION
Randomised controlled trials have demonstrated the
efficacy of IPT in reducing TB incidence in PLHIV infected with M. tuberculosis.7,8 If NAPs can take on
and implement this intervention in collaboration
with NTPs as part of a package of care and support,
this could have an important effect in reducing the
burden of TB in high HIV prevalence settings.
However, several unanswered research questions
and clear operational challenges to the widespread
scale-up of IPT have been discussed in this article,
and these have hindered, and will continue to hinder,
implementation in the field. Better and easier ways of
determining the presence of LTBI and ruling out active TB in PLHIV urgently need to be identified. Structures need to be in place for IPT to be delivered, and
this is best done in the context of pre-ART and ART
care, as discussed. Most NTPs in Africa have guidelines for screening childhood contacts of patients with
smear-positive pulmonary TB and administering IPT
to children aged <6 years who do not have active TB.
IPT for PLHIV
However, this is rarely implemented,62,63 usually because of inadequate structures and resources on the
ground. Lessons need to be learnt from these ongoing
failures.
There is also a definite risk that ‘sloppy’ IPT will
be inefficient and, worse, could lead to the development of drug-resistant TB, and particularly MDR-TB.
To avoid this situation, it is important to give IPT to
PLHIV who do not have active TB, and to carefully
monitor for symptoms and signs of TB during the
course of treatment. We believe it is better initially to
err on the side of caution. The steps we have outlined
would allow further evidence, experience and confidence to be gained in IPT management in the setting of
pre-ART and ART care, and they could pave the way
for further scale-up of this important intervention.
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RÉSUMÉ
On admet que le traitement préventif à l’isoniazide (IPT)
est une composante importante des activités de collaboration sur la tuberculose (TB) et le virus de l’immunodéficience humaine (VIH) pour réduire le fardeau de la
TB chez les sujets infectés par le VIH. Toutefois, au
niveau du pays, peu a été fait en vue d’une mise en œuvre
de l’IPT. Cet échec a été à la base d’un appel aux armes
récent sous la bannière des « Trois I » : lutte contre l’infection pour prévenir la transmission de la TB dans les
contextes de soins de santé, intensification du dépistage
des cas de TB et IPT. Dans cet article, nous faisons la revue du contexte de l’IPT. Nous discutons ensuite les importants défis que comporte l’IPT chez les sujets infectés
par le VIH, en l’occurrence la responsabilité et la reddi-
IPT for PLHIV
tion de comptes pour sa mise en œuvre, l’identification
de l’infection TB latente, l’exclusion d’une TB active et
la prévention d’une résistance à l’isoniazide, la durée du
traitement et la durée de l’efficacité protectrice. Nous
mettons également en évidence plusieurs problèmes de
recherche qui restent actuellement sans réponse. Nous
présentons finalement quelques suggestions pratiques sur
la façon d’étendre l’IPT sur le terrain, notamment la nécessité d’intégration de l’IPT dans un ensemble de soins
chez les sujets infectés par le VIH, la mise sur pied de projets opérationnels ayant comme philosophie « apprendre
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par l’action », l’élaboration d’arbres de décision pour
l’éligibilité à l’IPT, l’élaboration et la mise en œuvre des
soins avant l’ART et finalement les problèmes concernant l’obtention, la distribution, le suivi et l’évaluation.
Nous insistons sur la mise en œuvre de l’IPT, mais
uniquement s’il est assuré de manière sûre et structurée.
Le risque d’inefficience d’une IPT mal conduite est élevé
et, ce qui est plus grave, elle pourrait entraîner l’apparition de TB à germes multirésistants, ce qui doit être
évité à tout prix.
RESUMEN
Se admite que el tratamiento preventivo con isoniazida
(IPT) constituye un componente importante de las actividades conjuntas de los programas contra la tuberculosis (TB) y la infección por el virus de la inmunodeficiencia humana (VIH), las cuales tienen como objetivo
reducir la carga de morbilidad por TB en las personas
infectadas por el VIH. Sin embargo, poco se ha avanzado
en la aplicación del IPT a escala de los países. Como respuesta a esta insuficiencia, se promulgó recientemente
un llamado a la acción con la iniciativa de las ‘Tres Ies’ :
lucha contra la infección tuberculosa a fin de prevenir la
transmisión en los entornos de atención sanitaria, intensificación de la detección de casos y IPT. En el presente
artículo se recapitulan las informaciones previas sobre
el IPT. A continuación, se analizan los factores importantes que dificultan la aplicación de IPT en las personas con infección por el VIH, en particular la responsabilidad y el rendimiento de cuentas sobre su ejecución,
la detección de la infección tuberculosa latente, la exclusión de la TB activa, la prevención de la resistencia a iso-
niazida, la duración del tratamiento y la persistencia de
una protección eficaz. Asimismo, se destacan varios temas
de investigación que con frecuencia permanecen sin respuesta. Para terminar, se aportan sugerencias prácticas
sobre la ampliación de escala del IPT sobre el terreno,
como son la necesidad de integrarlo a un conjunto de
medidas de atención de las personas con infección por el
VIH, la introducción de proyectos operativos con estrategias basadas en el aprendizaje práctico, la elaboración
de diagramas con los criterios de indicación del IPT, la
concepción y la ejecución de la atención de salud previa
al tratamiento antirretrovírico y los aspectos relacionados con las adquisiciones, la distribución la supervisión
y la evaluación. Se respalda la aplicación del IPT, pero a
condición de que este se realice en forma segura y estructurada. El riesgo de ineficacia de un IPT ‘descuidado’ es evidente y, aún más, podría favorecer la aparición de TB multidrogorresistente, lo cual se debe impedir
a toda costa.