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INT J TUBERC LUNG DIS 11(5):534538

2007 The Union

Outcomes of HIV-infected children with tuberculosis who are


started on antiretroviral therapy in Malawi

C-N. Bong,* S. C. C. Chen, Y-J. Jong, T-S. Tok, C-F. Hsu,* E. J. Schouten, S. D. Makombe,
J. K-L. Yu,* A. D. Harries#**
* Taiwan Medical Mission, Mzuzu Central Hospital, Mzuzu, Malawi; International Medical Cooperation and
Development Center, Pingtung Christian Hospital, Pingtung, Kaohsiung Medical University, Kaohsiung, Taiwan;
HIV Co-ordinator, Ministry of Health, Lilongwe, Management Sciences for Health, Lilongwe, # Clinical HIV Unit,

Ministry of Health, Lilongwe, ** Family Health International, Malawi Country Office, Lilongwe, Malawi;
London School of Hygiene and Tropical Medicine, Keppel Street, London, United Kingdom

SUMMARY

SETTING: Mzuzu Central Hospital, in the northern re- tory of TB in the last 2 years and 354 with a non-TB di-
gion of Malawi, which provides free antiretroviral ther- agnosis. The three groups were similar in nutritional in-
apy (ART) to human immunodeficiency virus (HIV) in- dices and CD4-lymphocyte percentages. The 6-month
fected adults and children, including those with probability of survival was 0.86 in the active TB group,
tuberculosis (TB). 0.94 in the past history of TB group and 0.89 in the non-
O B J E C T I V E S : To compare outcomes in HIV-infected TB group. 12-month survival probability for the same
children who have been started on ART because of 1) groups was 0.86, 0.86 and 0.88, respectively.
active TB, 2) a past history of TB in the last 2 years and C O N C L U S I O N : HIV-infected children with active and
3) a non-TB diagnosis. previous TB who are started on ART have good out-
D E S I G N : Retrospective data collection using ART pa- comes that are similar to those of children started on
tient master cards and ART patient registers. ART due to a non-TB diagnosis.
R E S U L T S : Between July 2004 and September 2006, 439 K E Y W O R D S : TB; children; antiretroviral therapy; treat-
(11%) children of a total 3908 patients were started on ment outcomes; Malawi
ART. There were 29 with active TB, 56 with a past his-

THE DUAL EPIDEMIC of human immunodeficiency World Health Organization (WHO) Clinical Stage 3
virus (HIV) infection and tuberculosis (TB) is concen- (PTB, or TB lymphadenopathy in children) or in WHO
trated in sub-Saharan Africa. While the disease burden Clinical Stage 4 (EPTB, with the exception of TB lym-
from dual infection is predominantly felt in adults, phadenopathy in children).6,7 In principle, HIV-
children bear a substantial proportion of disease. A infected TB patients should benefit from ART, with a
country-wide study in Malawi found that 12% of reduction in HIV-related mortality and HIV-related
the national disease burden of TB and 1520% of the recurrence of TB disease. Reports on small numbers
burden of smear-negative pulmonary TB (PTB) and of adult patients treated in the United Kingdom,8 Tai-
extra-pulmonary TB (EPTB) was in children.1 Al- wan9 and Thailand10 indicate good outcomes among
though HIV-infected children with TB can do well HIV-infected TB patients treated with ART. However,
on anti-tuberculosis treatment, in Africa they have to our knowledge there have been no reports, partic-
significantly higher case fatality rates compared with ularly from the high-burden arena of sub-Saharan
non-HIV-infected children, with higher death rates Africa, on outcomes of HIV-infected children with TB
being found in those with lower CD4-lymphocyte treated with ART.
counts.24 The aim of the present study was to determine the
Many of the high-burden HIV-TB countries are outcome of HIV-infected children at Mzuzu Central
scaling up antiretroviral therapy (ART), and good Hospital, Northern Malawi, who were started on
progress is being made. By December 2005, 840 000 ART because of either active TB or a past history of
patients in Africa had been started on ART.5 HIV- TB within the last 2 years and to compare these out-
infected adults and children with TB are all poten- comes with those of HIV-infected children who did
tially eligible for ART, either because they are in not have TB.

Correspondence to: Professor Anthony D. Harries, Family Health International, Malawi Country Office, Arwa House,
3rd Floor, P O Box 30455, Lilongwe 3, Malawi. Tel: (265) 1 775 106. Fax: (265) 1 774 307. e-mail: adharries@malawi.net
Article submitted 27 October 2006. Final version accepted 11 January 2007.
Outcomes in children started on ART due to TB 535

METHODS quent upon early initiation of ART.14 HIV-infected


TB patients on ART were followed up monthly, and
Antiretroviral therapy
had to attend the TB clinic for monitoring and anti-
Mzuzu Central Hospital is the main referral hospital tuberculosis medication and the antiretroviral (ARV)
of the northern region of Malawi. Through the Rain- clinic for monitoring and ART drugs on the same day
bow Clinic, it has been providing free ART to eligible of each month.
HIV-infected patients since July 2004, in accordance
with national guidelines.11,12 Data collection and analysis
Children (defined as persons aged 14 years) who Characteristics and outcomes of children on ART were
had tested HIV-positive and who were considered el- recorded from the ART master card and ART register.
igible for ART first underwent a thorough clinical as- Children were divided into three groups: Group 1,
sessment that included weight, height, calculation of children started on ART because of active TB that
body mass index (BMI, kg/m2) and CD4-lymphocyte was being treated; Group 2, children started on ART
percentage measured on a Beckman Coulter EPICS because of a past history of TB within the last 2 years;
XL-MCL flow cytometer (Beckman Coulter Electron- Group 3, children started on ART due to a reason
ics, Miami, FL, USA). Provided there were no contrain- that was not TB. Characteristics of children between
dications, all children were treated with a generic, the groups were compared using the 2 test. Treat-
fixed-dose combination treatment consisting of stavu- ment outcomes were censored on 30 September 2006,
dine (SV), lamivudine (LAM) and nevirapine (NVP), and therefore follow-up time varied between individ-
with split-drug dosages being given according to body uals depending on when each child commenced ART.
weight, again in line with national recommenda- Survival estimates between groups were determined
tions.12 Children were also started on cotrimoxazole using the Kaplan-Meier method and compared using
preventive therapy (CPT) at the same time as ART, the Cox-Mantel (log-rank test). The level of signifi-
with dosages adjusted according to body weight and cance was set at P  0.05, and 95% confidence inter-
according to national guidelines. Once started on ART vals were used throughout. Data analysis was carried
and CPT, children were followed up, first at 2 weeks out using SAS system for Windows (Version 8.01,
and thereafter at 4-week intervals, with assessments SAS Institute, Cary, NC, USA).
and drugs distributed from the ART clinic. Charac-
teristics and standardised treatment outcomes were Ethical approval
recorded in ART treatment master cards and the ART The Malawi National Health Science Research Com-
register on a regular monthly basis. mittee does not require studies that use routine pro-
grammatic data collection to be formally submitted for
Anti-tuberculosis treatment and referral of ethical or scientific approval. As such, no formal sub-
TB patients for ART mission for this study was made to the Research Com-
Children with TB are diagnosed, registered and mittee. General measures were provided in the Rain-
treated according to national guidelines using a stan- bow Clinic to ensure patient confidentiality, consent for
dardised approach.13 Diagnosis relies mainly on a sug- HIV testing, and counselling and support for children
gestive clinical history and examination, a history of a and guardians on receiving a positive HIV test result.
positive family contact, sputum smear examination if
sputum can be produced and an abnormal chest ra-
RESULTS
diograph. In general, tuberculin skin testing is not
used because it is not available. New cases of TB are Between July 2004 and 30 September 2006, a total of
treated with a 2-month initial phase of rifampicin 3908 patients had been started on ART at Mzuzu Cen-
(RMP), isoniazid (INH), and pyrazinamide (with ad- tral Hospital. Of these, 439 (11%) were children aged
ditional ethambutol [EMB] for sputum smear-positive 14 years. There were 29 children started on ART due
patients), followed by a 6-month continuation phase to active TB, 56 due to a previous history of TB and 354
of INH and EMB, with drugs given in standardised due to other non-TB reasons. Of those with active TB,
dosages according to body weight. Children with re- 24 had pulmonary TB (one smear-positive and the re-
current TB are given a standard retreatment regimen mainder smear-negative or smear not done), and 5 had
that uses RMP throughout.13 All TB patients should extra-pulmonary TB (miliary TB in 3, TB peritonitis in
be offered HIV testing and counselling, usually dur- 1 and TB pleural effusion in 1). ART was commenced
ing the first 2 weeks of initial phase anti-tuberculosis during the continuation phase of anti-tuberculosis
treatment. treatment in all children and at a median of 74 days
For HIV-infected children with TB who were started after the first day of anti-tuberculosis chemotherapy.
on ART, the ART medication was begun in the con- In the group with a non-TB diagnosis, the principal
tinuation phase of anti-tuberculosis treatment because reasons for starting ART were severe presumed recur-
of concerns about drug-drug interactions with RMP rent bacterial pneumonia in 117 (33%), persistent fever
and NVP and immune reconstitution disease conse- for more than one month in 105 (30%), and severe
536 The International Journal of Tuberculosis and Lung Disease

Table Characteristics of children started on antiretroviral therapy at Mzuzu Central Hospital


according to active TB, a previous history of TB or a non-TB diagnosis

Group 1: Group 2: Group 3:


Children with Children with Children with
active TB previous TB non-TB diagnosis
n (%) n (%) n (%)
Number 29 56 354
Male 12 (41) 32 (57) 176 (50)
Female 17 (59) 24 (43) 178 (50)
Median age, years 7.0 9.0 5.4
1 0* 0* 9 (2)
15 10 (34) 14 (25) 176 (50)
614 19 (66) 42 (75) 169 (48)
WHO Clinical Stage
Stage 1 or Stage 2 with low CD4 percentage 0* 0* 35 (10)
Stage 3 18 (62) 51 (91) 234 (66)
Stage 4 11 (38) 5 (9) 85 (24)
BMI, median and range 14.7 (10.819.7) 14.3 (10.721.0) 14.8 (9.219.8)
Weight for height 70% 4 (14) 2 (4) 24 (8)
CD4 count %, median and range 8.9 (1.432.8) 10.5 (0.533.6) 12.3 (0.143.6)

* Variables of children in Group 2 compared with those in Group 3, where P  0.05.


TB  tuberculosis; WHO  World Health Organization; BMI  body mass index.

unexplained malnutrition that had not responded to yond 12 months in children with active TB compared
standard nutritional interventions in 39 (11%). with the other two groups is based on small numbers,
The main characteristics of children in each of and statistical comparisons in this case are not valid.
these groups are shown in the Table. Children with
previous TB were older than those without TB, but
DISCUSSION
otherwise demographic features, nutritional status
and CD4-lymphoycte percentages were similar be- We believe that this is the first report from sub-Saharan
tween the three groups. The probability of survival Africa to look at treatment outcomes of HIV-infected
(defined as being alive and on ART at Mzuzu Central children with active and previous TB receiving ART
Hospital) of the three groups is shown in the Figure. within the routine setting. The outcomes in general
The 6-month probability of survival was 0.86 for were good, with nearly 90% of children with active
children with active TB, 0.94 for children with a past and previous TB and with another non-TB diagnosis
history of TB and 0.89 for children with a non-TB di- alive 612 months after starting treatment. This was
agnosis. The corresponding 12-month probability of despite a high degree of malnutrition and immune de-
survival was 0.86 for children with active TB, 0.86 ficiency, as indicated by a low median BMI and low
for children with a past history of TB and 0.88 for median CD4 percentage in all three groups.
children with a non-TB diagnosis. There was no sig- This study has all the limitations of an operational
nificant difference in the outcomes for the three groups research study conducted within the routine system of
up to 12 months (log-rank test, P  0.59). The appar- a resource-poor country, and it raises some questions
ent difference in survival probability in the Figure be- for which at present we do not have the answers.
First, the diagnosis of TB in HIV-infected children is
notoriously difficult.4 In Malawi, the majority of chil-
dren are diagnosed according to clinical and radio-
graphic criteria only, which are often non-specific.
There is a general absence of tuberculin testing re-
agents in the country, although the results of such
testing are difficult to interpret in HIV-infected chil-
dren, particularly if they are malnourished.4 It is also
possible that some children in the non-TB group, par-
ticularly those with persistent unexplained fever for
1 month, had TB that was undiagnosed. An autopsy
study in South Africa found that 77% of children with
post mortem diagnosed TB had not been diagnosed
or treated for TB while alive,15 and it is likely that this
Figure Survival probability of children using a Kaplan-Meier scenario is also found in Malawi.
plot, started on antiretroviral therapy according to 1) active TB, Second, the outcome analysis was based on clinical
2) a past history of TB and 3) a non-TB diagnosis. TB  tuberculosis. and programmatic indices. There were no follow-up
Outcomes in children started on ART due to TB 537

measurements of CD4-lymphocyte counts or viral 2 Mukadi Y D, Wiktor S Z, Coulibaly I-M, et al. Impact of HIV
load, so we have no data on whether these children infection on the development, clinical presentation, and out-
come of tuberculosis among children in Abidjan, Cote dIvoire.
achieved good viral suppression or improvements in
AIDS 1997; 11: 11511158.
their immune system. 3 Madhi S A, Huebner R E, Doedens L, et al. HIV-1 co-infection
Third, split tablets of the adult ART formulation in children hospitalised with tuberculosis in South Africa. Int J
were used to treat the children, and despite good out- Tuberc Lung Dis 2000; 4: 448454.
comes we did not perform any pharmacokinetic mea- 4 Graham S M, Coulter J B S, Gilks C F. Pulmonary disease in HIV-
surements to provide data on plasma drug concentra- infected African children. Int J Tuberc Lung Dis 2001; 5: 1223.
5 World Health Organization and UNAIDS. Progress on global
tions. In Uganda16 and Cte dIvoire,17 half or quarter access to HIV antiretroviral therapy. A report on 3 by 5 and
tablets of SV, LAM and NVP were associated with beyond. Geneva, Switzerland: WHO/UNAIDS, March 2006.
impressive declines in viral load and increases in CD4- 6 World Health Organization. Antiretroviral therapy for HIV in-
lymphocyte count, and we assume, but cannot verify, fection in adults and adolescents in resource-limited settings: to-
that similar results were being achieved in our pa- wards universal access. Recommendations for a public health
approach. Geneva, Switzerland: WHO, 2006.
tients in Malawi.
7 World Health Organization. Antiretroviral therapy for HIV in-
Fourth, the Prevention of Mother-to-Child-Trans- fection in infants and children in resource-limited settings: to-
mission programme uses single dose NVP for the wards universal access. Recommendations for a public health
mother at labour and the child within 72 hours of approach. Geneva, Switzerland: WHO, 2006.
birth, and concerns have been raised that by inducing 8 Dean G L, Edwards S G, Ives N J, et al. Treatment of tubercu-
NVP drug resistance this single exposure might com- losis in HIV-infected persons in the era of highly active antiret-
roviral therapy. AIDS 2002; 16: 7583.
promise the effectiveness of triple-drug ART.1820
9 Hung C C, Chen M Y, Hsiao C F, et al. Improved outcomes of
Again, we have no data on which children may have HIV-1-infected adults with tuberculosis in the era of highly ac-
received NVP or measurements of HIV drug resistance tive antiretroviral therapy. AIDS 2003; 17: 26152622.
to confirm or refute this point. 10 Sungkanuparph S, Manosuthi W, Kiertiburanakul S, Vibha-
Finally, it is apparent from the survival probability gool A. Initiation of antiretroviral therapy in advanced AIDS
curves that there is significant early mortality in all with active tuberculosis: clinical experiences from Thailand.
J Infect 2006; 52: 188194.
groups, especially in children with active TB and a non-
11 Libamba E, Makombe S, Harries A D, et al. Scaling up antiret-
TB diagnosis. This high early mortality has been doc- roviral therapy in Africa: learning from tuberculosis control
umented in Africa amongst adults starting ART,2123 programmesthe case of Malawi. Int J Tuberc Lung Dis 2005;
and it requires further investigation. 9: 10621071.
Despite these uncertainties, the results of this study 12 Malawi Ministry of Health and Population. Treatment of AIDS.
provide reassuring evidence that HIV-infected chil- Guidelines for the use of antiretroviral therapy in Malawi. 1st
ed. Lilongwe, Malawi: Ministry of Health and Population,
dren with TB started on ART during the continuation 2003.
phase of anti-tuberculosis treatment do well, at least 13 Malawi Ministry of Health and Population. Manual of the
during 612 months of follow-up. The climate in National Tuberculosis Control Programme of Malawi. 5th ed.
which we now work in sub-Saharan Africa has Lilongwe, Malawi: Ministry of Health and Population, 2002.
changed, given the arrival of ARV drugs and scale-up 14 Kwara A, Flanigan T P, Carter E J. Highly active antiretroviral
programmes in most countries in the region.24 Chil- therapy (HAART) in adults with tuberculosis: current status.
Int J Tuberc Lung Dis 2005; 9: 248257.
dren must not be neglected in our endeavours to bring 15 Rennert W P, Kilner D, Hale M, Stevens G, et al. Tuberculosis
HIV and TB programmes together. in children dying with HIV-related lung disease: clinical-patho-
logical correlations. Int J Tuberc Lung Dis 2002; 6: 806813.
Acknowledgements 16 Barlow-Mosha L, Musoke P, Ajuna P, et al. Early effectiveness
The Taiwan Medical Mission to Malawi is sponsored by the Tai- of Triomune in HIV-infected Ugandan children. Abstract
wan International Cooperation and Development Foundation and WeOa0103. Third International AIDS Society Conference on
managed by Pingtung Christian Hospital, Taiwan. The Taiwan HIV Pathogenesis and Treatment, Rio de Janeiro, Brazil: 2005.
Medical Mission is based in Mzuzu Central Hospital in the northern 17 Fassinou P, Elenga N, Rouet F, et al. Highly active antiretrovi-
region of Malawi, and is cooperating with Malawian staff, periph- ral therapies among HIV-1-infected children in Abidjan, Cte
eral hospitals and the Malawi Ministry of Health to fight HIV dIvoire. AIDS 2004; 18: 19051913.
and AIDS. 18 Eshelman S H, Jackson J B. Nevirapine resistance after single
A D Harries is supported by Family Health International, USA, dose prophylaxis. AIDS 2002; 4: 5963.
and has an honorary position at the London School of Hygiene and 19 Flys T, Nissley D V, Claasen C W, et al. Sensitive drug-resistance
Tropical Medicine. E J Schouten is supported by Management Sci- assays reveal long-term persistence of HIV-1 variants with the
ences for Health, USA. J K-L Yu has a faculty support at Kaohsiung K103N nevirapine (NVP) resistance mutation in some women
Medical University, Kaohisung, Taiwan. C-N Bong is a consultant and infants after the administration of single-dose NVP: HIVNET
paediatrician and currently working as the head of Paediatrics De- 012. J Infect Dis 2005; 192: 2429.
partment at Mzuzu Central Hospital. 20 Jourdain G, Ngo-Giang-Huong N, Le Coeur S, et al. Intrapar-
tum exposure to nevirapine and subsequent maternal responses
to nevirapine-based antiretroviral therapy. N Eng J Med 2005;
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RSUM

C O N T E X T E : Hpital Central Mzuzu dans la rgion Nord active, 56 avaient des antcdents de TB au cours des 2
du Malawi, qui assure une thrapeutique antirtrovirale dernires annes et 354 avaient t diagnostiqus comme
(ART) gratuite aux adultes et aux enfants infects par le affection non-tuberculeuse. Les trois groupes ont t
virus de limmunodficience humaine (VIH), y compris similaires en ce qui concerne les indices nutritionnels et
ceux atteints de tuberculose (TB). les pourcentages de lymphocytes CD4. La probabilit de
O B J E C T I F S : Comparer les rsultats chez les enfants in- survie 6 mois a t de 0,86 dans le groupe de TB active,
fects par le VIH et chez qui lART a dbut en raison de 0,94 dans le groupe avec antcdents de TB et de 0,89
1) dune TB active, 2) dantcdents de TB au cours des dans le groupe de diagnostics autres que la TB. La pro-
2 dernires annes, et 3) dun diagnostic autre que la TB. babilit de survie 12 mois a t respectivement de 0,86,
S C H M A : Collecte des donnes rtrospectives partir 0,86 et 0,88 dans les mmes groupes.
des cartes principales et des registres des patients mis C O N C L U S I O N : Chez les enfants infects par le VIH et at-
sous ART. teints dune TB active ou antrieure et qui ont t mis sous
R S U L T A T S : Entre juillet 2004 et septembre 2006, 439 ART, les rsultats sont bons et similaires ceux des en-
enfants (11%) sur un nombre total de 3908 patients ont fants mis sous ART pour un diagnostic autre que la TB.
t mis sous ART. Parmi eux, 29 souffraient dune TB

RESUMEN

M A R C O D E R E F E R E N C I A : El Hospital Central Mzuzu en por antecedente de TB en los ltimos 2 aos y 354 por
la regin norte de Malawi, donde se suministra trata- un diagnstico diferente de TB. Los ndices nutricionales
miento antirretrovrico (ART) a los adultos y a los nios y los porcentajes de linfocitos CD4 fueron equivalentes
infectados por el virus de la inmunodeficiencia humana en los tres grupos. La probabilidad de supervivencia a
(VIH), incluidos aquellos con tuberculosis (TB). 6 meses fue 0,86 en el grupo con TB activa ; 0,94 en el
O B J E T I V O S : Comparar los desenlaces clnicos de los grupo con antecedente de TB ; y 0,89 en el grupo con
nios infectados por el VIH que haban comenzado diagnstico diferente de TB. La probabilidad de super-
ART por TB activa, antecedente de TB en los ltimos vivencia a 12 meses en estos mismos grupos fue 0,86 ;
2 aos o por un diagnstico diferente de TB. 0,86 y 0,88 respectivamente.
M T O D O S : Anlisis retrospectivo de los datos recogi- C O N C L U S I N : Los nios infectados por el VIH con TB
dos de las tarjetas de ART y de los registros de pacientes. activa y antecedente de TB que comienzan ART logran
R E S U L T A D O S : Entre julio de 2004 y septiembre de desenlaces clnicos satisfactorios, semejantes a los de
2006, de un total de 3908 pacientes, 439 nios (11%) nios con diagnstico diferente de TB que comienzan
comenzaron ART, de los cuales 29 por TB activa, 56 este tratamiento.