Memorandum submitted by Rana Chakraborty
MD MSc FAAP DPhil (Oxon), Nyumbani—Church of God Relief
Organisation
HIV/AIDS AND THE PROVISION OF ANTIRETROVIRALS—A
PAEDIATRIC PERSPECTIVE IN A RESOURCE-POOR SETTING
I. HIV/AIDS: GLOBAL
EPIDEMIOLOGY
Within a 25-year period AIDS has spread from
a few high-risk groups to become a worldwide pandemic. According
to statistics released from UNAIDS and the WHO over 40 million
people have been infected with HIV [1]. An estimated 14,000 new
infections occur daily. 95% of these occur in developing nations
where access to newer medical treatments are not readily available
or affordable. AIDS is now the leading cause of death in sub-Saharan
Africa and the fourth biggest killer worldwide. AIDS killed at
least 2.3 million Africans in 2004 resulting in a significant
drop in life expectancy. In the absence of an effective therapeutic
vaccine and inadequate treatment and care, most HIV-infected individuals
will die before the next decade.
II. THE HIV/AIDS
PANDEMIC: ECONOMIC
CONSIDERATIONS
Most of the deaths will occur among adults.
This loss will disproportionately affect economic growth and the
social fabric of family and society. In addition the reduced fertility
will combine to erode the base of the population pyramid and result
in an unsustainable "top-heavy" profile. The ability
to cope with the demands and consequences of HIV and AIDS is limited
by the funds available for health care. Countries most affected
by the disease are generally least able to pay for prevention
and treatment. In the 10 countries most severely affected by AIDS,
per capita health expenditure ranged from $3 to $246. Most countries
spent less than $100 per person annually [2].
III. THE IMPACT
OF AIDS ON
THE WOMEN
AND CHILDREN
OF AFRICA
HIV is predominantly spread through heterosexual
transmission with the result that nearly half of all affected
adults are young women of childbearing age. About one-third of
those currently living with HIV/AIDS are individuals aged 15-24.
Most are unaware of their status. Seroprevalence rates in many
antenatal settings have ranged from 15 to 44% [3].
(a) The Rise in the Numbers of Orphaned Children
The epidemic has had grave consequences on infants
and children. Just over 13 million children have been orphaned
because their parents have died of AIDS. This number is predicted
to increase throughout Africa in the forthcoming decade. Approximately
60% of these orphans will be uninfected. Voluntary and public
resources are unable to provide long-term care for these children
and they are initially cared for by relatives. However, many guardians
fall ill or become overwhelmed with dependents. The growing number
of street children and child-headed households are often the outcomes
of a chain of events that begin with HIV infection of a mother
and/or her partner.
(b) The Rise in the Numbers of HIV-Infected Children
A rapidly increasing number of children are
infected by mother-to-child-transmission either perinatally or
by breast-feeding. Vertical transmission rates of HIV in African
countries vary from 25-42% [4]. An estimated 600,000 new paediatric
infections occur each year; of which some 1500/day (> 90%)
occur in sub-Saharan Africa. 2.2 million children are currently
HIV-infected. In 2004 over 500,000 children lost their lives to
AIDS [1]. The estimated impact among infants and children under
five years of age has resulted in an increase in mortality in
that age group in sub-Saharan Africa from 1990. At the same time
all other regions have reported a decrease in mortality [5 &
table 1].
TRENDS IN DEATH RATES (PER 1,000 LIVE BIRTHS)
IN CHILDREN UNDER FIVE YEARS (SELECTED YEARS 1970-1999)
|
| Region | 1970
| 1980 | 1990
| 1997 | 1999
| % Change
1990-99
|
|
| East Asia & Pacific | 126
| 82 | 55
| 47 | 44
| -19% |
| Europe & Central Asia | na
| na | 34
| 29 | 26
| -22% |
| Latin America & Caribbean | 123
| 80 | 49
| 41 | 38
| -23% |
| Middle East & North Africa | 200
| 136 | 71
| 58 | 56
| -21% |
| South Asia | 209
| 180 | 121
| 104 | 99
| -18% |
| Sub-Saharan Africa | 222
| 189 | 155
| 159 | 161
| +4% |
| Developing countries | 167
| 135 | 91
| 87 | 85
| -6% |
| OECD | 26 |
14 | 9
| 6 | 6
| -26% |
|
IV. MOTHER-TO-CHILD
TRANSMISSION (MTCT) OF
HIV
In the absence of antiretroviral prophylaxis, reported transmission
rates of HIV ranged from 16-20% among large-cohort studies in
Europe & North America [6, 7] but up to 42% in sub-Saharan
Africa [4]. Differences in rates could be accounted for by variable
prevalence of breast-feeding, prematurity and elective Caesarean
section. However, vertical transmission of HIV infection is now
a rare event in industrialised countries, through a combination
of antiretroviral therapy, obstetric management and alternative
infant feeding methods.
Measures include improved uptake of antenatal HIV testing and
identification of infected women during pregnancy; provision of
antiretroviral therapy (ART) antenatally and during delivery,
and to the baby postnatally; delivery by elective caesarean section,
and by avoidance of breast-feeding. These interventions reflect
the recommendations of many studies including the landmark trial
from the Pediatric AIDS Clinical Trials Group (PACTG 076), which
demonstrated the efficacy of Zidovudine (AZT) in pregnancy and
postnatally, reducing vertical transmission by 67% [8]. However,
this regimen was not universally adopted because it was determined
to be effective only in non breast-feeding infants, expensive
and required intravenous administration of AZT during delivery.
In developing countries simple, inexpensive, short-course regimens
were therefore developed. Single-dose nevirapine, a non-nucleoside
reverse transcriptase inhibitor, administered to mothers and neonates
in the intrapartum period and soon after birth was shown to be
a cost-effective regimen for prevention of MTCT of HIV-1 in Uganda.
In this study, the transmission risk was reduced by approximately
50% in infants at three months post-partum with on-going breast-feeding
[9].
V. PAEDIATRIC HIV-1 INFECTION
IN AFRICA
Although 4% of the world's population of HIV-infected subjects
are children, 20% of all AIDS deaths occur in children. Early
studies indicated that 25% of children with perinatal infection
progressed very rapidly to AIDS within 1 year. The median time
for the remaining 75% was seven years [10]. Data from Malawi showed
89% mortality in HIV-infected children by three years of age [11].
The median age at enrolment was eight months, by which time some
infected infants would already have died (the recorded infant
mortality being 7%), suggesting that the study may have underestimated
the impact of HIV on childhood mortality.
Little is known about the causes of death among children affected
by the HIV pandemic in sub-Saharan Africa. Pulmonary and gastrointestinal
infections are major causes of morbidity and mortality but specific
aetiologies are not well documented in the medical literature
because of poor local infrastructure and access to health care
among populations that have been most affected. As a result, there
are a limited number of evidence-based publications. We have used
observations on a unique cohort of HIV-infected children who received
high-quality care. Extrapolating data from this group to HIV-infected
children residing elsewhere in sub-Saharan Africa may not be an
accurate reflection of the patterns of morbidity and mortality
observed. Nevertheless, the information presented might be useful
when developing management strategies to reduce HIV-related morbidity
effectively in children.
VI. INFORMATION FROM
A KENYAN
ORPHANAGE
Nyumbani orphanage in Kenya was founded in 1992, by Father
Angelo D'Agostino in response to increasing demands for comprehensive
care of abandoned HIV-infected orphans in Nairobi (www.nyumbani.org).
Nyumbani is spread across two acres of property and includes five
duplex cottages, each containing a family of approximately 16-18
children. In 2000, the orphanage housed 70 children referred by
social workers in hospitals when no caregiver could be identified.
The children were accepted into the orphanage at different ages
depending on the availability of spaces. Their ages ranged from
one month to 18 years; median age of entry was 2.2 years (range
0-12.7 years). The orphanage selected for HIV-infected children
with typical or slowly progressive disease. Those with rapid disease
progression would have died in infancy before identification was
possible. Routine care included adequate nutrition, micronutrient
supplementation, prophylactic cotrimoxazole three times weekly
and immunisations in line with the recommendations of the WHO
Expanded Programme. None of the children received ART. Medical
history prior to admission was often poorly documented since the
children had no identifiable caregiver.
(a) Survival, growth, morbidity and disease progression
Outcome measurements included age at death (if applicable),
opportunistic infections and longitudinal growth measurements:
weight, length and head circumference recorded longitudinally
at different ages as part of routine care. These were measured
using standardized growth curves and included weight for length,
and length for age. The z-score was estimated for each of these
indices. A cut-off value of less than -2 Standard Deviations (SD)
suggested severe stunting (length-for-age) or wasting (weight-for-length).
Survival was examined by adjusted Kaplan-Meier analysis.
67 children (39%) died between 1995 and 2000. Median survival
was 6.25 years. Survival was 0.56 [confidence intervals (CI):
0.46, 0.68] and 0.31 (CI: 0.22, 0.43) at five and 10 years of
age, respectively. By three years of age, 70% of the children
were still alive compared with only 11% of HIV-infected children
attending outpatient clinics in Malawi [11, 12].
Causes of morbidity included recurrent upper and lower respiratory
tract infections, acute and chronic gastrointestinal infections,
lymphocytic interstitial pneumonia and candidiasis. However, no
new cases of presumptive pulmonary tuberculosis were diagnosed
after admission to the orphanage.
The mean length-for-age and length-by-weight z scores were -1.65
and -0.39, respectively. A moderate degree of stunting was therefore
observed among the cohort in the absence of severe wasting. Severe
stunting was most often noted in older children in the home (mean
z score of -2.62 in children older than nine years of age) and
was present even with the provision of adequate and appropriate
nutrition.
Accelerated HIV disease progression in African children may occur
as a result of many factors including limited access to proper
nutrition, clean water and health care, as well as exposure to
a high prevalence of respiratory and gastrointestinal pathogens
in the general community. The care provided in the orphanage minimised
such co-factors. In the absence of ART, the aggressive management
of these orphans after admission may have reduced HIV-1 disease
progression, reduced overall mortality and improved quality of
life. If similar reports elsewhere can confirm our findings and
if the cost of ART becomes less prohibitive, developing orphanages
such as the one described in the future could be considered by
governments, non-governmental organisations and donor agencies.
Such an approach may be an effective way of delivering services
to the growing numbers of very vulnerable and needy immunocompromised
children in the southern hemisphere.
(b) The Provision of ART in the orphanage
Without an effective therapeutic HIV vaccine, providing cost-effective,
minimally toxic ART to the many individuals already infected with
HIV-1 is a global priority. The use of potent ART has resulted
in a considerable decrease in morbidity and mortality among adults
and children from Western populations who are infected with HIV-1.
Replicating these successes in resource poor settings where HIV-1
infection is endemic poses a significant challenge for governments,
non-governmental organizations, and donor agencies. In addition
to drug-induced toxicities and issues associated with therapy
adherence, the cost of providing continuous ART to large numbers
of HIV-1-infected individuals would be prohibitive for most developing
countries.
The Nyumbani Diagnostic Laboratory was established in 1998 to
provide standard haematological, biochemical and microbiological
testing facilities. In August 2000, the home received a donation
of antiretroviral drugs. Three antiretroviral-naive children (age
range, five to six years) were selected to receive these medications,
on the basis of CD4 T lymphocyte counts and past and current histories
of opportunistic infection. Given their clinical status, the deaths
of these three children were predicted to be most imminent, compared
with the predicted time of death for other children residing in
the home. The three children initiated a regimen of ART. New donations
in 2001 sustained their antiretroviral combination and allowed
other immunocompromised children in the orphanage to receive similar
therapy. ART was well tolerated by all three children with a several-log-fold
reduction in the plasma HIV viral load. At the same time, a sustained
increase in CD4 T lymphocyte count was observed. 14 months after
the initiation of therapy, children were seen fewer times for
sick visits, compared with the 14 months preceding the intervention,
with no documented AIDS-defining opportunistic infections. At
evaluation 26 months after the initiation of the regimen the three
children attended school regularly and rarely missed days because
of illness.
Additional enrolment from 2000 onward of 22 children with CD4
T lymphocyte counts of <200 cells/L for ART (consisting of
two nucleoside reverse-transcriptase inhibitors and either a non-nucleoside
reverse-transcriptase inhibitor, or a protease inhibitor) resulted
in a marked reduction in mortality among children in the home.
From 1995 through 2000, 67 children had died. In contrast from
2000-05 nine deaths occurred [13]. Currently 75% of the children
require ART with significant reductions in morbidity and mortality.
All children attend school appropriate for their age. A number
of adolescents raised in the home since childhood, have entered
vocational training or college in anticipation of re-joining the
wider community as adults.
VII. COMMUNITY-BASED
CARE -THE
LEA TOTO
PROGRAMME
(a) Infrastructure
Nyumbani's community based outreach program, Lea Toto (in Swahili
meaning "to bring up the child") provides a critical
multidisciplinary approach to support families affected by HIV
in the surrounding Nairobi communities. The Lea Toto outreach
program includes free medical care, family counselling, HIV transmission
and prevention education, door-to-door sensitisation and promotion
of behavioural changes. The over-arching goal of the Lea Toto
Program was to "improve the capacity of the Kangemi community
(an impoverished setting in Nairobi) to provide holistic care
within the family for HIV-infected children living in this community".
Under the Lea Toto Program, families with HIV positive orphans
receive physical care, psychological support and essential medical
supplies. The Program also managed community-based support to
HIV-infected orphans and enabled the Kangemi community to identify
and establish sustainable strategies to address the needs of HIV-infected
children and their families. In 2002 the programme was expanded
to care for 1000 HIV-infected children. In 2005, further extension
occurred to include two more sites, Kibera and Kariobangi, targeting
3,000 HIV-infected children.
The Lea Toto project uses the Home Based Care (HBC) model.
The goals of the HBC address the improvement of the quality of
life of the affected through a package of comprehensive care for
the client and his /her family. This package usually includes
basic medical and nursing care, counselling, and psychological
support, spiritual guidance, relief for social needs, prevention
of further spread of HIV and promotion of community empowerment,
self help and a spirit of community ownership and good neighbourliness.
This provides the most efficient way of addressing the complexity
of needs of persons affected by AIDS and their families, and in
this context, children living with HIV/AIDS.
The project team, with support from trained community health
workers, provide nursing care (including treatment of minor ailments
and maintenance of proper hygiene), as well as nutritional counselling
for children and their caregivers. The team also conducts training
for caregivers on how to recognize and treat minor ailments as
well as how to prevent transmission of bodily fluids. The training
also addresses other issues such as how to provide palliative
care for children; use a home based care kit provided by the project;
where and when to refer the child; and how to identify and facilitate
the transition between the various emotional stages experienced
by the child. After the training, they are able to complement
the work of the project team, based on a care-plan that is developed
by the project technical team for each individual child. Acute
medical care is provided through Nyumbani, which has dedicated
and trained staff and a laboratory that offers standard biochemistry,
haematology, microbiology and immunology facilities.
(b) The Provision of ART in the Lea Toto Programme
ART has been used on a more limited basis in resource-poor settings,
mainly due to the relatively high cost. Additionally there is
often a lack of infrastructure to provide safe and effective treatment.
Nevertheless several pilot projects have successfully demonstrated
the safe and effective use of ART in such environments. Farmer
et al treated HIV-infected adults in Haiti by applying structures
that were previously developed for treatment of TB with directly
observed therapy but adapted to HIV infection using community-based
health workers [14, 15]. Viral suppression in this setting was
comparable to plasma HIV viral loads documented in subjects receiving
treatment in more developed countries [16]. Other programmes,
including one in Nairobi, have utilized trained community health
workers to support treatment of adults with HIV infection from
impoverished settings with resulting good compliance and treatment
uptake [17]. However, all these pilot studies have been performed
in adults and there are no equivalent paediatric data. HIV-infected
children tend to have more complex issues surrounding adherence
and metabolism complicating the effective administration of ART.
Strong collaborative links have been established between
Nyumbani with the Universities of London (St George's and Great
Ormond Street hospitals) and Sydney. A demonstration project of
direct observed therapy (DOT) with ART in HIV-infected children
from Lea Toto is currently underway. The objectives of the collaboration
include:
(1) To assess the feasibility, safety and efficacy of
antiretroviral therapy in HIV-infected children in the Lea Toto
programme
(2) To assess the impact of DOT on response to ART
(3) To determine if early treatment is advantageous to
standard therapy in those children who do not show severe immunological
suppression.
The main outcome measures will be assessed at 12-15 months
and 24-30 months. These will include overall morbidity (bacterial
and opportunistic infections, hospitalisations), mortality, height/weight,
quality of life and CD4 count measurements. Outcome measures will
be compared in all groups of children studied and an intention
to treat analysis will be used.
The overall cost of therapy, delivery of medical care and
laboratory testing will be estimated per patient. Cost-benefit
analysis will be used to evaluate the use of ART in a resource-limited
setting. 2,000 HIV-infected from Lea Toto will be enrolled into
the project by 2007. Funding has been obtained from USAID, Glaxo-Smith-Kline
and the President's Emergency Funds for AIDS Relief (PEPFAR).
(c) Future Projects within the Lea Toto Programme
There are no outcome pharmacokinetic data in resource-poor
settings where HIV infection is endemic in children receiving
ART. Furthermore there is a shortage in population reference values
of antiretroviral medication in such children and plasma drug
concentrations are targeted to adult reference values, which may
be insufficient because of the unique features of paediatric HIV
infection. At the same time ART is becoming more widely available
in such communities oftentimes to HIV-infected children who are
malnourished, stunted, and significantly immunocompromised with
associated morbidity. In addition to non-compliance aberrant plasma
levels of ART may reflect pharmacokinetic effects including the
intake or composition of food and gastrointestinal motility. Both
these factors may affect plasma drug concentrations in HIV-infected
children receiving ART from resource-poor settings where infectious
diarrhoea, TB and malnutrition are common. We therefore plan to
measure drug concentrations of ART in all children receiving treatment,
and to adjust drug dosages according to concentration, the presence
or absence of viral suppression and clinical toxicity. This study
will be performed in collaboration with colleagues in the clinical
pharmacology department at the University of Liverpool.
Streptococcus pneumoniae is the most common bacterial cause
of pneumonia, lower respiratory tract infections and meningitis.
Respiratory infections and meningitis are responsible for around
76% of deaths among Kenyan children with HIV-infection [18]. It
is likely that a large proportion of these infections involve
S. pneumoniae. The effect of intervention with ART and
a new 9-valent pneumococcal vaccine, using explicit mathematical
models of the dynamics of pneumococcal carriage and disease will
be evaluated by members of the London-Sydney-Nairobi collaboration.
A recent study in The Gambia showed that a 9-valent vaccine was
effective against pneumonia, meningitis and blood stream infections
and reduced rates of death [19]. All recipients of ART in the
Lea Toto programme will also be eligible to be immunised with
this vaccine.
VIII. THE NYUMBANI
VILLAGE
Nyumbani Village will be a self-sustaining community to serve
the needs of uninfected orphans and grandparents affected by the
pandemic. Through group homes and community institutions, it is
hoped that the village will foster an environment allowing for
orphaned children to lead productive, safe and comfortable lives.
The Village provides a family-like setting for such children under
the stewardship of elderly adults and ensures that the community-based
clients and residents will receive sustenance, health-care and
education, aiming at their physical and spiritual development.
With an area of tillable land, the occupants will sustain
themselves through agriculture, poultry, dairy projects as well
as handicrafts and external services. The adolescents will benefit
from the knowledge of the elderly occupants, who in turn will
benefit from the support of the younger population. Vocational
opportunity in the form of training, tools, and start up financing
for trades, cottage industry and agricultural endeavours will
be provided with the goal of self-sustaining independence, financial
security and stability for residents, particularly maturing young
people.
IX. SUMMARY
The HIV epidemic in sub-Saharan Africa has resulted in very high
seroprevalence rates of infection among women of childbearing
age. Despite effective measures in Western countries to offset
mother-to-child transmission of HIV-1, a rapidly increasing number
of children in sub-Saharan Africa are infected either perinatally
or by breastfeeding, resulting in increased infant and childhood
mortality. The common causes of HIV-1-related morbidity and mortality
among HIV-infected African children, appear to be similar to those
experienced by HIV-infected children from Western settings before
highly active ART became the standard of care. In the absence
of ART, perinatal HIV-1 infection is most often associated with
accelerated disease progression compared with adults.
Developing homes such as the one described in this report which
are able to provide ART is an effective way of delivering desperately
needed services to the growing numbers of very vulnerable and
needy HIV-infected children in sub-Saharan Africa. The provision
of care for HIV-infected children within impoverished settings
is more challenging and requires resources, the development of
infrastructure and the recruitment of suitable personnel. Nevertheless
several pilot projects have successfully demonstrated the safe
and effective use of ART in such environments, although this has
not as yet been reproduced among a large cohort of HIV-infected
children.
November 2005
X. REFERENCES
1. UNAIDS. December 2004: "AIDS Epidemic Update
2004": http://www.unaids.org/
2. UNAIDS 2002. "HIV/AIDS: Population Impact and Policies
2001" Population Division, Department of Economic and Social
Affairs, United Nations. New York USA.
3. US Bureau of the Census. Recent HIV Seroprevalence Levels
by Country; February 1999. Research note 26. Washington DC.
4. Nduati R. Breastfeeding and HIV-1 infection. A review of
current literature. Adv Exp Med Biol 2000; 478: 201-10.
5. www.worldbank.org/poverty/data/trends/mort. World Bank
Data 2001.
6. European Collaborative Study Group. (1996). AIDS. 10:1675.
7. Pitt J, Brambilla D, Reichelderfer P, et al. (1997).
Journal of Infectious Diseases.175:567.
8. Connor EM, Sperling RS, Gelber R, et al. (1994).
New England Journal of Medicine. 331:1173-80.
9. Guay LA, Musoke P, Fleming T, et al. Intrapartum
and neonatal single-dose nevirapine compared with zidovudine for
prevention of mother-to-child transmission of HIV-1 in Kampala,
Uganda: HIVNET 012 randomised trial. Lancet. 1999 Sep 4;354(9181):795-802.
10. European Collaborative Study, Pediatrics 1994;
95: 815.
11. Taha TE, Graham SM, Kumwenda NI et al. Morbidity among
human immunodeficiency virus-1 infected and uninfected African
children. Pediatrics 2000; 106: 1-8.
12. Nathan LM, Nerlander LM, Dixon JR et al. Growth,
morbidity and mortality in a cohort of institutionalised HIV-1-infected
African children. J Aids 2003; 34: 237-241.
13. Chakraborty R, Musoke R, Palakudy T, Cross A and D'Agostino
A. Management of severely immunocompromised human immunodeficiency
virus type 1-infected African orphans with structured treatment
interruption: another kind of salvage therapy. Clin Infect Dis.
2003 Jun 1;36(11):1483-5.
14. Farmer P, Leandre F, Mukherjee J, Gupta R, Tarter L, Kim
J. Community-based treatment of advanced HIV disease: introducing
DOT-HAART (directly observed therapy with highly active antiretroviral
therapy). Bulletin of the World Health Organization 2001;79:1145-51.
15. Farmer P, Leandre F, Mukherjee J, et al. Community-based
approaches to HIV treatment in resource-poor settings. Lancet
2001;358:404-9.
16. Farmer P, Leandre F, Mukherjee J, et al. Community-based
approaches to HIV treatment in resource-limited settings. In:
XIV International AIDS Conference; 2002; Barcelona; 2002.
17. Obwogo S, Use of highly active anti-retrovirals in resource
poor slum home-care settings: the slum doctor programme model.
In: XIV International AIDS Conference; 2002; Barcelona; 2002.
18. Chakraborty R, Pulver A, Self-Pulver L, Musoke R, Aluvaala
B, Palakudy T, D'Agostino A and Rana F. The post-mortem pathology
of HIV-1-infected African children. Annals of Tropical Paediatrics,
International Child Health 2002. 22; 125-131.
19. Cutts FT, Zaman SM, Enwere G et al. Efficacy of nine-valent
pneumococcal conjugate vaccine against pneumonia and invasive
pneumococcal disease in The Gambia: randomised, double-blind,
placebo-controlled trial. Lancet. 2005;365(9465):1139-46.
| 
