Francoise, L

Hilderbrand, K

Kasper, T

English

MSF Field Research

20 E S S E N T I A L   D R U G S   M O N I T O R
Issue No. 32, 2003
F
➢  TOBY KASPER, DAVID COETZEE, FRANCOISE LOUIS,
ANDREW BOULLE, KATHERINE HILDERBRAND*
EW areas of public health have generated as much debate, controversy
and protest in recent years as the drive to expand access to antiretroviral
therapy – the drugs that have transformed AIDS from a death sentence
to a chronic condition – in developing countries. Several years ago, it
was a futile discussion: with a yearly cost of US$10,000 per patient, there was
little possibility of widespread access in developing countries. But, largely as a
result of a potent combination of generic competition and activism, prices have
plummeted, with triple therapy now being available for as little as US$209 a
year1, causing a huge shift in the debate about availability.
Demystifying antiretroviral
therapy in resource-poor settings
Today, the debate centres on if anti-
retroviral therapy is possible in severely
resource-constrained environments, and,
increasingly, on the best ways to deliver
these drugs. In a poor township 30
kilometers outside Cape Town, South
Africa, Médecins Sans Frontières set out
to grapple with both of these issues.
Khayelitsha has around 500,000 inhab-
itants – a figure swollen by a steady influx
of economic migrants from rural areas –
of whom 50% are unemployed and more
than 70% live in shacks. HIV sero-
prevalence rates at antenatal clinics are
above 24%, having risen with shocking
rapidity over the past 10 years.
The provincial government of the
Western Cape decided to launch South
Africa’s first government-run programme
to prevent mother-to-child transmission
(MTCT) of HIV in Khayelitsha. Zido-
vudine (AZT), first became available in
the township’s two maternity wards in
early 1999, and the programme has sub-
sequently become one of the continent’s
biggest, with more than 20,000 women
having accepted testing, and over 3,000
having received antiretroviral therapy.
Médecins Sans Frontières began support-
ing this MTCT programme in 1999,
before opening clinics to offer treatment
to the mothers, their infected children,
and others with HIV from the broader
community at three government primary
health care centres in April 2000. Despite
catering solely to those with HIV, the
centres were called “infectious disease
clinics”, out of a fear that labelling them
HIV clinics would generate stigma and
deter people from accessing services.
This concern turned out to be entirely
misplaced, as the community quickly
branded them AIDS clinics, and nonethe-
less the queues steadily lengthened.
Treatment was initially limited to oppor-
tunistic infections – the conditions that
arise with increasing frequency as HIV
erodes the immune system’s capacity to
ward off infections. But in May 2001, this
was broadened to include antiretroviral
therapy, making the project the first to
use antiretrovirals in government health
facilities outside the context of clinical
trials.
This step was motivated by both
humanitarian and public health princi-
ples: despite receiving quality care and
prophylaxis for opportunistic infections,
patients were getting sick and dying at
unacceptable rates and so needed access
to the only drugs that have been proven
to suppress HIV infection and thus ex-
tend life. Further, there was a clear need
to develop models for the delivery of
antiretroviral therapy in South Africa.
Thus the project was intended to demon-
strate that the use of antiretroviral therapy
at primary health care level was feasible,
affordable and replicable.
Impressive survival rates
Preliminary analyses recently pre-
sented at the XIV International AIDS
Conference in Barcelona provide strong
indications that poor black women and
men can indeed derive considerable ben-
efit from antiretroviral therapy without
undue toxicity. To date, 180 patients have
been placed on this therapy, selected from
among the 3,000 patients who have at-
tended the MSF clinics in Khayelitsha
(Box 1 gives details of the selection proc-
ess). These patients were extremely sick
when they began therapy, having a me-
dian CD4+ T cell count of 43, with as
many patients initiating therapy with
under 10 CD4+ T cells as above 100. In
contrast, a typical CD4+ T cell count in a
seronegative person would be in the
range of 800–1200, and it is well-estab-
lished that the risk of death increases
significantly as the count drops below 50.
Thus if untreated, the prognosis of this
group of patients would be
extremely poor, with death
within a year the sad reality
for most.
However, on antiretro-
viral therapy, their survival
was impressive. After nine
months of treatment, 88% of
the patients were alive. The
reason for this dramatic
improvement is simple:
patients with immune sys-
tems weakened by HIV
infection are prone to get
sick with infections that peo-
ple with healthy immune
systems can normally fight
off. On antiretroviral the-
rapy, the rates of these
opportunistic infections
were significantly reduced
“gold standard” of undetectable levels of
viremia (less than 125 copies in the test
available) or using a higher level that
some have suggested is more appropri-
ate to developing country contexts, as
shown in Graph 3.
These encouraging results occurred
with very few serious adverse events.
There were no deaths related to drug tox-
icity, and while 46% of patients reported
at least one side-effect, most of these
were minor, scoring only a 1 or a 2 on
the AIDS Clinical Trials Group grading
of adverse events, with 1 being the most
mild and 4 the most serious (64% were
grade 1, grade 2:19%, grade 3:11% and
grade 4:6%).
Three key factors
In analysing the programme’s success
to date and assessing the possibilities to
use it as a model in other settings, three
key aspects stand out.
First and most fundamentally, the
drugs must be affordable. In this case, it
meant beginning with brand-name drugs
which, although considerably cheaper
than in developed countries (or, indeed,
in South Africa a few years earlier), were
still much more expensive than generic
versions produced in countries such as
Brazil, India and Thailand. These alter-
natives were not registered in South
Africa, but after authorisation to use Bra-
zilian generic antiretrovirals was received
from the South African Medicines Con-
trol Council, a change to Brazilian drugs
has allowed twice as many patients to be
treated.
The second key to success was the
involvement of the community. This was
facilitated by giving all treatment at pri-
mary health care level, rather than at a
large reference hospital. Additionally, the
community was integrally involved in the
process of selecting patients for therapy,
which played a major role in guaran-
teeing local ownership over the project
as a whole (see Box 1 for more on the
selection process).
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
O
p
p
o
r
t
u
n
i
s
t
i
c
 
i
n
f
e
c
t
i
o
n
s
 
p
e
r
 
p
a
t
i
e
n
t
–
y
e
a
r
Incidence risk ratio: 3.19 (95% CI: 2.62–3.91)
69%
All (pre-ARV) All (on ARV)
➪
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
T
B
 
i
n
f
e
c
t
i
o
n
s
 
p
e
r
 
p
a
t
i
e
n
t
–
y
e
a
r
Incidence risk ratio: 6.81 (95% CI: 3.02–19.00)
85%
TB (pre-ARV) TB (on ARV)
➪
250
200
150
100
50
0
50–99 10–49 <10
B
a
s
e
l
i
n
e
 
c
o
u
n
t
Baseline               6 month
100–199
Graph 1
Impact of antiretroviral therapy on incidence rates of opportunistic
infections (all and TB only)
Graph 2
Median CD4+ T cell count counts at baseline
and six months, stratified by baseline count
(see Graph 1). The reduction was parti-
cularly striking for tuberculosis, which
is one of the major killers of people with
HIV/AIDS in South Africa.
Reduction in opportunistic infections
is largely attributable to the considerable
improvements seen in immunologic sta-
tus. After six months on therapy, the mean
increase in CD4+ T cell count was 143.
This meant that while 54% of patients
had below 50 CD4+ T cells at the start of
therapy, only 2% were still below this
level after six months; in contrast, none
were above 200 at baseline, while at six
months 53% had climbed above this
important threshold. Interestingly, even
patients with severely compromised
immune systems at initiation of therapy
experienced large improvements after
beginning antiretroviral therapy, as shown
in Graph 2.
These improvements were possible
because antiretroviral therapy effectively
suppressed viral replication in the large
majority of patients, thus allowing the
immune system to recover, instead of
having to concentrate its energy on fight-
ing off HIV infection. This success was
evident whether measuring using the
  A N N I V E R S A R Y   I S S U E21 E S S E N T I A L   D R U G S   M O N I T O R
Issue No. 32, 2003
Finally, the involvement of the pa-
tients themselves has been essential.
They are genuine partners in the project
at a number of levels:
➤ At the political level, when politicians
have questioned the validity of using
antiretroviral therapy in resource-
poor settings, it was the patients who
responded, writing letters to newspa-
pers and speaking out in the media.
➤ At the community level, they play an
important role in the support groups
run for patients on antiretroviral
therapy, with those who have been on
therapy for longer periods of time
helping mentor those beginning.
Also, a number of patients work
with a South African NGO, the Treat-
ment Action Campaign, on a major
community education initiative.
➤ At the individual level, patients have
educated themselves on the impor-
tance of adherence, allowing them
to take responsibility for their own
therapy, making it unnecessary to use
medical staff to observe them taking
their pills (see also Box 2).
influx of patients with HIV,
many of whom are dying,
despite the best efforts of the
staff. When antiretrovirals
are available, the staff’s role
shifts back from care of the
dying to being able to help
patients return to good
health, with an obvious
improvement in morale.
Additionally, access to
antiretroviral therapy pro-
vides an important reason
for patients to stay in the
medical system: in Khay-
elitsha, not a single patient
on antiretroviral therapy
has been lost to follow up,
in marked contrast with the
Box 1
Selecting patients for antiretroviral therapy
◆    ◆    ◆
Patient selection is one of the more difficult aspects of setting up a programme, as
the need inevitably outstrips the supply of drugs available. However, it is important
to note that, contrary to popular perception, not all people with HIV should immedi-
ately be placed on antiretroviral therapy. In Khayelitsha, the biological and clinical
criteria used to select patients include:
◆ a CD4+ T cell count of less than 200, and a WHO disease stage of 3 or 4, both
in line with WHO’s recently-released guidelines on antiretroviral therapy in
resource-poor settings;
◆ patients must live in Khayelitsha;
◆ patients must have regularly attended the clinics for at least three months
(instituted in light of the highly mobile nature of Khayelitsha’s population).
These requirements plus the fact that some patients chose not to take antiretroviral
therapy mean that the number of patients who were ultimately candidates to be
started on therapy has not overwhelmed the resources available.
Nonetheless, a system was introduced that involved the community in the process
of selecting patients. A number of community representatives – typically people
with experience with people with HIV (and including those with HIV themselves) –
met regularly to assess candidates and determine who would ultimately be placed
on therapy. Deliberations are based on a number of factors, such as the health of
the patient, their income level, the social support available to the patient and her/
his openness about HIV infection, and if other members of the same family are
already on antiretroviral therapy. Although the process is time-consuming, it has
proven a valuable way to fairly and equitably allot spots in the treatment pro-
gramme, as well as an important means of ensuring community ownership over
the programme.
Box 2
Patient-centred approaches to adherence
◆    ◆    ◆
The issue of how to ensure that antiretroviral therapy is taken regularly and appro-
priately has generated considerable discussion and controversy. Some even suggest
that the use of antiretroviral therapy in poor countries will only lead to the wide-
spread development of resistance. They advocate either that resources are not put
into making the drugs available or that they are only administered under strictly
controlled conditions, such as in the presence of medical staff (along the lines of
the DOTS model for TB, although the comparison is complicated by the greater
frequency of dosing of antiretroviral therapy and the fact that it is life-long rather
than of a limited duration). However, in Khayelitsha, an approach centred on
educating patients and empowering them to be actively involved in the treatment
programme has yielded very positive results.
This begins with the careful selection of a regimen that is easy to take – for example
a combination of nevirapine and co-formulated AZT/3TC, which amounts to two
pills twice a day – and setting the health care facilities within easy reach of the
patients (for example, at primary health care level). Once patients begin therapy
(after an educational process), a tripartite programme supports adherence:
◆ Individual support is available in the form of trained counsellors available during
clinic hours to answer questions, and, more informally, through “treatment
assistants,” a household member or neighbour whom each candidate for therapy
is requested to identify who can provide support on adherence;
◆ Peer support comes in the form of support groups run solely for patients on
antiretroviral therapy, and which serve both as valuable spaces for patients to
discuss barriers to adherence with others sharing similar experiences and as a
forum for ongoing education;
◆ Educational materials are provided to help patients fully appreciate the risks and
benefits of antiretroviral therapy, and understand the importance of adherence.
Research is ongoing to quantify the levels of adherence, but the dramatic improve-
ments in the surrogate markers of changes in viral load and CD4+ T cell counts
strongly suggest that adherence is good.
“People must know that a poor person like
me living in a shack can take these drugs
properly. They are my chance to live.”
Patient on antiretroviral therapy in Khayelitsha, South
Africa.
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Six months Three months Baseline
P
e
r
c
e
n
t
a
g
e
Undetectable (<125)                     <5000
Graph 3
Viral load (HIV RNA) at baseline, three and
six months
general experience in this highly mobile
township. Finally, the significant de-
creases in opportunistic infections (and
the resultant need for hospitalizations)
suggest that those who argue that
antiretroviral therapy is unattainable,
based on crude calculations of the cost
of drugs, are missing a fundamental
aspect of the provision of antiretroviral
therapy. That is that a considerable
percentage of the costs incurred by drug
purchases can be offset by drops in
hospitalisations and opportunistic in-
fections. This has been demonstrated in
Brazil2, and is quite likely to be true in
South Africa, a country that spends an
estimated R4 billion (approximately
US$400 million) on care and treatment
of people living with HIV/AIDS.3 Re-
search is ongoing in Khayelitsha to
quantify the magnitude of this offsetting
effect.
Finally, in contrast to those who ar-
gue that treatment and prevention are
inextricably opposed and competing for
resources, in Khayelitsha the synergy
The lessons
The project has revealed a
number of important lessons:
First and foremost, anti-
retroviral therapy can be safely
and effectively used in resource-
poor settings, and the time has
come to scale up from pilot projects to
widespread access.
Managing patients on antiretroviral
therapy is often easier than managing
patients not taking antiretrovirals. Pa-
tients in advanced HIV infection are
frequently ill with a variety of oppor-
tunistic infections, many of which are
difficult to diagnose and treat, particu-
larly at a primary health care level. In
contrast, patients on antiretroviral therapy
typically experience rapid improve-
ments in their health, and, particularly
after the first few months on antiretroviral
therapy (when the bulk of side-effects
occur), they can be followed by nurses.
In Khayelitsha, this was facilitated by
the development of standardised tools to
assist in the assessment and management
of adverse events.
The availability of antiretroviral therapy
bolsters the entire health system. South
Africa – and many other sub-Saharan
African countries – is experiencing a
major loss of medical staff, in part as a
result of poor working conditions and
low morale engendered by the enormous
between treatment and prevention has
been striking, with the availability of
treatment providing a powerful incen-
tive to learn one’s status. It was thus no
surprise that a recent survey of nine sites
around South Africa found that Khay-
elitsha had the highest rates of HIV
testing, and desire to be tested among
those who had yet to be tested, as well as
the highest levels of condom use.4 ❏
References
1. Médecins Sans Frontières. Untangling the web of
price reductions: a pricing guide for the purchase of
ARVs in developing countries. 2nd ed. Paris: Méde-
cins Sans Frontières; 2002. Available at URL: www.
accessmed-msf.org
2. Ministry of Health of the Federative Republic of Bra-
zil. Response: the experience of the Brazilian AIDS
Programme. Brasilia: Ministry of Health; 2002. Avail-
able at URL: http://www.aids.gov.br/final/biblioteca/
reposta/resp_ingles.pdf
3. National Treasury of the Republic of South Africa.
Intergovernmental fiscal review. Pretoria: National
Treasury of the Republic of South Africa; 2001.
4. Parker W, Oyosi S, Kelly K, Fox S. On the move:
the response of public transport commuters to HIV/
AIDS in South Africa. Johannesburg: Centre for
AIDS Development, Research, and Education;
2002. Available at URL: http://www.cadre.org.
za/pdf/On%20the%20Move%20Final%
20Report.pdf
* Toby Kasper was Head of Mission for MSF
South Africa at the time this paper was
written, and now works for the Global Fund
  A N N I V E R S A R Y   I S S U E
to Fight AIDS Tuberculosis and Malaria.
Francoise Louis works for MSF South Africa,
PO Box 27401 Rhine Road, 8050 Cape
Town, and David Coetzee, Andrew Boulle
and Katherine Hilderbrand work in the De-
partment of Public Health and Primary
Health Care, University of Cape Town,
South Africa.

Intergovernmental fiscal review. Pretoria: National Treasury of the Republic of South Africa;

Médecins Sans Frontières. Untangling the web of price reductions: a pricing guide for the purchase of ARVs in developing countries. 2nd ed. Paris: Médecins Sans Frontières;

On the move: the response of public transport commuters to HIV/ AIDS in South Africa. Johannesburg: Centre for AIDS Development, Research, and Education;

Demystifying antiretrovial therapy in resource-poor settings

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