Good article on ARV drug resistance
-----------------------------------
Education and debate
ANTIRETROVIRAL THERAPY IN AFRICA
Warren Stevens, health economist, Steve Kaye, virologist, Tumani
Corrah, director
MRC Laboratories, PO Box 273, Banjul, Gambia, West Africa
Correspondence to: W Stevens <wstevens@mrc.gm>
Source:
BMJ 2004;328:280-282 (31 January), doi:10.1136/bmj.328.7434.280
http://bmj.bmjjournals.com/cgi/content/full/328/7434/280
We should stop and think about the risks of resistance, and ways
of minimising them, before increasing access to antiretroviral
therapy in Africa
Summary points
Antiretroviral therapy is becoming more affordable for develop-
ing countries
Infrastructure is also essential to deliver the complex and sen-
sitive drug regimen
DOTS has been suggested as a method for delivering antiretrovi-
ral therapy, although it has limited success for tuberculosis in
much of Africa
Suboptimal adherence to antiretroviral therapy is likely to re-
sult in the transmission of drug resistant virus strains within
the community
Other methods for ensuring adherence need to be developed and
evaluated
Demands for the introduction of antiretroviral therapy into Af-
rica have been growing over the past few years. On the face of
it, the availability of antiretroviral therapy at what seems to
be an affordable price is good news. The treatment can produce
dramatic clinical improvements in people with symptomatic HIV
disease and, when used optimally, can delay the progression of
disease. However, the potential short term gains from reducing
individual morbidity and mortality may be far outweighed by the
potential for the long term spread of drug resistance if the ex-
perience of adherence to treatment for tuberculosis is repeated.
Without due forethought and planning, antiretroviral therapy is
likely to be introduced to Africa in a random and haphazard way,
with inconsistent prescribing practices and poor monitoring of
therapy and adherence. This risks the rapid development and
transmission of drug resistance.
HIV drug resistance
Virus strains with reduced sensitivity to zidovudine, the first
drug used to treat HIV infection, were first observed in 1989,
three years after it was introduced.1 Subsequently, resistance
to every currently licensed antiretroviral drug has been ob-
served.2 Drug resistance within an individual patient is not
confined to a single compound, and cross resistance between
drugs of the same class is the rule rather than the exception.3
Drug resistance arises by natural selection, mutant strains be-
ing selected when the virus replicates in sub-limiting drug con-
centrations. The only way to prevent resistance is to use a drug
regimen that reduces virus replication to virtually zero (com-
monly equated with a plasma virus load below 50 RNA copies/ml).
In this circumstance, the probability of a mutant arising to all
the drugs used in a highly active antiretroviral therapy regimen
is very low. However, should the concentrations of the drugs
fall sufficiently to allow appreciable virus replication, the
chances of a resistant mutant being selected increase.
The concentration of antiretroviral drugs at their active site
varies for several reasons including eating habits, exercise
habits, and concurrent illnesses. However, the main cause of
variation is the timing of the dosing schedule. Concentrations
of the drug peak shortly after a dose is taken and then wane un-
til the next dose is taken. Antiretroviral regimens are designed
so that the trough concentrations of the drugs are never suffi-
cient to allow appreciable virus replication.4 The longer a dose
is delayed, the lower the concentration falls and the more virus
replication occurs. Thus, intermittent therapy and poor adher-
ence are the principal factors leading to drug resistance. Al-
though most resistant strains are poor at replicating and do not
persist in the absence of drugs,5 viral variants are archived as
provirus in long lived memory T cells6 and will be rapidly se-
lected when therapy is resumed.
The only sure way to avoid the development of drug resistance is
to adhere strictly to therapy. Failure to completely suppress
virus replication has been shown to result in the development of
resistance even at high levels of adherence (> 92%).7
Implications of resistance
From a public health viewpoint, drug resistant strains are
transmissible and pathogenic. Currently, in industrialised coun-
tries, up to 23% of incident infections are with virus strains
resistant to one or more drugs.8 The higher the incidence of in-
fection, the more rapidly resistant variants can spread. People
infected with a drug resistant virus are more likely to have
their treatment regimen fail allowing the virus to develop re-
sistance to other drugs in the combination. Good adherence to
therapy, resulting in undetectable virus loads, will reduce vi-
rus transmission within the community. There is no reason to
suppose that the drug resistance problems being encountered in
industrial countries will not occur in developing countries.
The development of drug resistance is also of concern for the
infected individual whose therapy fails as a consequence. Be-
cause of cross resistance within drug classes, people in whom
the first antiretroviral therapy regimen fails often have poorer
responses to subsequent regimens containing drugs of the same
classes.9 10
In industrialised countries, therapy is routinely monitored by
assaying plasma virus load.11 This measure shows the most imme-
diate response to changes in virus replication. Unless monitor-
ing of virus load is adopted alongside the introduction of anti-
retroviral therapy in developing countries, the risks of drug
resistance arising and being transmitted are greatly increased.
At present, the necessary laboratory infrastructure for such
monitoring is not available in most countries of sub-Saharan Af-
rica.
Drug regimen compliance in Africa
Evidence suggests that adherence with drug treatment in Africa
is low compared with that in industrialised nations. Treatment
for malaria rarely exceeds three doses, yet suboptimal dosing is
still seen in 60-70% of cases in Africa.12 Treatment with anti-
retroviral therapy depends on long term, regular, time specific
dosing, much like diabetes or tuberculosis (which is more common
in Africa).
It has been suggested that giving antiviral therapy through the
directly observed treatment short course (DOTS) strategy devel-
oped to monitor treatment for tuberculosis would ensure the nec-
essary adherence. Yet, DOTS itself has met with mixed success,
particularly in Africa (table). A decade after it was introduced
in Africa, treatment completion rates still range from low (37%)
to moderate (78%).15 Problems that have been documented include
the time and expense of travel to and from health centres,
availability of drugs, and the time and costs needed to super-
vise treatment.16
Table: Success rates of directly observed treatment short course
(DOTS) for tuberculosis in sub-Saharan African countries with
HIV-1 prevalence over 5% (data for most recently available year,
1995-2000)13 14
Directly observed treatment for antiretroviral therapy has been
tested in developed countries and met with mixed success. Esti-
mates of average rates of non-adherence to antiretroviral ther-
apy ranged from 50% to 70%. Adherence rates below 80% are asso-
ciated with detectable virus in most patients.7 With directly
observed treatment for antiretroviral therapy still under devel-
opment in industrialised nations, its introduction into a part
of the world where adherence rates are generally much lower
seems unconsidered. Other methods of increasing adherence to tu-
berculosis treatment have been suggested and tested throughout
the developing world.17 However, these have not achieved adher-
ence greater than 70% and have not been tested on a large scale.
Directly observed treatment is not the only way that antiretro-
viral therapy has been delivered. Nevertheless, it is the model
on which most programmes are based. Studies reporting successes
in delivering antiretroviral therapy in Africa have had rela-
tively strict exclusion criteria. Study populations have tended
to be urban with above average education and income, and, as
such, are probably not representative of most African patients
requiring treatment.18 19 These studies are, however, a movement
in the right direction as they improve our understanding of what
can be achieved and what levels of infrastructure and adherence
management are required.
Difficulties of antiretroviral programmes
A major problem we face in introducing antiretroviral therapy to
Africa is the inadequate infrastructure to deal with the number
of people infected. In developed countries the number of people
likely to be poor adherers is relatively small. Treatment of
this group is seen as beneficial not only to the individual but
also to the wider community because it gives increased protec-
tion against spread of infection. In Africa, a higher proportion
of patients are likely to fall into the category of potential
poor adherers unless resource intensive adherence programmes are
available.
Ideally, the way forward for antiretroviral therapy in Africa
would be to introduce treatment in controlled settings. Research
programmes are needed to tackle the problems of delivery and the
challenges of providing the infrastructure to ensure effective
access to antiretroviral therapy. We cannot afford inconsistent
prescribing practices and poor monitoring of therapy and adher-
ence.
A rational approach is required in which systematic delivery and
proved methods for maximising adherence are as important as pro-
curing the drugs themselves. This should be led by a respected
international organisation that has the objectives of overcoming
short term suffering as well as preventing a similar disaster in
the long run, by insisting that antiretroviral policies incorpo-
rate a phase of piloting systems that seek to maximise adher-
ence.
--
Editorial by Loewenson and McCoy and Paper p 249 Contributors
and sources: WS has worked with the World Bank in predicting the
effect of HIV in West Africa, and with the Department for Inter-
national Development and the London School of Hygiene and Tropi-
cal Medicine on the economics of tuberculosis control pro-
grammes. SK has worked on monitoring HIV drug resistance in tri-
als of antiretroviral therapy conducted in the United Kingdom
and Europe. TC has been in charge of the clinical services pro-
vided by the MRC unit in the Gambia since 1986 and has special-
ised in the care and treatment of patients infected with HIV and
tuberculosis.
Competing interests: None declared.