|
Modelling HIV/AIDS
epidemics in Botswana and India: impact of interventions to prevent
transmission*
Nico J.D. Nagelkerke,1,
2
Prabhat Jha,3
Sake J. de Vlas,1
Eline L. Korenromp,1,
3
Stephen Moses,2,
4
James F. Blanchard,4
& Frank A. Plummer2,
4
http://www.scielosp.org/scielo.php?script=sci_arttext&pid=S0042-96862002000200003&lng=es&nrm=iso
OBJECTIVE: To describe a dynamic
compartmental simulation model for Botswana and India, developed to
identify the best strategies for preventing spread of HIV/AIDS.
METHODS: The following interventions
were considered: a behavioural intervention focused on female sex
workers; a conventional programme for the treatment of sexually
transmitted infections; a programme for the prevention of
mother-to-child transmission; an antiretroviral treatment programme for
the entire population, based on a single regimen; and an antiretroviral
treatment programme for sex workers only, also based on a single
regimen.
FINDINGS: The interventions directed
at sex workers as well as those dealing with sexually transmitted
infections showed promise for long-term prevention of human
immunodeficiency virus (HIV) infection, although their relative ranking
was uncertain. In India, a sex worker intervention would drive the
epidemic to extinction. In Botswana none of the interventions alone
would achieve this, although the prevalence of HIV would be reduced by
almost 50%. Mother-to-child transmission programmes could reduce HIV
transmission to infants, but would have no impact on the epidemic
itself. In the long run, interventions targeting sexual transmission
would be even more effective in reducing the number of HIV-infected
children than mother-to-child transmission programmes. Antiretroviral
therapy would prevent transmission in the short term, but eventually its
effects would wane because of the development of drug resistance.
CONCLUSION: Depending on the country
and how the antiretroviral therapy was targeted, 25–100% of HIV cases
would be drug- resistant after 30 years of use.
Keywords HIV
infections/epidemiology/prevention and control/drug therapy; Disease
outbreaks/prevention and control; Disease transmission//prevention and
control/prevention and control; Computer simulation; Models,
Theoretical; Botswana; India (source: MeSH, NLM).
Mots clés HIV,
Infection/épidémiologie/prévention et contrôle/chimiothérapie; Epidémie/
prévention et contrôle; Transmission maladie/ prévention et contrôle;
Simulation ordinateur; Modèle théorique; Botswana; Inde (source: MeSH,
INSERM).
Palabras clave Infecciones por
VIH/epidemiología/prevención y control/quimioterapia; Brotes de
enfermedades/prevención y control; Transmisión de enfermedad/prevención
y control; Simulación por computador; Modelos teóricos; Botswana; India
(fuente: DeCS, BIREME).
Bulletin of the World Health
Organization 2002;80:89-96.
Introduction
The human immunodeficiency virus
(HIV) epidemic is still out of control in most of sub-Saharan Africa
(1–3); in Botswana, for example, one in three adults is infected. In
Asia, HIV seroprevalences in many countries have been growing steadily,
Thailand being a notable exception. HIV is threatening India, in
particular, although the epidemic is still in its early stages there
(4).
Measures to control the epidemic are
urgently needed. Randomized trials and epidemiological studies suggest
that certain interventions are effective in preventing HIV transmission
or mortality, particularly those listed below.
1. Interventions focusing on
high-risk individuals, such as female sex workers, in order to increase
their use of condoms and encourage the adoption of other safer sex
practices (5).
2. Treatment of bacterial sexually
transmitted infections (STIs) in order to reduce the prevalence of these
cofactors for HIV transmission (6–8).
3. Prevention of mother-to-child
transmission through peripartum antiretroviral treatment of mother and
child, possibly followed by the avoidance of breastfeeding (9–11).
4. Highly active antiretroviral
therapy (HAART), an intervention that targets morbidity and mortality
but may also affect transmission — either positively by making
individuals less infective or negatively by leading to higher-risk
behaviour or increasing the lifespan of infected individuals (12).
The benefits of these interventions
both in epidemics that are at an early stage or are full-scale are
largely unknown. This paper reports the results obtained using
mathematical models to explore the medium-term impacts of these
interventions if they are sustained on a countrywide scale in a
low-prevalence setting and in a mature HIV epidemic, with heterosexual
spread.
Methods
We developed a dynamic compartmental
model for the HIV-1 epidemics in Botswana and India. Parameters were
chosen to resemble the epidemic situations in India (13) and Botswana,
except that the populations were considered to be closed. However, this
does not entirely reflect reality, especially in Botswana, where many
men migrate to South Africa for work and acquire HIV infection there (3,
15).
The model assumed unsafe sex work to
be important in driving the epidemics. Female sex workers and their
clients were assigned separate compartments to reflect this assumption,
which is supported by the finding in India that approximately 80% of
cases of STIs presenting at sexually transmitted disease clinics are
first-generation infections derived from sex work (16). Furthermore,
early female HIV infections occurred predominantly among female sex
workers, while monogamous women who were infected probably became so
after their husbands had visited such workers (4, 18). Less information
is available for Botswana but, as elsewhere in sub-Saharan Africa,
unsafe sex work probably plays a very important role in the transmission
of HIV (19–24).
Modelling carried out by UNAIDS has
suggested that in India by 2010 a total of 25 million people will be
living with HIV/AIDS under a worst-case scenario, with the corresponding
number being 5 million under a best-case scenario, i.e. an adult
seroprevalence of approximately 1–5%. Our model corresponds to a
scenario in which prevalence grows from its current level of
approximately 1% of the sexually active population to an equilibrium
level of almost 5%. For Botswana, where HIV prevalence levels are
already high, no major growth of the epidemic is anticipated. Model
parameters and initial values were set to reflect an equilibrium
HIV/AIDS prevalence of about 30% of the sexually active adult
population. The most important intrinsic differences assumed between
Botswana and India were as follows: the rate at which men became clients
of female sex workers, which was taken to be four times higher in
Botswana than in India; and in the number of infections caused by
infected individuals among low-risk individuals of the opposite sex,
which was twice as high in Botswana as in India, reflecting the higher
frequency of non-commercial extramarital sex in sub-Saharan Africa (25).
The model
In the model, individuals moved
between sex-specific compartments. For example, for women there were two
groupings, female sex workers and low-risk, each of which was split into
one uninfected component and three infected components, as follows:
infected with HAART-sensitive strains, but not receiving HAART; infected
with drug-sensitive strains and undergoing HAART; and infected with
resistant strains, irrespective of treatment. We used the ModelMaker
computer program (Cherwell, Old Beaconsfield, England) to construct the
model.
Fig. 1
shows the model structure, whose formal description can be examined in
the full version of the present paper (26).
Interventions
It was assumed that the four
interventions modelled would begin in 2003 and continue until 2033.
Female sex worker interventions
The objective of these interventions
is to increase the use of condoms in contacts between female sex workers
and their clients. In India there are probably several million such
workers, with a far greater number of clients. Since many men from
Botswana often find temporary work in South Africa, their contact with
female sex workers is probably even more widespread than that of
Indians. In both countries the use of condoms during sex worker–client
contacts is generally low. Focused interventions have proved very
effective in increasing condom use in this context. This reduces HIV
transmission not only among sex workers and their clients but also in
the general population, because of the core role of these groups in
spreading infection (27–29). Many peer-mediated female sex worker
intervention programmes in India and Africa have reported increases in
condom use of 80% or more among those reached (30–33). We conservatively
assumed that this intervention reduced the proportion of unprotected
contacts from 67% to 25%. We were also conservative in not assuming an
additional reduction in the risk of transmission per female sex
worker–client contact through a reduction in STI prevalence.
STI management
Epidemiological studies support the
hypothesis that STIs are associated with increased HIV susceptibility
and infectiousness. However, confounding makes it difficult to estimate
these cofactor effects reliably from observational studies (34).
Improved STI management has proved effective in a controlled community
trial in Mwanza, United Republic of Tanzania, with a reduction in HIV
transmission of approximately 40% (6). In Rakai, Uganda, however,
failure to reduce HIV transmission through an STI mass-treatment
programme sparked debate about such interventions (35–41).
Nevertheless, we assumed that STI
management would cause a 30% reduction in HIV transmission parameters.
Arguably, this was a considerable simplification of reality and required
averaging over partnerships with and without STI. The average effect of
the intervention possibly also varied between risk categories, e.g.
female sex workers and other women, depending on largely unknown factors
such as the extent of its uptake. The intervention was assumed to have
no effects on sexual behaviour. It is worth noting that the way in which
the 30% reduction was achieved made no difference to our predictions. An
increase in the use of condoms among the general population could be
equally effective.
Maternal interventions
A number of regimens can reduce
mother-to-child, i.e. vertical, transmission of HIV. The intervention in
the model consists of HIV screening during antenatal care, administering
nevirapine or other antiretrovirals (42) to mother and child, and
providing alternatives to breastfeeding. It is possible to prevent
almost all transmission when breastfeeding is avoided (43). We assumed a
modest 50% reduction in mother-to-child transmission, from 33% to 16.5%,
in order to reflect that regimens including formula feeding might not be
available in parts of the developing world. We also assumed that there
would be no effect in women with HAART resistance and that 100% of women
would be reached. In Botswana, 90% of all pregnant women have been
reported to attend antenatal clinics (14). In India the corresponding
proportion might be as low as 60% (44), and reaching all women would
require much effort.
HAART
HAART has had a dramatic impact on
the mortality of HIV patients in developed countries (45, 46) but its
long-term effects are unclear (47).
We assumed a single standard
combination regimen, the most plausible method of implementation. Under
therapy HIV-infected individuals are assumed to be uninfectious because
of low viral loads (48). However, individuals under treatment engender
drug-resistant strains at an annual rate of 25%, after which they become
infectious again and spread resistant strains. After resistance has
developed there are no benefits from treatment. HAART increases the life
expectancy of an individual with drug-susceptible HIV by 4 years. We did
not assume changes in sexual behaviour as a result of the availability
of HAART since findings on this issue are contradictory (6, 50).
Two HAART programmes were
considered: one in which all infected individuals were recruited at an
annual rate of 50%; and one in which only female sex workers were
eligible and were also recruited at an annual rate of 50%. These rates
are probably higher than would be achieved in practice, and would result
in an average interval of 2 years between infection and receipt of HAART.
For each of the two interventions, two scenarios were explored: a "no
counselling" scenario in which individuals were as infectious as other
HIV-positive individuals; and an "effective counselling" scenario in
which drug-resistant individuals spread 50% less HIV than HIV-infected
individuals not receiving HAART. However, individuals with primary
resistance (i.e. originally infected with resistant strains) were always
considered to be as infectious as drug-susceptible HIV positives not
receiving HAART.
Results
Fig. 2
shows the projected adult HIV seroprevalence over time in both
countries, following intervention. In India the female sex worker
intervention was the most effective, with a fivefold decline in HIV
seroprevalence after 30 years relative to the level in the absence of
intervention. The STI intervention was the next most effective, with a
two- to threefold decline in seroprevalence. After an initially positive
impact, all the HAART interventions resulted in a levelling off of
seroprevalence at about 20–30% below baseline levels. In Botswana the
STI intervention fared best, followed by the female sex worker
intervention. The performance of the HAART interventions was similar to
that in India.
Fig. 3
shows the effect of HAART interventions on the prevalence of drug
resistance among adult HIV-positive individuals. In India, resistance
increased rapidly, independently of the type of HAART programme. In
Botswana, the increase in resistance was slower if HAART was restricted
to female sex workers because more infections occurred outside this
group than in India. The rate of development of resistance improved
somewhat as a result of counselling. In general, the rate of development
of resistance increased with HAART usage.
Fig. 4
shows the proportions of HIV-infected neonates for the various
interventions. In India, although the intervention aimed at preventing
mother-to-child transmission had the greatest impact initially, the
female sex worker intervention ultimately surpassed it and the STI
treatment intervention was ultimately as effective. In Botswana, the STI
treatment and the intervention aimed at preventing mother-to-child
transmission were about equally effective, and both performed better
than the female sex worker intervention. Of course, the latter
intervention would have little impact on overall HIV transmission.
In order to explore the sensitivity
of our findings with respect to the assumptions on the development of
drug resistance under HAART, we re-ran the model using annual rates of
developing resistance of 10% and 5%. We also developed a version of the
model in which HAART was restricted to the treatment of only late-stage
disease. Although resistance developed more slowly than shown here,
essentially the same patterns of HIV seroprevalence ensued over time
(25).
Discussion
We did not include male circumcision
in our models. Although the frequently found association between male
circumcision and lower HIV prevalence suggests that it reduces male
susceptibility to HIV, it needs to be confirmed in a clinical trial
(51–53).
Female sex worker and STI
interventions
Both the female sex worker and STI
interventions had lasting effects on adult prevalence of HIV and thereby
on vertical transmission. Our finding that female sex worker
interventions had a high impact on the epidemic was consistent with the
core group concept of HIV/STI epidemiology. Surprisingly, however, these
interventions did not have the same effectiveness ranking in India and
Botswana: in India, the female sex worker intervention had the greatest
impact, whereas STI management was the most effective intervention in
Botswana. In India the modelled effect of the female sex worker
intervention apparently drove the epidemic to extinction by reducing the
basic reproductive number, R0, below unity, whereas the STI intervention
did not have this effect (54). In Botswana, where higher levels of
transmission were assumed, neither of the two interventions alone would
push R0 below unity. In view of this failure to eliminate transmission,
the STI intervention, which was assumed to reduce all types of HIV
transmission by an average of 30%, provided the best protection for the
general population.
HAART
The various HAART-related
interventions all had dramatic short-term effects on HIV prevalence, and
had even greater short-term effects on incidence (26). With a very high
recruitment rate and a low rate of developing resistance (50% and 25%
per annum respectively), most HIV-positive individuals would be on HAART
within a few years and still be drug-sensitive. Since these individuals
were assumed not to be infectious, a high recruitment rate would
initially reduce transmission. In the long run, however, these effects
waned due to widespread drug resistance. Once resistance spreads,
prevention of mother-to-child transmission also becomes difficult. The
greater the success in recruiting patients, the more rapid is the spread
of resistant strains. It is doubtful, however, whether our assumed high
recruitment rates are feasible since frequent HIV screening of the
population would be necessary.
In our model we ignored the
"bathtub" effect, whereby HIV-infected individuals are most infectious
shortly after infection and again when they become severely
immunosuppressed and develop AIDS, with an intervening period of reduced
infectiousness (55). Individuals are rarely identified very early after
they become infected, so a high recruitment rate for HAART may be less
effective in reducing transmission than is suggested by our model.
Although the development of drug
resistance can be delayed (56), it cannot be completely avoided (57).
Generalized drug resistance can be expected to occur unless the
development and availability of new drug regimens keeps pace with the
development of drug resistance. Although our predictions about the
development of widespread resistance to HAART may seem pessimistic, we
believe they are not unrealistic. Experience with antibiotics has shown
that resistance can develop and spread rapidly and may outpace the
development of new drugs (58). Tuberculosis treatment is short and
curative, making the problem of development of resistance potentially
avoidable (59). Nevertheless, resistance to a range of drugs is becoming
a problem in the treatment of tuberculosis in many parts of the world.
Modelling methods
Our approach, involving
compartmental modelling, is based on the expectation that the model
system behaves sufficiently like the real world. However, it ignores
much of the complexity of sexual behaviour. Few details are known about
sexual networking in India and Botswana, or even in developed countries,
where more research has been conducted. The use of more refined
modelling methods, such as microsimulation, would therefore be
inappropriate (60–62). Our knowledge of baseline parameters, such as
transmission probabilities, is also imprecise. Consequently, our
projections of the effects of interventions are subject to substantial
uncertainty. Nevertheless, it is probable that the conclusions about
prioritization are sufficiently robust if the assumed effect sizes of
interventions are realistic. Whether this is the case is not always
clear. For the female sex worker and STI interventions, empirical data,
much of it from Africa, support our choices. Nevertheless, since there
are few empirical data on STI interventions in India or Botswana,
assumptions about their impact are speculative. Assumptions about the
possible effects of interventions targeting mother-to-child transmission
are more certain, with a proven efficacy of at least 50%. For HAART
interventions, no long-term empirical data are available. We believe
that our assumed 25% annual rate of developing resistance is realistic.
While a 10% rate appears to be achievable under trial conditions, an
annual rate of 40% has been observed in clinical practice, driven mainly
by non- adherence to demanding regimens (63). In contrast to what has
been done in some other models, we did not assume that drug-resistant
strains would revert to being drug-sensitive when the selective pressure
of treatment was removed (64, 65). Because resistant strains are
increasingly found in drug-naive patients (66–74), such strains must be
both transmissible and able to retain their resistance. Besides, in the
absence of frequent sensitivity testing, as is likely to be the case in
many developing countries, drug treatment and its selective pressure can
often be expected to continue long after the development of resistance.
In our simulations we have explored
and shown the effects of only single interventions. In practice,
however, interventions need not be implemented individually. Several
interventions can be implemented simultaneously or consecutively. In
fact, this has been the approach in Thailand, where general education
was combined with a focused female sex worker programme, STI treatment,
and a mother-to-child transmission component. The effect of combining
interventions on the incidence of HIV infection is non-linear but can be
explored using our model. Such interventions may, for example, have
strongly positive synergistic effects, in which case the combination of
interventions would make elimination possible. As a rule it appears that
any additional intervention that changes the course of the epidemic from
a rising or endemic prevalence into one with R0 less than 1 has a
disproportionate impact on the incidence of infection. For India, a
female sex worker programme may achieve this objective, but for Botswana
more may be needed. Computer simulations, not reported here, exploring
the effects of additional control measures beyond this point indicate
that they would have a relatively small impact but that they would lead
to a quicker decline in the incidence of infection.
While mathematical modelling may
provide important insights, the task of identifying which strategy would
be sufficient to drive R0 below unity is complex. This cannot be done
with certainty because the state of the epidemic, the value of
transmission parameters, and the effect of interventions are not
precisely known and are in a state of flux. Even predictions of the
course of HIV transmission in the absence of interventions have been
highly variable (75). Uncertainty analysis is best performed by
considering the effects of interventions predicted by a range of models
rather than a range of parameter values. This is because certain model
structures may overestimate or underestimate the effects of specific
interventions. Several HIV transmission models have been developed and
could be adapted to include considerations relating to HAART and drug
resistance (76).
Conclusions
Because of the above uncertainties,
we recommend a dynamic approach to interventions. In practice, HIV/AIDS
prevention and control programmes should address a broad range of
issues, but when modelling suggests that a given intervention may be
sufficient to control an epidemic, as may be the case with sex worker
interventions in India, it would seem wise to give the highest priority
to this intervention and to monitor its impact. When modelling casts
doubt on the adequacy of a single intervention, as in Botswana, it would
seem advisable to direct resources to a more comprehensive package of
interventions. Research and surveillance are essential for identifying
implementation problems, monitoring impact, and validating and updating
models. Standard sentinel surveillance may need refinements so that a
response to interventions can be rapidly detected. Because effective
interventions change incidence more rapidly than prevalence,
surveillance could utilize the time lag between different enzyme-linked
immunosorbent assays (ELISAs) to obtain improved estimates of incidence
(77, 78). It is also important to monitor process outputs. For example,
effective female sex worker interventions should lead to a reduction in
STI incidence and in the percentage of male STI patients reporting
unprotected sex with such workers as their probable source of infection.
If interventions do not achieve adequate changes in these measures,
increased programme efforts may be required. The dynamic nature of HIV
intervention programmes requires that they be continuously evaluated to
ensure that the results predicted by modelling exercises are reflected
by what is occurring in practice.
Conflicts of interest: none
declared.
Résumé
Modélisation de l'épidémie de VIH au
Botswana et en Inde : impact des interventions destinées à empêcher la
transmission
OBJECTIF: Décrire un modèle
compartimental dynamique de simulation pour le Botswana et l'Inde,
élaboré dans le but d'identifier les meilleures stratégies de prévention
de la propagation du virus de l'immunodéficience humaine (VIH).
MÉTHODES: Les interventions suivantes ont été examinées : une
intervention comportementale axée sur les prostituées ; un programme
classique de traitement des infections sexuellement transmissibles ; un
programme de prévention de la transmission mère-enfant ; un programme de
traitement antirétroviral destiné à l'ensemble de la population et
reposant sur un schéma thérapeutique unique ; un programme de traitement
antirétroviral axé uniquement sur les prostituées et reposant également
sur un schéma thérapeutique unique.
RÉSULTANTS: L'intervention axée sur les prostituées et celle axée sur
les infections sexuellement transmissibles sont intéressantes du point
de vue de la prévention à long terme de l'infection à VIH, mais on ne
sait pas exactement laquelle serait la plus efficace. En Inde, une
intervention axée sur les prostituées pourrait conduire à l'extinction
de l'épidémie. Au Botswana, aucune intervention n'y parviendrait à elle
seule, mais la prévalence du VIH pourrait baisser de près de 50 %. Les
programmes axés sur la transmission mère-enfant pourraient réduire la
transmission du VIH aux nourrissons, mais n'auraient aucun impact sur
l'épidémie elle-même. A long terme, les interventions axées sur la
transmission sexuelle pourraient même être plus efficaces pour réduire
le nombre d'enfants infectés par le VIH que les programmes mère-enfant.
Le traitement antirétroviral empêcherait la transmission dans un premier
temps, mais ses effets iraient en diminuant du fait de l'apparition
d'une pharmacorésistance.
CONCLUSION: Selon le pays et la façon dont le traitement serait ciblé,
la proportion de cas résistants serait de 25 à 100 % au bout de 30 ans
d'utilisation des antirétroviraux.
Resumen
Modelización de la epidemia de VIH
en Botswana y la India: efecto de las intervenciones de prevención de la
transmisión
OBJETIVO: Describir un modelo
dinámico de simulación por compartimentos para Botswana y la India,
desarrollado con objeto de identificar las mejores estrategias para
prevenir la propagación del virus de la inmunodeficiencia humana (VIH).
MÉTODOS: Se consideraron las siguientes intervenciones: una intervención
conductual centrada en las profesionales del sexo, un programa
convencional de tratamiento de las infecciones de transmisión sexual; un
programa de prevención de la transmisión maternoinfantil; un programa de
tratamiento antirretrovírico para la totalidad de la población, basado
en un solo régimen; y un programa de tratamiento antirretrovírico
destinado únicamente a las profesionales del sexo y basado también en un
solo régimen.
RESULTADOS: Tanto las intervenciones centradas en las profesionales del
sexo como las centradas en las infecciones de transmisión sexual
tuvieron resultados prometedores para prevenir la infección por el VIH a
largo plazo, pero resultaba difícil determinar su importancia relativa.
En la India, una intervención centrada en las profesionales del sexo
conduciría a la extinción de la epidemia. En Botswana, ninguna de las
intervenciones tendría por sí sola ese resultado, pero la prevalencia de
infección por el VIH se vería reducida casi en un 50%. Los programas
contra la transmisión maternoinfantil permitirían reducir la transmisión
del VIH a los lactantes, pero no tendrían ningún efecto en la epidemia
en sí. A largo plazo, las intervenciones focalizadas en la transmisión
sexual serían incluso más eficaces que los programas de prevención de la
transmisión maternoinfantil en lo que respecta a reducir el número de
niños infectados por el VIH. El tratamiento antirretrovírico prevendría
la transmisión a corto plazo, pero a la larga sus efectos tenderían a
desaparecer como consecuencia del surgimiento de farmacorresistencia.
CONCLUSIÓN: En función del país y del perfil de destinatarios de la
terapia antirretrovírica, el 25%-100% de los casos de infección por el
VIH serían resistentes a los medicamentos al cabo de 30 años de
tratamiento.
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*
Based on: Nagelkerke NJD, Jha P, de Vlas SJ, Korenromp EL, Moses S,
Blanchard JF et al. Modelling HIV/AIDS epidemics in Botswana and India:
the effects of interventions. (CMH Working Paper Series, Paper No. WG5:
4. Available at: URL:
http://www.cmhealth.org/docs/wg5_paper4.pdf).
1
Department of Public Health, Erasmus University Rotterdam, Rotterdam,
The Netherlands (email:
nagelkerke@mgz.fgg.eur.nl). Correspondence should be
addressed to Dr Nagelkerke.
2
Departments of Medical Microbiology and Medicine, University of
Manitoba, Winnipeg, Canada.
3
World Bank, Washington, DC, USA.
4
Department of Community Health Sciences, University of Manitoba,
Winnipeg, Canada.
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