[Ip-health] Lancet: The case for expanding access to highly active antiretroviral therapy to curb the growth of the HIV epidemic

[Ira Glazer]

http://www.thelancet.com/journals/lancet/article/PIIS0140673606691629/fullt=
ext

The Lancet 2006; 368:531-536

Dr Julio SG MontanerMD, Robert HoggPhD, Evan WoodPhD, Thomas KerrPhD,
Mark TyndallMD, Adrian R LevyPhD, and P Richard HarriganPhD


Continuing expansion of the HIV/AIDS pandemic has been recognised as an
exceptional challenge to global health, international development, and
world security. UNAIDS estimates that there were more than 38 million
people living with HIV at the end of 2005, with just over 4 million new
infections that year. While most new cases continue to emerge from
developing nations, even in developed countries HIV incidence remains
unacceptably high. The high incidence is not likely to change in the
foreseeable future because: (1) HIV-prevention strategies are only
partly effective and remain severely underused; (2) a preventive vaccine
remains elusive; and (3) current treatment strategies cannot eradicate
HIV infection. Nowadays, the exceptional threat to humanity that the HIV
pandemic represents, and the similarly exceptional interventions that
will be needed to stem the relentless global growth of AIDS deaths and
new HIV infections, is widely recognised.

Highly active antiretroviral therapy (HAART), first introduced in 1996,
substantially reduced AIDS-related hospital admissions and death rates
in both developed and developing nations. Despite these encouraging
results, the early optimism generated by HAART was tempered by regimen
complexities, adverse effects, toxicities, and cost. In the past decade,
HAART regimens have become markedly simpler, better tolerated, less
toxic, and more effective. As a result, expansion of HAART programmes in
developing nations has become a welcome reality. Although concerns have
been expressed with regard to the potential negative effects of
suboptimal adherence leading to HIV-drug resistance in settings where
scale-up of HAART is taking place, recent data suggest that good
adherence can be attained in resource-limited settings and in
marginalised populations in developed nations.

The important role that the provision of HAART has in the overall
strategy to control the advance of the HIV/AIDS pandemic is now
generally agreed. However, a great deal of attention has been focused on
the potential negative effect of HAART on the overall expansion of the
pandemic if enhanced access to the treatment was to promote an increase
in risky behaviours. By contrast, the potential direct contribution of
HAART to reducing the spread of HIV has received only limited attention.
We examine here the potential role of HAART in HIV prevention and the
resulting effect this would have on the cost-effectiveness of the
treatment. We also discuss a theoretical HAART-driven strategy to
control the continued expansion of the HIV/AIDS pandemic.


HAART and HIV prevention

HIV causes AIDS. The transmission of HIV from infected to uninfected
people through exposure to an infected person's bodily fluids (mainly
semen, vaginal secretions, breast milk, and blood) is established. More
recently, HAART has been shown to reduce HIV-1-RNA plasma concentrations
predictably to undetectable concentrations in most treated patients.
International guidelines have uniformly recognised that sustained
complete suppression of HIV-1-RNA is needed to achieve a steady increase
in CD4-positive T-lymphocyte (CD4) cell count as well as a beneficial
clinical response, and to avoid the emergence of drug resistant HIV
mutants. Furthermore, the use of HAART leads to a marked reduction in
HIV-1 RNA concentrations in both the female genital tract and in semen.

Evidence of the effect of HAART on the prevention of HIV transmission
can be derived from experience in the mother-to-child-transmission
setting. Here, even before the HAART era, the key role of maternal
plasma HIV-1-RNA concentrations in HIV transmission had been clearly
established. Subsequently, clinical trials have shown that reducing the
mother's plasma HIV-1-RNA concentration with HAART dramatically reduces
mother-to-child transmission of HIV. Since the widespread availability
of HAART, mother-to-child transmission of HIV has become exceedingly
rare in developed nations.

Consistent results have emerged from several studies of HIV
sero-discordant heterosexual couples. In a study from Uganda, Quinn and
colleagues showed that viral load is the main predictor of the risk of
heterosexual transmission of HIV-1, and that transmission is rare in
those with plasma HIV-1-RNA concentrations of less than 1500 copies per
mL. In this study there were no cases of HIV transmission for couples in
which the index case had plasma HIV-1-RNA of less than 400 copies per
mL. Similarly, in a study from Thailand, Tovanabutra and co-workers
showed a dose-response effect between viral load and risk of HIV
transmission within sero-discordant heterosexual couples. No cases of
HIV transmission were seen when the index case's plasma HIV-1-RNA was
less than 1100 copies per mL in the same study.

Additional studies to assess the effect of HAART on HIV incidence in
sero-discordant couples have also been shown reduced HIV transmission.
Before the HAART era, use of zidovudine alone was associated with a 50%
reduction in HIV transmission in a study of Italian sero-discordant
couples. In the HAART era, a study of Spanish sero-discordant couples
showed that no HIV sero-conversions took place in the sexual partners of
HAART treated patients, use of HAART being independently associated with
an 86% reduction in HIV transmission in multivariate analyses. As a
result, Hosseinipour and colleagues have asked whether HAART can be used
to curb the spread of HIV. However, a possible role for HAART in
reducing HIV transmission was substantially tempered by several
mathematical modelling studies, which consistently suggested that any
possible benefit derived from the use of HAART in this setting could be
readily offset if expanded use of HAART results in increased HIV-risk
behaviour.

These concerns have been alleviated by an ecological study from Taiwan,
which provided compelling evidence about the effect of HAART on HIV
transmission. The study showed a 53% reduction in new positive HIV tests
after the introduction of free access to HAART. This reduction took
place without any change in rates of syphilis, used as a marker of
sexual risk behaviour during the study. In British Columbia, Canada, new
HIV infections fell between 1995 and 1998 after the introduction of
HAART by about 50%, and have remained unchanged to the present despite a
noticeable increase in syphilis rates (Rekart M, British Columbia Centre
for Disease Control, personal communication).

Further ecological evidence of an effect of HAART on HIV transmission
can be derived from a detailed review of the UNAIDS statistics. In 2005,
about 38,600,000 people were estimated to be living with HIV or AIDS
worldwide, with more than 4,000,000 new HIV infections and 2,800,000
AIDS-related deaths in that year. HIV-prevalent cases are the source of
new HIV infections, so investigation of the ratio between new and
prevalent cases on a regional basis is of interest.Their are clear
regional differences, which correlate inversely with regional
availability of HAART. Use of HAART is fairly widespread in western and
central Europe and North America, intermediate in Oceania and Latin
America, and limited in the rest of the world.

Ecological evidence has some limitations that should be recognised. The
accuracy of the HIV prevalence and incidence data are not known, and our
calculations could be affected by this. Also, the number of transmitted
cases might not be exactly proportional to prevalence of HIV infection
in a given area, because a limited number of individuals with very high
viral load could contribute a disproportionate number of transmission
events. Finally, HAART might be only one of several factors that
contribute to reduced transmission in areas where such treatment is
accessible. We must stress that we do not see HAART as a replacement for
strengthening of the prevention effort, but rather as an essential part
of it.
Cost effectiveness of HAART revisited.

Traditionally, HAART has been deemed to be cost effective on the basis
of patient-centred outcomes; however, this fails to consider the effect
of HAART on HIV transmission. Regional incidence to prevalence ratios
can be used to estimate the number of new HIV infections that have
failed to materialise in 2005 in any given region. For example, to raise
the index in North America to the level seen in developing countries,
where access to HAART is limited, would take nearly 100,000 additional
HIV infections in North America. The precise proportion of these missing
new infections that are directly attributable to the use of HAART is not
clear; however, on the basis of the data from Taiwan and British
Columbia, a 50% or so yearly reduction in new HIV cases can reasonably
be attributed to the introduction of HAART. This proportion would
represent about 43,000 new cases in North America in 2005, which in turn
translates to an averted HAART cost of US$10.3 billion, based on an
estimated lifetime treatment cost, in 2001, of US$241,000 per person
treated.

HAART use is estimated to have averted 400 new infections in British
Columbia in 2005. This would represent a total cost, in 2001,of US$96.4
million of averted lifetime treatment expenditure, in addition to the
direct health benefit of HAART to the HIV-infected individuals. This is
particularly striking if we consider that 3963 individuals received
HAART in British Columbia in that same year for a total HAART cost
(using patented drugs) of US$49 million. On the basis of these data,
HAART, which was already deemed cost effective on a patient-centred
basis, has generated an additional substantial cost saving once its
effect on HIV transmission is considered.


A potential HAART-driven HIV-control strategy

The patient-centred approach to HIV management is based on the use of
HAART to modify the natural history of the disease with the expectation
that HIV infection will be transformed into a manageable chronic
condition. This approach is supported by many clinical trials and
population-based studies showing that health outcomes, such as death or
progression to AIDS, can be delayed as long as individuals are highly
adherent to therapy and start treatment with CD4-cell counts of greater
than 200 per =CE=BCL. No additional patient-specific benefit has been
documented when treatment was initiated at earlier stages of the
disease. As a result, a large global effort is currently underway to
expand access to HAART for individuals with AIDS-related symptoms or
CD4-cell counts of less than 200 per =CE=BCL. The =E2=80=9C3 by 5=E2=80=9D =
plan proposed to
expand the use of HAART regimens to an additional 3 million HIV positive
individuals by 2005. Despite substantial progress, the =E2=80=9C3 by 5=E2=
=80=9D plan has
failed to meet its target. In fact, the number of new HIV infections in
2005 was more than double the number of individuals who started HAART in
the same year.

Current estimates are that between 30% and 40% of HIV-infected
individuals globally are in need of HAART. In view of the
well-characterised and relentless decline of CD4-cell count in untreated
HIV-infected individuals, most currently infected individuals will
become eligible for HAART within a decade. Most of the 38 million HIV
positive individuals already infected worldwide will become eligible for
HAART therapy by the year 2015. The continued expansion of the global
HIV/AIDS caseload threatens to make the current HAART strategy
unsustainable.

In view of the potential effect of HAART on HIV transmission, what would
be the implications of an alternative prevention-centred strategy for
the use of HAART? This approach would be based on the notion that new
HIV infections are overwhelmingly contributed to by index HIV-infected
individuals who are not on HAART. A prevention-centred approach would
therefore argue that treating 100% of HIV-infected individuals at once
could greatly reduce HIV transmission. While this would be costly in the
short term, it could prove highly cost effective. The short-term cost of
treatment of all HIV-infected individuals would be more than offset by
the number of new infections that it would prevent. In fact, as the
cohort of today's HIV-infected individuals on HAART matures, after about
20=E2=80=9340 years this cohort will no longer be interacting substantially=
 with
the populations at risk, therefore drastically reducing the likelihood
of new infections. Although treating 100% of HIV-infected individuals
worldwide might not be feasible or even ethically acceptable at this
time, given the state of the pandemic, consideration of this possibility
is worthwhile.

We have, therefore, developed a hypothetical population-based model to
illustrate the potential effect of a prevention-centred approach on the
worldwide HIV pandemic (unpublished). The model estimates the rate of
decline in HIV prevalence in low-income and middle-income countries. We
have assumed that all HIV-infected people would be given therapy in the
first year and that, after the first year, there would be no new HIV
infections. We also assume the cost of HAART therapy, with use of
generic medications, would remain at the present cost of US$365 per
person per year. However, the model incorporates a moderate increase in
the yearly cost of therapy at 3% per year for future inflation. We also
assume that the death rate will fall initially with the use of HAART,
but increase to baseline levels in a stepwise fashion as the population
receiving treatment needs more complicated therapeutic regimens. This
optimistic population-based model shows that, in 45 years, HIV
prevalence could be reduced by more than 70 times from more than 7 cases
per 1000 people to less than 0.1 case per 1000. The number of
HIV-infected people could be reduced from 38 million to less than 1
million. The cost of therapy would be about US $7 billion per year, with
costs declining from $15 to $1 billion. Such a programme would be
expected to cost $338 billion over 45 years. The prospect of treating
nearly 40 million HIV-infected individuals worldwide seems daunting
today but, in view of the limited effect of current efforts on global
prevention of new infections, this approach merits consideration if it
can offer a means to control the relentless growth of the pandemic.

The logistical and infrastructural challenges that lie ahead for this
kind of approach are substantial. Many of the same structural obstacles
that have faced HAART scale-up programmes, such as poor health
infrastructure, a scarcity of trained health-care workers, and
rural-based populations, would be multiplied many fold. One additional
important concern is the potential for increased transmission of
drug-resistant strains of HIV with expansion of HAART use. However,
drug-resistant HIV might be less transmissible. A study from Montreal
showed that increased population rates of suppression of plasma HIV RNA
as a result of HAART were associated with reduced rates of resistance in
the community. Further reassurance is provided by examination of the
early history of antiretroviral therapy in developed nations. Between
the introduction of zidovudine in 1986 and HAART in 1996, treatment of
HIV infection relied exclusively on the use of single and dual
nucleoside analogues. Nucleoside resistance in this context was an
almost universal occurrence in treated individuals within a year of
starting therapy. Despite this resistance, an epidemic of
primary-nucleoside-resistant HIV did not materialise, and in fact the
rates of primary resistance to nucleosides continue to be modest.
Zidovudine and lamivudine remain highly effective and in widespread use
in developed nations. As has previously been proposed, we conclude that
fear of emergence of drug resistance should not prevent expansion of
HAART programmes, even in developing countries. However, any effort
directed toward the expansion of HAART programmes should include careful
monitoring of resistance.

Previous concerns about the cost and acceptability of HAART regimens
have been alleviated in recent years. The availability of generic
stavudine, lamuvidine, and nevirapine in a fixed dose combination tablet
at US$1 a day set a precedent by making the expansion of HAART
programmes feasible in developing countries. This specific treatment
would not be appropriate for the implementation of a global universal
treatment programme, because of the potential for nevirapine and
stavudine toxicity. However, an alternative one pill once daily HAART
regimen with a fixed-dose combination of tenofovir, emtricitabine, and
sustiva is now available. This represents a simple, safe, and
well-tolerated regimen that would be viable at all stages of the
disease; with a single-dose scheme, without food restrictions, with no
refrigeration needs, and limited need for laboratory monitoring. This
opens the door to consideration of the effect of different levels of
expansion of HAART coverage on HIV transmission.


Conclusions

The present approach to the management of HIV/AIDS is clearly not
sustainable, and the status quo no longer acceptable if we hope to
control the continued growth of the HIV global pandemic. A
prevention-centred approach to the use of HAART, as discussed here,
would be challenging and would need careful consideration of associated
emerging ethical issues. However, expanded free access to HAART on a
global scale provides a potential means to curb the growth of the HIV
pandemic. As such, expansion of HAART programmes could have a major role
in the much needed strengthening of the prevention effort. This
hypothetical but testable approach deserves to be urgently and
thoroughly evaluated in highly controlled environments. The global
expansion of HAART programmes now underway provides a unique opportunity
to further characterise the effect of HAART on HIV incidence in various
settings. Monitoring of HIV incidence should be an integral part of
HAART expansion programmes.