[procaare] Part 4 - Harvard Consensus Statement on ARV Treatment for AIDS in Poor Counties

[Richard Marlink <marlink@hsph.harvard.edu>]

*The Harvard 'Consensus Statement on Antiretroviral Treatment for AIDS in Poor Countries;
has been broken into 6 parts in text format to be easily received by forum members. To
view the entire document online, please go to: http://aids.harvard.edu - ProCAARE
Moderator*

PART 4

Consensus Statement on Antiretroviral Treatment for AIDS in Poor Countries

By Individual Members of the Faculty of Harvard University (*1)
[* To see the list of 148 signatories, please go to website as noted at the top *]

Proposal for Treatment of HIV Infection in Poor Countries

We hypothesize that the widespread treatment of AIDS with HAART in the world's poorest
countries is both feasible and effective, and urge that this hypothesis be tested
immediately. We propose that broad availability of HAART be phased in over the next 3- 5
years through simultaneous, large- scale pilot programs designed to determine the best
treatment strategies for use in poor countries. These pilot programs would provide
treatment immediately, while concurrently maximizing adherence; limiting the development
of drug resistance; utilizing existing infrastructure; building new infrastructure; and
monitoring drug flow to ensure compliance of drug distributors with international
agreements on discounted pricing and carefully controlled distribution. A proportion of
the persons receiving treatment in these programs would also enrol in intensive clinical
trials, which would collect state- of- the- art virological, immunological, and clinical
information; this information, such as CD4 cell counts and viral loads, would optimize
treatment protocols and determine treatment efficacy through scientific methodology. We
also emphasize the importance of full local involvement of HIVinfected communities in the
design and implementation of treatment and trials. Large- scale pilot programs, coupled
with scientifically rigorous clinical studies, would not only make treatment available
immediately, but would gather the critical data necessary to improve future treatment.

It is only through these efforts that we can address the most critical questions regarding
widespread AIDS treatment in resource-poor settings.

[*Points 1 to 4 in Part 3*]

5. What questions should be asked in order to define the standard of care for AIDS
treatment in resource poor settings?

The rapid expansion of treatment into resource- poor countries is necessary not only to
provide life- prolonging therapies, but also to answer important questions that will
improve future care. As in developed countries, clinical trials should define the "Best
Practices" for AIDS treatment in poor countries and use them to develop treatment
guidelines. The important scientific issues that should be addressed include the
following:

(a.) Which HAART regimens are the best tolerated and have the lowest risk of adverse drug
reactions requiring advanced medical care or immediate physician intervention, both of
which are less likely to be available in poor countries?
(b.) Does the therapeutic outcome of HAART vary depending on whether a DOT protocol is
used; and does it matter whether treatment is supervised by a lay person living in the
patient's community or a more skilled health worker to whom a patient must travel?
(c.) What level of adherence to HAART can be achieved, and what social or programmatic
factors can help promote the highest levels of adherence?
(d.) Does the therapeutic outcome of HAART vary according to treatment initiation based on
clinical signs and symptoms of AIDS or treatment based initiation based on laboratory
tests, such as CD4 cell counts or HIV viral loads?
(e.) Which symptomatic signs or inexpensive laboratory diagnostics most reliably predict
when HAART should be initiated?
(f.) Does HAART efficacy and development of resistance vary according to the subtype of
HIV that is being treated?
(g.) Does treatment for tuberculosis and other opportunistic infections enhance the
effectiveness and sustainability of AIDS treatment? Answers to these questions are vital
to the systematic and rational improvement of AIDS treatment in poor countries. Rather
than reject AIDS treatment because countries are too poor to adequately provide it, AIDS
treatment must be performed differently in diverse settings due to constraints in
infrastructure, skilled medical workers, and finance.

6. How should AIDS drugs be procured and treatment financed?

Financial arrangements for large- scale distribution of AIDS treatment should be based on
three premises:

(1) discounts and marketplace competition for AIDS drugs have reduced their price by 90%
or more during the past year; (2) AIDS treatment will always be more expensive than poor
countries can afford, meaning that international aid is key to financing the effort; and
(3) treatment should be offered in conjunction with greatly scaled up programs designed
for prevention, since treatment and prevention must go hand in hand.

Last year, a number of the world's major pharmaceutical firms (Boehringer Ingelheim,
Bristol Myers Squibb, GlaxoSmithKline, Hoffman La Roche, and Merck) reached an agreement
with UNAIDS to furnish antiretroviral drug therapy to poor governments at reduced cost.
(*36) This "Accelerating Access" initiative has led to agreements on price reductions in
four countries Cote d'Ivoire, Rwanda, Senegal and Uganda with nearly twenty other
countries in various stages of negotiations. In general, the Accelerating Access ground
rules are that, in exchange for discounts of up to 90%, recipient countries pledge to
respect patent rights and to institute safeguards that prevent the lower priced drugs from
entering illicit, black market trade.

By early 2001, the Accelerating Access initiative had had little effect in scaling up AIDS
treatment, even in the countries where price agreements were in force. Not only were the
Accelerating Access prices still significantly above production cost (around $950 - $1,850
annually for a HAART regimen, depending on the specific "cocktail"), but they remained far
too high for the impoverished countries to purchase out of their own resources or to
provide the medical services needed for their effective delivery. In short without donor
assistance the lowincome countries have been unable to take advantage of these reduced
prices. (*37)

Prices have continued to fall rapidly in early 2001. As a result, several generic drug
makers, most notably Cipla of India, have offered to supply generic products at prices
lower than the Accelerating Access initiative. (*38) In addition, two major pharmaceutical
companies involved in the original initiative, Merck and Bristol Myers Squibb, have
announced further, deeper price cuts to offer their drugs at or below production cost.
(*39,*40) Similarly Abbott laboratories announced its decision to offer two antiretroviral
drugs and a clinical test product in Africa at no profit (*41) . Finally, Merck and
GlaxoSmithKline have recently announced that they will sell discounted drugs not only
directly to governments but also to non- governmental organizations and charities working
in poor countries. These dynamic developments reflect the willingness of these companies
to assist in this effort, various recent price quotations, and evidence on production
costs, we estimate that a typical HAART regimen can cost $500 a year, and possibly less.
(*42)

While prices in this range are critically important and necessary to achieve a large
expansion of AIDS treatment, they are not sufficient. Five hundred dollars per patient per
year (patient- year) remains far above what most poor economies can afford without donor
assistance.

To illustrate, Ghana, Nigeria and Tanzania have a per capita gross national product (GNP)
under $400; out of these funds, public- sector health budgets are $8/ patient- year or
less  far too little to deal with basic health needs, much less AIDS treatment. (*43,*44)
Furthermore, obligations to pay foreign debt often outstrip the entire health budget in
these countries. With AIDS poised to reduce the growth of income in these impoverished
economies, it is virtually certain that additional loans taken on to deal with AIDS could
never be repaid. The provision of international aid purely as grants, not loans, is
therefore the only fiscally sound policy for such impoverished countries; and substantial
grant support will also be needed for a few middle- income countries, such as South Africa
and Botswana, where prevalence of HIV infection is high, so that the fiscal burden would
once again be too large for the country to manage out of its own resources. (*45)

Applying these current facts, we can approximate the amount of international aid that
would be needed for a wide- scale AIDS treatment effort, using , for example, a DOT- HAART
approach in a research setting in Sub- Saharan Africa (Annex A). Taking into account the
costs of the drugs themselves, plus estimates for DOT operational costs, research to
monitor and improve the effectiveness of HAART in the field, and associated material costs
for clinical supplies such as diagnostic tests, we calculate the cost of DOT- HAART to be
about $1,123/ patient- year in SubSaharan Africa. Assuming that 1 million patients in Sub-
Saharan Africa will receive treatment within three years, total requirements for
international aid using this approach are projected to be $1.1 billion annually by year 3.
In addition to the cost of antiretroviral therapy, UNAIDS has estimated that $3 billion
per year is also needed for Sub- Saharan Africa for prevention, community support and
treatment other than antiretroviral therapy (*46) .

If the AIDS treatment protocols prove successful, as we expect, up to three million people
in Sub- Saharan African countries could become HAART recipients within a five- year time
frame. By year 5 of the scaling up of this effort, therefore, we anticipate that donor
assistance on the order of $3.3 billion would be needed for antiretroviral treatment for
the region. These are ambitious targets, but they still would not cover large numbers of
people in African that need care. Even more extensive coverage would likely require a
significant expansion of basic health infrastructure into regions that now lack access to
medical services. We have not calculated those additional infrastructure costs, but would
add that they are investments that should be supported by the donor community in any
event, not only for treating AIDS patients but for fighting a vast range of diseases that
are currently claiming millions of lives in Sub- Saharan Africa.

Since Africa represents approximately 80 percent of the worldwide HIV- infected population
that would require international donor support (low- income and/ or high- prevalence
countries), total global costs would be around 25 percent higher than the African costs.
Thus, in three years, total cost projections of a global treatment effort would be around
$1.4 billion and about $4.2 billion by year 5. India would represent about three- fourths
of the non- African HIV- positive population requiring international grant support. We
note that scaling up AIDS treatment must be accompanied by scaling up tuberculosis
treatment as well, especially since TB is the leading  opportunistic infection related to
AIDS in Africa.

Beyond the five- year horizon, the cost to the donor community will be subject to three
forces. First, significant reductions in treatment costs are expected; this would be due
not only to economies of scale and learning curves in drug production and delivery of
medical services, but also to the introduction of new and increasingly effective
treatment. Considerable research is also underway to produce an effective HIV vaccine,
which if successfully developed could fundamentally reduce the costs of both prevention
and treatment in later years. Second, the incidence of new infections is expected to peak
and then decline. Increased treatment efforts presumably would correspond with scaled- up
prevention efforts, which would result in decreased viral transmission, fewer AIDS cases,
and ultimately, fewer candidates for HAART. Third, however, it is anticipated that
initially the population of eligible patients will rise, especially as effective treatment
protocols extend the lives of those currently suffering from AIDS. We cannot, at this
point, make detailed cost estimates beyond a five- year horizon. We do believe, though,
that the first two factors (declining treatment costs and a reduction in incidence)
suggest that costs to the donor community will peak at several billion dollars per year,
especially if treatment programs are complemented by intensive prevention programs, as
recommended.

In order to broaden treatment access in a scientifically effective manner, we propose a
coordinated global program. The international donor community, with significant U. S.
participation, should provide financial and scientific support, while the recipient
countries should commit to the needed political and scientific partnership. To achieve
effective international coordination with appropriate scientific support, we propose a
centralized funding and managerial structure at the international level, under World
Health Organization (WHO) and UNAIDS leadership and with strong backing from international
scientific institutions including the NIH and the CDC. Specifically, we recommend the
following:

(a.) A single, global HIV/ AIDS Prevention and Treatment Trust Fund should be established
with joint WHO and UNAIDS leadership, and with strong support from international
scientific institutions including the NIH and CDC. This trust fund would receive
contributions from donor governments for AIDS treatment, prevention efforts, other related
health care, and operational research in affected countries.
(b.) Project expenditures from the Trust Fund would be conditional on satisfying two
principles: (i) All project proposals should originate in the recipient country by the
government or a non- governmental organization backed by governmental support. This
approach would ensure that the projects considered for funding are those for which there
is confirmed political support and would avoid the pitfall where failed projects are
blamed on a lack of political backing. (ii) All project proposals should undergo
independent, expeditious review by a panel of experts external to the donors themselves
and on accepted ethical, scientific, medical and public health principles. This process
should be modeled on the "peer review" practices common in scientific funding agencies,
but which are absent in international aid agencies. Expert review would ensure that only
those  projects likely to have a measurable impact on health outcomes would qualify for
donor funding. This principle is imperative to reassure taxpayers in wealthy governments
that the international aid effort is deserving of support. (*47)

7. How should the success or failure of this effort be evaluated?

The objective of our proposal is to provide HIV therapy for persons with symptomatic HIV
infection in order to prolong life; reduce HIV transmission; reduce transmission of
tuberculosis and other opportunistic infections; and stabilize decimated social structures
in a context in which the efficacy of interventions can be monitored and objectively
evaluated. A key component of this effort would be the rapid accumulation and
dissemination of information, including health outcomes of trials, recommended treatment
guidelines, and solutions to operational barriers in resource- poor settings. Moreover,
disseminating this information would require a multilingual website to publish reports in
a standard format and, in poor countries, continuing education and training for scientists
and physicians who are routinely isolated from the global scientific community. We
recommend the following:

(a.) All interventions should be carefully monitored to determine efficacy of treatment
regimens, prevention of transmission, and emergence of drug resistance.
(b.) Outcome data must be rapidly and widely shared.
(c.) Guidelines for standards of care should be developed, disseminated, and revised on a
regular basis.

REFERENCES
*****************
*36 Other firms manufacturing antiretroviral drugs (e. g., Abbott), or offering other
drugs useful for AIDS treatment (e. g., Pfizer) chose not to participate in this original
agreement.
*37 M. Schoofs and M. Waldholz. Drug Companies, Senegal Agree To Low- Cost HIV Drug Pact.
Wall Street Journal (October 24, 2000).
*38 D. McNeil. Indian Company Offers to Supply AIDS Drugs at Low Cost in Africa. New York
Times (February 7, 2001). Cipla announced discounted prices of $350 (for Doctors Without
Borders) and $600 (for governments) to purchase its versions of stavudine, lamivudine and
nevirapine.
*39 H. Collins. Merck Cuts Prices for AIDS Drugs in Africa. Philadelphia Inquirer (March
8, 2001).
*40 M. Petersen and D. McNeil. Maker Yielding Patent in Africa For AIDS Drug. New York
Times (March 15, 2001).
*41 Reuters, Abbott to Sell AIDS Drugs, Tests at No Profit in Africa, March 27, 2001.
*42 This is based on the raw materials cost of zidovudine, lamivudine and nevirapine,
supplied to us by various manufacturers.
*43 GNP data are 1999 per the World Bank: http:// www. worldbank. org/ data/ countrydata/
countrydata. html.
*44 WHO. World health report. Geneva: WHO, 2000.
*45 Among middle- income countries ($ 755 per capita GNP in 1999), prevalence is greater
than 2 percent of adults in Botswana, South Africa, Thailand, Dominican Republic, and
Guyana. These countries, like the low- income countries, will need grant support, with
levels depending on the prevalence rate and national income.
*46 AIDS Epidemic Update: December 2000, www. unaids. org, page 20.
*47 In the words of a former deputy administrator of USAID, "To ensure that the use of
[aid] funds [is]... well informed from a scientific point of view, [aid agencies] should
form a series of scientific advisory committees that would periodically review overall
policies... as well as the allocation and use of [aid] funds." Source: C. Lancaster
(2000). Transforming Foreign Aid. (Institute for International Economics: Washington),
page 92.

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