[procaare] Part 3 - 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 3

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 enroll 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.

1. Who should be treated?

Recent guidelines in developed countries, based in part on cumulative toxicities of the
antiretroviral drug regimens, recommend deferral of HAART until the later stages of HIV
infection and that treatment be guided by laboratory tests such as CD4 cell count and
viral load. Current U. S. guidelines, for example, recommend initiating HAART at CD4
counts less than 350 cells/ mm 3 or viral loads greater than 30,000 copies /ml of plasma
(*32) While the optimal timing of therapy in resource poor nations has not been studied,
starting treatment in the later stages of disease makes practical sense. It is those late
in the course of the disease whose survival time is most enhanced by HAART and who are
most easily identified as candidates for treatment on the basis of clinical signs and
symptoms, even without facilities to perform CD4 or viral load testing.

However, as with other aspects of scaling up HAART, who should be treated, and when, are
questions for clinical, epidemiological, and operational research to answer. That is, all
largescale efforts to provide AIDS treatment should be carefully monitored and designed to
reap the maximum benefits, and the maximum amount of information regarding the efficacy of
the proposed protocols. This said, we recommend treatment for HIV- infected individuals as
follows:

(a.) Multiple pilot programs, including a subset of the population in clinical trials,
should be initiated in parallel in different locales, since the logistics of drug delivery
and response to therapy may vary from place to place. All programs, and especially the
clinical trials, should be supported by the public scientific institutions of wealthy
countries (e. g. the National Institutes of Health (NIH), Centers for Disease Control and
Prevention (CDC), and their counterparts in other countries), UNAIDS, and academic
research centers.

(b.) Among the planned programs, consideration should be given to rapidly starting a
several large- scale countrywide trials, to be conducted initially over a period of about
three years. Trials of this breadth are essential for assessing the feasibility of
countryscale AIDS treatment, with a view to overcoming a range of possible barriers. The
countries in which these trials are conducted should be selected based on strong
governmental support and some existing infrastructure to back the effort. With adequate
infrastructure development and support as part of the programs (discussed below), such
trials could enroll several tens of thousands of patients within a country, or what might
be a sizeable fraction of the AIDS patients in a small country.

(c.) In areas with access to CD4 counts and/ or viral load testing, selection of persons
to treat should be based on these laboratory measurements and should initially use the
treatment guidelines accepted in wealthy countries. The outcome of treatment based on
these selection criteria and guidelines should be rigorously assessed as experience
accumulates to bring improvements to future treatment decisions.

(d.) In areas without access to CD4 counts or viral load testing, selection of persons to
treat should be based on HIV seropositivity and AIDS- defining clinical signs and
symptoms. To ensure that symptom- based treatment does not compromise timely treatment,
studies should be done to correlate the clinical criteria with laboratorybased CD4 and
viral load measurements, which could be furnished by a network of international reference
laboratories (discussed below).

(e.) Consideration should be given to designing pilot programs and clinical trials to
treat both adults and children.

(f.)  Consideration should be given to designing pilot programs to contribute directly to
preventing the spread of infection. For purposes of prevention, particular groups that
should be targeted include HIV- infected pregnant women, and groups involved in high- risk
behavior for transmission. Such programs would promote and assess the potential role of
HAART in reducing the transmission of HIV on a population scale.

(g.) Since tuberculosis is the major cause of death in persons with AIDS, treatment for
tuberculosis should be available to protect both HIV- infected individuals and to prevent
their transmitting tuberculosis to their family members and close contacts.

2. What treatments should be used, and how should they be delivered?

With many antiretroviral drugs on the market, a large range of HAART regimens are
available in wealthy countries. The ideal regimen should be potent and well tolerated;
should have low drug toxicity; should be simple for the patient to take; and should not be
prone to development of drug resistance. There are as yet no proven data that one
particular regimen is best for initiating therapy, and therefore, several treatment
regimens should be available for use in poor countries. In addition, almost all treatment
data have focused on HIV subtypes prevalent in the U. S. and Europe. No data exist to
indicate which antiretroviral regimens are optimal for treatment of the most globally
prevalent HIV subtypes, such as HIV- 1C.

Ultimately, operational rather than biomedical considerations may make one regimen
preferable to another. Complicated treatment regimens often require multiple drugs to be
taken at different times throughout the day. The recent development of new, fixed- dose
combinations, which combine several antiretroviral drugs in a single tablet, can help make
HAART easier for the patient to take and thus can help forestall the development of
resistance. Brand name products such as Trizivir (GlaxoSmithKline) already combine three
drugs (zidovudine, lamivudine, and abacavir) into a single tablet taken twice daily, and
forthcoming products from a generic manufacturer (Cipla) will combine other drug
combinations (zidovudine, lamivudine, and nevirapine; and stavudine, lamivudine and
nevirapine) into a single tablet with similarly simple dosing. (*33) In addition, several
currently available drugs (e. g., didanosine, efavirenz) and others in development (e. g.,
tenofovir, emtricitabine, and BMS 232,632) can be administered once daily, and this holds
out the prospect of once- daily HAART regimens. A DOT- HAART regimen taken once daily
would make possible a high level of patient adherence to drug treatment as has previously
been seen in well- run, DOT- based tuberculosis treatment programs in poor countries.
(*30,*31) . This approach could also be augmented through small cash incentives or through
recruitment of health workers from the community, both of which have been shown to improve
adherence. (*34)

In summary, simplified dosing regimens of antiretroviral drugs, combined with direct
observation and/ or other strategies to improve patient adherence to medication are likely
to be effective in poor countries. We accordingly recommend the following:

(a.) HAART regimens should be chosen based on established efficacy, safety, ease of
administration and tolerability.
(b.) DOT programs should be formally evaluated and compared to other treatment delivery
and patient monitoring programs.
(c.) Treatment proven to be sub- optimal in wealthy nations, such as the use of only one
or two nucleoside inhibitors, should not be used.
(d.) DOTS treatment for tuberculosis should be integrated into the treatment protocol for
those persons infected with both HIV and TB.
(e.) An expanded effort to track the development of antiviral drug resistance has to be
part of clinical trials

3. Where should treatment be administered?

International support for treatment should be made available in any resource poor country
where there is political support locally and at the highest levels for providing access to
AIDS treatment on a scientifically monitored basis. The international community should be
prepared to reciprocate this interest with technical and financial assistance to build the
needed infrastructure for treatment and monitoring. The existing local infrastructure and
resources would determine the type of treatment and methods of monitoring that are
initially used: e. g., treatment based on CD4 cell counts and/ or HIV viral load
monitoring, or treatment based on symptomatic illness, such as in the Harvard- Haiti
protocol. In those areas where existing treatment infrastructure is lacking, this should
not be cited as an impasse by which to forego treatment.

Efforts should be initiated to build the clinical and diagnostic capacity to furnish and
monitor therapy, making use in the interim of geographically distant infrastructures
(including those in wealthy countries) to monitor the efficacy of interventions and the
potential adverse effects of the antiretroviral drugs. Research efforts also should be
directed toward understanding how different levels of locally available laboratory
infrastructure affect therapeutic outcomes, and whether alternative, lowercost
technologies for CD4 cell count and viral load testing are useful and reliable in poor
countries. (*35) We accordingly recommend the following:

(a) International support for treatment should be made available in all low- income or
high prevalence nations where there is political support locally and at the highest levels
for providing access to AIDS treatment on a scientifically monitored basis.
(b) Where the political will exists for treatment, the international community should
assist in providing necessary infrastructure to support the rapid expansion of pilot
programs for treatment, as well as the scientifically rigorous clinical trials that would
accompany those programs.
(c) Until such time as all necessary infrastructure is in place, the local capacity to
provide clinical and diagnostic support services, as well as treatment of tuberculosis and
opportunistic infections should determine the type and intensity of the treatment programs
instituted.
(d) The international community should redouble its aid effort to build the needed
infrastructure, delivery capacity and monitoring capacity necessary to achieve the best
therapeutic outcomes in poor countries without delay, once the precise infrastructure
requirements are known.
(e) Efforts should be initiated immediately to expand education and training of health
care providers and scientists from poor countries to support these efforts.

4. What diagnostic and supportive testing should be performed?

While AIDS treatment in resource- poor countries may necessitate different clinical
guidelines and practices, acceptable practices must be instituted to ensure the safety and
efficacy of treatment. This includes, for example, establishing standards for monitoring
the clinical signs and symptoms suggestive of drug toxicity (e. g., jaundice, neuropathy).
These will vary according to the drugs utilized and may include hematologic, renal, and
hepatic assessments. Because different drugs have different toxicities, the monitoring
standards and laboratory tests required in an individual situation should be determined by
the HAART regimens utilized in a particular area.

In addition, where possible, blood should also be monitored for drug efficacy, as measured
by increased CD4 cell counts and reduced HIV viral load, and where patients are not
responding to therapy, for drug resistance. The frequency of such monitoring will vary
over time. Initial response to therapy should be monitored by measuring CD4 cell counts
and viral load at baseline and after several months of therapy. If viral suppression (i.
e., treatment success) is achieved and maintained, monitoring frequency may be reduced.
The role of viral resistance testing for individuals in whom regimens are failing is still
being evaluated in wealthy countries and cannot be recommended for routine use in poor
countries at this time. However, blood specimens should be stored, if possible, for
eventual resistance testing, so studies can be conducted evaluating both the utility and
cost- effectiveness of resistance testing in these settings.

In summary:
(a.) Toxicity monitoring should be done by clinical examination and appropriate laboratory
testing of blood specimens.
(b.) Specific laboratory tests and their frequency should be dictated by the HAART
regimens being utilized.
(c.) CD4 cell counts and/ or HIV viral load should be monitored at intervals, wherever
possible, to assess the benefits of therapy.
(d.) Specimens should be stored for eventual studies evaluating the usefulness of viral
drug resistance testing in resource- poor countries.
(e.) Clinical correlation between CD4 cell count and viral load with AIDS and
opportunistic infections specific for each locale should be determined.
(f) Efforts should be initiated immediately to develop less expensive monitoring assays,
but this should not delay the implementation of treatment programs.

REFERENCES
***********
*32 Department of Health and Human Services (DHHS) and the Henry J. Kaiser Family
Foundation (2001). Guidelines for the Use of Antiretroviral Agents in HIV- Infected Adults
and Adolescents. Available at: http:// www. hivatis. org/ guidelines/ adult/ Feb05_ 01/
pdf/ AAFEB05B. PDF.
*33 Personal communication to the authors, Dr. Y. K. Hamied, Cipla Ltd. (March 2001).
*34 J. Volmink and P. Garner (2001). Interventions for promoting adherence to tuberculosis
management (Cochrane Review). Issue 1, 2001. Oxford: Update Software.
*35 The WHO has collected information on alternative CD4 and viral load measurement
technologies that are both established and less expensive than those customarily used in
wealthy countries. A useful summary of these alternative technologies, with costs, is
found in "Laboratory Requirements for the Safe and Effective Use of Antiretrovirals":
http:// www. who. int/ HIV_ AIDS/ antiretroviral_ modules/ indexar. htm.

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