[procaare] Part 2 - 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 2

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 *]

HIV Treatment in High-Income Countries

Partially effective treatment for HIV- infected individuals was first introduced in 1986.
Zidovudine (AZT), the first antiretroviral drug used for treating HIV infection, was shown
to reduce both deaths and the disease's accompanying opportunistic infections in
individuals with advanced HIV infection. 15 For the next several years, incremental
advances were made with the discovery of other antiretroviral drugs, including didanosine
(ddI), lamivudine (3TC), and stavudine (d4T) among others. However, the benefits of single
drug treatments were relatively short- lived; treatment failures often occurred within
months to a few years and usually were associated with the emergence of viruses resistant
to the very drugs used to fight them.

A conceptual breakthrough occurred when it was shown that combining two or three
antiretroviral drugs in "cocktail" regimens could delay the emergence of drug resistance
and lead to a more profound and prolonged benefit than could individual drugs. (*16 *17
*18) New classes of drugs, the protease inhibitors and non- nucleoside reverse
transcriptase inhibitors, allowed for more potent three- drug antiretroviral regimens.
These regimens, known highly active antiretroviral therapy (HAART), have resulted in the
reduction of HIV levels in the blood, often to undetectable levels, and have markedly
improved immune function in HIV- infected individuals. (*19)

The advent and widespread application of HAART has dramatically changed the typical course
of HIV infection and AIDS. Once almost uniformly deadly, HAART has transformed HIV
infection into a chronic condition that frequently remains without symptoms for many
years, with resultant gains in life expectancy. Moreover, with the ability of HAART to
dramatically decrease viral replication, the chance of transmitting the virus has
diminished correspondingly; indeed, antiretroviral drugs administered during labor and
delivery have dramatically reduced (by well over 50%) maternal to- newborn transmission of
HIV, saving thousands of infants from the complications and early death associated with
AIDS. (*20) Coincident with the introduction of these therapies, AIDS death rates during
the past six years have plummeted in the United States and other wealthy countries (Figure
1).

Current U. S. government recommendations suggest treatment of all individuals with
moderately advanced to advanced HIV infection using HAART regimens of three or more
antiretroviral drugs. (*21) Recommendations in other high- income countries are similar.
(*22,*23) Although these drug regimens all have associated side effects, inconvenience and
high cost, improvements have already been made to develop less toxic, more convenient
fixed- dose combination tablets and cheaper treatment regimens. As a result, it is
reasonable in 2001 to expect people diagnosed relatively early in the course of HIV
infection to live long and productive lives. Finally, recent cost effectiveness studies
indicate that HAART represents a highly cost- effective medical intervention, comparable
in quality- adjusted years of life to treatment of hypertension. (*24)

HIV Treatment in Low- Income Countries

The picture of success and continued improvement in the prevention and treatment of AIDS
in high- income countries is in stark contrast to what has been seen in low- income
countries. In the low income countries, the overwhelming proportion of HIV- infected
persons have no access to HAART. In sub- Saharan Africa, for example, this lack of
treatment access has translated into rapidly escalating death rates (Figure 1). A few
middle- income developing countries, notably  Brazil and Thailand, and more recently Costa
Rica, have introduced HAART successfully within nationally funded programs; however, these
countries have approximately 10 times the per capita income of the poorest countries and
roughly one order of magnitude lower HIV prevalence. The lack of feasibility studies in
poorer countries has impeded the widespread dissemination of HAART to many of the places
where it is needed most.

Nevertheless, HAART has been delivered successfully in poor settings. One example is the
Harvard- affiliated Clinique Bon Sauveur in Haiti, established by Partners in Health in
the middle of a squatter settlement of persons displaced by a hydroelectric dam. Starting
in 1998, HAART was made available to a small number of late- stage AIDS patients, whose
disease no longer responded to the treatment of opportunistic infections. In the Harvard-
Haiti protocol, HAART is prescribed to patients based on easily observed clinical signs
and symptoms, rather than advanced laboratory tests, such as CD4 cell counts and viral
load, which are not currently available in this poor and rural setting.

The guidelines for initiation of HAART in this program include the following:
 Absence of active tuberculosis
 Recurrent opportunistic infections that are difficult to manage with either
antibacterial or antifungal drugs
 Chronic diarrhea with wasting
 Unexplained and significant weight loss
 Severe neurologic complications attributable to HIV
 Severe lowering of red and/ or white blood cell counts

One of the key arguments against AIDS treatment in low- income countries is the belief
that patients will fail to take antiretroviral drugs consistently and therefore, not only
will become resistant to these drugs but also transmit resistant virus. To ensure that
patients take antiretroviral drugs regularly, the Harvard- Haiti protocol dispenses drugs
using the principles of directly observed therapy (DOT), which have been demonstrated to
be effective in treating tuberculosis and reducing the emergence of drug resistant
strains. Each HIV- infected patient is assigned an accompagnateur, (a "companion", most
often a community health worker) who observes ingestion of the HAART medications daily and
offers support to the patient and family. Directly observed therapy of HAART (or DOT-
HAART) ensures that the HIV- infected patient is taking medications regularly, and this
promotes the best clinical outcome for the patient and minimizes the opportunities for
drug resistance to develop. (*25) Dozens of patients have been enrolled in the Harvard-
Haiti project, and all have had a positive clinical response, characterized by weight gain
and the abatement of AIDS- related symptoms, and the medications have been well tolerated.
(*26)

The DOT model for delivery of HAART is particularly compelling for several reasons. First,
a widespread, successful global infrastructure has already been established for DOT- based
tuberculosis treatment programs, (*27,*28) through which HAART might be effectively
delivered.

Second, substantial overlap exists between those infected with tuberculosis and AIDS,
since tuberculosis is the major opportunistic infection of HIV disease in poor country
settings. Third, DOT is cost- effective (i. e., an efficient use of limited resources) in
poor, low- wage settings, as it is labor- rather than resource- intensive and requires
only community workers with little training. Fourth, the tight control of drug dispensing
in DOT blocks the development of a black market in antiretroviral drugs. This matter, in
particular, is of considerable importance to those seeking efficacious AIDS treatment as
well as to pharmaceutical companies, who need protection from a black market when
providing drugs at deeply discounted prices.

HAART delivery in poor settings has not been limited to Haiti. Both Senegal and Côte
d'Ivoire have seen successful distribution of HAART. (*29,*30,*31) In Senegal, 86 patients
have been treated in a pilot program for over two years. These studies show that persons
in poor countries are able to adhere to medications and that AIDS treatment can be
successfully delivered. Based on clinical trial data from developed countries, there is
ample reason to expect that AIDS treatment in these settings will result in similarly
significant gains in extending life and health.

REFERENCES
***********
*15 M. Fischl et al, The efficacy of azidothymidine (AZT) in the treatment of patients
with AIDS and AIDS- related complex. A double- blind, placebo- controlled trialNEJM 1987;
317: 192- 197
*16 S. Hammer et al, A trial comparing nucleoside monotherapy with combination therapy in
HIV- infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. AIDS
Clinical Trials Group Study 175 Study TeamNEJM 1996: 335: 1081- 90
*17 S. Hammer et al, A controlled trial of two nucleoside analogues plus indinavir in
persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic
millimeter or less. AIDS Clinical Trials Group 320 StudyNEJM 1997; 337: 725- 733
*18 M. Hirsch et al, A randomized, controlled trial of indinavir, zidovudine, and
lamivudine in adults with advanced human immunodeficiency virus type 1 infection and prior
antiretroviral therapyJ Infect Dis 1999; 180: 659- 665
*19 C. Carpenter et al., Antiretroviral therapy in adults: updated recommendations of the
International AIDS SocietyUSA Panel JAMA 2000; 283: 381- 390
*20 Perinatal HIV Guidelines Working Group (2001). Public Health Service Task Force
Recommendations for Use of Antiretroviral Drugs in Pregnant HIV- 1- Infected Women for
Maternal Health and Interventions to Reduce Perinatal HIV- 1 Transmission in the United
States. Available at: http:// www. hivatis. org/ guidelines/ perinatal/ Jan24_ 01/
PERJAN01. PDF.
*21 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.
*22 British HIV Association Writing Committee (2000). British HIV Association Guidelines
for the treatment of HIV- infected adults with antiretroviral therapy. Available at:
http:// www. aidsmap. com/ bhiva/ bhivagd1299. htm.
*23 J. Delfraissy. Prise en charge thérapeutique des personnes infectées par le VIH.
(Paris: Flammarion, 2000).
*24 K. Freedberg et al.( 2001). The Cost Effectiveness of Combination Antiretroviral
Therapy for HIV Disease. NEJM 344: 824- 831.
*25 Improvements in clinical outcomes due to DOT- HAART, compared with self- administered
therapy (SAT) were reported in U. S. trials. M. Fischl, et al, "Impact of Directly
Observed Therapy on Long- Term Outcomes in HIV Clinical Trials," Abstract 528, 8 th
Conference on Retroviruses and Opportunistic Infections, Chicago, February 4  8, 2001, at
http:// www. retroconference. org.
*26 P. Farmer, et al, "Community- Based Approaches to HIV Treatment: DOT- HAART in
Resource- Poor Settings" Lancet (in press, 2001)
*27 M. Desvarieux et al. (2000). A novel approach to directly observed therapy for
tuberculosis in an HIV- endemic area. Am J Public Health 91: 138- 41.
*28 P. Kamolratanakul et al, (1999) Randomized controlled trial of directly observed
treatment (DOT) for patients with pulmonary tuberculosis in Thailand. Trans R Soc Trop Med
Hyg 93: 552- 7.
*29 P. Sow, "Clinical, Immunological and Virological Effectiveness of Antiretroviral
Therapy in a Resource- Poor Setting: The Senegalese Experience" Abstract 490, 8 th
Conference on Retroviruses and Opportunistic Infections.
*30 R. Landman, et. al., "Evaluation at 6 months of a Once- a- Day HAART Regimen in
Treatment- Naive HIV- 1- Infected Adults in Senegal (ANRS 12- 04 Study)" Abstract 491, 8
th Conference on Retroviruses and Opportunistic Infections.
*31 Y. Diop, et al, "Prospective Trials of CBV + IDV in West Africa" [Cote- d'Ivoire],
Abstract 492, 8 th Conference on Retroviruses and Opportunistic Infections.

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