Antiretroviral Therapy in Resource-Poor Settings
Decreasing Barriers to Access and Promoting Adherence
Joia S. Mukherjee, MD, MPH,* Louise Ivers, MD, MPH, DTMH,* Fernet Leandre, MD,†
Paul Farmer, MD, PhD,* and Heidi Behforouz, MD*
access to the clinic and the medications. Because some of the
Summary: Since 2002, the HIV Equity Initiative of the non-
risk factors for nonadherence described in North American
governmental organization Partners in Health has been expanded in
studies, such as active drug use, are more common in poor
conjunction with the Haitian MOH to cover 7 public clinics. More
populations,5 when ART was introduced in resource-poor set-
than 8000 HIV-positive persons, 2300 of whom are on antiretroviral
tings, there was fear that adherence would be a major problem
therapy (ART) are now followed. This article describes the
and promote widespread resistance to ART.6,7 However,
interventions to promote access to care and adherence to ART
studies in developing countries have shown comparable or
developed in reference to the specific context of poverty in rural Haiti.
better levels of individual adherence than what is seen in North
User fees for clinic attendance have been waived for all patients with
American and European populations.8,9 Resource-limited
HIV and tuberculosis and for women presenting for prenatal services.
settings, however, present unique challenges to ART adher-
Additionally, HIV testing has been integrated into the provision of
ence. A multitude of structural barriers prevent access to health
primary care services to increase HIV case finding among those
care and the regular supply of antiretroviral drugs. These
presenting to clinic because of illness, rather than solely focusing on
include the cost of medical care, drugs, lack of integration of
those who present for voluntary counseling and testing (VCT). Once
HIV testing with primary health care, tuberculosis, STI and
a patient is diagnosed with HIV, medications and monitoring tests are
women’s health services, and the difficulty on making
provided free of charge and transportation costs for follow-up
follow-up appointments during the long distances, family
appointments are covered to defray patients’ out-of-pocket expenses.
responsibilities, and the prohibitive cost of transportation.
Patients are given home-based adherence support from a network of
These factors affect the patient’s ability to take medications as
health workers who provide psychosocial support and directly
prescribed by the health care provider.
observed therapy. In addition, the neediest patients receive nutritional
This article discusses the interplay between access and
support. Following the description of the program is an approxima-
adherence in resource-poor settings and, based on our work
tion of the costs of these interventions and a discussion of their
in rural Haiti with poor communities, outlines strategies to
decrease barriers to access and to increase adherence to ART. Finally, based on our experience, we estimate the costs of
Key Words: adherence, antiretroviral therapy, community health
implementing these access and adherence support strategies in
workers, nutrition, resource-poor settings, user fees
(J Acquir Immune Defic Syndr 2006;43:S123–S126)
Adherence to antiretroviral therapy (ART) delays the
Since 1998, the nongovernmental organization (NGO)
progression to AIDS1,2 and the development of antire-
Partners in Health (PIH) has been providing ART to people
troviral resistance.3 Much of the medical literature on
through a charity hospital, the Clinique Bon Sauveur, in Haiti’s
adherence to ART is focused on measuring the individual
Central Department under the HIV Equity Initiative (HEI). In
patient’s ability to take ART as prescribed.4 The underlying
2002, the initiative was expanded into the public clinics in
assumption in much of this body of work is that once the
collaboration with the Haitian Ministry of Health (MSPP) and
medicines are prescribed, the patient has regular and reliable
now covers 7 public clinics, following more than 8000 HIV-positive persons, 2300 of whom are on ART. Most of thepeople served by the clinics are poor subsistence farmers or
From the *Division of Social Medicine and Health Inequalities, Brigham and
have been migrant workers in urban Port-au-Prince or the
Women’s Hospital, Harvard Medical School, Boston, MA; and †Zanmi
plantations of the Dominican Republic. The prevalence of HIV
is 5% among people attending the general clinics and 2%
Supported by Frank Hatch Fellowships (J. S. Mukherjee and H. Behforouz),
Partners In Health (F. Leandre), the Clinton Foundation (F. Leandre), the
among pregnant women. The lessons learned from the early
Eli Lilly Foundation (J. S. Mukherjee), and the National Institutes of
phase of the HEI was that the context of poverty factors such as
Health (L. Ivers, H. Behforouz, and J. S. Mukherjee).
lack of access to transport, food insecurity, and user fees for
Reprints: Joia Mukherjee, MD, MPH, Division of Social Medicine and Health
medical care, posed more significant barriers to adhering to
Inequalities, Brigham and Women’s Hospital, Harvard Medical School, 641
long-term therapy than a patient’s individual behavior. Several
Huntington Avenue, Boston, MA 02115 (e-mail: jmukherjee@pih.org).
Copyright Ó 2006 by Lippincott Williams & Wilkins
critical components were put into place to decrease these
J Acquir Immune Defic Syndr Volume 43, Supplement 1, December 1, 2006
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
J Acquir Immune Defic Syndr Volume 43, Supplement 1, December 1, 2006
barriers. First, all services and medications are provided free ofcharge to the patient. It has been documented by severalprojects that user fees are a significant barrier to seeking HIVtesting, obtaining laboratory evaluations, and attendingfollow-up appointments.10 Such cost sharing is detrimentalto long-term adherence, as data from Senegal11 and Botswana9indicate. In the HEI, user fees for services (visits andmonitoring) and all medications are waived entirely. Alltreatment is given free of charge (including not only ART butdrugs for opportunistic infections, family planning, andmedications for other conditions such as hypertension).
Second, HIV testing, treatment, and care are provided in
the context of primary care services. This is particularlyimportant and primary care clinics were revitalized byproviding essential medicines and paying stipends to MSPP
FIGURE 1. VCT uptake with introduction of HIV–primary health
staff in rural areas where patients routinely walk 4 or more
care integration: Lascahobas versus Cange. (From Walton D,
hours to seek care. Most of the people attending the
Farmer P, Lambert W, et al. Integrated HIV prevention and care
PIH/MSPP clinics come only when they are ill rather than
strengthens primary health care: lessons from rural Haiti.
to seek testing for HIV per se. In the context of primary health
J Public Health Policy. 2004;25:137–158; with permission.)
care, ill patients are screened for tuberculosis, treatable causesof diarrheal disease, sexually transmitted diseases, and otherconditions that may be associated with HIV. As part of the
therapy to HIV patients requiring ART. The development and
evaluation of the ill patient, HIV testing may be offered by the
activities of these workers have been described in detail
clinician, if indicated. This strategy, sometimes called ‘‘opt
out’’ or ‘‘routine offer’’ HIV testing, has been found to beacceptable in many settings, particularly when ART isavailable.12,13
The third aspect of the program to increase access and
The Zamni Lasante proposal written to the Global Fund
adherence to HIV treatment is an attempt to minimize the
to Fight AIDS, Tuberculosis, and Malaria and, later, the
significant out-of-pocket expenses. Studies from several
President’s Emergency Plan for AIDS Relief included the
settings have shown that costs such as payment for trans-
staffing and essential medications that would be needed to
portation to and from a clinic serve as a deterrent to ART
increase the provision of primary health services that would be
adherence. Patients attending PIH/MSPP clinic receive
expected for the population at each site. The improvement in
a monthly transportation stipend to attend follow-up appoint-
general health services, done with money for HIV scale-up,
ments. Transportation for emergency visits is also covered by
served to markedly increase the utilization of primary health
the program.14 Similarly, a lack of food has been associated with
care. With this context, we presumed the uptake of HIV testing
poor adherence to ART, and provision of food and micro-
nutrients has been shown to improve outcomes15–17 Many
To discern whether or not the packages of interventions
families throughout the developing world spend more than 50%
described previously (discontinuing user fees, integrating HIV
of their household income on food, and food production and
testing with primary health care, and providing transport fees
wage earning are adversely affected when an adult has
and other material assistance to patients) increased the overall
AIDS.18,19 Therefore, the PIH/MSPP program provides food
uptake of HIV testing and the use of health care services,
or cash transfers for food to the most vulnerable patients.
records were analyzed from the Lascahobas MSPP clinic from
The fourth aspect of the HEI program to support adher-
the beginning of the integrated PIH/MSPP program in October
ence and minimize barriers to access is the use of community
2002 through the end of 2003. The results of that analysis,
health workers. Community health workers perform active
which have been published elsewhere,22 are seen in Figure 1.
case finding for HIV and tuberculosis and provide a link
The number of VCT sessions at Lascahobas increased
between the patient, family, community, and clinic. Their daily
dramatically after initiation of the program and compares
role is to give psychologic support and directly observed
favorably with the rates reported from the referral center in
TABLE 1. Use of Services After the HIV–Primary Health Care Integrated Model of Care Was Implemented
MSPP–Zanmi Lasante Community Partnership
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
J Acquir Immune Defic Syndr Volume 43, Supplement 1, December 1, 2006
Antiretroviral Therapy in Resource-Poor Settings
TABLE 2. Approximate Costs of Adherence and Access Interventions in the PIH/MSPP HEI
Monthly visits to clinic, normal user fee $0.05 per month 3 12 months
Yearly CD4 cell count, radiographs, hemoglobin, liver function tests
Transportation fees for monthly clinic visit
Monthly transport fee $5 per month 3 12 months
Community health worker paid $500 per year for coverage of 5 patients
Cange Clinique, Bon Sauveur, where HIV VCT and full
a delay in the need for second-line ART. Second-line
primary health care services have been available since 1986.
antiretroviral medications, typically lopinivir/ritonovir, teno-
With this series of interventions, 40,000 HIV tests were
fovir, and abacavir, are not available as generic drugs and cost
performed in 2005. 2300 patients are on ART. Of the 1500
approximately $1500 US per patient per year. Thus, each year
patients who have been on ART for more than 1 year, fewer
the need for a second-line regimen is delayed, $13,000 US is
than 100 have died or had clinical or immunologic failure that
saved in antiretroviral costs. Additionally, patients are more
required a change to second-line ART, suggesting excellent
likely to remain healthy and out of the hospital if resistance is
adherence to ART and medical follow-up. Virologic monitor-
ing has not yet been performed in this population because of
In the United States, where adherence support is not
universal, approximately 50% of patients on a new anti-
Although there are many facets to the HEI adherence
retroviral regimen develop a detectable viral load (the precursor
and access interventions, some of the costs can be estimated.
of resistance) at the end of 1 year,23 but little has been done to
Table 2 outlines the cost of the various interventions. The
provide financial support for adherence programs.
transportation fee averages $60 US per patient per year. The
The challenge of administering long-term therapy in set-
cost of waiving the MSPP user fee for 12 monthly visits is $6
tings of extreme privation is significant. Although adherence
US per patient per year. The cost of waiving the cost for
to ART is much discussed in the public health arena, little has
ancillary tests (including a yearly CD4 cell count, radiographs,
been done to advocate for financial support of initiatives that
and routine laboratory monitoring tests) is approximately $20
have been shown to improve adherence. HIV program should
US per year. This standard package adds up to approximately
be rooted in sole primary health care to benefit a greater
$86 US per year per patient. Community health workers are
proportion of the community. HIV diagnosis, treatment, and
paid approximately $500 US per year and follow, on average, 5
monitoring should be provided free of charge in poor
patients, adding a cost of $100 US per patient per year. The
communities to ensure that drugs are taken properly and not
total cost of the adherence package is $186 US per year.
shared with family members or sold. Additionally, with the
Patients who have severe wasting and children with HIV
millions of dollars being invested in the scale-up of ART,
who have signs of malnutrition receive nutritional support. We
a lack of food security in the most heavily HIV-burdened
estimate that the cost of food for the patients who are
countries threatens HIV programs and the health and survival
economically and nutritionally the neediest is approximately
$450 US per year. This intervention is currently beingevaluated in partnership with the World Food Program.
1. de Olalla PG, Knobel H, Carmona A, et al. Impact of adherence and
highly active antiretroviral therapy on survival in HIV-infected patients.
Scale-up of HIV testing and treatment cannot be done
J Acquir Immune Defic Syndr. 2002;30:105–110.
2. Bangsberg DR, Perry S, Charlebois ED, et al. Non-adherence to highly
without improving access to primary health care and
active antiretroviral therapy predicts progression to AIDS. AIDS. 2001;15:
integrating HIV services with that context. Moreover,
adherence programs in resource-poor settings must work to
3. Bangsberg D, Hecht F, Charlebois E, et al. Adherence to protease
inhibitors, HIV-1 viral load and development of drug resistance in an
The low rate of treatment failure, indicated by few
indigent population. AIDS. 2000;14:357–366.
4. Lucas GM, Chaisson RE, Moore RD. Highly active antiretroviral therapy
deaths and few patients needing to change to second-line ART,
in a large urban clinic: risk factors for virologic failure and adverse drug
suggests that adherence to medical follow-up and antiretroviral
reactions. Ann Intern Med. 1999;131:81–87.
medication is excellent in the HEI. Monitoring of virologic
5. Steiner JF, Prochazka AV. The assessment of refill compliance using
response and for the development of resistance within the
pharmacy records: methods, validity and applications. J Clin Epi. 1997;50:105–116.
cohort of patients on ART is planned for this year. Additional
6. Harries AD, Nyangulu DS, Hargreaves NJ, et al. Preventing antiretroviral
work is planned to focus on measuring the impact and cost of
anarchy in Africa. Lancet. 2001;358:410–414.
individual interventions on clinic attendance and adherence. A
7. Frater AJ, Dunn DT, Beardall AJ, et al. Comparative response of African
first-line nevirapine-based generic antiretroviral regimen costs
HIV-1 infected individuals to highly active antiretroviral therapy. AIDS.
approximately $150 US per person per year. Our basic
8. Orrell C, Bangsberg DR, Badri M, et al. Adherence is not a barrier
package of support costs approximately $186 US. Investments
to successful antiretroviral therapy in South Africa. AIDS. 2003;17:
in adherence, if effective, should yield a return in the form of
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
J Acquir Immune Defic Syndr Volume 43, Supplement 1, December 1, 2006
9. Weiser S, Wolfe W, Bangsberg D, et al. Barriers to antiretroviral adherence
in HIV-infected women from Tanzania. Am J Clin Nutr. 2005;82:
for patients living with HIV infection and AIDS in Botswana. J Acquir
Immune Defic Syndr. 2003;34:281–288.
17. Fawzi WW, Msamanga GI, Spiegelman D, et al. A randomized trial of
10. Russell S. The economic burden of illness for households in development
multivitamin supplements and HIV disease progression and mortality. N
countries: a review of the studies focusing on malaria, tuberculosis and
HIV/AIDS. Am J Trop Med Hyg. 2004;71(Suppl 2):147–155.
18. Rutengwe RM. Identifying strategic interventions for improving
11. Laniece I, Ciss M, Desclaux A, et al. Adherence to HAART and its
principal determinants in a cohort of Senegalese adults. AIDS. 2003;17
settlement, South Africa. Asia Pac J Clin Nutr. 2004;13(Suppl):
12. Centers for Disease Control. Introduction of routine HIV testing in
19. Smith Fawzi MC, Lambert W, Singler JM, et al. Factors associated with
prenatal care—Botswana, 2004. MMWR Morb Mort Wkly Rpt. 2004;53:
forced sex among women in rural Haiti: implications for the prevention
of HIV and other STDs. Soc Sci Med. 2005;60:679–689.
13. Westheimer EF, Urassa W, Msamanga G, et al. Acceptance of HIV testing
Le´andre F, Mukherjee JS, et al. Community-based
among pregnant women in Dar-es-Salaam, Tanzania. J Acquir Immune
approaches to HIV treatment in resource-poor settings. Lancet. 2001;
14. Rowe KA, Makhubele B, Hargreaves JR, et al. Adherence to TB
21. Farmer P, Le´andre F, Mukherjee JS, et al. Community-based approaches to
preventive therapy for HIV-positive patients in rural South Africa:
the treatment of advanced HIV disease, introducing DOT-HAART. Bull
implications for antiretroviral delivery in resource-poor settings? Int J
World Health Organ. 2001;79:1145–1151.
22. Walton D, Farmer P, Lambert W, et al. Integrated HIV prevention and care
15. Ndekha MJ, Manary MJ, Ashorn P, et al. Home-based therapy with ready-
strengthens primary health care: lessons from rural Haiti. J Public Health
to-use therapeutic food is of benefit to malnourished, HIV-infected
Malawian children. Acta Paediatr. 2005;94:222–225.
23. Gross R, Bilker WB, Friedman HM, et al. Effect of adherence to newly
16. Villamor E, Saathoff E, Manji K, et al. Vitamin supplements,
initiated antiretroviral therapy on plasma viral load. AIDS. 2001;15:
socioeconomic status, and morbidity events as predictors of wasting
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Thai J Pharmacol Vol. 31, No.1, 2009 Original article P03 Effect of Ketoconazole on the Pharmacokinetics of Risperidone in Healthy Thai Male Volunteers Werawath Mahatthanatrakul1*,Nachanada Rujimamahasan1*, Wibool Ridtitid1,Mlinee Wongnawa1, Somchai Sriwiriyajan1 ,Jutima Boonliang2 ,Weerachai Pipatrattanaseree2 1Department of Pharmacology, Faculty of Science, 2Departmen
Fusiones y adquisiciones en el sector eléctrico: Experiencia internacional en el análisis de casos CEER Centro de Estudios Económicos de la Regulación Universidad Argentina de la Empresa Lima 717, 1° piso C1073AAO BUENOS AIRES, ARGENTINA Teléfono: 54-11-43797693 Fax: 54-11-43797588 E-mail: ceer@uade.edu.ar http://www.uade.edu.ar/economia/ceer (Por favor, mire las últimas páginas de est