December 9, 2004
Antiretroviral Therapy in Sub-Saharan Africa: Adherence Lessons From Tuberculosis and Leprosy
Summary: Declining drug costs and increases in international donor interest are leading to greater availability of antiretroviral treatment programmes for persons living with the human immunodeficiency virus in parts of sub-Saharan Africa. Ensuring adequate adherence to antiretroviral drug therapy is one of the principal challenges facing successful implementation in Africa, where 70% of the world's infected persons live. Tuberculosis and leprosy are two diseases of global importance whose control programmes can provide important lessons for developing antiretroviral drug adherence strategies. This paper examines various approaches used in tuberculosis and leprosy control which could help enhance adherence to antiretroviral therapy in resource- limited settings.
Keywords: drug adherence, antiretroviral therapy, human immunodeficiency virus, acquired immunodeficiency syndrome, tuberculosis, leprosy
Tuberculosis (TB) and leprosy are two infectious diseases of global public health importance, each with a history of successful control programmes developed in resource-limited settings. In each case treatment adherence has been maximized by strategies that have been refined over several decades and have much to offer, conceptually, to the development of antiretroviral therapy programmes.
In sub-Saharan Africa the human immunodeficiency virus (HIV) continues to threaten social, economic and demographic structures through deaths of working-aged adults and the increasing burden of orphans. Seventy percent of the 40 million individuals infected worldwide live in this region1. Current efforts to slow the epidemic have primarily emphasized prevention. In the past the high cost of antiretroviral (ARV) drugs, exceeding US $10,000 per person per year, limited access and effectively removed drug therapy from the list of priority approaches to HIV/AIDS control2. Recently, competition from generic drug suppliers and public pressure has made ARVs available for less than US$300/person/year. In addition, attitudes towards ARV use in Africa have changed due to the growing appreciation of the devastating human and economic impact of HIV/ AIDS and experience from successful pilot programmes in resource- limited settings3-4. Treatment is now also seen as a way of promoting the prevention agenda by encouraging counselling and testing.
Highly active antiretroviral therapy (HAART) regimens available in 2004 require a daily schedule of medications with significant potential side effects. Current knowledge suggests a need for life- long therapy with an estimated 95% adherence required to suppress HIV virus to undetectable levels and minimize development of drug resistance. Even in the industrialized world only 40-50% of patients are able to achieve optimal HAART adherence goals5,6.
The Global Fund to Fight AIDS, Tuberculosis and Malaria and the World Health Organization/UNAIDS 3 by 5 Initiative (treating three million people by 2005) in concert with other organizations and the pharmaceutical industry are now working to accelerate access to care, including ARV therapy, in resource-limited settings7-9. As a result, plans are being developed to scale-up ARV therapy rapidly in several areas of sub-Saharan Africa10. These developments highlight the importance and urgency of developing/identifying strategies to facilitate ARV adherence in resource-limited settings.
The greatest challenge in tuberculosis control is achieving high and sustained adherence to the antimicrobial regimen. Short courses are typically six to nine months in duration, but lifelong antibiotics have been recommended for profoundly immunosuppressed persons, especially those who are HIV-infected with low CD4+ T-cell counts. Critical to TB therapy success has been the use of 'directly observed therapy' (DOT). In this strategy, health care workers, or their surrogates, directly supervise patients taking anti-TB drugs. Initially introduced in India and Hong Kong, DOT made possible a shift in TB care from long-term hospital stays to ambulatory clinics where patients received directly observed intramuscular injections of streptomycin11. In the United States, despite a 20-30% treatment failure rate largely due to adherence problems, self-administered treatment was nonetheless the primary approach through the 1980s. DOT was considered unjustifiably expensive and, by some, an infringement on patient privacy and therefore, civil liberties11.
Attitudes towards DOT changed in the US when a marked increase in multidrug-resistant TB (MDR-TB) occurred in the 1990s. This was linked to many factors including: the HIV/AIDS epidemic, prison living conditions, substance abuse, increased immigration from highly endemic countries, treatment mismanagement and decreased funding for public health systems nation wide12. As a result, in 1993 the Centers for Disease Control and Prevention (CDC) recommended DOT for all patients in communities where completion rates were less than 90%12. DOT was justified as it was an effective tool in combatting high rates of treatment failure, drug resistance and disease relapse. Subsequent declines in TB incidence in the US suggest that the DOT strategy was critical as a cost-effective response to a re-emerging infectious menace12.
Variations of DOT strategies exist based on number of doses observed and degree of patient support. In DOT all doses are observed, in modified DOT (M-DOT), a portion of the doses is observed and the rest are self-administered. In enhanced DOT (E- DOT), every dose is observed and patients are linked to primary health care, psychiatric, and substance abuse services13. Controlled clinical trials are not available to test these strategies, but comparisons have been made between programmes that serve similar populations. Unsupervised strategies, i.e. without a DOT component, have completion rates of only 41-82%. With E-DOT, a 90% completion rate with less than 5% relapse contrasts with typical DOT completion rates of 85-87%13. The DOT strategy is credited with improving adherence in resource-limited settings, even for the extended courses required for the treatment of MDR-TB14. Directly observed therapy has proven more effective than behavioural/educational approaches alone because it recruits health care workers and/or community and family members to improve on 'patient-only' reliability15.
Both TB and HIV are highly stigmatizing infectious diseases that are over-represented globally in marginalized populations living in poverty. Principal differences are that TB treatment is curative in a 'short course' of less than one year, while presently available HAART is lifelong and limited to prolongation and improvement of quality of life13. Globally, 'active' TB cases are the primary target population for treatment, in sub-Saharan Africa, the primary target for HAART will likely be only a subset of infected individuals with advanced disease due to resource constraints. Dosing intervals for TB range from once daily to twice weekly while adequate regimens for HIV require dosing one to three times per day. These differences and the burden of lifelong HIV treatment suggest that HAART programmes will be more complex than short course DOT-TB programmes.
Today in sub-Saharan Africa people with HIV are referred to as the 'living dead' as were those infected with Mycobacterium leprae in medieval Europe16,17. Leprosy is found almost exclusively in resource-limited settings and is transmitted through inhalation or skin-to-skin contact. The sub-clinical (paucibacillary or tuberculoid) form of leprosy is not aggressive and has high rates of self-healing. The aggressive form (multibacillary or lepromatous) can result in severe disfigurement and disability. When drug treatment became available the stigma associated with the disease lessened enormously, even though it remained incurable and required lifelong therapy17,18. However, advances in therapeutics in the last two decades have resulted in the cure of an estimated 10 million people worldwide. Treatments of relatively short duration (six months for paucibacillary and 12 months for other forms) have resulted in a 90% reduction in global prevalence and a decreasing incidence from 12/10,000 in 1985 to less than 1/10,000 in 2000. These events have enabled the World Health Organization (WHO) to declare leprosy eliminated as a worldwide public health threat17,18.
Initially, all forms of leprosy were treated with dapsone monotherapy; given daily for five years in paucibacillary disease and lifelong for multibacillary. Its slow, weak bactericidal activity, coupled with poor adherence resulted in the development of resistant strains of M. leprae19. With the advent of multidrug therapy (MDT) in 1981 the WHO promulgated specialized vertical programmes focused on case finding and treatment with highly active anti-leprosy therapy. Programme success was attributed to early detection and treatment of new cases, consistent supply of free drugs (provided by the WHO), short duration of therapy, low treatment toxicity and low relapse rates19.
During the 1990s, as the number of cases declined, control was maintained by shifting leprosy care from vertical programmes to integration into established health care systems, typically at the district level. This allowed closer access to \the at-risk population, earlier detection and treatment, expansion of drug coverage, reduction in disability and improved cost- effectiveness17,18. Horizontal integration helped to de-stigmatize the disease both within communities and among health care workers. Community advocacy increased the public's awareness that drug treatment was provided free, was curative, and could reduce spread of infection20. Adherence improved as the length of drug protocols were shortened and simplified. Today, single-dose combination drugs are used for single lesion disease while treatment for paucibacillary leprosy has been condensed to two drugs for six months' duration. MDT for multibacillary disease has been reduced to 12 months from 24(19).
Historically, DOT strategies were prevalent in medically supervised 'leprosy colonies,' but DOT has not been a prominent feature of modern, outpatient leprosy control programmes. The reason for this is unclear, perhaps community health workers may not have been comfortable administering DOT because of potential stigma by association or leprosy patients did not want to attend public DOT clinics. Alternatively, an individual's motivation to comply with treatment for such a disfiguring disease may be so overwhelming that DOT was unnecessary.
An alternative to DOT, 'accompanied multidrug therapy' did evolve; patients were encouraged to bring a relative or friend ('buddy') as their 'accompanying' person to ensure that the drug regimen, possible side effects and the importance of uninterrupted treatment were understood20. Drugs were either dispensed at regular intervals or an entire course was provided at the start of therapy, thereby eliminating interruptions due to shortages or poor access20. To facilitate adherence, drugs were often dispensed in easy-to- understand blister packs. In addition there was no commercial market for leprosy drugs; HIV drugs, in contrast, are likely to be highly valued in the marketplace, creating an additional challenge.
Parallels exist between leprosy and HIV; both attack individuals in their most productive stage of life causing severe economic hardship and creating enormous stigma. Both are chronic diseases that disproportionately affect the poor and disadvantaged, and both require adherence to treatment regimens for optimal success - cure as the goal in leprosy and control of disease progression in HIV/ AIDS.
Adherence lessons for HIV/AIDS
Now that resources are becoming available, it is anticipated that a rapid scale-up of ARV therapy will soon get under way in sub- Saharan Africa. Strategies are needed to address the challenges of dealing with AIDS as a chronic disease, including drug adherence.
Based on the Haiti experience it is likely that HIV-infected populations in sub-Saharan Africa will be highly motivated to participate in antiretroviral programmes21. It is also to be expected that adherence will be challenging because of factors related to the treatment regimen: side effects, complexity and cost. Given its current life-long course, treatment fatigue and complacency will reduce antiretroviral adherence. Additional obstacles, especially prevalent in resource-limited settings include reluctance or inability to disclose HIV status due to social stigma, negative attitudes and beliefs about HAART, and possibly, difficulties in coping with the complexity of the drug regimen. Operational challenges include ensuring a stable, continuous lifelong supply of free or low cost drugs, and providing good quality counselling and knowledgeable, sympathetic medical teams21.
Distribution programmes in sub-Saharan Africa will need to adapt to local conditions and cultures and use combinations of strategies to enhance adherence. As with leprosy, vertical approaches to antiretroviral therapy may be appropriate initially but eventually programmes will need to integrate into the existing health care systems. Doing so will promote the prevention agenda, further de- stigmatize the disease, and help educate the medical profession and the public.
At diagnosis, the therapeutic course of action for HIV differs from TB and leprosy. Depending on the stage, treatment may not be initiated for many years until the patient becomes symptomatic or reaches a more severe level of immune dysfunction (e.g. CD4+T cell count
In prevention of mother-to-child transmission programmes in widely varying settings health care worker attitudes are vital in contributing to a woman's willingness to take antiretroviral therapies25,26. It is likely that an encouraging, well-informed health care worker cadre would be equally essential for success in prolonged HAART use.
Health care providers in resource-limited settings will need to assess an individual's motivation and commitment to adhere to chronic HAART before initiation of treatment. Conditions for enrolment into a HAART programme might include successful attendance at multiple follow-up visits, bringing a 'buddy' to the medical encounter, and consistent adherence with opportunistic infection prophylaxis. A patient with poor motivation would, if appropriate, be either deferred from programme entry or would be started on DOT. Once 'weaned' from DOT, if judged reliable, patients could be started on self-administered therapy under the supervision of a 'buddy', as in leprosy control. Those who fail to return at selected intervals or fail to reach target adherence rates would be candidates for further education, reinforcement or re-institution of a DOT programme. Strategic therapeutic interruptions for social and educational reasons may also be considered. A multi-disciplinary adherence team with medical, nursing and social services skills should be an integral part of any HAART programme, to ensure that a rise in high-risk behaviour is discouraged when HAART leads to greater patient mobility, optimism and sexual activity27. TB and leprosy require time-limited, sustained therapeutic adherence. In the case of AIDS, indefinite supervised therapy in the setting of this currently incurable disease is neither realistic nor sustainable. Patients will therefore need to acquire skills for long- term self-adherence and monitoring will need to continue after completion of the supervised programme.
As the benefits of ARV treatment become evident, it is anticipated that fear and stigma surrounding HIV/AIDS will lessen, more people will undergo voluntary counselling and testing and enrolment in treatment programmes will increase22. As approaches to ARV therapy evolve in sub-Saharan Africa, lessons from TB and leprosy programmes can be integrated into comprehensive adherence strategies.
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(Accepted 20 January 2004)
S E Reid MD MPH1,2, C A Reid RN MPH1,2 and S H Vermund MD PhD1,2
1 Centre for Infectious Disease Research in Zambia, PO Box 34681, Plot 5977 Benakale Road, Northmead, Lusaka, Zambia; 2 Division of Geographic Medicine, Department of Medicine, University of Alabama at Birmingham, Alabama, USA
Correspondence to: Dr Stewart Reid
E-mail: [email protected]
Copyright Royal Society of Medicine Press Ltd. Nov 2004