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Doubts about DOT: antiretroviral therapy for resource-poor countries

Liechty, Cheryl A; Bangsberg, David R


Introduction: Directly observed therapy programs developed for tuberculosis (TB) have been suggested as a model for the provision of HIV medications in resource-poor countries in order to ensure adherence and prevent drug resistance.

Methods: Opinions were formed based on a review of scientific literature regarding the effectiveness of witnessed dosing in directly observed TB therapy programs, adherence to HIV antiretroviral therapy in resource-rich and resource-poor settings, relationship between adherence and HIV antiretroviral drug resistance, HIV viral load and risk of HIV transmission, and stigmatization concerns related to HIV and TB in resource-poor settings.

Results/conclusions: We suggest that the enthusiasm for HIV directly observed therapy programs is premature based on: equivocal evidence that witnessed dosing is superior to self administered therapy; mistaken assumptions that resource-poor countries are a ‘special case’ with respect to adherence; possible paradoxical impact of good adherence on HIV drug resistance; unproven efficacy of antiretroviral therapy in preventing HIV transmission; and potential stigmatization of daily antiretroviral dosing.

From the the Epidemiology and Prevention Interventions Center, Division of Infectious Diseases, and the San Francisco General Hospital AIDS Program, San Francisco General Hospital, UCSF, and The Academic Alliance, Kampala, Uganda.

Correspondence to D. Bangsberg, EPI Center, RM 301, Building 100, San Francisco General Hospital, 1001 Potrero Avenue, San Francisco, California 94110, USA.

Received: 8 July 2002; revised: 11 October 2002; accepted: 22 January 2003.

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Recent price reductions and the introduction of ‘off-patent’ antiretroviral medications bring new hope that HIV antiretroviral treatment may be more widely available in resource-poor countries where over 90% of HIV infections occur [1]. Many believe that poor adherence to antiretroviral therapy will accelerate widespread drug resistance in Africa, [2–4] and some believe that treatment should be delayed until we can ensure adherence [5]. Will ‘widespread, unregulated access to antiretroviral drugs in sub-Saharan Africa lead to the rapid emergence of drug resistant viral strains, spelling doom for the individual, curtailing future treatment options, and [lead] to transmission of resistant virus’, as has been suggested? [2] Based on these concerns, directly observed therapy programs for tuberculosis (TB) have been proposed as a model for the provision of HIV medications in resource-poor countries to ensure adherence and prevent drug resistance [2,6–11].

We believe that calls for directly observed therapy programs to provide routine HIV care are premature. Witnessed dosing has unclear efficacy in improving adherence and reducing HIV transmission, and may paradoxically promote drug resistance. Furthermore, requiring directly observed therapy may impose substantial barriers to antiretroviral access in resource-poor countries.

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Experience with directly observed therapy and TB

Enthusiasm for directly observed HIV therapy is based on experience with TB treatment [12]. The WHO began to promote Directly Observed Treatment, Short-course (DOTS) worldwide in 1993 [13]. DOTS is a multifaceted approach to TB control, where observed pill-taking is just one component. Community and local government commitment, case detection by sputum smear microscopy, stable drug supply, and standardized systems for case follow-up are essential activities of successful DOTS programs. The success of DOTS has been documented by observational studies in numerous settings [14–17].

While these observational studies suggest that DOTS programs achieve higher cure rates than historical controls, the impact of witnessed therapy has rarely been isolated from other components of the DOTS strategy. Only three randomized trials in resource-poor countries have compared witnessed dosing with self-administered therapy. A South African study found self-administered therapy was equivalent to clinic-based directly observed therapy [18]. In Thailand, directly observed therapy was superior to self-administered therapy in rural but not urban settings [19]. In Pakistan, clinic-based directly observed therapy, family administered directly observed therapy, and self-administered therapy were equivalent [20,21]. As has been argued elsewhere, the success of TB control programs depends more on the strength of diverse structural components, including reliable drug supply and distribution, than solely on witnessed dosing [22].

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Evidence that directly observed therapy improves HIV treatment outcomes

Experience with directly observed therapy to treat HIV is limited. Comparing two non-randomized cohorts of prisoners, Fischl found that 100% of those receiving directly observed therapy achieved viral suppression to < 400 HIV RNA copies/ml plasma, compared to 81% of those receiving self-administered therapy [23]. Encouraging rates of viral suppression have also been observed in a voluntary modified directly observed therapy program in Rhode Island [24]. Working in the context of a well-developed directly observed TB therapy program in Haiti, Farmer and colleagues have provided combination HIV antiretroviral therapy to 170 end-stage AIDS patients. In the absence of intensive laboratory monitoring, patients had excellent clinical responses to therapy and drug toxicity was rare. Individuals severely debilitated by the manifestations of end-stage AIDS have been able to return to work and care for their families [25].

While provocative, these initiatives do not demonstrate clear superiority of directly observed therapy to improve treatment outcomes. Retrospective chart review data reported by Hader suggests that directly observed HIV therapy in a residential treatment setting does not guarantee viral suppression in treatment-experienced patients [26]. Notably, viral load differences seen in the Fischl study did not translate into a difference in CD4 cell counts, a more reliable predictor of clinical outcome. The program led by Farmer has demonstrated remarkable success. However, it is impossible to know how much of the effect is due to the merits of community driven and supportive healthcare, stable medication supply and distribution, the medication alone, or witnessed dosing.

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Are resource-poor countries a ‘special case’?

Many believe that widespread poverty in resource-poor countries makes adherence a special concern for the provision of HIV therapy. USAID administrator Andrew Natsios has argued that Africans would be unable to adhere to antiretroviral regimens because they ‘don't know what Western time is,’ and ‘do not know what you are talking about,’ when asked to take drugs at specific intervals [27]. However, early data suggest that adherence to combination antiretroviral therapy is at least as good as in resource-rich settings. Two recent South African studies found that adherence ranged from 88 to 95% in clinical trial settings that included impoverished participants [28,29]. In two separate studies with virologic outcomes, 65 and 92% of individuals living in South African townships maintained undetectable viral loads, better than in many clinic cohorts in wealthy countries [30–32].

These early recipients of antiretroviral therapy may not be representative of the larger HIV-positive population in resource-poor countries. Nonetheless, there is no evidence to suggest that adherence will be less in resource-poor countries. Studies with objective adherence measures indicate that HIV-positive individuals in wealthy countries take roughly 70% of their medication [33–38]. There is nothing to preclude equal or better adherence in resource-poor countries. The relatively uniform distribution of poverty in resource-poor settings is unlikely to concentrate mental illness and substance abuse to the degree found in resource rich settings and may therefore have different impacts on adherence.

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Drug resistance

The public health imperative to prevent the emergence of multi-drug resistant TB has generated much of the enthusiasm for directly observed TB therapy [39,40]. Drug resistant HIV is cited as an analogous concern. Early predictions that non-adherence to HIV therapy would lead to drug resistance, however, were based on a small number of patients either on protease inhibitor monotherapy or without well-characterized measures of adherence [41–44]. Recent findings argue for a revision of this view. In a cross-sectional study of adherence and resistance to protease inhibitor combination antiretroviral therapy, protease resistance mutations were seen only in patients with 65–100% adherence. Resistance to nucleoside reverse transcriptase inhibitors was also more common in highly adherent individuals [37]. In separate reports, Walsh, Howard, Gallego, and Kuritzkes confirmed these findings [45–48]. These cross-sectional analyses have been confirmed with prospective analyses suggesting that the accumulation of new drug resistance mutations occurs most rapidly in patients with high levels of adherence but incomplete viral suppression, thus creating maximal drug pressure to select for and maintain resistant virus with impaired fitness [49]. Because only one of two daily doses are observed during modified directly observed therapy, perfect adherence is not assured and once daily directly observed HIV therapy may place patients in an adherence window of 80–90% that maximally selects for drug resistant virus [50,51]. Improving adherence from levels too low to create drug resistance to levels optimal for drug resistance will likely improve short-term clinical outcomes, but will, nonetheless, compromise a key public health rationale for this approach [52,53].

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Preventing HIV transmission

Observations by Quinn and colleagues indicate that the viral load is closely associated with the risk of HIV transmission in untreated serodiscordant heterosexual couples [54]. Preventing HIV transmission is the strongest rationale for making adherence interventions a requirement of therapy. However, the assumption that treatment will prevent transmission and that treatment with directly observed therapy will prevent more transmission than treatment with self-administered therapy has not yet been tested. Even if this assumption is correct, we still must face the question of why calls for directly observed HIV therapy are limited to sub-Saharan Africa, and not North America or Western Europe.

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Impact on individual rights

Hurtig and colleagues have discussed the negative impact of directly observed TB therapy programs on human rights [55]. Because HIV is more stigmatizing than TB and requires lifelong therapy, the impact of similar HIV initiatives on confidentiality and liberty would be greater. Daily meetings with a health worker will disclose HIV infection to family, peers, and employers. In many countries hardest hit by HIV, the stigma of this disease is at least as powerful, if not more so, than in wealthy nations [56]. Although the prospect of access to treatment may encourage individuals to determine their HIV status, the linkage of treatment to directly observed HIV therapy may paradoxically lower the use of counseling and testing services due to confidentiality concerns. In the USA, fears regarding HIV disclosure have led to a delay in treatment [57]. These issues underscore the potential impact of compromising privacy by linking treatment to directly observed therapy programs.

Stigma is created and modified by social context. Both the Haitian and Rhode Island directly observed HIV therapy initiatives were designed to minimize stigma. In Haiti, ‘accompagnateurs’ deliver therapy to emphasize the partnership between the community health worker and patient rather than the act of witnessed dosing. Large scale directly observed HIV therapy programs across international boundaries will have more difficulty addressing societal factors that reinforce stigma. Thus, the Haiti and Providence examples may become the exception rather than the rule.

In the case of TB, compromised confidentiality and restrictions in movement have been deemed an acceptable social price to pay for effective disease control. These concerns are similar in kind, but greater in magnitude for HIV than for TB. If we are to allow a curtailment of individual rights among those seeking HIV treatment, we must demonstrate that powerful public health benefits will follow from this approach.

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Balancing individual with population benefits

The appropriate role of directly observed HIV therapy will be decided largely by balancing the interests of individuals with those of populations. Directly observed HIV therapy may provide clinical benefit to some individuals. However, data to characterize this benefit are limited. The main attractions of directly observed HIV therapy are twofold. One is the perception that monitored medication dosing will prevent drug resistance. The other is that directly observed therapy may reduce transmission [58]. Thus, the perceived population benefits, more than individual gains, drive support for directly observed HIV therapy. These population benefits are the clearest justification for limitations on individual freedom and threats to confidentiality imposed by directly observed therapy. Yet, it is these benefits that are most in question.

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Concluding remarks

While we suggest restraint in the enthusiasm for directly observed HIV therapy as part of routine HIV care, we do not want to minimize the importance of developing effective and culturally appropriate voluntary adherence interventions to improve individual treatment outcomes globally. Adherence is both the greatest challenge and the single most important determinant of clinical outcome [59–61]. Optimal adherence strategies, including optional and voluntary directly observed HIV therapy, should be evaluated in several areas: virologic and immunologic outcomes, clinical outcomes, and transmission.

While the public health advantages of directly observed HIV therapy are in question, the impact on individual freedoms is not. We do not require direct observation of HIV therapy in resource-rich countries, and unless rigorous studies find important differences in adherence, there is no rationale for a different approach in resource-poor settings. Daily monitoring of adherence should either be optional and voluntary or confer an unequivocal public health benefit. The rationale for delivering HIV therapy to resource-poor countries is based on equity. We should not assume inequity with respect to people's ability to self-direct their medical care, including adherence to therapy.

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Sponsorship: Supported by The Doris Duke Charitable Foundation and NIMH #54907h,63,011,66654. The Epidemiology and Prevention Interventions Center and The San Francisco General Hospital AIDS Program are components of the UCSF AIDS Research Institute.

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HIV antiretroviral therapy; Africa; resource-poor; adherence; resistance; directly observed therapy

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