Introduction
Whereas the distribution of highly active antiretroviral therapy (HAART) in high-income countries has proved to be effective in drastically reducing the morbidity and mortality associated with HIV infection [1], HAART coverage in developing countries remains extremely low, with only 300 000 patients receiving antiretroviral drugs at the end of 2002 out of an estimated 5–6 million individuals who are in immediate need [2]. Several factors have, however, combined to make HIV treatment in these countries more feasible than before: continuing sharp reductions in the prices of antiretroviral drugs, commitments by governments in over 90 countries to develop and implement national AIDS plans [2], and the advent of the Global Fund to Fight AIDS, Tuberculosis and Malaria [3], along with funding commitments by the World Bank through its Multi-Countries HIV/AIDS Programme and bilateral programmes, including President Bush's call for US$15 billion over 5 years to fight AIDS in 14 of the most affected countries in Africa and the Caribbean. The goal of scaling-up access to antiretroviral drugs has been endorsed by the international community since the Declaration of Commitment unanimously adopted by the Special Session of the United Nations General Assembly in June 2001 [4]. World Health Organization (WHO) Director-General J.W. Lee has recently declared that the failure to deliver antiretroviral drugs to those who need it is ‘a global health emergency', and WHO and other United Nations organizations have committed themselves to expanding access to antiretroviral drugs to 3 million people in the developing world by 2005 (`3 by 5') [5].
The experiences of middle-income countries, such as Brazil [6], Chile [7] and Thailand [8], which have introduced antiretroviral drugs in their programmes of HIV/AIDS care, as well as pilot studies in low-income countries in sub-Saharan African and the Caribbean, including Côte d'Ivoire, Senegal, Uganda and Haiti [9–10], have demonstrated that access to these therapies is medically feasible. Economic arguments suggesting that access to antiretroviral drugs will never be cost-effective in comparison with the alternative use of resources for improving public health in developing countries are increasingly challenged, in parallel to the growing international awareness that the impact of the epidemic on economic and human development, and consequently the economic benefits of treatment, have been greatly underestimated [11]. Therefore, other arguments now come into the forefront in the current debates about scaling-up access to antiretroviral drugs. The risk of the dissemination of resistant viral strains as a result of suboptimal anti-HIV drug regimens, inadequate prescription or patients’ non-compliance with drug regimens raises an effective threat to public health that may mitigate the overall benefit of expanding antiretroviral drugs [12]. In this paper, however, we argue that referring to these issues of resistance and adherence as an argument to withhold or delay access to HAART in developing countries implicitly imposes a double standard of thinking that should be rejected: arguments that are not even considered in the north serve as dogma to limit access to treatment in the south. Moreover, such discriminatory double standards may weaken the practical capacity of healthcare professionals and public health authorities in developing countries to face the sociobehavioural issues and their associated risks of resistance, that are related to access to HAART in low-resource settings.
Adherence is required for a successful response to highly active antiretroviral therapy
Adherence and therapeutic success
A high level of adherence is required to obtain virological success for HIV-infected patients treated with HAART [13,14]. Although the minimum threshold of adherence necessary for the clinical effectiveness of HAART remains unclear, current data suggest that patients must take a high proportion (95% or more) of antiretroviral drug doses to maintain suppression of viral replication, that failure rates increase as adherence levels decrease [15], and that a lack of strict adherence is a co-factor in clinical progression to AIDS [16] and death [17]. The level of adherence required for sustained immunovirological responses differs, however, according to the time from initiation of treatment: initial adherence during the first months of HAART clearly needs to be 100%, whereas limited deviations from total adherence may have a lesser impact after the first year of HAART [18].
Adherence and resistance
Although non-adherence has often been argued to be the major cause of viral resistance [19], the relationship between adherence and resistance is bi-directional. Among treated patients who are not fully suppressed by HAART, adherent patients are indeed more likely to develop drug resistance [20,21]. When such patients switch to another regimen, success is associated with the patient's adherence to the new regimen and with the sensitivity of the virus to drugs of the new treatment regimen, as assessed by viral genotyping [22]. Among patients who are fully suppressed by HAART, adherent patients are less likely to develop virological failure associated with viral resistance [23].
Adherence is similar in developing countries than in developed countries
Drug access initiatives in Côte d'Ivoire, Senegal and Uganda have demonstrated the feasibility of the delivery and monitoring of antiretroviral drugs in the context of existing healthcare infrastructures in sub-Saharan African countries [9]. The referral centres of the initiatives, which include public, not-for-profit and private healthcare structures, have been able to provide adequate clinical expertise, laboratory facilities, drug storage and stock management for the use of antiretroviral drugs. The clinical, immunological and virological outcomes of HAART have been similar to those reported in Brazil [24] and high-income countries. Among recent evidence, the Senegalese prospective observational cohort study of feasibility, effectiveness, adherence, toxicity and viral resistance, as well as a once-a-day HAART study, has shown that the clinical and biological results are comparable to those seen in western cohorts, despite differences in the HIV-1 subtype distribution and a more advanced disease stage when treatment was initiated [25,26].
Evidence about adherence in developed countries
In Europe and north America, cross-sectional studies among HAART-treated patients have indicated that 20–40% do not fully take their regimens as prescribed at any point in time [27], and longitudinal studies suggest that no more than one third remain always 95–100% adherent to HAART during follow-up [28–30]. In the APROCO cohort of patients started on a protease inhibitor (PI)-containing regimen in France, the proportion of highly adherent patients is stable (approximately 55–60%) at each timepoint when adherence was measured. However, only 31% of patients were always highly adherent after 20 months of follow-up [28], and this proportion dropped to 26% after 36 months of follow-up. Finally, one out of four or five HAART-treated patients exhibit phenotypic and genotypic resistance to at least one PI [31]. These observations logically have not led to recommendations for withholding HAART in developed countries.
Evidence about adherence in developing countries
Despite scattered reports of drug-resistant HIV in Africa [32], which underscore the need for surveillance [33], there is no evidence currently that viral resistance is a greater problem in cohorts of patients treated in developing countries [34–37]. Studies from Botswana [38], Brazil [39], Senegal [40], and South Africa [41] show that, once financial barriers to access to drugs have been overcome, adherence to HAART can be as high, and sometimes even higher, among HIV-infected patients in developing countries as that generally observed in OECD countries. Experimental community-based programmes had already shown that clinics delivering primary care for individuals with HIV/AIDS in Uganda can successfully implement isoniazid prophylaxis for tuberculosis, with the majority of patients (75–80%) completing their full course of therapy and remaining fully adherent [42]. There is now evidence from pilot community-based programmes, in Haiti [10] and South Africa [43], showing that antiretroviral treatment can be successfully implemented and good adherence obtained within primary care settings delivering antiretroviral drugs to very low-income populations.
We would argue that the greater risk of the broad dissemination of resistant viruses may come from the unregulated availability of antiretroviral drugs that will inevitably occur in developing countries in the absence of structured efforts by public health authorities to improve access to treatment. Observations from Côte d'Ivoire and Senegal have provided evidence that drug resistance rates were higher in these countries before the introduction of organized drug access initiatives for antiretroviral drugs [36,37]. There have already been reports of unregulated ‘anarchic’ distribution of antiretroviral drugs in sub-Saharan Africa [44,45]. In Uganda, representatives of private business have expressed concerns about irrational prescriptions of antiretroviral drugs when made available through pure private channels outside the drug access initiative, and have strongly advocated in favour of the public regulation of their use [46].
Adherence should be monitored as antiretroviral drug programmes are being implemented
The United Nations’ ‘3 by 5’ goal implies a massive increase of HIV-infected patients gaining access to antiretroviral drugs. In such a context of scaling-up, previous results about the feasibility and effectiveness of HAART would have to be confirmed. Monitoring adherence to treatment should be one of the priorities of monitoring and evaluation, as well as of the operational research agendas that would be carried out alongside the implementation of antiretroviral drug delivery programmes in developing countries.
Adherence measurement
An estimation of adherence by the prescribing physician, as he interacts with the patient, has been shown to be a non-valid method [47,48]. Biomedical scientists sometimes argue that an ‘objective’ assessment can only be obtained through technical devices because, according to social scientists themselves, self-reported measures of medication adherence are subject to social desirability and recall bias [27]. They argue that pill counts performed by pharmacists delivering the drugs, electronic monitoring (MEMS caps) and bioassays measuring plasmatic concentration of drugs should become the ‘gold standards’ of adherence assessment [49,50]. Such techniques will, however, be difficult to implement on a routine basis in low-resource settings, and are also subject to bias and practical limitations [51].
The cross-validation of patients’ self-reports by pharmacological techniques, pill counts or MEMS caps has been shown to optimize the sensitivity of adherence measurement [52,53]. In practice, although self-report may underestimate non-adherence, especially when data collection is directly part of the patient/medical staff relationship, patients’ reports through validated self-administered questionnaires or face-to-face interviews [54] can be used for operational monitoring and evaluation. Patients’ self-reports have been shown to present sufficient validity for monitoring purposes, with an actual significant correlation between virological success and self-reported adherence in HAART-treated patients [13,14,28,55–57]. The lack of sensitivity of self-reports might be partly corrected if the questionnaire includes several questions referring to various time periods including the previous 3 or 4 days [54,58].
Adherence is a changing behaviour driven by patients’ experience
Until recently, the predominant approach among healthcare professionals has been focused on attempts to identify a priori patients most ‘at risk’ of exhibiting non-adherent behaviours [59,60]. This ‘predictive’ approach has sometimes provided justifications for denying or delaying access to antiretroviral treatment in certain patients who could be ‘suspected’ of being at high risk of non-adherence. In the case of HIV-infected injecting drug users in developed countries, it has been shown that such a-priori opinions were rather an expression of professionals’ adhesion to social stereotypes than an effective knowledge of patients’ actual behaviours [61–63]. The a-priori assumption that HIV-infected patients from resource-poor countries are a ‘special case’ with respect to adherence also refers to social stereotypes with potential discriminatory overtones [64], and is not supported by the existing evidence. The ‘predictive’ approach was based on the results of cross-sectional studies and did not take into account the dynamic aspect of adherence behaviour. Longitudinal studies have challenged this approach by bringing evidence that non-adherence cannot reliably be predicted on the sole basis of a few patient characteristics that clinicians could easily identify before the initiation of HAART [65].
In the French APROCO and Italian ICONA cohorts, short-term non-adherence was rather related to the evolutions that affected a number of psychobehavioural factors during the first 4 months of treatment, notably the impact of perceived toxicity associated with treatment [66,67]. Medically diagnosed adverse events have also been found to be a strong predictor of non-adherence [68]. Furthermore, adherence failure that may occur in the long-term is associated with the perception of long-time side-effects such as lipodystrophy [69] and with the deterioration of some dimensions of health-related quality of life [70,71].
A dynamic approach to adherence, continuously monitoring the impact of experience with HAART on patients’ daily lives, is needed for improving the management of HIV/AIDS care. Adherence results from a learning by experience and routinization process that may necessitate differential periods of apprenticeship among patients, according to socio-environmental conditions [27,65].
Adherence can be improved by sociobehavioural interventions
Results obtained from observational studies have encouraged the design of randomized trials to test whether sociobehavioural interventions could increase adherence behaviour. A psycho-educative intervention was shown to be effective in establishing adherence behaviour among patients starting HAART, and this was associated with a virological benefit [72]. Another study showed similar positive results on adherence and on virological outcomes in a sample of patients who were HAART treated [73], regardless of the timing and type of their antiretroviral therapy. In that study, patients who were randomly assigned in the intervention group were offered to participate in consultations given by a trained nurse. Other simple interventions targeting educational aspects have also been shown to be effective in increasing adherence despite the lack of virological benefit [74]. It is also important to underline that the use of simple and inexpensive adherence aids (pill boxes, timers) is associated with better adherence [75], and that the feasibility of using simple alarm devices has already been successfully tested in some African settings [76].
In developed countries, peer-driven interventions were also found to be effective especially among vulnerable groups such as injecting drug users [77]. The experience in central Haiti has suggested that directly observed therapy programmes developed for tuberculosis should be the model of choice for the provision of HIV medications in resource-poor countries in order to ensure adherence and prevent drug resistance. This experience clearly suggests that peer support at the community level is a useful tool to improve adherence to antiretroviral treatment in poor rural villages and neighbourhoods, sometimes located at long distance from the health centres delivering the drugs [10]. It should, however, not be interpreted as definitive evidence that witnessed dosing is superior to self-administered therapy [64]. Such generalization in favour of the systematic use of HIV directly observed therapy programmes, which would be a way to deliver treatment under some form of coercive control, may again mistakenly reflect stereotypes about a presumed incapacity of patients in low income communities to adhere to treatment.
Because healthcare professionals and non-governmental organizations in developing countries already have extensive experience in dealing with social and community support to HIV-infected patients, effective psychosocial interventions could probably be easily implemented in the context of antiretroviral drug programmes in low-resource settings to the extent that their design is adapted to the sociocultural environment.
A trade-off between minimizing costs and maximizing adherence?
WHO guidelines for antiretroviral drugs in resource-limited settings advocate the use of the least expensive options for first and second-line treatment [78]. Consequently, the most frequently recommended and prescribed HAART combinations in developing countries use non-nucleoside reverse transcriptase inhibitors (NNRTI), because such regimens are less expensive, easier to synthesize, and better tolerated with a lower pill burden. Although one observational study suggested that adherence may be higher when NNRTI are used instead of PI [79], it is still unclear whether deviation from total adherence has the same impact on virological response according to the class of drugs used.
On the one hand, pharmacokinetics studies of NNRTI show a long-lasting duration of plasma half-lives, suggesting that skipping a dose may have less detrimental impact on virological success [80]. On the other hand, the genetic barrier of NNRTI drugs is very weak, because a single mutation is able to confer viral resistance, contrasting with PI, for which several mutations are required to confer resistance [81]. Moreover, the high power of PI especially of lopinavir [82] is susceptible to minimizing the impact of skipping a dose when compared with other types of drugs. Prospective studies comparing the relationship between long-term virological success and adherence to PI or NNRTI should be conducted in developing countries to answer this question. This would be useful to clarify the difficult trade-offs between antiviral potency, cost and patients’ adherence, acceptability and tolerance when choosing the initial HAART regimen and switching regimens anytime it becomes necessary. Another unresolved question is raised by new therapeutic strategies, including structured therapeutic interruptions of which the benefits and risks are currently being assessed in clinical trials in the north and in the south [83,84].
In summary, the available data do not support the hypothesis that adherence to HAART and the incidence of resistance are a greater problem in the context of developing countries than it is in the industrialized world. Withholding treatment on the basis of such an assumption would mean setting a different ethical standard in the north and in the south. Monitoring adherence and viral resistance, as well as promoting psychosocial support to patients (notably in the initial phase of antiretroviral therapy), should be an integral part of the global package of activities provided for the scaling-up of access to efficient HIV care in developing countries.
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