‘This is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.’
Winston Churchill, London, 10 November 1942
The year 2006 marked 25 years since the first description of AIDS and 10 years since the advent of the potent, combination antiretroviral therapy (ART) that has had such a dramatic success in reducing AIDS and prolonging the duration and quality of life of those living with HIV infection [1–4]. The first publications demonstrating dramatic reductions in the rates of AIDS and death in those receiving combination ART in the developed world occurred only 2 years before the International AIDS Conference held in Durban, South Africa in July 2000. This was the first occasion on which the bi-annual International AIDS Conference was held in a developing country heavily affected by HIV infection, and as a result it highlighted the glaring disparities between those with access to ART in developed countries and the plight of the great majority of the HIV-infected, who live in countries lacking the capacity to offer subsidized access to combination ART to their HIV-infected population.
As a consequence of this and other factors such as the work of the Joint United Nations Programme on HIV/AIDS (UNAIDS) in maintaining a dialogue with the pharmaceutical industry, and the creation of a dedicated HIV/AIDS department at the World Health Organization (WHO), a substantial effort was mounted to enable universal access to ART throughout the developing world . At a United Nations General Assembly Special Session convened in June 2001, the world's nations signed up to this commitment, and the creation of the Global Fund to fight AIDS, Tuberculosis and Malaria was endorsed as part of a Declaration of Commitment on HIV/AIDS . Two years later WHO and UNAIDS launched the joint ‘Three by Five’ programme, which aimed to place 3 million people on first-line combination ART by the year 2005. By the end of 2005, although the programme had not reached the hoped for 3 million people, it had managed to place at least one million people on therapy, and a momentum had been established. In April 2007 WHO/UNAIDS/UNICEF launched a progress report demonstrating that over 2 million people had access to ART in low and middle-income countries by the end of 2006. In the meantime we have seen more individuals placed on first-line ART as part of the US President's Emergency Plan for AIDS Relief (PEPFAR), as well as other access schemes promoted by non-governmental organizations such as Médicins Sans Frontières (MSF). As with any major humanitarian endeavour, however, the work has only just begun, and many challenges lie ahead. In this article we will review the progress in providing universal access to care for the HIV infected including first-line ART, identify and examine problems and lessons learned, and move on to discuss how clinical research must continue to form an integral element of efforts to provide access to second and subsequent combination therapies for those in whom first-line combination ART has failed.
Access to combination antiretroviral therapy in resource-limited settings
Guidelines for the provision of antiretroviral drugs in resource-limited settings make recommendations regarding first and second-line therapy . In the great majority of resource-limited settings, however, the reality is that only first-line therapy can be routinely offered on a subsidized basis. The issue of subsidization is important, as evidence suggests that the provision of medications free of charge is associated with a significantly increased probability of virological suppression in resource-limited settings [8–12]. First-line combination ART usually consists of (often fixed-dose combinations of) a non-nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside analogue reverse transcriptase inhibitors (NRTI) (NNRTI/2NRTI; e.g. nevirapine, stavudine and lamivudine or variations thereof, with zidovudine in place of stavudine, or with efavirenz in place of nevirapine). Recommendations for second-line therapy after the failure of first-line therapy usually include an HIV protease inhibitor (PI). In comparison with the cost of an NNRTI/2NRTI combination, however, therapy including a PI-containing regimen, even if administered as a single agent, is substantially more expensive, and therefore such regimens have generally been beyond the reach of most developing country programmes and individuals . We know from experience in the developed and developing world that a proportion of those accessing first-line therapy will inevitably begin to fail over time, and that a proportion will not be able to tolerate the therapy [14–17]. In the case of intolerance, simple substitutions within a class can often be made. Such substitutions are dealt with in the WHO resource-limited setting guidelines. The ‘4S’ principle of simple clinical management, i.e. when to start therapy, when to substitute for toxicity, when to switch for failure and when to stop form a useful framework for clinical decision making. As universal access to first-line ART continues, however, the problem of when to switch for failure, and therefore how to manage and provide access to second-line therapy and beyond, is becoming an increasingly pressing issue.
Assessing the performance of developing country antiretroviral access schemes
The provision of combination ART to HIV-infected individuals in developing countries was greeted in many quarters with scepticism, particularly around operational issues such as medication adherence . Outcomes from programmes to date have, however, demonstrated that adherence to therapy and treatment outcomes are at least comparable to those observed in the developed world . It is of significant concern that a body of evidence has already accumulated to suggest that many patients in these programmes are accessing combination ART too late in the course of their disease, and that as a result, there is substantial mortality in the first 3–6 months after commencing therapy [11,20–25]. The causes of the early mortality are not well defined, but are consistently seen in patients with late-stage disease (i.e. WHO stage III–IV disease) and low CD4 cell counts, suggesting that delays in the initiation of ART, waiting for recovery from opportunistic infections, new or undiagnosed opportunistic infections, severe immune reconstitution inflammatory syndromes, nutritional deficiencies or endocrine abnormalities may all play single or synergistic roles [26–29] (Fig. 1). Dedicated research into the causes of this early mortality must form a fundamental part of their future prevention and management. However, once this unacceptable early mortality is accounted for, the outcomes of such programmes are similar if not better than outcomes reported in developed countries. The largest access programme reported to date has an estimated crude regimen failure rate of 13 per 100 patient-years; (95% confidence interval 12–14) .
An intrinsic aspect of the process of making ART available in developing countries in which health systems and infrastructure are often weak has been the capacity to coordinate and integrate the delivery of ART with other healthcare services that are likely to identify and care for HIV-infected patients. For example, the intersection between HIV and tuberculosis has long been a major public health concern , and this has been recently amplified by descriptions of extensively drug-resistant tuberculosis among HIV-infected patients in KwaZulu-Natal Province, South Africa . Evidence exists that the availability of a tuberculosis clinic at the site of ART access reduces mortality . These descriptions have also highlighted deficiencies in laboratory infrastructure in developing countries, and have brought calls for an urgent focus on improved infrastructure as well as research into better diagnostics . Other operational issues that require research are myriad, and include the study of comparative adherence support mechanisms, the effects of task shifting, and the place of various new diagnostic technologies within ART roll-out programmes.
What are the current recommendations for second-line agents in resource-limited settings?
The current WHO adult and adolescent guidelines recommend the use of a PI once first-line failure has been confirmed (Table 1) . The guidelines do not make recommendations on the use of one PI over another because of a lack of comparative evidence. They advise that nelfinavir is an acceptable alternative choice as the PI component, although it has been shown to be less potent than a ritonavir-boosted PI . A survey that compared WHO recommendations with various national adult ART guidelines in WHO/UNAIDS ‘Three by Five’ target countries found a poor concordance for second-line recommendations (Fig. 2) .
In any case, despite the WHO recommendations, the relative costs of PIs, even the ritonavir pharmacokinetic ‘booster’ dose of 100 mg, are considerably greater than the cost of recommended first-line combinations, and unlike first-line agents there exist no WHO pre-qualified generic versions. Therefore, despite guideline recommendations few developing countries can offer state-subsidized access to second-line therapy for their HIV-infected populations. In addition, one of the four second-line NRTI recommended in the WHO guidelines (abacavir) is either not available in many developing countries, or is prohibitively expensive. In addition, the hypersensitivity reaction associated with its use in up to 8% of patients makes its widespread deployment in resource-limited settings problematic, and the allele (HLA-B*5701) testing that appears to reduce the hypersensitivity reaction risk is expensive and not routinely available .
Are there alternatives to the provision of standard protease inhibitor-based second-line regimens?
Structured treatment interruption
One rationale for trials investigating the use of structured treatment interruption was the potential for such an intervention to reduce the cost of the provision of combination ART. Unfortunately, despite apparent early promise for this strategy, a large, well-conducted study of structured treatment interruption conducted across diverse settings and using straightforward criteria for the initiation and cessation of ART (i.e. interrupt therapy if CD4 cell count > 350 cells/μl and recommence therapy if CD4 cell count < 250 cells/μl) found that treatment interruption was associated not only with an increased risk of AIDS-defining opportunistic infection and death, but, surprisingly, an increased risk of adverse events such as cardiovascular, hepatic and renal disease previously thought to be associated with ART (Fig. 3) . Smaller, underpowered studies of structured treatment interruption have produced divergent results; however, two studies conducted in resource-limited settings suggested that structured treatment interruption is associated with increased morbidity and HIV-related illness [37,38]. As a result, structured treatment interruption cannot be recommended.
In an effort to find ways to lower the cost of access to PI, attention has turned to the potential for reduced doses of ritonavir-boosted PIs to confer sufficient efficacy compared with the licensed doses. Published early phase data from the development of a number of agents suggest room for manoeuvre in dosing, and pharmacokinetic and clinical outcome data from the use of reduced doses of some PIs similarly suggest that reduced doses in particular settings may not only confer adequate efficacy, but possibly improved tolerability. A number of studies of reduced-dose ritonavir-boosted indinavir in both developed and developing world settings have demonstrated comparable efficacy and acceptable pharmacokinetics compared with the full dose, and a 96-week clinical outcome study performed in regional Thailand has reported outcomes at least equivalent to those observed in contemporary randomized trials [39–44]. Early phase dose-ranging studies of agents such as ritonavir-boosted lopinavir and atazanavir suggest that reduced doses provide similar efficacy and possibly better tolerability than the recommended licensed doses [45,46], and there is now discussion about the implementation of properly designed and powered randomized controlled trials of reduced-dose versus full-dose PIs to establish whether PI dose reductions may be an effective strategy for use in resource-limited settings.
Even in a situation in which a ritonavir-boosted PI may become affordable, however, the optimal standard NRTI backbone in those who have failed first-line ART remains unknown; another issue for which clinical research is needed to determine reliable answers. Cost is a further problem; the WHO guidelines recommend combinations of either didanosine or tenofovir combined with either abacavir or lamivudine. Whereas didanosine (enteric-coated formulation, US$103 per person per year (ppy) for 250 mg a day) and lamivudine (US$48 ppy for 150 mg twice a day) are available at low cost, abacavir is either unavailable or is expensive (US$456 ppy for 600 mg a day). Updated Médicins Sans Frontières pricing guidelines quote US$194 ppy for a 300 mg tablet of generic tenofovir and US$265 ppy for a generic, fixed-dose combination of tenofovir/lamivudine 300/300 mg, reflecting recent announcements from Gilead regarding non-exclusive licensing agreements with generic manufacturers in India to manufacture and distribute tenofovir, thereby making this recommended second-line NRTI agent more affordable for developing countries, pending WHO prequalification . To complicate matters further, at the time of finalizing this article for publication (8 May 2007), former US President Bill Clinton announced an agreement with two Indian generic manufacturers to produce a once daily fixed-dose combination of efavirenz/tenofovir/lamivudine at an estimated cost of US$339 ppy. This attractive combination includes drugs currently recommended for first and second-line regimens. Table 2 summarizes the current costs of relevant antiviral agents and fixed-dose combinations.
Ritonavir-boosted protease inhibitor monotherapy
There has recently been interest in the potential use of ritonavir-boosted PI as single agent therapy for the maintenance of control of HIV infection once this has been established with combination ART. Studies to date have used either ritonavir-boosted indinavir , lopinavir [48–50], or atazanavir [51,52], and have demonstrated reasonable efficacy for the maintenance of virological suppression. A randomized comparison in which ritonavir-boosted lopinavir monotherapy was compared with ritonavir-boosted lopinavir and zidovudine/lamivudine 300/150 mg twice a day in a fixed-dose combination found a better overall response to therapy in the standard triple-therapy arm . A recently published study that investigated the feasibility of ritonavir-boosted atazanavir as maintenance in patients with HIV-RNA levels less than 20 copies/ml for a minimum of 12 months was terminated prematurely according to preprotocol stopping rules because of five cases of virological failure in a total of 15 recruited patients .
Intriguingly, in those virologically failing therapy on regimens consisting of ritonavir-boosted PI monotherapy, or with those agents in combination with NRTI, resistance testing has failed to demonstrate primary PI resistance mutations [51,52,54]. This observation has been a puzzle, but recent investigations have begun to elucidate plausible alternative mechanisms of drug resistance in these situations . Whereas the use of ritonavir-boosted PI as monotherapy as a second-line option may be reasonable and would save cost, the best evidence suggests that efficacy is inferior to conventional combination ART . This still leaves open the question of whether two active nucleoside agents are necessary to provide durable virological suppression in second-line therapy. It is feasible that a single additional NRTI may be equally as effective as two NRTI, but there are to date no data to guide us.
New antiretroviral therapy classes
It is likely in 2007 that there will be at least two new classes of antiretroviral agent licensed for use in developed countries: HIV integrase inhibitors (raltegravir; Merck and Co., Whitehouse Station, New Jersey, USA) and HIV entry inhibitors (maraviroc; Pfizer, New York, USA). The emergence of these agents may well revolutionize the use of ART in the next few years. Whereas in the past the use of such new agents in developing countries may have been considered impossible, at least in the short term, the assumptions underlying such attitudes are now increasingly coming under question. There is therefore interest in implementing research trials of such agents in resource-limited settings, not simply to provide sufficient research subjects to amass data for use in the developed world, but to inform decision making directly about the clinical management of HIV infection in the developing world. It is not unreasonable to believe that if these agents demonstrated improved safety and tolerability compared with currently available antiretroviral agents, then their implementation, even at relatively high prices, may translate into greater simplicity, efficiency and savings in the long term.
Whatever the case, there can be no effective answer to questions about the use of dose-reduced boosted PIs, optimal NRTI backbones, emerging new classes and other unknowns in the absence of properly conducted clinical research designed to provide definitive answers. These examples emphasize the need to merge the process of providing access to ART with a clinical research agenda that helps us determine what defines best practice.
How can clinical research contribute to our understanding of best practice for second-line antiretroviral therapy in developing countries?
The story of the evolution of HIV prevention, treatment and care over the past quarter century is one of the great achievements in human health. The success of the current approaches to the pathogenesis, treatment and prevention of AIDS is in large part attributable to committed and sustained efforts in basic and clinical science that have provided the evidence on which our contemporary approaches to HIV prevention and care are based. As a result of this continuous scientific effort, we probably now know more about the relationship between HIV, its human host, and the environmental determinants of infection than any other disease process . The great bulk of scientific knowledge and evidence regarding HIV and the optimal therapy of HIV infection has been gathered in the developed world. For the past 10 years or so, however, efforts to conduct basic and clinical research relevant to developing world settings have been made. The HIV Netherlands Australia Thailand Research Collaboration has, for example, since its establishment in 1996, conducted a high-quality, locally relevant research agenda that has informed treatment responses and policy, provided an environment that provides academic education and training that helps develop local research expertise, enabled patient access to care including effective combination ART, and developed a model of routine patient management . From this and other experiences in the developing world, we have learnt much about differences in particular populations with regard to important endpoints, such as adverse drug reactions and antiretroviral pharmacokinetics, pharmacogenomics and pharmacodynamics [58–60].
Since the turn of the 21st century there has been a welcome focus on improving access to HIV prevention and care in the developing world. Programmes such as the WHO/UNAIDS ‘Three by Five’ initiative, the Global Fund to fight AIDS, Tuberculosis and Malaria, the US President's Emergency Plan for AIDS Relief and the World Bank's Multicountry HIV/AIDS programme for Africa have all helped to increase the profile of the devastating problem of HIV in developing countries, and have committed funds in an attempt to intervene. The most effective interventions for HIV prevention and care in developing countries are, however, to a large extent, unknown, as are the specific circumstances that inhibit access to HIV testing, prevention and care . Although there is clear evidence of substantial increases in the numbers of individuals gaining access to ART, various studies inform us that clinical outcomes are not at the level that we would now expect for those accessing treatment in developed countries. In addition, the history of HIV prevention in developing countries has provided only limited success stories. The major initiatives and programmes focus their attention on the promotion of ‘best practice’ and ‘proven and effective interventions’. Unfortunately, however, none commits any portion of their funds to clinical research that may help determine exactly what these best practices and interventions might be.
We believe that the only means by which we can better understand and therefore better intervene in the prevention and treatment of HIV infection in developing countries is to promote a sound, scientifically based understanding of these issues, which must be done in parallel with the current efforts to improve access to HIV prevention and care. Such research should not be seen as an additional burden on the various funding bodies but, on the contrary, should be seen as the major means by which we can refine our understanding of what is, and what is not, effective. Additional benefits would include the transfer of knowledge and capacity to individuals within the affected communities, the establishment of research partnerships and programmes to promote a deeper understanding of HIV and associated infections, as well as training in basic and clinical research and technology transfer. Such partnerships and the associated opportunities might also help retain locally trained health personnel, and therefore help to solve one of the most vexing contemporary problems of HIV prevention and care in the developing world [62–64]. We therefore call for the major HIV funding bodies to reconsider their positions on funding for research into HIV prevention and care in developing countries. We believe that without such funding we will be destined to continue repeating mistakes that, in the absence of appropriate research, we cannot know we are committing in the first place.
In conclusion, we are approaching the end of the initial phase of the attempt to provide global, universal access to HIV care including ART. The effort has met with considerable success. In order to continue that success we must ensure that we do not forget that it has been underwritten by a major, sustained scientific endeavour. This enterprise must be continued in order that we may improve the delivery of care and treatment to HIV-infected individuals in the developing world. One of the next major challenges is to find the will and the funding to open up access to, and promote the clinical research of, second-line combination ART. Given the successes to date, we believe that this problem can, and will, be surmounted soon.
Disclaimer: The production of this special Supplement was supported by the World Bank, the Joint United Nations Programme on HIV/AIDS and the World Health Organization. The findings, interpretations and conclusions presented in this paper do not necessarily reflect the views of these institutions or their constituent agencies or governments.
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