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The history of antiretroviral therapy and of its implementation in resource-limited areas of the world

Vella, Stefanoa; Schwartländer, Bernardb; Sow, Salif Papac; Eholie, Serge Pauld; Murphy, Robert L.e

doi: 10.1097/QAD.0b013e32835521a3
Special Reviews

HIV/AIDS not only represents the most severe epidemic in modern times, but also the greatest public health challenge in history. The response of the scientific community has been impressive and in just a few years, turned an inevitably fatal disease into a chronic manageable although not yet curable condition. The development of antiretroviral therapy is not only the history of scientific advancements: it is the result of the passionate ‘alliance’ towards a common goal between researchers, doctors and nurses, pharmaceutical industries, regulators, public health officials and the community of HIV-infected patients, which is rather unique in the history of medicine. In addition, the rapid and progressive development of antiretroviral therapy has not only proven to be life-saving for many millions but has been instrumental in unveiling the inequities in access to health between rich and poor countries of the world. Optimal benefits indeed, are not accessible to all people living with HIV, with challenges to coverage and sustainability in low and middle income countries. This paper will review the progress made, starting from the initial despairing times, till the current battle towards universal access to treatment and care for all people living with HIV.

aDepartment of Pharmacology and Therapeutic Research, Istituto Superiore di Sanità, Rome, Italy

bEvidence, Innovation and Policy Department, UNAIDS, Geneva, Switzerland

cDepartment of Infectious Diseases, Fann Hospital University of Dakar, Senegal

dDepartment of Infectious Diseases, Treichville Hospital University of Cocody, Abidjan, Côte d’Ivoire

eCenter for Global Health, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

Correspondence to Stefano Vella, MD, Director, Department of Pharmacology and Therapeutic Research, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. Tel: +39 06 49906015; fax: +39 06 49902012; mobile: +39 3482650598; e-mail: stefano.vella@iss.it

Received 8 April, 2012

Accepted 23 April, 2012

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Early history of antiretroviral therapy

Two years following the initial description of the AIDS in 1981 [1,2] and after the isolation, in 1983, of HIV-1 [3,4] huge efforts started in an attempt to control the virus.

The initial years were characterized by treatment failures and disappointments [5]. However, by 1985, a diagnostic antibody test was developed [6] and clinical trials began with direct acting dideoxynucleoside reverse transcriptase inhibitors (NRTIs), the first being azidothymidine (AZT) [7,8]. By 1987, treatment with AZT was found associated with a greater survival at 24 weeks [9], but this benefit was short-lived; by 48 weeks, survival benefits were no longer observed [10–14]. Despite its limitations and side effects, AZT, later called zidovudine (ZDV), was approved in 1987 for use in patients with advanced HIV. In short succession, three other NRTIs were approved for use in HIV-1 infection: zalcitabine (ddC), didanosine (ddI) and stavudine (d4T). Each had its own particular toxicities and none is widely used today. To avoid the toxicity profiles, attempts were made to administer drugs sequentially and to alternate therapies [15]. These approaches were not very effective and, clinically, patients continued to fare poorly except for a reduction in some of the rates of adverse reactions.

Combination NRTI therapy was the next approach taken with somewhat encouraging results. When ZDV was administered with ddC or ddI, the impact in terms of CD4+ lymphocyte increase and survival was better. Results, however, were still not durable [16,17] and, despite the limited clinical benefit, tolerability remained poor. An unfortunate effect of the dideoxynucleoside class is that these drugs also inhibit cellular DNA polymerase-α and mitochondrial polymerase-λ which is dose-dependent. Relatively safer treatments were provided with lower, less frequently administered doses which resulted in better tolerability and safety. In the case of ZDV, the major adverse events are neutropenia, anemia, myositis, nausea and vomiting. It was generally believed at the time that ZDV as a treatment agent would not be used for a long time as it would soon be replaced by more effective and safer alternatives. This of course was not to be the case, and the survival rate and the quality of life of patients remained for a long time quite poor.

A step forward occurred when the cytidine analog lamivudine (3TC) was developed. Whereas monotherapy was associated with the rapid development of resistance, the drug was synergistic with many of the other nucleosides including ZDV and was relatively well tolerated [18]. In addition to combining lamivudine with ZDV, it was also given successfully with d4T; however, none of the dual nucleoside combinations, when administered without a third drug, could durably control HIV infection. Thymidine analogs were also progressively dismissed because of their toxicities. However, the most important result obtained with the initial use of NRTIs was the demonstration that the treatment of HIV-infected pregnant women substantially decreased HIV transmission to the newborn. Today, antiretroviral therapy to prevent mother-to-child transmission is based on triple drug combinations as the global standard, but single–double drug treatment was also used initially and represented an important proof of concept [19].

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The new era of antiretroviral therapy

The next advance in HIV therapeutics came with the development of drugs from different classes: non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors, both classes having a direct effect on HIV. Nevirapine, the first NNRTI to be approved in 1996, has had a long-lived history and is still in use in many parts of the world. Resistance develops quickly if nevirapine is administered as a monotherapy or as an add-on drug to a failing regimen; however, when given as part of a three-drug regimen in which two nucleosides are also administered, the combination is quite effective. The first trial to demonstrate this effect was the Italy, Netherlands, Canada, Australia Study (INCA Study), which showed that triple combination was completely suppressive and superior to either of the dual nucleoside therapy control arms [20].

The first protease inhibitor to be approved was saquinavir in 1995. Its formulation was a hard gel capsule which had very poor bioavailability. Because saquinavir and many of the other protease inhibitors are metabolized by the cytochrome 3A4 isoenzyme of the CYP P450 system, a combination of saquinavir with ritonavir, another protease inhibitor and a potent inhibitor of CYP 3A4, was attempted. Although quite effective, tolerability was compromised [21]. Eventually, high-dose saquinavir combined with low-dose ritonavir helped to set the standard for pharmacologically enhanced protease inhibitor therapy which represents the recommended usage for all protease inhibitors today.

Indinavir is a protease inhibitor, approved in 1996, which substantially changed the treatment landscape, ushering in the highly active antiretroviral therapy (HAART) era. Approval came quickly, following the results of several large trials [22] and one relatively small but very important study, Merck 035. In this 97-patient study, the arm that contained indinavir, ZDV and lamivudine, the triple combination, had sustained HIV suppression throughout the study and beyond [23]. Despite this milestone advance, indinavir was a relatively difficult drug to take requiring thrice-daily administration without food. Side effects were common including nephrolithiasis and metabolic disturbances, including lipodystrophy, with its characteristic abdominal fat accumulation. Side effects and unfavorable pharmacokinetics, coupled with approval of more convenient and better tolerated protease inhibitors [24], eventually led to the decline in indinavir usage.

During the Vancouver AIDS Conference in 1996, the successful impact of triple combination therapy was reported. The result was a consequence of not only the availability of new drugs from different classes but also of: the understanding that HIV infection, even during the clinically latent phases of the disease, is characterized by an important viral turnover with continuous high-level virus replication [25–28]; the demonstration that measured concentration of HIV in plasma (the ‘viral load’) was predictive of the subsequent risk of disease progression and death [29]; and the elucidation of the molecular, functional and clinical impact of drug resistance to antiretroviral drugs [30,31]. All these advancements supported the critical need to fully suppress HIV replication in order to stop virus mutation. It also highlighted the essential need to monitor treatment by measuring plasma HIV load [32].

Within a few short years after the publication of the first International AIDS Society–USA recommendations for antiretroviral therapy [33], a dramatic decrease in morbidity and mortality associated with expanded use of protease inhibitor-containing regimens was described in the probably most cited study in the history of antiretroviral therapy [34]. Indeed, for the first time, this ‘new’ disease, which had become the leading cause of death of young persons in the industrialized world, was turned into a chronic manageable condition. However, not without costs. The newly developed therapies were associated with important short, mid and long-term toxicities. Quality of life of patients on the combination treatments available at that time – requiring multiple daily dosing and a large number of pills – remained poor for quite some time.

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The past decade

Over the past years, progress in antiretroviral therapy has been characterized by the availability of new potent, and relatively safer antiretroviral drugs belonging to old classes (NRTI, NNRTI and protease inhibitor) [35,36] and to new classes (entry/attachment inhibitors and integrase inhibitors) [37–41] (Table 1). Moreover, independent strategic clinical trials and long-term cohort studies [42–45] have been conducted to complement those performed by the pharmaceutical industry for registration purposes. These studies, with the competent contribution of the community of people living with HIV/AIDS (PLWHA), oriented research efforts and influenced the accelerated regulatory approval of many new drugs.

Table 1

Table 1

Even the once very difficult ‘salvage’ strategies for patients with multiple failures have been progressively more successful. For example, protease inhibitors, lopinavir initially and, more recently, darunavir, and the integrase inhibitor raltegravir, have had a dramatic impact on treatment of patients who have failed a prior regimen [46–48].

As observed in initial studies, the early years of HAART were characterized by some unsuccessful approaches. These included trying to make ‘strategic interruptions’ of therapy with the hope of reducing the burden of drug toxicities [49], or maintaining patients (because of the lack of alternative regimens) on previously used drugs, an approach taken hoping for a reduced ‘fitness’ of the virus. Attempts also included the use of combinations of four drugs, which proved only more toxic but not more efficacious.

Single tablet, fixed-dose, once-daily combinations [50–52] have subsequently become available, and have been associated with even higher treatment success rates, mainly because of improved adherence.

Different ‘standard-of-care’ initial regimens are currently available in industrialized countries, and are mainly composed of a nucleoside/nucleotide dual ‘backbone’ and a third drug, that can be chosen among four different classes: NNRTI, protease inhibitor, integrase inhibitors or CCR5 inhibitors. All antiretroviral regimens are today comparably potent, convenient and with relatively good tolerability. Individual choices are influenced by factors such as patient characteristics, disease status, presence of pre-existing HIV mutations and virus genotype. Recent innovative uses of antiretroviral drugs include class-sparing options, and simplification strategies which may increase tolerability, improve adherence and possibly reduce costs [53–58].

Milestones in the progressive development of antiretroviral therapy (Table 2) have translated into improved life expectancy [59–63], the exception being patients with low baseline CD4+ lymphocytes at the start of therapy. These patients unfortunately represent today a rather consistent proportion of the HIV population, both in high-income and limited-resource settings.

Table 2

Table 2

One important question which still remains unanswered is the best timing to initiate therapy. Numerous large cohort studies have already demonstrated that treating patients earlier is associated with significant survival and clinical benefit. Guidelines for starting therapy have progressively shifted away from the initial threshold of ‘less than 200 CD4+ lymphocytes/μl’ from the early post-Vancouver era (mainly justified by therapy induced toxicities and complexities). Today, WHO guidelines recommend the start of treatment at less than 350 CD4+ cells/μl and in many industrialized countries national guidelines now recommend treatment to begin at less than the 500 CD4+ cell/μl level [64]. Most recently, a debate has started to consider treatment at the time of HIV diagnosis, irrespective of CD4+ cell levels, highlighting the potential benefits of early treatment on patient health and on the transmission of the virus [65,66]. This strategy has taken on the term ‘test and treat’.

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Challenges to the recent therapeutic approaches

With the augmentation of patient's life expectancy, new challenges start to emerge, including the increased frequency of non-AIDS defining comorbidities [67,68]. Cardiovascular and metabolic diseases, including diabetes, bone disease, non-AIDS-defining cancers, renal impairment, neurocognitive deficits were noted, possibly associated with antiretroviral therapy toxicities [69] but also with the diffuse ‘inflammatory’ condition due to HIV infection, as well as to the observed accelerated aging of the HIV-infected patients [70,71].

Additional foreseen progress in antiretroviral drug development in the coming years (Table 3) may allow further perfection of the current antiretroviral strategies and the overall care of HIV-infected persons. Potent antiretroviral combinations, together with innovative therapeutic interventions targeting HIV reservoirs, are currently being studied in attempts to eradicate HIV and cure the disease [72–77].

Table 3

Table 3

The progress made in HIV pathogenesis and pharmacology over the past 30 years has been exceptional. The inequities in access to HIV care and treatment between rich and poor countries of the world. The inequities will be reviewed in the following section of this article.

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The history of access to antiretroviral therapy in resource-limited settings

In industrialized countries, rapid uptake of antiretroviral treatment gave rise to the so-called ‘Lazarus syndrome’, with treatment almost miraculously restoring the health of many people terminally ill. However, at an average cost of up to US$ 20 000 per person per year, the vast majority of PLWHIV outside the industrialized world could not have access to such therapy. Delivery of complex treatment regimens needed advanced health systems, and the cost exceeded by several orders of magnitude the average overall health budgets of most resource-limited countries.

These apparently ‘insurmountable’ obstacles allowed the world community to ignore the inequity between rich and poor countries with regard to treatment access: treatment as an essential part of a comprehensive response to HIV/AIDS in developing countries was viewed as impossible.

Important milestones, however, have been reached in the long and winding road towards universal access to therapy (Table 4).

Table 4

Table 4

In 1995, Peter Piot of the Joint United Nations Programme on HIV/AIDS (UNAIDS), in the pre-HAART era, initiated a dialog with the pharmaceutical industry to work towards delivering antiretroviral therapies at affordable prices in poor nations. This action was crucial not only because different companies produced different components of the drug cocktails, but also because antitrust laws made discussion of pricing schemes between pharmaceutical companies impossible. As a consequence, the UNAIDS Drug Access Initiative was launched in December 1997, and the first patients received drugs in Uganda and Cote d’Ivoire in early 1998.

In 1999, when the Drug Access Initiative had been in operation for almost 2 years, awareness was growing that antiretroviral drugs could be obtained at a very low price. In Uganda, one of the treatment centers started receiving generic supplies from India, and the Drug Access Initiative in Cote d’Ivoire began sourcing generic ZDV from Spain. The experience of the Brazilian AIDS control program with local production of antiretrovirals at lower cost added evidence to the efficacy of generic drugs.

The Accelerating Access Initiative was launched in May 2000. This effort included the pharmaceutical companies, UNAIDS, WHO, the World Bank, United Nations International Children's Emergency Fund, and the United Nations Population Fund. As a consequence, the price of first-line treatment decreased to around $1200 per year. This initiative stimulated the development of treatment access plans in 39 countries, all of which concluded individual pricing agreements with the companies.

The 13th International AIDS Conference in Durban in July 2000, the first to be held in Africa, focused the world's attention on the continent most seriously affected by the AIDS epidemic. Brazil had been a pioneer among developing countries in providing treatment as early as 1996 and small-scale projects by nongovernment organizations – such as that of Partners in Health in Haiti – also showed promising results. Durban started a worldwide movement for treatment access focused directly on the needs of the world's poorest countries [78]. In April 2001, African leaders came together during the first African Summit on HIV/AIDS, Tuberculosis and Other Infectious Diseases in Abuja, Nigeria. In his opening address, the United Nations Secretary General, Kofi Annan, proposed the creation of a Global Fund, dedicated to the battle against HIV/AIDS and other infectious diseases. Among five priorities for action, he concluded that ‘…we must put care and treatment within everyone's reach’.

The first edition of the WHO treatment guidelines for resource-limited settings was published in March 2002 (including the first mention by WHO of the 3 by 5 target – 3 million treated by 2005). These guidelines presented simplified schemes for treatment and clinical diagnosis, including reduced laboratory support.

The Board of the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFTAM) held its inaugural meeting in January 2002. The WHO prequalification program of generics and the Global Fund's decision to make generic antiretrovirals eligible for funding were important milestones. In addition, countries responsible for procurement used competitive mechanisms leading to increasing market penetration of antiretrovirals, with prices progressively decreasing from 2002 to the present day. The prospect of substantial new resources for countries’ AIDS programs, together with the preparedness of drug companies to further reduce prices, held enormous promise [79]. In April 2002, WHO took the important step forward by adding 10 antiretroviral drugs to its List of Essential Medicines.

Another breakthrough came in 2003 when fixed-dose combination therapies – reducing the number of pills per day from 10–15 to as few as two – gave generic drugs a competitive edge over their brand-name counterparts for reasons other than price, which went down to 150–250 US$ per year for the first line regimens.

In 2003, US President George W. Bush announced that the US government would contribute US$15 billion to the worldwide AIDS response over the next 5 years. Treatment formed a major component of the initiative, explicitly targeting ‘to support treatment for two million HIV-infected people, to prevent seven million new HIV infections and to support care for 10 million people infected and affected by HIV/AIDS, including orphans and vulnerable children’: the Presidential Emergency Plan for AIDS Relief (PEPFAR) was thereby established.

Just afterwards, the WHO launched the ‘3 by 5’ program, in order to further speed up access to ART in resource-limited settings. The proposed guidelines focused on the first-line therapy with two NRTI and one NNRTI. These are simplified drug regimens with fixed-dose combinations, easy to use and to prescribe at the primary level by doctors and nurses.

Today, according to UNAIDS, more than seven million PLWHIVs have access to ART. This success was considered unattainable just a few years ago. However, many challenges remain. These include late initiation of therapy with subsequent impaired response and the need to address active opportunistic infections, high tuberculosis (TB) coinfection, limited access to second and third-line treatments, insufficient use of viral load monitoring to detect early failure, limited access to diagnostic and treatment of long-term complications and, overall, limited health system infrastructure and healthcare human resources. In fact, health professionals dealing with ART were initially only senior doctors and infectious diseases specialists. The current practice in the resource-limited countries is that nurses, health officers, lab and pharmacy technicians have taken over.

Cumulative mortality at 12 months in adults initiating ART in low-income countries ranges between 8 and 26%. The main factors associated with a risk of early mortality are immunosuppression, severe malnutrition, late-stage disease, presence of active tuberculosis when ART is initiated, anemia and active cryptococcal disease. The shift to the 2010 WHO guidelines which set eligibility for treatment at 350 CD4+ cells/μl has started to address these severe short comings.

Indeed, treatment failure is more difficult to diagnose when plasma HIV-1 RNA viral load measurements and genotypic resistance tests are only available for a selected minority of patients in resource-limited settings. Early diagnosis of treatment failure can support strategies for treatment adherence, and transform treatment failure into successful treatment prior to the establishment of a resistance, because virologic failure precedes by many months immunological and clinical failure. Therefore using CD4+ cell counts as a criterion for switching treatment regimens implies continuation of ineffective treatment for a longer period of time and thus an accumulation of NRTI resistance.

Second-line and third-line drugs are not routinely available because of the difficulty of identifying which patients need to switch but mainly because of high prices. In 2009, only 1.4–5.2% of adults receiving ART in resource-limited settings were on second-line antiretroviral therapy. This figure is well below what one would expect after more than 5 years of the implementation of large international ART access programs. Thousands of patients have already failed first-line ART and are not receiving optimal treatment. Considering the amount of time spent under a failing first-line regimen, optimizing the choice of the NRTI backbone associated with a second-line protease inhibitor remains a challenge. It is highly likely that many second-line treatments currently offered in sub-Saharan African countries are suboptimal.

Finally, achieving universal access to treatment, prevention and care implies attaining knowledge of HIV infections in many populations. It also requires testing be done early, that is before the symptoms of severe HIV illness occur and to link the newly diagnosed patients to effective treatment and care. This challenge is difficult for weak health systems in low-income countries, in particular in the rural setting, which is an important reason to work towards the decentralization (’at point of care’) and the integration of services.

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Conclusions

Despite significant advancements in the industrialized world, in resource-limited settings the situation is still dramatic: optimal benefits are not accessible to all HIV-infected people because of the challenges to coverage and costs.

The most recent UNAIDS report (available at: http://www.UNAIDS.org), however, highlights what is already working there:

Fig. 1

Fig. 1

Fig. 2

Fig. 2

  1. improved access to HIV testing services enabled 61% of pregnant women in eastern and southern Africa to receive testing and counseling for HIV (up from 14% in 2005);
  2. close to half (48%) of pregnant women in need received effective medicines to prevent mother-to-child transmission (PMTCT) of HIV in 2010;
  3. antiretroviral therapy, which not only improves the health and well being of people living with HIV but also stops further HIV transmission, was available for 6.65 million people in low and middle-income countries. This number accounts for 47% of the 14.2 million people eligible (Fig. 1);
  4. increased access to HIV services has resulted in a 15% reduction of new infections over the past decade and a 22% decline in AIDS-related deaths in the past 5 years (Fig. 2).

Global progress in both preventing and treating HIV infection emphasizes the benefits of sustaining investment in HIV/AIDS over the long term. Prevention remain a major objective ([80,81], this issue); however, advances in HIV science and program innovations in the past 10 years add hope for future progress. In times of economic austerity it will be essential to rapidly and globally apply new science and technologies, including innovative pharmaceutical approaches, to improve the efficiency and effectiveness of HIV prevention and care programs for all infected people, and in all countries of the world.

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Acknowledgements

Contribution to the manuscript: all authors have contributed substantially to the production of the manuscript.

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Conflicts of interest

No competing interests from any of the authors for this historical review.

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Keywords:

AIDS; antiretroviral therapy; HIV; resource-limited settings

© 2012 Lippincott Williams & Wilkins, Inc.