Chapter 6.7: HIV-AIDS

Priority Medicines for Europe and the World
"A Public Health Approach to Innovation"

Background Paper

Human Immunodeficiency Virus/AIDS:
Opportunities to Address Pharmaceutical Gaps

By Warren Kaplan, Ph.D., JD, MPH

7 October 2004

Table of Contents

Executive Summary

Burden of Disease

Treatment Options

Pipeline of Potential Products

Public and Private Funding

1. Introduction

2. What are the Epidemiological Trends for Europe and the World?

3. What is the Control Strategy? Is There an Effective Package of Control Methods Assembled into a “Control Strategy” for Most Epidemiological Settings?

4. What is Known of the Affordability, Feasibility, and Sustainability
of the Control Strategy?

4.1 Economic Burden

5. Why Does the Disease Burden Persist?

6. What Can Be Learnt from Past/Current Research into Pharmaceutical
Interventions for this Condition?

6.1 Introduction

6.2 Antiretroviral Drug Resistance

6.3Adverse Events

6.4HIV Vaccines

7. What is the Current “Pipeline” of Products that Are to Be Used for
this Particular Condition?

8. What is the Current Status of Institutions and Human Resources Available to Address the Disease?

8.1 Introduction

8.2Barriers to HIV Vaccine Development

8.3 Public Funding for HIV/AIDS in the European Union

8.4 Public Funding for HIV/AIDS in the United States

9. Ways Forward from a Public Health Viewpoint with Regard
to Public Funding

9.1 Gaps Between Current Research and Potential Research Issues
which Could Make a Difference

9.2 What is the Comparative Advantage of the EU with Regard
to Public Funding of Pharmaceutical R&D?

10. Conclusion

References

Appendix

Executive Summary

Burden of Disease

As of the end of 2003, there were 40 million persons around the world living with HIV infection and AIDS. Some places are clearly more affected by HIV/AIDS than others. The profound social and economic upheaval which took place in the former Soviet Union in the 1990s has resulted in a sharp increase in the incidence of substance abuse, prostitution, HIV, and other sexually transmitted infections. With an estimated 1 million HIV-positive individuals at the end of 2001 compared with only 30 000 at the start of 1995, Eastern Europe and Central Asia are the regions of the world with some of the fastest growing HIV rates. In Central Europe, epidemics that began in the late 1980s have remained at low levels and do not seem to be expanding.

The European burden of HIV/AIDS is not matched by the HIV/AIDS epidemic in the rest of the world, but to the extent that epidemics that began twenty years ago are still continuing in Europe and the world, there is a clear duality of interest for policy makers.

Treatment Options

The commercial market for antiviral therapeutics will ensure that there will be no shortage of private research funding for the immediate future. Opportunities exist for public funding of research. Both private and public funders, however, should consider the following:

  • Efficacy is not optimal for the present repertoire of antiviral medicines
  • Antiviral therapy alone will not end the epidemic and a comprehensive approach including antivirals and vaccines and microbicides remains essential.
  • Because the HIV genome mutates very rapidly, during the course of an infection, resistance to antivirals is common. Resistance patterns are complex and cross-resistance is likely.
  • The long-term, adverse events and toxicity profiles can be worrisome and fatal.
  • As with any complicated treatment regimen, tolerability is often a problem and adherence is difficult
  • Costs of treatment can be significant- upwards of ten to fifteen thousand USD per patient per year in the US.
  • An effective HIV vaccine could be, optimistically, at least 5 years from reality.

Pipeline of Potential Products

The pipeline of potential antiviral products is large and growing, although dynamic. The absolute numbers of products in the pipeline can change from year to year as programs are introduced and removed for various reasons. New targets of mechanism of action, such as fusion inhibitors and integrase inhibitors, remain active research areas.

Public and Private Funding

Given the number of institutions and human resources involved in HIV treatment, we can state with some confidence that the private sector has already heavily invested in addressing this disease in the developed countries. The United States has by far the greatest financial and human resource contribution in this regard. European public and private research funding for HIV vaccines is small compared to the United States but recent efforts in the Sixth Framework Program are encouraging.

Based upon what we understand to be the epidemiology of HIV/AIDS in expanded Europe and the rest of the world, and the current states of private and public sector institutions in this regard, we believe the European Union can, from a public health viewpoint, fill treatment gaps in the following areas:

  • Target affected populations, especially women, injecting drug users (IDUs), children, adolescents, older adults, and across racial/ethnic groups. Conduct studies that permit evaluation of potential differences in response to therapy due to gender and/or racial/ethnic differences. We suggest that the European and Developing Countries Clinical Trials Partnership (EDCTP) should be used as a vehicle for undertaking research into these special groups.
  • Enhance capabilities for long-term follow up and evaluate the long-term effects of therapy and the implications of these findings on public health.
  • Evaluate the effects of co-infection, especially with hepatitis B virus (HBV), hepatitis C virus (HCV), tuberculosis (TB), or malaria, on the management of HIV disease.
  • Conduct comparative studies in preclinical and clinical evaluation of HIV vaccine candidates and clinical evaluation of anti-HIV therapeutics. This can be accomplished by having the EU support the International AIDS Vaccine Initiative (IAVI).
  • Promote innovative mechanisms of funding to attract additional investigators to undertake multidisciplinary research on microbicides discovery and development.
  • Promote innovative mechanisms to fund an enterprise specifically directed to study fixed dose combination medicines with a view to develop and assess acceptable formulations.
  • Expand capacity (infrastructure and human resources) and strengthen coordination to conduct Phase II/III vaccine, microbicides and fixed dose combination clinical trials.

1. Introduction

AIDS is the deadliest epidemic of our time. More than 22 million people have already died of AIDS – 3 million of them in 2003 alone. The infective agent, human immunodeficiency virus (HIV) has already infected more than 60 million people around the world. AIDS is the leading cause of infectious disease mortality, surpassing tuberculosis and malaria.[1]

2. What are the Epidemiological Trends for Europeand the World?

We briefly summarize this situation with regard to Table 1 and Figure 1 (taken from reference 5), below. In the United States, death rates from AIDS began to decline in the late 1990s, probably due to expanded use of new antiretroviral therapies (ART) that prevent progression of HIV infection to AIDS. This decline has now slowed and AIDS incidence increased 2 percent in 2002 (over 2001). This means that the overall epidemic in the U.S. is actually continuing to expand. [2], [3] ,[4]

In other parts of the world, there also have been steady increases in the number of people living with HIV/AIDS, as well as in the number of AIDS deaths. The number of people living with HIV/AIDS continues to increase most markedly in sub-Saharan Africa, with Southern Africa registering the highest prevalence. Asia and the Pacific as well as Eastern Europe and Central Asia continue to experience expanding epidemics.[5] The total number of people living with HIV also continues to rise in high-income European countries. It is estimated that 1.6 million people are living with HIV in these developed countries—a figure that includes the 80,000 who were newly infected in 2003. 5

Table 1

Figure 1

As Figure 1 (taken from Figure 10 of reference (5)) illustrates, the number of annual AIDS deaths has continued to slow in Western Europe, due to the widespread availability of antiretroviral treatment. In Western Europe, just over 10% of newly diagnosed HIV cases in 2002 were caused by injecting drug use, although, in Portugal, this mode of transmission caused almost half the total HIV infections in 2002.5 These patterns underscore the need for prevention (and treatment) programs that reach injecting drug users—including those in prisons and those who belong to marginalized minorities. The situation with regard to Eastern Europe is characterized by the fact that the number of newly diagnosed HIV infections is still increasing (See Figure 2, reproduced as original Figure 6 from reference 6 ).

Figure 2

Driving the epidemics in Eastern Europe is widespread risky behavior—injecting drug use and unsafe sex— among young people.[6] HIV continues to spread in Belarus, Moldova and Kazakhstan, while more recent epidemics are now evident in Kyrgyzstan and Uzbekistan (see Figure 2). By some estimates, there could be as many as 3 million injecting drug users in the Russian Federation alone, more than 600,000 in Ukraine and up to 200,000 in Kazakhstan. 6 In Estonia and Latvia, it has been estimated that up to 1% of the adult population injects drugs, while, in Kyrgyzstan, that figure could approach 2%. Most of these drug users are male and many are very young—in St Petersburg, studies found that 30% of them were under 19 years of age, while, in Ukraine, 20% were still in their teens. 6, [7] The exception to the trend was Poland, where the Catholic church had organised a major campaign to destigmatise the disease early on. As a result Poland’s HIV prevalence is about 0.1%—one of the lowest in Europe. 7

3. What is the Control Strategy? Is There an Effective Package of Control Methods Assembled into a “Control Strategy” for Most Epidemiological Settings?

In particular, for more than 10 years, drug discovery efforts have concentrated on the HIV-1 enzyme targets reverse transcriptase (RT) and protease (PR). Viral load can be reduced by combining RT and PR inhibitors in highly active antiretroviral therapy (HAART) regimens. Highly active antiretroviral therapy is generally a combination of at least three drugs for HIV-1 infection and this has led to substantial reductions in morbidity and mortality.[8] Many HAART regimens result in near-complete suppression of HIV-1 replication. HAART is now the standard-of-care therapy. However, there are concerns about both the long-term effects of HAART and the ability of HIV-1 to evolve resistance to these drugs and so HAART therapy must be flexible. 8

Table 2 is list of antiviral medicines approved in the United States and the dates of their respective approvals

Table 2

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Chapter 6.7: HIV-AIDS

•AZT 1987

•ddI 1991

•ddC 1992

•d4T 1994

•3TC 1995

•saquinavir 1995

•indinavir 1996

•ritonavir 1996

•nevirapine 1996

•delavirdine 1997

•nelfinavir 1997

•efavirenz 1998

•abacavir 1998

•amprenavir 1999

•lopinavir 2000

•tenofovir 2001

•T-20 (Fusion inhibitor) 2003

  • Fosamprenavir 2003

6.7-1

Chapter 6.7: HIV-AIDS

T-20 marks the first new class since the protease inhibitors (PI) were introduced in late 1995. While T-20 has provided some heavily treatment-experienced patients with the means of constructing an effective and enduring antiretroviral regimen, its twice daily subcutaneous injection, cost and limited availability may limit its widespread use.[9]

In an important study that was terminated early, the triple fixed dose combination of AZT, 3TC and abacavir (Trizivir ) was found to be significantly less effective than an efavirenz (Sustiva)-based regimen in treatment-naive patients.9 While Trizivir® clearly still has a place among the drugs used to treat HIV, it is also not as effective when used as the whole regimen and not part of anti-HIV therapy. Two other seemingly potent triple “free combination” regimens fared far worse than Trizivir in studies. The combination of tenofovir, abacavir and lamivudine was dramatically less effective than the combination of efavirenz with abacavir and lamivudine. Didanosine (ddI or Videx) when used with tenofovir and lamivudine was effective in only one of the 30 patients who received this combination.9

New attempts to block HIV-1 infection have diversifed to consider many steps in the viral life cycle of HIV-1 that are crucial to infection. These steps include virus–cell attachment, virus entry and virus uncoating. [10] The reverse transcription of viral cDNA, nuclear import and integration into the host cell's genome are also potential sites of inhibition. One antagonist of viral entry (e.g., fusion inhibitors) has been approved by the FDA (Table 2) and others are now in, or approaching, human clinical trials. Fusion inhibitors are directed against both the viral glycoproteins that interact with receptors and co-receptors on the host cell membrane. The co-receptors CCR5 and CXCR4, are likely targets for therapeutic advances.10

The design of post-entry inhibitors remains problematic; the more advanced inhibitors include agonists of the integrase enzyme, which mediates viral cDNA integration into the host cell's genome. Design of new viral-entry inhibitors also considers the escape pathways adopted by the evolving HIV-1 virus in response to inhibition of its normal entry route. It is predicted that the most successful therapeutic approach will be a 'cocktail' of inhibitors, which block infection at several points, including the potential escape pathways.10

4. What is Known of the Affordability, Feasibility, and Sustainability of the Control Strategy?

4.1 Economic Burden

The global HIV/AIDS epidemic, through its devastating scale and impact, constitutes a global emergency and undermines social and economic development throughout the world and affects all levels of society. It is no longer a health crisis but has been transformed into a development crisis. The HIV/AIDS epidemic has erased decades of progress in combating mortality and has seriously compromised the living conditions of current and future generations. [11]

5. Why Does the Disease Burden Persist?

In brief, HIV and AIDS persists in large part because of risky behavior, governmental neglect and denial, inexorable growth of antiviral resistance and complex structural/societal factors. These structural factors that influence HIV transmission are deep seated within society. In the medium or long term, they can be addressed through sustained, pro-poor economic growth; poverty-reduction policies and programs; control of drug trafficking; effective judicial reforms to reduce overcrowding in prisons; improvement of employment opportunities for young adults; curtailment of human trafficking; and improvement of the public health infrastructure to support testing, counseling, tuberculosis control, and other population-based approaches to HIV/AIDS and tuberculosis. 11 Surveillance (both serological and behavioral surveillance) is weak in many parts of the world (e.g., Eastern European and Central Asian countries) and HIV/AIDS programs are based on information that is neither appropriate to the highest-risk groups nor reliable as a general population estimator. Currently, they neither support program planning nor help define the dynamics of the epidemic in the region.

A safe, effective and affordable vaccine is the best hope to bring the AIDS epidemic under control. There is widespread belief among scientists that development of such a vaccine is possible. Yet, twenty years into the epidemic, the AIDS vaccine research effort faces extraordinary hurdles. These include: inadequate funding, insufficient focus on the scientific roadblocks, lagging industry investment, little public information as to why vaccine clinical trials have failed, few candidate vaccines in the pipeline, little urgency among affected communities and a lack of leadership in the overall effort.

6. What Can Be Learnt from Past/Current Research into Pharmaceutical Interventions for this Condition?

6.1 Introduction

Multiple ART drug combinations continue to successfully reduce viral load and restore immune responses in many HIV-infected individuals. However, these regimens also can result in serious toxicities and side effects, single- and multiple drug-resistance, and other complications that make them unacceptable for some individuals. We might expect that such side effects and complications will increase as HIV-infected individuals continue to survive longer on various drug regimens and we might expect therefore more deaths occurring from liver failure, kidney disease, and cardiovascular complications in this patient population. Better antiretroviral drugs and treatment regimens are needed with less toxicity, increased activity in viral and cellular reservoirs, reduced ability to develop drug resistance, improved pharmacodynamics and pharmacokinetics, easier compliance, and lower cost. While the incidence of certain opportunistic infections (OIs) and malignancies has decreased with the advent of HAART, the number of cases of TB, multiple drug resistant TB, and other coinfections such as Hepatitis B virus and Hepatitis C virus has increased.

6.2 Antiretroviral Drug Resistance

Drug-resistant HIV-1 is a cause of growing clinical and public-health concern. [12] In many patients, combination antiretroviral therapy fails to achieve complete viral suppression (virological failure). Continuing viral replication during therapy leads to the accumulation of drug-resistance mutations, resulting in increased viral load and a greater risk of disease progression. Patients with drug-resistant HIV-1 infection have three therapeutic options: a change to a “salvage” regimen with the aim of fully suppressing viral replication; interruption of therapy; or continuation of a partially effective regimen.12 The first strategy is preferred for most patients failing their first or perhaps their second regimen. However, the best approach remains unclear for patients who have failed multiple treatment regimens and who have limited options for complete viral suppression. The management of such patients requires a careful understanding of the pathogenesis of drug-resistant HIV-1, the clinical consequences of virological failure, the potential benefits and limitations of diagnostic assays, and the likelihood that agents in development will be effective.

Several consistent conclusions have emerged from clinical trials on use of antiretrovirals under drug resistant conditions.