Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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 6.7-1 Chapter 6.7: HIV-AIDS Table of Contents Executive Summary......................................................................................................................... 3 Burden of Disease ................................................................................................................ 3 Treatment Options .............................................................................................................. 3 Pipeline of Potential Products ........................................................................................... 3 Public and Private Funding ............................................................................................... 4 1. Introduction ......................................................................................................................... 5 2. What are the Epidemiological Trends for Europe and the World? ........................... 5 3. What is the Control Strategy? Is There an Effective Package of Control Methods Assembled into a “Control Strategy” for Most Epidemiological Settings? ............ 8 4. What is Known of the Affordability, Feasibility, and Sustainability of the Control Strategy? .................................................................................................... 9 4.1 Economic Burden ................................................................................................... 9 5. Why Does the Disease Burden Persist?.......................................................................... 9 6. What Can Be Learnt from Past/Current Research into Pharmaceutical Interventions for this Condition? .................................................................................. 10 6.1 Introduction .......................................................................................................... 10 6.2 Antiretroviral Drug Resistance .......................................................................... 10 6.3 Adverse Events ..................................................................................................... 11 6.4 HIV Vaccines ......................................................................................................... 12 7. What is the Current “Pipeline” of Products that Are to Be Used for this Particular Condition? ............................................................................................... 13 8. What is the Current Status of Institutions and Human Resources Available to Address the Disease? ....................................................................................................... 21 8.1 Introduction .......................................................................................................... 21 8.2 Barriers to HIV Vaccine Development .............................................................. 22 8.3 Public Funding for HIV/AIDS in the European Union ................................... 23 8.4 Public Funding for HIV/AIDS in the United States......................................... 25 9. Ways Forward from a Public Health Viewpoint with Regard to Public Funding ............................................................................................................. 26 9.1 Gaps Between Current Research and Potential Research Issues which Could Make a Difference ......................................................................... 26 9.2 What is the Comparative Advantage of the EU with Regard to Public Funding of Pharmaceutical R&D? ..................................................... 28 10. Conclusion ......................................................................................................................... 29 References ....................................................................................................................................... 30 Appendix 6.7-2 Chapter 6.7: HIV-AIDS 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 crossresistance 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. 6.7-3 Chapter 6.7: HIV-AIDS 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. 6.7-4 Chapter 6.7: HIV-AIDS 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 Europe and 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 6.7-5 Chapter 6.7: HIV-AIDS Table 1 Figure 1 6.7-6 Chapter 6.7: HIV-AIDS 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 6.7-7 Chapter 6.7: HIV-AIDS 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 •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 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, 6.7-8 Chapter 6.7: HIV-AIDS 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 6.7-9 Chapter 6.7: HIV-AIDS 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. A greater degree of viral suppression is observed when more antiretroviral drugs are used, particularly when a new therapeutic class is used.13, 14 , 15 Patients with early-stage HIV-1 disease, lower viral loads, or both, have a better virological response to salvage therapy than patients with later-stage disease. 16, 17 6.7-10 Chapter 6.7: HIV-AIDS The presence of genotypic or phenotypic resistance is associated with a poor virological response to subsequent salvage therapy. 13, 18 , 19 Complicated and unpredictable drug interactions can occur during the construction of novel salvage regimens. These interactions can result in suboptimum drug exposure and accelerated drug toxicity. 13, 20, 21 One question that has not been adequately addressed in clinical trials is whether antiretroviral drugs should be used in sequence on the basis of resistance patterns—ie, should one drug be used first because failure of that drug is less likely to compromise future options? Unfortunately, resistance to one drug commonly confers cross-resistance to other drugs within the same therapeutic class, which suggests that sequencing strategies based on resistance should not be used. Cross-resistance is particularly common within the nonnucleoside reverse transcription inhibitor (NNRTI) class. A single mutation commonly precludes the use of all other NNRTIs.22, 23 Although the situation is more complicated within the nucleoside reverse transcription inhibitor (NRTI) class, resistance to one drug commonly confers cross-resistance to most if not all NRTIs (lamivudine may be an exception).23 When to switch therapy in a patient with multi-drug resistant HIV-1 infection is controversial as changing therapy at the earliest signs of virological failure risks rapid utilisation of all therapeutic classes, and is in many cases impracticable owing to drug toxicity, adherence barriers, and drug costs. By contrast, continuation of the same therapy risks the accumulation of drug-resistance mutations and the unpredictable immunological and clinical consequences related to continuing viral replication. The number of patients with highly resistant HIV-1 is growing.24 New drugs are developed in a slow and step-wise manner, so construction of new multidrug regimens is difficult. New assays are also being developed, but they are expensive and their clinical role remains poorly defined. Nonetheless, there is still only limited evidence that virological failure and the emergence of drug resistance leads to rapid clinical progression. The interval from the onset of virological failure to the loss of CD4-positive T cells is surprisingly long. 6.3 Adverse Events Several factors have combined to increase attention on the toxicity of HAART, particularly since HIV-1 eradication seems unlikely in the near term. 25, 26 The severity of the HIV epidemic led to accelerated licensing of many antiretroviral agents, but we know very little about long-term safety. 27,28,29,30,31 The sustained benefits of HAART have led to far greater numbers of HIV-1-infected patients receiving at least three drugs for greater periods of time and drug-related toxicity is being increasingly recognized because of the declining incidence of HIV-1-associated opportunistic disease. Lastly, there are now at least 18 antiretroviral drugs available in four drug classes and so the number of potential HAART combinations is huge. Toxicities from NRTIs and NtRTIs include myopathy (zidovudine); neuropathy (stavudine, didanosine, zalcitabine); hepatic steatosis and lactic acidaemia (didanosine, stavudine, zidovudine); nephrotoxicity (tenofovir) and possibly also peripheral lipoatrophy (possibly all 6.7-11 Chapter 6.7: HIV-AIDS NRTIs, although predominantly with stavudine); and pancreatitis (didanosine). The most serious mitochondrial toxicities are lactic acidosis and pancreatitis. No diagnostic (metabolic or serological) assay predicts who will develop toxicity. 27, 28 Drug hypersensitivity typically manifests as a rash.32 Drug hypersensitivity to drugs in HIV-1-infected patients is about 100 times more common than in the general population.33 The overall size of the problem actually rather substantial; drug hypersensitivity complicated 3–20% of all prescriptions in one large series.34 Nevirapine, delavirdine, efavirenz, abacavir, and amprenavir are common antiretroviral drugs that cause hypersensitivity. About 50% of antiretroviral hypersensitivity resolves spontaneously despite continuation of therapy. A syndrome (or syndromes) of lipodystrophy affecting HIV-1-infected patients was first described only 2 years ago. The main clinical features are peripheral fat loss in the face, limbs, and buttocks and central fat accumulation within the abdomen, breasts, and over the spine. Metabolic features significantly associated with lipodystrophy include elevated blood lipids, insulin resistance and type 2 diabetes mellitus. 35 36 37 38 Most antiretroviral regimens, especially NNRTIs and protease inhibitors, have not been studied in pregnancy with sufficient thoroughness to enable recommendations to be made as to safety and efficacy. No antiretroviral has been rated by the U.S. Food and Drug Administration as category A (well demonstrated lack of risk to human fetuses in the first trimester). Drugs rated as category B (safe in animal studies) are didanosine, saquinavir, ritonavir, and nelfinavir. We note the United States-based Antiretroviral Pregnancy Registry is intended to provide an early signal of any major teratogenic effect associated with a prenatal exposure to the products monitored through the Registry. The Registry is a voluntary prospective, exposure-registration, observational study designed to collect and evaluate data on the outcomes of pregnancy exposures to antiretroviral products. For instance, sufficient numbers of first-trimester exposures to nelfinavir have been monitored to detect a 2-fold increase in the prevalence of overall birth defects but the numbers are not sufficient to detect any increased rate of specific defects.i 6.4 HIV Vaccines Is prevention of infection achievable or even feasible by the use of HIV vaccines? In general, scientists would not expect that a previous infection or vaccination would provide absolute protective immunity against reinfection by HIV. 39 40 Sterilizing immunity i.e, the absence of any infection of a host cell by the agent, rarely been seen with any vaccine and seems unattainable with HIV.41 Instead, it has been argued that a reasonable vaccine should be directed not at prevention of HIV infection but at control of the spread of infection and at the development of clinically apparent disease. Furthermore, evidence from the poliomyelitis, measles, rubella, mumps, and influenza virus vaccine trials indicates that neither killed nor live-attenuated (nonpathogenic) viruses have prevented infection of immunized hosts by wild-type virus. 42 43 44 45 46 HIV incorporates its genetic material into the chromosome of the See Covington DL, Conner SD, Doi PA, Swinson J, Daniels EM 2004. Risk of birth defects associated with nelfinavir exposure during pregnancy.Obstet Gynecol. 103:1181-1189. i 6.7-12 Chapter 6.7: HIV-AIDS host cell and this infection can then lead to high-level or to low-level virus replication, or the virus can remain latent within the infected cell.47 Moreover, by contrast with other viruses for which there is a vaccine, the HIV infected cell can be the source of transmission and must be recognized by the immune system. Hopefully, a vaccine will stimulate the immune system sufficiently to maintain control of this virus, as is seen in the few HIV-infected individuals living for more than 20 years without symptoms and treatment. 48 In some of these patients, the virus could eventually emerge to cause disease, but only late in life when the immune system ages. Thus, in principle pathogenesis but not infection could be prevented or at least delayed a long time by vaccine. Early efforts in developing an HIV vaccine mainly concentrated on the induction of circulating neutralizing antibodies by HIV vaccines containing HIV envelope proteins.49 The analysis of HIV infection in immunized individuals revealed the disheartening possibility of disease acceleration attributable to antibody production 50 51 52. The phenomenon of enhancement of HIV infection by HIV-specific antibodies has been regularly reported.53 54 55 56 Cell–cell contact is the most effective means of HIV spread but neutralizing antibodies are ineffective against this mode of transmission.57,58 In contrast with most other viruses for which we have a vaccine, HIV does not necessarily kill the cell it infects so that, unless the infected cells are killed by a strong cellular immunological response, the infected cell will continue seeding HIV particles that can spread to various tissues in the host. 50 Indeed, there is some current consensus that cellular, NOT antibody-based immune responses, especially those mediated by CD8 cytotoxic/suppressor (CTL) and CD4 helper T lymphocytes, are needed to control HIV. Vaccines capable of inducing cell-mediated responses may be critical for controlling the spread of HIV. 50 Since one of the major challenges in designing an effective HIV vaccine is the immense variability of viral antigens, it is significant that the HIV genome undergoes frequent change due to error-prone RNA polymerase-driven replication and recombination. For this reason, a vaccine that contains only limited antigenic diversity, for example, recombinant vaccines, may be not up to the task of handling mutants that “escape” the existing vaccine repertoire of antigens. The theoretical number of peptides to represent all variants of an individual HIV immunogen could be enormous. 59 (See Appendix 6.7.1) 7. What is the Current “Pipeline” of Products that Are to Be Used for this Particular Condition? Tracking pharmaceutical pipelines over time reveals various therapeutic candidates appearing and disappearing, only to be replaced by other hoped-for products. Thus, snapshots of HIV pipelines need to be viewed as a ‘work in progress’. Table 3 is adapted from information provided by the Pharmaceutical Manufacturers of America (http://www.phrma.org/newmedicines) but it is not intended to be a fully comprehensive view of the U.S. pipeline. The pipelines of 2002 and any new and continuing interventions in 2003 (in blue) are listed. Thirty five different organizations are involved in developing this pipeline; most of them are based in the United States. We attempted to place each 6.7-13 Chapter 6.7: HIV-AIDS intervention into its appropriate therapeutic class (e.g., protease inhibitor, NNRTI, and so on) although this is not always possible. Table 3. ANTIVIRALS 2002 Company TRIAL PHASE I Medicine Interferon Sciences Hemispherx Biopharma Triangle Pharmaceuticals II Interferon alpha IFN alpha X amdoxivir (purine nucleoside analog) GS7340 Viread® tenofovir Gilead Sciences Gilead Sciences Zeria USA Samaritan Pharmaceuticals Samaritan Pharmaceuticals Bristol-Myers Squibb Ancer 20 Injection procaine HCl X X X X X X procaine HCL atazanavir (protease inhibitor) CA X AMD071 X Achillion Pharmaceuticals Achillion Pharmaceuticals Beta-L-Fd4C Bristol-Myers Squibb BMS 561390 (NNRTI) X Sarawak MediChem calanolide A (NNRTI) X Pfizer X X Beta-L-Fd4C Sarawak MediChem calanolide A X capravirine (NNRTI) X Pfizer capravarine Pfizer Pfizer AG-1859 UK 427 6.7-14 III X X amdoxovir (purine nucleoside analog) Gilead Sciences AnorMed 2003 X X X Chapter 6.7: HIV-AIDS ANTIVIRALS Company Triangle Pharmaceuticals (now Gilead sciences) Bristol-Myers Squibb Bristol-Myers Squibb GlaxoSmithKline 2002 Roche/Trimeris Roche Boehringer Ingelheim X X Epivir® (once-daily dosing) X aspartyl protease inhibitor 678248 (NNRTI) 695634 (NNRTI) 810781 (integrase inhibitor) 873140 CCR5 antagonist X X X X X lamivudine + abacavir X X NDA lamivudine + abacavir Fuzeon™ enfuvirtide GEM®92 MIV-310 X X X X X X X X MIV-310 peptide T peptide T PRO 542 PRO 542 S-1360 (integrase inhibitor) SPD 754 X SPD 754 SPD 756 SPD 756 X X X T-1249/R724 (fusion inhibitor) X R724 (fusion inhibitor) Protease inhibitor X tipranavir (PI) 6.7-15 III X (NDA) entecavir GlaxoSmithKline Shire Pharmaceutical Dev. Shire Pharmaceutical Dev. Shire Pharmaceutical Dev. Shire Pharmaceutical Dev. Roche/Trimeris II Coviracil® emtricitabine entecavir GlaxoSmithKline Hybridon Medivir edivir Avanced Immuni T Avanced Immuni T Progenics Pharmaceuticals Progenics Pharmaceuticals Shionogi-GlaxoSmithKline TRIAL PHASE I Medicine GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline Roche/Trimeris 2003 X X Chapter 6.7: HIV-AIDS ANTIVIRALS 2002 Company 2003 TRIAL PHASE I Medicine Boehringer Ingelheim Tibotec (J&J) Tibotec Tibotec GlaxoSmithKline/Vertex TMC125 TMC 114 (PI) 433908 or VX-175 (protease inhibitor) 640385 (protease inhibitor) Zerit® stavudine extended release CCR5 receptor antagonist Schering-Plough X X X X X NDA X CCR5 receptor antagonist Schering-Plough Amerimmune Pharmaceuticals X Cytolin® X Enzo Biochem HGTV43 (gene therapy) X United Biomedical HIV therapeutic (vaginal microbicide) X Biosyn SciClone Pharmaceuticals Zadaxin® thymalfasin United Biomedical United Biomedical VaxGen VaxGen Aventis Pasteur Aventis Pasteur Aventis Pasteur Aventis Pasteur Aventis Pasteur AIDS vaccine Wyeth Pharmaceuticals Wyeth Pharmaceuticals X X X AIDSVAX® X X AIDSVAX (vCP1452) X X vCP1452 (vCP1521) 6.7-16 X X vCP1521 tat toxoid X HIV 1090 X X EP HIV-1090 DNA-based vaccine DNA-based vaccine X X AIDS vaccine FR FR FR FR III X TMC125 (NNRTI) GlaxoSmithKline/Vertex Bristol-Myers Squibb Epimmune Epimmune II tipranavir (PI) X X X Chapter 6.7: HIV-AIDS ANTIVIRALS Company GlaxoSmithKline 2002 Medicine X HIV recombinant vaccine HIV recombinant vaccine HIV recombinant vaccine Therion Biologics AlphaVax IAVI Emory Vaccine Center, NIAID 6.7-17 X X HIV recombinant vaccine Merck Therion Biologics TRIAL PHASE I HIV recombinant vaccine GlaxoSmithKline Merck 2003 X X HIV recombinant vaccine HIV vaccine HIVA.DNA-MVA X X X HIV vaccine X II III Chapter 6.7: HIV-AIDS Table 4 summarizes (as of early 2004) what we would consider “me too” anti-HIV candidates, insofar as they fall into the three common classes of antiretrovirals. Protease Inhibitors Estimated Approval Tipranavir Phase III Boehringer-Ingelheim 2005 TMC 114/r Phase I/II Tibotec/J&J 2007 Capravirine Phase III Pfizer 2006 TMC 125 Phase II Tibotec/J&J 2006 Calanolide-A Phase II Advanced Life Sciences/Sarawak MediChem 2007 Amdoxovir (DAPD) Phase II Emory Univ./University Georgia 2007 Alovudine (MIV-310) Phase II Medivir 2006 D-D4FC (Reverset) Phase II Incyte/Pharmasset 2006 Phase II Achillion 2007 Non-Nucleoside RTIs Nucleoside RTIs Elvucitabine 126,443) (ACH- of Our most recent information (shown in Table 5) on compounds in the pipeline (February 2004) and we use a non-industry source.60 New compounds and organizations are appearing. New classes include zinc finger compounds, CXCR4 inhibitors, attachment inhibitors, CCR5 inhibitors, fusion inhibitors, integrase inhibitors. 6.7-18 Chapter 6.7: HIV-AIDS Table 5 Attachment and Fusion Inhibitors: These prevent the virus from attaching to a new cell and breaking through the cell membrane. Because digestive acids break them down, most of these drugs are given by injections or intravenous infusion. AMD070 is a drug that blocks the CXCR4 receptor that HIV sometimes uses to attach to a cell. It is in Phase I trials by AnorMED. BMS-488043, is an attachment inhibitor in Phase II trials by Bristol Myers Squibb. It attaches to the virus, not the target cell. So far, it shows good strength against HIV and only minor side effects. FP21399 by Fuji Pharmaceuticals was tested for safety in a Phase I trial as a single infusion or a series of 4 weekly 1-hour intravenous infusions. The drug produced viral load decreases and CD4+ cell increases. Side effects were minor, including blue-tinted urine and temporary blue marks on the skin. There have been no recent reports on its status. GW873140 by GlaxoSmithKline is in Phase I studies. It appears to bind very tightly to CCR5 receptors on the cell surface. The main side effects are mild cramping, diarrhea and nausea. PRO 542 by Progenics Pharmaceuticals is in Phase II trials. It blocks fusion by binding to a protein on the outside of the virus. Schering C (SCH-C) and Schering D by Schering Plough block the CCR5 receptor on CD4 cells. At present SCH-D looks more promising than SCH-C. There is some concern about heart irregularities with Schering C but not with Schering D. No serious toxicities have been seen with SCH-D in Phase I. TAK-220 by Takeda blocks the CCR5 receptor. It is in Phase Ib/IIa trials. TNX-355 by Tanox blocks the CD4 receptor. It is a genetically engineered drug, a "monoclonal antibody." It may be administered by intravenous infusion or as a twicemonthly injection. No significant side effects have shown up yet. It is entering Phase II trials. UK-427,857 by Pfizer blocks the CCR5 receptor. Pfizer will continue to develop it. It is in Phase II trials Integrase Inhibitors After HIV's genetic code is changed from a single strand to a double strand by the reverse transcriptase enzyme, it gets inserted (integrated) into the genetic code of the infected cell. Then the HIV genetic code gets "read," producing new viruses. Scientists hope that integration will be another point in the HIV life cycle that can be targeted by drugs. Zinc Finger Inhibitors The inner core of HIV is called the nucleocapsid. It is held together by structures called "zinc fingers." Zinc finger inhibitors (or zinc ejectors) are drugs that can break apart these structures and prevent the virus from functioning. Scientists believe that the nucleocapsid core cannot mutate very easily, so a drug that works against zinc fingers might be effective for a long time. Unfortunately, zinc fingers are not only used by the HIV virus. Drugs that attack them could have serious side effects. One zinc finger inhibitor -- azodicarbonamide (ADA) -- has been tested in a Phase I/II trial. Antisense Drugs These are a "mirror image" of part of the HIV genetic code. The drug locks onto the virus to prevent it from functioning. One antisense drug, HGTV43 by Enzo Therapeutics, is starting Phase II trials. Another, GEM92 by Hybridon showed good results in a Phase I study. However, GEM92 is not being developed at present. 6.7-19 Chapter 6.7: HIV-AIDS We next analysed the U.S. clinical trials database (www.clinicaltrials.gov) to develop another estimate of the pipeline activity- the clinical trial sponsoring organizations. Figure 3 summarizes the information as of 2003. The number in parenthesis on the X axis is the proportion of total clinical trials (of all subject matter) relegated to HIV-related subject matter. ii The greatest total number of clinical trials related to HIV (primarily early stage Phase I trials) is being sponsored by the National Institutes of Health although many more NIH trials are being conducted in other areas, as the fraction of total NIH trials directed to HIV is just 13%. This should be compared to the proportion of total industry- sponsored trials relegated to HIV (32%). Figure 3 350 Phase I Phase II Phase III Phase IV 300 250 200 Number of HIVRelated Trials 150 100 50 0 NIH (13%) Other Federal Government (5%) All industry (32%) University/Other Organizations (2%) There is far less information about European HIV clinical trials. United Kingdom's Medical Research Council (MRC) and the NHS Research and Development Programme have made important progress through a meta-register of controlled trials (www.controlled-trials.com), established by Current Controlled Trials, a publisher. We searched for “HIV related“ trials in several registers, including the UK Medical Research Council and the NHS register. We located 28 HIV trials- 22 of them sponsored by the MRC. With regard to vaccines, from the first trial in 1987 to 1996, 23 vaccine candidates underwent phase I trials, 2 candidates phase II trials, and 2 candidates phase I/II trials. From 1997 to the end of 2002, 34 candidate vaccines underwent phase I trials, 6 candidate vaccines phase II trials, 7 candidates phase I/II trials and 2 candidate vaccines phase III trials.iii The search term “HIV” included HIV therapeutics, HIV diagnostics, drug to drug comparisons, opportunistic infections, side effects (cardiac effects, lipodystrophy and the like). iii Independent Evaluation of the International AIDS Vaccine Initiative, April 2003, available on the IAVI website at http://www.iavi.org/pdf/IAVIIndependentEvaluation.pdf ii 6.7-20 Chapter 6.7: HIV-AIDS 8. What is the Current Status of Institutions and Human Resources Available to Address the Disease? 8.1 Introduction Given the number of institutions and human resources involved in the HIV pipeline, we can state with some confidence that the private sector is already heavily investing in addressing this disease. The United States has by far the greatest financial and human resource contribution in this regard (see Section 7). We note, however, that although there is no paucity of private funding with regard to HIV protein and “small molecule” therapeutics, this appears not to be the case for HIV vaccines. We analyzed patent filings in the European Patent Office searchable database (http://www.european-patent-office.org/espacenet/info/access.htm) with a view towards determining which entities own the various EPO filings. We are not concerned in this analysis with measuring ‘innovation’ activity in this regard since some innovation is neither patentable nor, even if patentable, is submitted for IP protection. However, an overall view of the ownership activity in the field is useful. We searched the EPO database for patents and patent applications in the following chemical classes by cross-referencing these chemical classes with the search terms “HIV” or “immunodeficiency”. Table 6. Chemical Classifications used in EPO Database Search Class A61K31: medicinal preparations containing organic active ingredients Class C07D401 Class C12N15 preparations containing N heterocyclics vectors and plasmids Class C07D417 N, S-containing heterocyclic organic compounds C07K16 Class A61 K38 Immunoglobulins Preparations containng peptides Results are presented below in Figure 4. Sixty six percent (2 out of every 3) of the HIVrelated EPO patents and patent applications (n= 817) in these chemical classes are owned by United States entities. 6.7-21 Chapter 6.7: HIV-AIDS Figure 4 Ownership of HIV-related IP (EPO) 10% 1% 2% USA CA Europe JP/Asia 18% Eastern Europe Other 3% 8.2 66% Barriers to HIV Vaccine Development On a worldwide basis, private industry investment in HIV vaccine development is extremely limited. Biotech and pharmaceutical company interest in HIV vaccine development is extremely low.61 This is true for all vaccines, in general where only a few R&D based companies are developing vaccines but this is because the vaccine market is smaller than the pharmaceutical market. Private financing tends to favor less risky investments. Opportunities for expanded private/public partnerships and inter-company collaboration are being overlooked. In terms of the number of companies with active programs and the number of approaches being pursued, the overall picture seems quite discouraging. Only a handful of companies have reasonably secure programs of any size. Aventis and Chiron have broad based HIV vaccine programs that are pursuing a number of approaches. Merck & Co. has what appears to be a substantial program currently focused on only a single approach. GSK has a broad based HIV vaccine program in early development including an HIV vaccine using proteins and a proprietary adjuvant and an HIV immunotherapeutic using DNA and a novel delivery system. The smaller biotech companies (like Therion and Alphavax) have programs that are largely limited to a single scientific approach. The question is whether these smaller programs will continue if the approach being pursued proves unsuccessful. Other commonly noted reasons for limited industry involvement include liability concerns and the opportunity costs of HIV vaccine research compared to development of other products with a shorter and more certain development timeline. Public Private partnerships (See Chapter 8.1) have been initiated to address this limited industry involvement. The International AIDS Vaccine Initiative (IAVI) is a global organization working to speed the development and distribution of preventative AIDS vaccines by mobilizing support through advocacy and education, accelerating scientific 6.7-22 Chapter 6.7: HIV-AIDS progress, encouraging industrial participation, and assuring global access. IAVI has raised more than US$280 million in the several innovative international vaccine development partnerships, bringing together researchers and scientists in industrialized and developing countries, to move promising vaccine candidates toward clinical testing. The European Union is a donor and policy advocacy partner of IAVI. IAVI has catalyzed the international community, articulating a pathway for the development of an AIDS vaccine, and advocating for increased investment and competition in the development of an AIDS vaccine. Research into the development of an HIV vaccine is progressing and is being supported by the public sector, but international collaboration is needed for success. We note the South African Vaccine Initiative (SAAVI) was established in 1999 as a joint initiative by the South African Medical Research council, a private utility company , and the South African government. Given the comparative lack of capacity and resources in many developing countries, no one consortium currently has the required capacity, budget, infrastructure, or product pipeline to develop an effective HIV vaccine, particularly with limited private sector involvement.62 Global integration and collaboration, maximizing international partnerships, and effectively mobilizing resources are key.62, 63 In June 2004, the G-8 countries endorsed the development of a global HIV vaccine consortium, as first described in reference.63 (See Appendix 6.7.2) 8.3 Public Funding for HIV/AIDS in the European Union In early 2004, the government of Ireland assumed the Presidency of the European Union and, of particular interest in this present context, made it clear that a key priority would be the challenge presented by the HIV/AIDS pandemic in developing countries and a concerted European Union response to it. Specifically, there is understandable concern on the threat posed by HIV/AIDS to the countries of Eastern Europe and Central Asia. Various countries have developed funding for HIV/AIDS and levels of funding vary. In 1992, the Agence Nationale de Recherche sur le Sida (ANRS) was set up in France. It has an annual budget of over 50 million euros, the vast majority of which funds scientists and organisations, such as the INSERM (Institut National de la Santé et de la Recherche Médicale) [French national institute for medical research], hospitals and universities involved in work on AIDS. ANRS funds work in developing countries is a priority with a total investment of €10 million in 2003. The Medical Research Council of the UK has a budgeted resource income in 2004/2005 of about £500 million and we do not know which fraction is this is directed to HIV/AIDSrelated activities. 8.4.1 Fifth Framework Program In the period from 1998 to 2002, under the Fifth Framework Program for Research and Technological Development, the European Commission has made substantial investments in a broad range of research activities related to HIV/AIDS, Malaria and TB. Over € 109 million has been committed to research on these three poverty related diseases. A total of 77 projects were supported: 32 of these on HIV/AIDS, 24 on malaria and 21 on tuberculosis. Vaccine research accounted for 56% of the total budget, 31% for drug discovery and research and 6.7-23 Chapter 6.7: HIV-AIDS 13% for research on health policy and health systems. A detailed description of the budget allocated to these research areas for the 3 diseases is reported in figures 1 and 2. These research projects have involved about 500 research institutions in total, from 21 countries in Europe, 21 in Africa, 11 in Latin America, 7 in Asia and the USA, as well as from 18 industries. Further breakdown of the funding is provided in Figure 5. We note, without further comment, that the amount of HIV/AIDS-specific funding was more than an order of magnitude less than that of the NIH. Figure 5. Budget allocation corresponding to the diseases and to the type of research during the 5th Framework Programme for Research and Technology Development. 8.4.2 Sixth Framework Program The total Sixth Framework Program has budget allocation of about €16 billion. The Povertyrelated Diseases unit (RTD-F3 unit) is funding research aimed at combating HIV/AIDS, Tuberculosis, and Malaria and the total amount allocated is significantly greater than in the Fifth Framework- approximately €1.1 billion. There are several projects currently under negotiation following the first call for proposals. One such action will be funded only if the negotiation is successfully completed. This project is the development, up to clinical phase I, of a specific HIV microbicide for the prevention of sexual transmission/acquisition of HIV, based on the interruption of viral replication at the mucosal level. A second project has been funded. The aim of this project is to develop mucosally delivered vaccines against HIV and TB which will induce local immunity able to neutralise the pathogens at their port of entry and systemic immunity able to prevent systemic spread of the infection. The total cost of this latter project is about € 18million and the EU contribution is € 15.25 million. The European and Developing Countries Clinical Trials Partnership (EDCTP) is a Sixth Framework- supported partnership between European and developing countries to enable clinical trials for drugs and vaccines against HIV/AIDS, as well as against tuberculosis and malaria. The EDCTP program intends these trials to managed by both Europe and Africa, as well as intending the trials to provide support for clinical research capacities in developing countries. The EDCTP has a total budget of € 600 million for the period 2003-2007. Apart 6.7-24 Chapter 6.7: HIV-AIDS from the one third from Community funding, €200 million will come from Member States' activities and further €200 million will be sought from industry, charities and private organizations. Specific activities of the EDCTP include, among other, accelerating clinical trials of new and improved existing products, in particular drugs and vaccines, in developing countries; ensuring that research effectively addresses the needs and priorities of developing countries, helping to develop and strengthen capacities in developing countries including the promotion of technology transfer. 8.4 Public Funding for HIV/AIDS in the United States The National Institutes of Health in the United States represents the largest and most significant public investment in AIDS research in the world – a comprehensive program of basic, clinical, and behavioral research on HIV infection and its associated opportunistic infections and malignancies. See Figures 5 and 6. The President's budget request for the AIDS research programs of the NIH for Fiscal Year 2005 is $2,930,397,000- an increase of $80,445,000 above the comparable FY 2004 appropriation.1 It is not clear that the European Union can match this fiscal commitment. Figure 5 Federal Funding for HIV/AIDS by Category—FY 2004 (US$ Billions) International* $1.9 10% Cash & Housing Assistance $1.8 9% Prevention $0.9 5% Care $11.0 59% Research $3.0 16% 6.7-25 Chapter 6.7: HIV-AIDS Figure 6 : Federal Funding for HIV/AIDS Research—FY 1995-2004 (US$ Millions) 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 There are problems with current HIV therapeutics. Among these are inadequate knowledge of pharmacology (bioavailability, tissue distribution, others), emergence of drug resistant HIV variants, adverse effects, metabolic abnormalities and toxicities, poor adherence to complex, multi-drug regimens, and primary infection with drug-resistant and multi-resistant HIV variants. Thus, notwithstanding the large pipeline and private sector investments, therapeutics discovery and development remains a critical activity. There are several obvious therapeutic “gap” areas: new delivery or formulation methods to enhance the clinical potential of anti-HIV drugs (FDA-approved or those undergoing clinical testing) in infected adults and children; validating new viral and cellular targets for HIV inhibition and for developing new drugs (or developing new agents against existing targets). Continued development of HIV vaccines and microbicides We briefly provide some further details on these issues. 9.1.1 Important viral or host targets yet to be exploited The most commonly used therapies target 2 viral enzymes, reverse transcriptase (RT) and proteases (PR), and a great deal of research is being done on improving dosing, overcoming problems of viral resistance, reducing toxicities, etc. However, not enough emphasis is being placed on identifying new targets that, for instance, would not be affected by viral RT or PR resistance. Some of the targets that might be important include structural elements (such as the highly conserved zinc finger motif of the HIV nucleocapsid or the viral enzymes 6.7-26 Chapter 6.7: HIV-AIDS integrase and RNase H), regulatory and accessory proteins, processes (such as transcription, nuclear import and export of viral nucleic acid, and macromolecular interactions), and host targets (adhesion molecules, transcription factors, cell death, and signaling pathways). One important aspect of working on a new target for an anti-HIV drug is to validate the target in vivo using an animal model. 9.1.2 Candidates for development as topical microbicides Research in this area is still in relatively early stages. 64 Such agents might be HIV-specific or nonspecific, and one challenge has been to identify chemical classes of potential microbicides. Nonhuman primates are being used to study topical microbicides for the prevention of sexual transmission, but such a model has not yet been validated (ie, there is no "gold standard" to match any success against) and the development of other animal models may prove useful. Also, some experimental drugs that are not suitable for systemic use because of toxicity or unfavorable physical characteristics (eg, solubility) may be applicable as topical microbicides. Current expectations about returns, and the uncertainty about development success, have discouraged independent, private-sector investment. Public-sector support has been instrumental to the progress made so far, and will continue to be essential, even after the first microbicide is registered. In FY 2001, the US National Institutes of Health invested only $47 million in microbicide R&D --less than 2% of the Institute's AIDS-related research budget. 65 In early 2004, the European Union awarded $13.7 million to an international consortium of universities, research institutes and biotechnology companies to develop new microbicides that could prevent HIV transmission through the sexual transmission of HIV. This is the largest ever commitment of funds for microbicide work which has not gotten the attention of major pharmaceutical companies but could prevent millions of people from being infected with HIV. 9.1.3 Fixed Dose Combinations66 Fixed dose combination (FDC) medications have the potential to address one of the main therapy-related factors affecting adherence to antiretroviral (e.g., HAART) medication, the complexity of the dosing regimen. Moreover, although no data are available, FDCs in principle may be better than free combinations in slowing or even eliminating resistance to antivirals. Multiple interruptions when using free dose combinations of pills creates the risk of monotherapy on some drugs and not in others. However, this risk can be the same with a FDC using components with different half-life e.g d4T + 3TC + nevirapine). This fact, coupled with the in vivo mutation rates of the HIV-1 genome, rapidly leads to drug resistance to one or more of the free combination drugs. Effectiveness of FDCs, however, depends on detailed knowledge of the epidemiology and microbial ecology of HIV. Efforts should be directed at developing fixed dose combinations (FDCs) of antiretroviral drugs for treatment of HIV infection. Brandname and generic companies have developed FDC antivirals but various technical, regulatory and legal barriers exist that may prevent their wider dissemination. 64 It is essential to document the long-term effectiveness of FDC formulations in clinical settings. 9.1.4 Needs-based Approach to R&D iv The author acknowledges the work of Dr. Bernard Pécoul, formerly of Médecins Sans Frontières as the basis for this section. iv 6.7-27 Chapter 6.7: HIV-AIDS Drawing on experiences of treating HIV/AIDS patients with ARVs in resource-poor settings several questions remain with regard to HIV/AIDS in both Europe and the rest of the world: 1) How can existing tools be made available to persons living with HIV and AIDS in order to improve and lengthen their lives? 2) How can the research agenda be adapted to the needs of persons living with HIV and AIDS. The following recommendations for an HIV/AIDS research agenda apply with equal force in both developed and developing countries. Cheaper prices will have no impact by themselves if treatment protocols are not simplified and this can be accomplished using protocols based on fixed dose combinations. Selected combinations must also produce fewer side-effects, a necessary condition for expanding the use of ARVs. The simplification of second-line and paediatric therapies is also a priority. Simplifying treatment and monitoring means that prescribing responsibility can be delegated from doctors to nursing staff, that health workers can be trained to monitor patients, and that community workers or other persons living with HIV and AIDS can be coached to support patient compliance. Decentralising and demedicalising care within a well defined framework and in a way that is adapted to local conditions will be key to success, whether the setting is eastern Europe or sub-saharan Africa. Further research is needed in this domain to define guidelines for reducing medical consultations to a minimum, and sharing the burden of patient care with community groups, etc. There is a clear need for a public research initiative to develop tools specifically adapted to local conditions and emphasis should be placed on developing drugs that produce few sideeffects and tend not to induce resistance. Different treatment strategies should also be investigated, for instance drugs with prolonged effect, or with different modes of administration. 9.2 What is the Comparative Advantage of the EU with Regard to Public Funding of Pharmaceutical R&D? The European Union cannot match the private or public funding levels of the United States with regard to HIV research and development. However, 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 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 saw previously that the mission of the EDCTP is to accelerate the development of new clinical interventions to fight HIV/AIDS, malaria and tuberculosis in developing countries (DC's), particularly sub-Saharan Africa, and to improve generally the quality of research in relation to these diseases. We believe the opportunities clearly exist to conduct clinical studies into these specialized populations using the EDCTP. Enhance capabilities for long-term followup and evaluate the long-term effects of therapy and the implications of these findings on public health. 6.7-28 Chapter 6.7: HIV-AIDS 10. Evaluate the effects of co-infection, especially with hepatitis B virus (HBV), hepatitis C virus (HCV), tuberculosis (TB), or malaria, on the management of HIVdisease. Evaluate the clinical and public health impact of prophylactic and therapeutic interventions for coinfections/opportunistic infections (OIs) endemic to international settings. Conduct comparative studies in preclinical and clinical evaluation of HIV vaccine candidates and clinical evaluation of anti-HIV therapeutics. We believe that EU should 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 institution 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 microbicides and fixed dose combination clinical trials. Conclusion As of the end of 2003, there were 40 million persons around the world living with HIV infection and AIDS. This epidemic, which began in the late 1980s is continuing to expand in various parts of the world. The commercial market for antiviral therapeutics (primarily funded via the U.S. pharmaceutical industry) will ensure that there will be no shortage of private research funding for the immediate future. The pipeline of potential antiviral products is large and growing. The European Union cannot match the private or public funding levels of the United States with regard to HIV research and development. However, the European Union can contribute from a public health viewpoint: The EU can target affected populations, especially women, injecting drug users (IDUs), children, adolescents, older adults, and across racial/ethnic groups. The European and Developing Countries Clinical Trials Partnership (EDCTP) should be used as a vehicle for undertaking research into these special groups. The EU can conduct comparative studies in preclinical evaluation of HIV vaccine candidates and comparative clinical evaluation of antiHIV therapeutics, in large part through support of the EDCTP and, possibly, the International AIDS Vaccine Initiative (IAVI). Promote innovative mechanisms of funding to attract additional investigators to undertake multidisciplinary research on fixed dose combination antivirals and microbicides discovery and development. If treatment is simplified and made more easily accessible, the stigma of AIDS will diminish, which in turn will contribute to curbing the epidemic. HIV positive people will also become less infectious to their partners, leading to a decrease in transmission. AIDS must become a treatable chronic disease. When that happens, we can begin to reverse the decline in life expectancy and reduce the human and economic impact of the AIDS epidemic in Europe and the world. 6.7-29 Chapter 6.7: HIV-AIDS References 1 DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH Fiscal Year 2005 Budget Request Jack Whitescarver, Ph.D. Director, Office of AIDS Research April 1, 2004 2 Centers for Disease Control Year-End HIV/AIDS Surveillance Report for 2002 (CDC, 2003). 3 .“Centers for Disease Control and Prevention HIV Prevention Strategic Plan Through 2005,” (CDC, 2001). 4 .“HIV/AIDS Update – A Glance at the HIV Epidemic,” (CDC, 2001). 5 UNAIDS/WHO, 2003, AIDS epidemic update, December 2003, ISBN 92 9173 304 0, Geneva, Switzerland, available at http:/ www.unaids.org, last accessed 20 May 2004. 6 UNAIDS/WHO, 2003, AIDS epidemic update, “HIGH-INCOME COUNTRIES”, December 2003, ISBN 92 9173 304 0, Geneva, Switzerland, available at http:/www.unaids.org, last accessed 22 May 2004. 7 Author unknown, 2004. Eastern Europe and Russia face world's fastest growing HIV epidemic BMJ 2004;328:486 8 Carr A & Cooper DA. 2000. Adverse effects of antiretroviral therapy Lancet 2000; 356: 1423–30. 9 Becker SL, 2004, New Targets, New Drugs, Failed Trials and the Need for More Information, available at http://www.thebody.com/tpan/janfeb_04/new_targets.html, last accessed 23 May 2004. 10 Moore JP & Stevenson M. 2000. New Targets for Inhibitors of HIV-1 Replication. Nature Reviews Molecular Cell Biology 1, 40 –49. 11 AIDS economic impact 42.“The Impact of AIDS” (Department of Economic and Social Affairs, United Nations, 2003). 12 Deeks SG. 2003. Treatment of antiretroviral-drug-resistant HIV-1 infection Lancet 2003; 362: 2002– 11 13 Hammer SM, Vaida F, Bennett KK, et al. 2002. Dual vs single protease inhibitor therapy following antiretroviral treatment failure: a randomized trial. JAMA 288: 169–80. 14 51 Gulick RM, Hu XJ, Fiscus SA, et al. 2000. Randomized study of saquinavir with ritonavir or nelfinavir together with delavirdine, adefovir, or both in human immunodeficiency virus- infected adults with virologic failure on indinavir: AIDS Clinical Trials Group Study 359. J Infect Dis 182: 1375–84. 15 Benson CA, Deeks SG, Brun SC, et al. 2002. Safety and antiviral activity at 48 weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside reversetranscriptase inhibitors in human immunodeficiency virus type 1-infected protease inhibitor-experienced patients. J Infect Dis 185:599– 607. 16 Mocroft A, Phillips AN, Miller V, et al. 2001. The use of and response to second-line protease inhibitor regimens: results from the EuroSIDA study. AIDS 15: 201–09. 17 Hall CS, Raines CP, Barnett SH, Moore RD, Gallant JE. 1999. Efficacy of salvage therapy containing ritonavir and saquinavir after failure of single protease inhibitor-containing regimens. AIDS 13: 1207–12. 18 Zolopa AR, Shafer RW, Warford A, et al. 1999. HIV-1 genotypic resistance patterns predict response to saquinavir- ritonavir therapy in patients in whom previous protease inhibitor therapy had failed. Ann Intern Med 131: 813–21. 6.7-30 Chapter 6.7: HIV-AIDS 19 DeGruttola V, Dix L, D’Aquila R, et al. 2000. The relation between baseline HIV drug resistance and response to antiretroviral therapy: re-analysis of retrospective and prospective studies using a standardized data analysis plan. Antivir Ther 5: 41–48. 20 Fletcher CV, Acosta EP, Cheng H, et al. 2000 Competing drug-drug interactions among multidrug antiretroviral regimens used in the treatment of HIV-infected subjects: ACTG 884. AIDS 14: 2495–501. 21 Hsu A, Isaacson J, Brun S, et al. 2003. Pharmacokinetic-pharmacodynamic analysis of lopinavirritonavir in combination with efavirenz and two nucleoside reverse transcriptase inhibitors in extensively pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 47: 350–59. 22 Hirsch MS, Brun-Vezinet F, D’Aquila RT, et al. 2000. Antiretroviral drug resistance testing in adult HIV-1 infection: recommendations of an International AIDS Society-USA Panel. JAMA 283: 2417–26. 23 Harrigan PR, Larder BA. 2002. Extent of cross-resistance between agents used to treat human immunodeficiency virus type 1 infection in clinically derived isolates. Antimicrob Agents Chemother 46: 909–12. 24 Ledergerber B, Egger M, Opravil M, et al. 1999. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1patients: a prospective cohort study. Lancet 353: 863–68. 25 Finzi D, Blankson J, Siliciano JD, et al. 1999. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med 5: 512– 17. 26 Wong JK, Hezareh M, Günthard HF, et al. 1997. Recovery of replication competent HIV despite prolonged suppression of plasma viremia. Science 278: 1291–95. 27 Carr A & Cooper DA. 2000. Adverse effects of antiretroviral therapy Lancet 356: 1423–30. 28 Lewis W, Dalakas MC.1995. Mitochondrial toxicity of antiviral drugs. Nat Med. 1: 417–21. 29 Brinkman K, ter Hofstede HJM, Burger DM, Smeitink JAM, Koopmans PP. 1998. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS 12: 1735–44. 30 Dalakas MC, Monzon ME, Bernardini I, Gahl WA, Jay CA. 1994. Zidovudine-induced mitochondrial myopathy is associated with muscle carnitine deficiency and lipid storage. Ann Neurol 35: 483–87. 31 Lai KK, Gang DL, Zawacki JK, Cooley TP. 1991. Fulminant hepatic failure associated with 2_-3_dideoxyinosine (ddI). Ann Intern Med 115: 283–84. 32 .Carr A, Cooper DA. 1995/1996. Pathogenesis and management of HIV-associated drug hypersensitivity. In: Volberding P, Jacobson MA, eds. AIDS clinical review New York: Marcel Dekker, 1996. 33 Roujeau J-C, Stern RS. 1994. Severe adverse cutaneous reactions to drugs. N Engl J Med 331: 1272–85. 34 Coopman MA, Johnson RA, Platt R, Stern RS. 1993. Cutaneous disease and drug reactions in HIV infection. N Engl J Med 328: 1670–74. 35 Gervasoni C, Ridolfo AL, Trifirò G, et al. 1999. Redistribution of body fat in HIV-infected women undergoing combined antiretroviral therapy. AIDS 13: 465–72. 6.7-31 Chapter 6.7: HIV-AIDS 36 Carr A, Samaras K, Thorisdottir A, Kaufmann G, Chisholm DJ, Cooper DA. 1999. Diagnosis, prediction, and natural course of HIV protease inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus. Lancet 353: 2893–99. 37 Dube MP, Johnson DL, Currier JS, Leedom JM. 1997. Protease inhibitor associated hyperglycaemia. Lancet 350: 713–14. 38 Walli R, Herfort O, Michl GM, et al. 1998. Treatment with protease inhibitors associated with peripheral insulin resistance and impaired glucose tolerance in HIV-1-infected patients. AIDS 12: F167–74. 39 Vardas E, Kreis S. 1999. Isolation of measles virus from a naturally-immune, asymptomatically reinfected individual. J Clin Virol 13: 173–79. 40 Pedersen IR, Mordhorst CH, Glikmann G, von Magnus H. 1989. Subclinical measles infections in vaccinated seropositive individuals in arctic Greenland. Vaccine 7: 345–48. 41 Levy JA. 2001. What can be achieved with an HIV vaccine? Lancet 357: 223–24 42 Whittle HC, Aaby P, Samb B, Jensen H, Bennett J, Simondon F. 1999. Effect of subclinical infection on maintaining immunity against measles in vaccinated children in West Africa. Lancet 353: 98–102 43 Damien B, Huiss S, Schneider F, Muller CP. 1998. Estimated susceptibility to asymptomatic secondary immune response against measles in late convalescent and vaccinated persons. J Med Virol 56: 85–90. 44 Sutter RW, Patriarca PA, Brogan S, et al. 1991. Outbreak of paralytic poliomyelitis in Oman: evidence for widespread transmission among fully vaccinated children. Lancet 338: 715–20. 45 Harcourt GC, Best JM, Banatvala JE. 1980. Rubella-specific serum and nasopharyngeal antibodies in volunteers with naturally acquired and vaccine-induced immunity after intranasal challenge. J Infect Dis. 142: 145–55. 46 Fogel A, Gerichter CB, Barnea B, Handsher R, Heeger E. 1978. Response to experimental challenge in persons immunized with different rubella vaccines. J Pediatr. 92: 26–29. 47 Levy JA. HIV and the pathogenesis of AIDS, 2nd edn. Washington, DC: American Society of Microbiology, 1998. 48 Pantaleo G, Menzo S, Vaccarazza M, et al. 1995. Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N Engl J Med.332: 209–16. 49 Bourinbaiar AS, Metadilogkul O & Jirathitikal V. 2003. Mucosal AIDS Vaccines, Viral Immunology 16: 427–445. 50 Berman, P.W., Gray, A.M., Wrin, T., et al. 1997. Genetic and immunologic characterization of viruses infecting MN-rgp120-vaccinated volunteers. J. Infect. Dis. 176:384–397. 51 Kahn, JO., Steimer, KS., Baenziger, J., et al. 1995. Clinical, immunologic, and virologic observations related to human immunodeficiency virus (HIV) type 1 infection in a volunteer in an HIV-1 vaccine clinical trial. J. Infect. Dis. 171:1343–1347. 52 McElrath, M.J., Corey, L., Greenberg, P.D., et al. 1996. Human immunodeficiency virus type 1 infection despite prior immunization with a recombinant envelope vaccine regimen. Proc. Natl. Acad. Sci. USA 93:3972–3977. 53 Fust, G. 1997. Enhancing antibodies in HIV infection. Parasitology 115:S127–S140. 54 Homsy, J., Meyer, M., Tateno, M., et al. 1989. The Fc and not CD4 receptor mediates antibody enhancement of HIV infection in human cells. Science 244:1357–1360. 6.7-32 Chapter 6.7: HIV-AIDS 55 Robinson, WE., Jr, Montefiori, DC., and Mitchell, WM. 1998. Antibody-dependent enhancement of human immunodeficiency virus type 1 infection. Lancet 1:790–794. 56 Bourinbaiar, AS., Borkowsky, W., Krasinski, K.M., et al. 1997. Failure of neutralizing gp120 monoclonal antibodies to prevent HIV infection of choriocarcinoma-derived trophoblasts. J. Biomed. Sci. 4:162–168. 57 Phillips, DM., and Bourinbaiar, AS. 1992. Mechanism of HIV spread from lymphocytes to epithelia. Virology 186:261–273. 58 Wentworth, P. Jr., McDunn, JE., Wentworth, AD., et al. 2002. Evidence for antibody-catalyzed ozone formation in bacterial killing and inflammation. Science 298:2195–2199. 59 Meyer, D., Anderson, D.E., Gardner, M.B., et al. 1998. Hypervariable epitope constructs representing variability in envelope glycoprotein of SIV induce a broad humoral immune response in rabbits and rhesus macaques. AIDS Res. Hum. Retro. 14:751–760. 60 The Body: An AIDS and HIV Information Resource: HIV Drugs in Development at http://www.thebody.com/treat/newdrugs.html , last accessed 23 May 2004. 61 Author unknown, 2004. Background Document Making An HIV Vaccine Available For The Developing World: The European Union’s Strategy And Actions, at http://europa.eu.int/comm/external_relations/us/summit_05_00/hiv_vaccine_eu_strategy.htm, last accessed 24 May 2004. Tucker TU & Mazithuela G. 2004. Development of an AIDS vaccine: perspective from the South African AIDS Vaccine Initiative. BMJ 329: 454-456. 62 63 Klausner RD et al. 2003. The Need for a Global HIV Vaccine Enterprise. Science 300: 2036-2039. International Partnership for Microbicides, http://www.ipm-microbicides.org, last accessed 23 May 2004. 64 Global Campaing for Microbicides at http://www.global-campaign.org/bigpharma.htm, last accessed 20 May 2004. 65 World Health Organization, 2003. FIXED DOSE COMBINATIONS FOR HIV/AIDS, TUBERCULOSIS, AND MALARIA, Current status and future challenges from clinical, regulatory, intellectual property, and production perspectives, 15-17 December 2003, at http://www.who.int/medicines/organization/par/FDC/FDCmain.shtml, last accessed 25 May 2004. 66 6.7-33