Download HIV/AIDS: Opportunities to Address Pharmaceutical

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).
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