Recognizing the Value of Innovation in HIV/AIDS Therapy - White Paper | December 2012
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White Paper | December 2012 Recognizing the Value of Innovation in HIV/AIDS Therapy Catherine Augustyn, Brigham Walker, and Thomas F. Goss, PharmD Boston Healthcare Associates, Inc., Boston, MA and Washington, DC
INTRODUCTION research that must be conducted to secure FDA
regulatory approval, these studies are designed
In the last two decades, we have seen for controlled evaluation of safety and efficacy.
remarkable progress against HIV/AIDS Therefore, pre-approval trials are limited in their
(human immunodeficiency virus/acquired ability to capture the broader and longer-term
immunodeficiency syndrome), transforming the clinical and quality-of-life benefits that may be
disease from an acute, fatal illness to a chronic associated with a specific therapy as physicians
condition. In the United States, death rates have accumulate evidence using the new agents in
fallen 79 percent since 1995 as a result of highly real-world settings.
active antiretroviral therapy (HAART, or ART
as is more commonly used today) and other We selected HIV/AIDS as a case study for this
new medications.1 Advances in treatment have analysis because significant gains in clinical
increased survival, slowed progression, prevented outcomes have been achieved over the past 15
hospitalizations, and allowed patients to lead full years, which are clearly documented in scientific
lives. In retrospect, the clinical improvements literature. This paper evaluates how step-wise
produced by novel treatment options for HIV/AIDS progress was achieved over time and the
have been far above what could have been ways in which biopharmaceutical innovations
anticipated or achieved at the time of the initial have enabled better disease management and
introduction of these individual medicines. improved quality of life for patients.
Understanding how this progress was achieved —
as well as how the evidence supporting it evolved This white paper is the second installment in a
— is important to sustaining an environment for series of papers focused on recognizing value in
future advances. biopharmaceutical innovation. The previous white
paper, Recognizing Value in Oncology Innovation
This progress has been realized through a (June 2012), demonstrated how the full clinical
complex process of incremental gains that have value of a cancer therapy typically evolves
unfolded over many years. Although not well- significantly after FDA approval. These reports
characterized or understood, this innovation illustrate how this evolution frequently reveals
process has involved the step-wise accumulation that for many therapies, greater clinical value is
of treatment improvements over time, which realized based on real-world experience than
has taken place as research has continued to was able to be demonstrated prior to launch.
accumulate evidence that has driven changes These reports also acknowledge that, at times,
in HIV treatment. Our understanding of how real-world experience can prove a medicine
certain novel therapies may be optimally to be less valuable than initially expected.
applied to patient care changes and improves
as HIV therapies are introduced and evaluated
in real-world clinical practice, resulting in new Background on HIV/AIDS
approaches to treatment, which incrementally
increased efficacy and tolerability. The key HIV infection is one of the most prevalent
element to ensuring continued, and at times, infectious diseases in the world, affecting more
unexpected innovation that drives improved than 34 million people globally in 20112 and 1.2
patient outcomes is to ensure flexible access to
million people in the United States as of 20083.
therapeutic options. This access supports the
step-wise process that has been central to clinical In people infected with HIV, the virus gradually
gains made in HIV and many other disease areas, compromises the immune system by entering
and has enabled patients around the world to live and taking over T-cell lymphocytes. The adoption
longer and better than ever before.
of antiretroviral therapies to treat HIV/AIDS
Since medical progress with individual starting in the 1990s has led to sharp mortality
compounds may be realized gradually over declines and greatly improved quality of life.
time, the optimal role and full value of a therapy These medicines have fundamentally changed
typically cannot be known at the time of Food
HIV from an acute fatal illness to a manageable
and Drug Administration (FDA) approval or U.S.
market launch. Although one of the distinctive chronic disease.
features of new medicines is the rigorous clinical
Recognizing the Value of Innovation in HIV/AIDS Therapy | 1Evolution of the Treatment of HIV Infection: 1980s to Present
FIGURE 1. Evolution of the Treatment of HIV Infection: 1980s to Present
New Indications Today
HIV/AIDS
Chronic,
Earlier Use manageable
condition
Use in
1980s–1990s Combinations
HIV/AIDS
Acute, fatal
illness NEW DRUG APPROVALS
In this white paper, we will explore the treatment Combination Therapy
of HIV/AIDS and highlight the various ways
in which additional clinical value – including The treatment paradigm for HIV/AIDS has evolved
improved survival and quality of life – has been dramatically over the last several decades to the
realized over time. The pathways identified here point where combination therapy has become
show some of the ways our understanding of a the mainstay in HIV/AIDS treatment. Combination
medicine’s value changes over time, including therapy has been shown to provide the best
a few that are shared in common with cancer opportunity for clinical response and disease
treatments, as discussed in the previous white remission in HIV/AIDS patients, even beyond
paper: initial expectations.
• Use in combination with other agents The value of combination therapies in the
• Use earlier in treatment line and earlier in treatment of HIV/AIDS cannot be overstated.
disease state These combinations are critical to preventing the
• Use in different disease indications* development of viral resistance and successfully
treating the primary infection. Highly active
FDA approval often marks the “starting point” antiretroviral therapy describes a type of
for a number of additional evaluations of a novel combination regimen used in HIV/AIDS treatment
therapy. Following launch, a larger body of that typically includes two nucleoside analogue
evidence is developed through real-world practice reverse transcriptase inhibitors (NRTI) and either
and ongoing research. In the case of HIV/AIDS, a non-nucleoside analogue reverse transcriptase
antiretroviral therapies have proven to be inhibitor (NNRTI), a protease inhibitor (PI), or an
effective in a broader cohort of patients than were integrase inhibitor (II).
represented in the clinical trial data submitted for
initial FDA approval. Individual and combination In the current era, all four classes are indicated
therapies have created new opportunities for for use in combination with other antiretroviral
improved disease control and remission, particularly agents for the treatment of HIV infection.
when used in patients with earlier disease stages However, this understanding has evolved
who were not included as part of pre-approval significantly over time based on rigorous
trials, reinforcing that it is important to recognize evaluation of new combinations, as new classes
that the full clinical value and potential of a of agents have been discovered and approved. In
therapy may only be identified and realized the early stages of HIV/AIDS therapy, combination
through a “step-wise transformation” over time.
* This may include both new indications approved by the FDA and off-label uses supported by research and deemed clinically appropriate
by physicians. The evidence in this paper focuses on new FDA-approved indications.
2 | Recognizing the Value of Innovation in HIV/AIDS Therapyregimens were not available and viral resistance An examination of the death rates among HIV-
quickly became a challenge. It has taken time and infected individuals over the stages described
real-world clinical practice to identify and test above (pre-HAART, early-HAART, and late-HAART)
a variety of HAART combinations, which today reveals a similar change in the United States as
yield improved efficacy and better tolerability and these innovative therapies and combinations
safety profiles than ever before. were introduced. While the death rate does not
represent a comprehensive measure of mortality,
Since 1996, HAART combination regimens have it can be indicative of a trend, and in this case
significantly reduced the mortality rate of HIV- shows the rapid decline in deaths among
infected patients.4 According to 2010 Centers individuals infected with HIV when the use of
for Disease Control and Prevention (CDC) data, HAART therapies increased through the 1990s
the age-adjusted number of deaths per 100,000 (See Figure 2).
due to HIV in the United States has decreased
by 79 percent over the last two decades.1 The Since the 1990s, certain HAART regimens have
Kaiser Family Foundation attributed this dramatic yielded better outcomes in HIV patients over
improvement as “largely due to [the adoption of] time as their use has been refined in a real-world
highly active antiretroviral therapy.”5 More than population. An analysis presented in 2008 at
30 treatment options for HIV have been developed the 9th International Congress on Drug Therapy
since 1987, arming physicians with increasingly in HIV Infection compared the efficacy of first-
more therapeutic options that support these kinds line HAART regimens in 2006 to those used in
of improvements in patient survival.6 1998.8 The analysis included 146 patients starting
first-line HAART during these years (67 in 1998;
Over time, moving from the pre-HAART era in 79 in 2006). HIV suppression at 48 weeks was
which no HAART regimens were available, to observed in 59.1 percent of patients in 1998 and
the early- and then late-HAART eras in which 88.6 percent in 2006 (P < 0.001). In a multivariate
not only have more antiretroviral therapies been analysis, virologic suppression was independently
developed but also new combinations have associated only with two factors: at least 48-week
been tested, clinical outcomes have improved adherence and being treated in 2006 versus 1998.
dramatically. The multitude of antiretroviral agents These results support an independent association
approved in the past two decades has allowed between better outcomes and the specific year of
clinicians to tailor therapy to a patient’s specific treatment, suggesting that the availability of new
needs and viral profile. antiretroviral agents allows for more refined and
effective combination therapy.
One large study by Danish researchers assessed
the mortality rates of 3,990 HIV-infected These observations may be explained by a
individuals and 379,872 general-population number of potential factors, including earlier
controls from the pre-HAART (1995-96), early- diagnosis and treatment, better tolerance of
HAART (1997-99), and late-HAART (2000-05) eras. available regimens leading to improved efficacy
In these distinct phases, new medicines became of, and adherence to, treatments, and adoption of
available and researchers discovered more better understood treatment combinations.
effective combinations. Researchers reported that
the highest mortality rate among HIV-infected In addition, in recent years we also have seen
patients – 124 per 1,000 person years – was significant advances in antiretroviral therapy
observed in the pre-HAART period, falling to 38 dosing that have led to simpler regimens
per 1,000 in the early-HAART period, and further with reduced pill burden on patients. These
to 25 in 1,000 in the late-HAART period.7 These co-formulations combine two or more
data support the hypothesis that developing and antiretroviral medications into one dosage
making available more therapeutic options can form with the same clinical impact, meaning
provide opportunity for clinical breakthroughs as HIV treatment is more effective today in part
new combination regimens are tested over time. due to improved patient adherence.
Recognizing the Value of Innovation in HIV/AIDS Therapy | 3FIGURE 2. HIV DeathHIV Death
Rates andRates
HAARTand HAART Treatment
Treatment AdvancesAdvances (U.S., 1990–2010)
(U.S., 1990-2010)
Pre-HAART Early-HAART Late-HAART
59% Increase 67% Decrease Progress Continues: 49% Decrease
18
16
Deaths per 100,000 resident population
with HIV (age-adjusted) in the U.S.
14
12
10
8
6
4
2
0
1990 1995 2000 2005 2010
Sources:
U.S. Department of Health and Human Services (HHS), Centers for Disease Control and Prevention (CDC), National Center for Health Statistics (NCHS), “Health, United
States, 2011 with Special Feature on Socioeconomic Status and Health,” Table 22, http://www.cdc.gov/nchs/data/hus/hus11.pdf, (2012);
S.L. Murphy, J. Xu, and K.D. Kochanek, “Deaths: Preliminary Data for 2010,” U.S. HHS, CDC, NCHS, National Vital Statistics Reports 60, no. 4: (2012);
U.S. HHS, CDC, NCHS, “Health, United States, 2010 with Special Feature on Death and Dying, http://www.cdc.gov/nchs/data/hus/hus10.pdf, (2011);
K.D. Kochanek, J. Xu, S. L. Murphy, et al., “Deaths: Preliminary Data for 2009,” U.S. HHS, CDC, NCHS, National Vital Statistics Reports 59, no. 4: (2011);
U.S. HHS, CDC, NCHS, “Health, United States, 2009 with Special Feature on Medical Technology,” Table 38, http://www.cdc.gov/nchs/data/hus/hus09.pdf, (2010);
U.S. HHS, CDC, NCHS, “Health, United States, 2008 with Special Feature on the Health of Young Adults,” Table 41, http://www.cdc.gov/nchs/data/hus/hus08.pdf, (2009);
U.S. HHS, CDC, NCHS, “Health, United States, 2003 with Chartbook on Trends in the Health of Americans,” Table 42, http://www.cdc.gov/nchs/data/hus/hus03.pdf, (2003);
U.S. HHS, CDC, NCHS, “Health, United States, 1996-97 and Injury Chartbook,” Table 44, http://www.cdc.gov/nchs/data/hus/hus97cht.pdf (1997).
Earlier Use of Advanced The 2011 Department of Health and Human
Services (HHS) Guidelines for the Use of
Therapies in Disease Antiretroviral Agents in HIV-1-Infected Adults
Management and Adolescents affirm that there is evidence
to support the benefits of viral suppression and
In addition to an increased use of combination immunologic response in patients with higher
therapy, the treatment paradigm for HIV/AIDS has pre-treatment CD4 counts (immune response
evolved to reflect the benefits of initiating therapy cells) – in other words, with earlier-phase disease.9
earlier to better control disease progression. In HIV-infected individuals who are not treated
Real-world clinical practice and recent data adequately, CD4 counts generally decrease as
support the notion that earlier initiation of HIV progresses. A low CD4 count indicates a
treatment in the disease cycle leads to improved weakened immune system and a higher chance
long-term outcomes and immunologic response. of acquiring opportunistic infections. However,
today patients previously considered to be in
The effectiveness of ART therapy to treat HIV “pre-treatment” phase (with higher CD4 counts)
patients has driven not only widespread use often receive early ART treatment and are able to
of combination therapy, but also progressively derive short- and long-term benefits.
earlier use in the timeline of disease progression.
4 | Recognizing the Value of Innovation in HIV/AIDS TherapyThe median CD4 count for newly diagnosed patients waited to begin treatment until their
patients is around 200 cells/mm3.Yet the HHS CD4 count fell below 250 cells/mm3 or they had
Guideline Panel gave its highest recommendation an AIDS-related illness. The findings were robust
that antiretroviral therapy be initiated in all patients enough that the study was unblinded four
with a CD4 count as high as 500 cells/mm3.The years early.
Guideline Panel based its recommendation on
several recent developments:9
• A report from the recent NA-ACCORD cohort
Use in Additional
study10 demonstrating survival benefit with Disease Indications
initiation of antiretroviral therapy at “pre-
treatment” CD4 count levels greater than 500 Improved understanding of disease pathology –
cells/mm3; in many cases at the molecular level – has had
a direct impact on the development of ART and
• The study observed patients who started
other HIV treatments over the past two decades.
treatment at CD4 counts greater than 500
With a better understanding of how the disease
cells/mm3 or after CD4 counts dropped
evolves and progresses, therapies have become
below this threshold.
more targeted and have proven to be beneficial
• The risk of death was 94 percent higher not only for the treatment of the disease but
among the 6,935 patients who deferred also for the prevention of transmission, leading
therapy until CD4 counts fell to less than to new uses and indications for many
500 cells/mm3 compared with rates in the treatment regimens.
2,200 patients who started therapy while
CD4 count was greater than 500 In the case of HIV infection, access to multiple
cells/mm3. treatment options has enabled clinicians and
• Growing awareness that untreated HIV researchers to uncover additional and inherent –
infection may be associated with development but previously unrecognized – secondary values
of many non-AIDS-defining diseases, including of individual regimens. Although by their nature
cardiovascular disease, kidney disease, liver antiretrovirals do not lend themselves to new
disease, and malignancy; and indications as much as some other disease areas
(e.g., oncology), even in this area, potential for
• Availability of antiretroviral regimens that are
use in new populations has been uncovered.
more effective, more convenient, and better
tolerated than antiretroviral combinations no
Preventing Maternal-Fetal Transmission
longer in use.
Antiretrovirals were developed and first approved
for patients with primary HIV infection. Yet certain
Citing its own evolution over time, the Guideline
antiretrovirals have provided additional specific
Panel summarized its findings by stating that
benefit to infected pregnant women and their
prior concerns about long-term toxicity, reduced
unborn children, helping to drive down the rate of
quality of life, and the potential for drug
maternal fetal HIV transmission.
resistance previously acted as barriers to its
recommendation of earlier treatment initiation.9
The most salient example is zidovudine (ZDV,
But this year, the Guideline Panel concluded that
Retrovir®), which was initially approved by
increasing evidence supports earlier initiation of
the FDA in 1989 to treat HIV infection, but
antiretroviral therapy.
subsequently was approved for the prevention of
maternal-fetal HIV-1 transmission.12 In February
Extending the research showing the benefits
1994, results from the Pediatric AIDS Clinical
of early treatment, researchers have found that
Trials Group indicated a 67 percent reduction
early use of antiretroviral treatments reduced the
in perinatal HIV transmission using ZDV.13
chances of transmission to an uninfected partner
Two months later, the CDC issued provisional
by 96 percent.11 This large international study
guidelines supporting the use of the therapy
compared an early treatment group, in which
for this purpose, followed by formal FDA
the HIV-infected partner initiated ART treatment
approval, and finally published consensus
immediately, with a deferred group, in which
recommendations jointly issued by the
Recognizing the Value of Innovation in HIV/AIDS Therapy | 5Reductions in Mother-to-Child HIV Transmission
U.S. Public Health Service Task Force (USPHSTF)
and CDC.14 FIGURE 3. Reductions in Mother-to-Child
HIV Transmission
Antiretroviral use for the purpose of preventing
perinatal HIV transmission has increased 35%
dramatically in the United States, and 30%
25–30%
transmission rates have diminished. One multi-
state study determined that from 1993 – before 25%
approval of ZDV for the specific indication
20%
– to post-approval in 1996, infected pregnant
women were increasingly offered ZDV over 15%
other therapies. The authors asserted that “the
10%
proportion of HIV-infected pregnant women
offered prenatal ZDV increased from 27 percent 5%
to 85 percent, the proportion offered intra-partum 2%
ZDV increased from 5 percent to 75 percent, and 0%
1994 2002
the proportion offered neonatal ZDV increased
from 5 percent to 76 percent.”15 The expanded
use of ZDV for this subsequent indication has Source: Centers for Disease Control and Prevention, “Achievements
contributed dramatically to driving maternal HIV in Public Health: Reduction in Perinatal Transmission of HIV Infection
transmission rates down from 30 percent to less – United States, 1985-2005,” MMWR, 55 (2 June 2006) 21, 592-597
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5521a3.htm.
than two percent.14 (See Figure 3.)
The updated HHS guidelines specifically Prevention of HIV Infection in
encourage the treatment of infected pregnant High-Risk Populations
women to prevent maternal-fetal HIV-1 Building on the successful use of ART in the
transmission. The guidelines now recommend prevention of maternal-fetal HIV-1 transmission,
that a combination regimen be initiated in all researchers have worked to establish the use
infected pregnant women – even those who of these therapies to help prevent HIV infection
would not be candidates based on their own in high-risk populations. Recent evidence has
clinical presentation – with the goal of preventing led to the approval of emtricitabine/tenofovir
perinatal transmission of HIV to the fetus.9 This disoproxil fumarate (Truvada®) in July 2012 for
updated recommendation reflects a focus on the prevention of HIV/AIDS in uninfected people,
decreasing maternal-fetal HIV transmission, and or pre-exposure prophylaxis (PrEP). This is the
therefore an emerging consideration of risk to first approval of its kind.
both a mother and her fetus.
Emtricitabine/tenofovir disoproxil fumarate is
Based on these kinds of clinical observations, already approved, in combination with other
physicians and patients can make more informed antiretroviral agents, for treatment of HIV-1
decisions today about the differential risks and infection in adults and pediatric patients ages 12
rewards of regimens with similar approved and older.16 It will now be used, in combination
indication profiles. Furthermore, because with safe sex practices and other prevention
guidelines now support the use of antiretroviral strategies, by uninfected individuals who are at
therapies for the prevention of maternal-fetal high risk of HIV infection and who may engage in
HIV-1 transmission, physicians and patients sexual activity with HIV-infected partners.17
together can consider and select the optimal
therapy regimen based on family planning and The new indication was approved based on two
risk to a woman’s fetus. This is another example of large clinical trials. The iPrEx trial conducted by
incremental research leading to increased utility the National Institute of Allergy and Infectious
and optimized treatment selection that was not Diseases (NIAID) found that a once-daily oral dose
proven at the time of approval of certain therapies of emtricitabine/tenofovir disoproxil fumarate
like ZDV. provided protective efficacy of 44 percent among
men and transgender women who have sex
6 | Recognizing the Value of Innovation in HIV/AIDS TherapyPreventative Drug Treatment Reduces Risk of Infection
with men compared with placebo. Efficacy was
strongly connected with adherence; participants FIGURE 4. Preventative Drug Treatment
who took PrEP medication on 90 percent or Reduces Risk of Infection
more days during the treatment period had an
estimated 73 percent HIV risk reduction, while FTC/TDF resulted in
those who took PrEP medication on more than 50 73% few infections
47 than placebo
percent of days had an estimated 50 percent HIV
risk reduction.18 (See Figure 4.) Placebo
A study conducted by the CDC among FTC/TDF*
heterosexual men and women in Botswana
showed that emtricitabine/tenofovir disoproxil
fumarate reduced the risk of acquiring HIV 13
infection by 62 percent.19 The Partners PrEP study
indicated a reduced risk of transmission from one Number of patients infected
partner to the other of 75 percent when compared *FTC/TDF is emtricitabine combined with tenofovir. Data reflect study
to placebo.16 This study, with clinical sites in results through May 2011 as reviewed by the Partners PrEP Study
Kenya and Uganda, was conducted among Data and Monitoring Board.
heterosexual couples where one partner is
Source: University of Washington International Clinical Research
HIV positive.
Center press release, “Pivotal Vital Study Finds that HIV Medications
are Highly Effective as Prophylaxis Against HIV Infection in Men
and Women in Africa,” (Date through May 2011) http://depts.
Conclusion washington.edu/uwicrc/research/studies/files/PrEP_PressRelease-
UW_13Jul2011.pdf.
This paper illustrates the substantial clinical
gains that have been made in the treatment
of HIV/AIDS, and some of the important factors Over the past two decades, a greater understanding
in these gains, over the past two decades. has evolved of the optimal clinical role and value
HIV/AIDS has evolved from a lethal disease to of new HIV treatments, both alone and in different
one that is chronic, manageable, and preventable combination therapies, as well as the value of
for patients who have access to medicines. their utilization at earlier stages of the disease
Mortality rates related to HIV infection are at cycle. Early combination regimens are recognized
an all-time low, and the availability of multiple to offer the best opportunity for disease control
antiretroviral options allows physicians to select and remission. What is more, many of these
the optimal combination regimen to achieve treatments have been shown to provide
undetectable viral load and to prevent or delay previously unrecognized benefit in a variety of
the development of drug resistance. Even patients new preventative and prophylactic indications.
who have failed prior treatment regimens or For example, certain antiretrovirals now provide
suffer from drug-resistant virus can generally tremendous opportunity for the management of
achieve positive outcomes with today’s extensive pregnant women who are infected with HIV and
therapy options. some have been shown to prevent infection in
adults.
These gains have been made slowly but steadily
through a complex process of “step-wise It is important to recognize that these broader
transformation” that involves introduction of a benefits are frequently not proven at the time of
series of incremental improvements in treatment initial FDA approval. An assessment based on
over time. The introduction of new medicines available evidence at the time of launch would
is clearly fundamental to advancing treatment. have substantially underestimated the full clinical
However, this paper focuses on another value of these treatments to patients with
important, but less recognized aspect of medical HIV/AIDS. Over time, real-world practical
progress: the evolution of our understanding experience and a growing body of published
of value of new medicines over time through clinical data documenting this experience have
continued research and use in real-world revealed unforeseen elements of value for
clinical practice. individual therapies. Because the optimal role
Recognizing the Value of Innovation in HIV/AIDS Therapy | 7and full value of an individual therapy cannot be research, innovation, and patient care. On the
known at the time of FDA approval – for HIV and other hand, flexible policies that are sensitive to
other disease areas – it is important that patients, the way the evidence of value emerges over time
and the clinicians who care for them, have access will help ensure that new treatments are properly
to a full range of treatment options. valued and available to patients. Such policies,
which are in line with the incremental scientific
Policymakers can foster this continued progress, process, will also promote future advances by
and the evolution of knowledge that supports properly incentivizing innovation. Continued
it. Policy approaches that seek to assess the innovation and evolution with both existing and
definitive value of a therapy at the time of as-yet undiscovered therapies provide hope for
introduction will fail to capture its full value over future clinical advances that will benefit individual
time and will act as a disincentive to long-term patients and society as a whole.
Endnot e s
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8 | Recognizing the Value of Innovation in HIV/AIDS TherapyBoston Healthcare Associates, Inc. Boston Healthcare helps biopharmaceutical, medical device, and diagnostics companies unlock the value of innovation in the global healthcare marketplace. Clients rely on Boston Healthcare to create opportunities, navigate complexity, grow their businesses, and achieve their objectives through reimbursement and market access strategy, health economics and outcomes analysis, market and pricing strategies, and business development support—all delivered to help clients capture value. Boston Healthcare’s unique approach, combining strategic consulting with a deep understanding of the evidence-driven value environment, gives clients a real-world edge in assessing, creating, and capturing growth opportunities. For more information, visit www.bostonhealthcare.com. Funded by a grant from the Pharmaceutical Research and Manufacturers of America. Recognizing the Value of Innovation in HIV/AIDS Therapy White Paper | December 2012
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