The
NEW ENGLA ND JOURNAL
of
MEDICINE
Perspective november 28, 2013
The Quest for an HIV-1 Vaccine — Moving Forward Dan H. Barouch, M.D., Ph.D.
Related article, p. 2083
V
accines have historically been the most effective biomedical interventions for controlling global infectious diseases. The development of a safe and effective vaccine against human immunodeficiency virus type 1 (HIV-1) is therefore a critical research priority. Although other HIV-1 prevention efforts based on behavioral risk reduction, male circumcision, topical microbicides, preexposure prophylaxis, and treatment as prevention have had substantial effects on HIV-1 transmission rates, it is likely that a vaccine will be required to end the global HIV-1 epidemic. The challenges in the development of a prophylactic HIV-1 vaccine, however, are unprecedented in the history of vaccinology. First, HIV-1 exhibits tremendous global genetic diversity as well as mutational capacity that can evade both humoral and cellular immune responses. The generation
of vaccine antigens that will elicit immunologically relevant and broadly cross-reactive immune responses thus represents a major challenge. Second, HIV-1 rapidly integrates into the host genome and establishes a latent reservoir that cannot be eliminated by conventional antiretroviral drugs or virus-specific immune responses. A vaccine will therefore most likely need to induce potent and functional virus-specific antibodies that block establishment of initial infection, in addition to high levels of T lymphocytes for virologic control. Third, there are no known examples of spontaneous immune-mediated clearance of HIV-1 infection indicative of natural immunity, and thus the pre-
cise types of immune responses that need to be induced by a vaccine are not well understood. Fourth, although a series of broad and potent neutralizing monoclonal antibodies have recently been discovered, such antibodies are induced only in a subgroup of HIV-1–infected persons after several years of infection and typically exhibit extensive somatic hypermutation. No method currently exists to induce such antibodies by vaccination. Over the past 30 years, only four HIV-1 vaccine concepts have been evaluated in clinical efficacy trials. The relative paucity of such trials speaks to the tremendous scientific and logistic challenges associated with HIV-1 vaccine development. The vaccine platforms that have been evaluated in efficacy studies have included purified HIV-1 envelope (Env) proteins, recombinant adenovirus and poxvirus vectors, and plasmid DNA
n engl j med 369;22 nejm.org november 28, 2013
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF EXETER on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved.
2073
PERS PE C T IV E
The Quest for an HIV-1 Vaccine
Env glycoprotein trimer Outer domain glycan site
Top view
Quaternary V1-V2 glycan site
CD4binding site Glycan shield
Membrane proximal external region
HIV-1
Structure of HIV-1 and Expanded View of the Envelope (Env) Glycoprotein Trimer. COLOR FIGURE Targets of virusspecific neutralizing antibodies are shown, including the quaternary Draft 5 11/13/13 V1V2 glycan site, the outer domain glycan site, the CD4binding site, and the mem Author Barouch brane proximal external region. From Nabel GJ. DesigningFigtomorrow’s vaccines. 1 # N Engl J Med 2013;368:55160. Title
vaccines. The first concept that was evaluated was the AIDSVAX Env gp120 protein vaccines, which were tested in two phase 3 efficacy studies in the United States and Thailand and were reported in 2003 to have no efficacy in the populations studied.1,2 The second concept that was evaluated was an adenovirus serotype 5 (Ad5) vector expressing the internal proteins Gag, Pol, and Nef. This vaccine was shown in a phase 2b efficacy study in North 2074
ME
and SouthDEAmerica in 2007 to Malina Artist Knoper have no efficacy and in fact may AUTHOR PLEASE NOTE: have increased the riskand type ofhasHIV-1 Figure has been redrawn been reset Please check carefully 3 acquisitionIssue indate certain subgroups. 11/28/13 A parallel study involving the same vaccine in South Africa was terminated shortly after initiation, and unblinded follow-up also showed increased rates of HIV-1 infection in vaccinees. The third concept that was evaluated was a prime–boost vaccine regimen that involved the canarypox ALVAC vector followed
n engl j med 369;22
nejm.org
by the AIDSVAX Env gp120 proteins. This was a phase 3 study (RV144) conducted in a low-risk population in Thailand that showed in 2009 a 31% reduction in the rate of HIV-1 acquisition.4 Vaccine-elicited antibodies against the first and second variable loops (V1-V2) of Env correlated with a reduced risk of HIV-1 infection,5 although the applicability of these findings to other vaccine platforms remains unclear. The fourth HIV-1 vaccine concept for which clinical efficacy testing has been completed is described in this issue of the Journal (see pages 2081–2090). This vaccine was produced by the National Institutes of Health (NIH) Vaccine Research Center and included priming with DNA vaccines and boosting with Ad5 vectors expressing Env, Gag, and Pol. The trial was a phase 2b efficacy study (HVTN 505) conducted in the United States in men or transgender women who have sex with men. Vaccinations were halted at the interim analysis in April 2013 because of lack of efficacy. Although the vaccine induced both humoral and cellular immune responses in the majority of recipients, the levels of neutralizing antibodies, nonneutralizing antibodies, and V2specific antibodies were low. There was, however, no evidence of increased rates of HIV-1 acquisition among vaccinees, although unblinded follow-up of participants is still ongoing. Despite the lack of efficacy, this study represents an important contribution to the HIV-1 vaccine field. It was a well-designed study that reached a clear conclusion on which future research can build. Future HIV-1 vaccine candidates will need to elicit im-
november 28, 2013
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF EXETER on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved.
PE R S PE C T IV E
The Quest for an HIV-1 Vaccine
mune responses that are either qualitatively different from or quantitatively superior to those induced by the DNA–Ad5 vaccine. It also appears that preclinical evaluation of future vaccine candidates should involve stringent challenge models, since the DNA– Ad5 vaccine afforded substantial protection against challenges with the easy-to-neutralize simian immunodeficiency virus (SIV) strain E660 (SIVsmE660) in rhesus monkeys but failed to protect against the more difficult-to-neutralize virus SIVmac251. In addition, despite the need to offer the best available HIV-1 prevention meth-
sibility that vaccination strategies could be developed to induce such antibodies. Emerging data on the structure of the HIV-1 Env glycoprotein and the ontogeny of Envspecific B-cell responses have led to the design of novel immunogens. The impressive virologic control achieved by virus-specific T lymphocytes in certain settings has also suggested important new strategies for improving cellular immune responses. Moreover, preclinical studies involving stringent challenge models have shown that several novel vaccine candidates have substantially better protective efficacy
There are clear reasons for optimism in the quest to develop an HIV-1 vaccine. The modest protection achieved in the RV144 study provides the proof of concept that an HIV-1 vaccine is in fact possible. ods to all participants, potentially including preexposure prophylaxis with antiretroviral drugs, it is still operationally feasible to conduct rigorous clinical efficacy trials of HIV-1 vaccines. There are clear reasons for optimism in the quest to develop an HIV-1 vaccine. The modest protection achieved in the RV144 study provides the proof of concept that an HIV-1 vaccine is in fact possible. There have also been major advances in our basic understanding of HIV-1 immunology and virology that inform vaccine design. The discovery of many new broad and potent neutralizing antibodies to the Env An interactive glycoprotein (see diagram graphic showing and interactive graphic, the structure of HIV-1 available with the full text and targets of neutralizing of this article at NEJM antibodies is available at NEJM.org .org) has raised the pos-
than previously tested vaccine regimens. The HIV-1 vaccine pipeline currently encompasses several concepts that are moving toward clinical efficacy trials. Vaccine candidates for which efficacy studies are planned include ALVAC– gp120 vaccines specifically designed for South Africa and Thailand, which build directly on the results of the RV144 study, as well as novel vaccine regimens that include poxvirus vectors with greater potency than ALVAC vectors, alternative serotype adenovirus vectors that are biologically different from and superior to Ad5 vectors, mosaic antigens that provide improved immunologic coverage of global HIV-1 diversity, improved Env protein immunogens, and adjuvants with increased potency. Additional concepts that
have shown considerable promise in preclinical studies include replicating vaccine vectors, such as cytomegalovirus vectors, and novel strategies for generating broadly neutralizing antibodies, including stabilized Env trimers that mimic the native viral spike, scaffolds that display specific antibody epitopes, and immunogens designed to stimulate particular B-cell lineages. Yet HIV-1 vaccine development remains slow and challenging. It is therefore critical to capitalize now on the wealth of basic scientific advances and the current pipeline of vaccine candidates to accelerate the development of an HIV-1 vaccine. One important lesson from the efficacy studies conducted to date is that the results of these studies are often surprising. Regardless, both positive and negative outcomes of clinical efficacy trials provide critically important feedback that affects preclinical and early-phase clinical studies and informs the development of the next generation of HIV-1 vaccine candidates. Testing only four HIV-1 vaccine concepts for clinical efficacy over the past three decades is insufficient given the scope of the global HIV-1 epidemic. We clearly need more “shots on goal.” We should therefore accelerate the advancement of a diverse series of novel and promising HIV-1 vaccine candidates into clinical efficacy trials over the next several years. Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; and the Ragon Institute of Massachusetts General Hospital, the Massachusetts Insti tute of Technology, and Harvard University, Cambridge, MA.
n engl j med 369;22 nejm.org november 28, 2013
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF EXETER on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved.
2075
PERS PE C T IV E
The Quest for an HIV-1 Vaccine
1. Flynn NM, Forthal DN, Harro CD, Judson FN, Mayer KH, Para MF. Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection. J In fect Dis 2005;191:654-65. 2. Pitisuttithum P, Gilbert P, Gurwith M, et al. Randomized, double-blind, placebo-con trolled efficacy trial of a bivalent recombi nant glycoprotein 120 HIV-1 vaccine among
injection drug users in Bangkok, Thailand. J Infect Dis 2006;194:1661-71. 3. Buchbinder SP, Mehrotra DV, Duerr A, et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-con trolled, test-of-concept trial. Lancet 2008;372: 1881-93. 4. Rerks-Ngarm S, Pitisuttithum P, Nita
yaphan S, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med 2009;361:2209-20. 5. Haynes BF, Gilbert PB, McElrath MJ, et al. Immune-correlates analysis of an HIV-1 vac cine efficacy trial. N Engl J Med 2012;366: 1275-86. DOI: 10.1056/NEJMp1312711 Copyright © 2013 Massachusetts Medical Society.
Medicare’s Physician Value-Based Payment Modifier — Will the Tectonic Shift Create Waves? Alyna T. Chien, M.D., and Meredith B. Rosenthal, Ph.D.
F
or at least two decades, the Centers for Medicare and Medicaid Services (CMS) has been transforming itself from a passive payer to an active purchaser of health care, a process that was accelerated by the passage of the 2010 Affordable Care Act (ACA). One ACA provision ushered in a new payment paradigm for physicians — the Physician ValueBased Payment Modifier (PVBM).1 The PVBM seeks to financially reward physicians who provide health care that is high value — both high in quality and low in cost.2 Although the PVBM is being rolled out to physicians in large groups first, the legislation requires that the PVBM be applied to all physicians and groups by January 1, 2017.1 The PVBM reward formula is a simple, relative system in which performance is assessed in two dimensions (quality and cost), with payments accruing to physicians who have above-average performance along both dimensions. Physicians who perform worse than average or choose not to be involved will be paid less; physicians with average performance will experience no change. The maximum bonus is about 2%
2076
of Medicare fees, and the maximum penalty is approximately 1%. For CMS, scoring physicians relative to one another achieves budget neutrality. For physicians, it eliminates the effects of common shocks to performance, such as an influenza epidemic or vaccine shortage. The key disadvantage of this incentive structure is the inherent uncertainty for physicians about the amount of improvement that will be necessary to receive a bonus or avoid a penalty. Although the PVBM will eventually affect all the approximately 600,000 physicians who currently bill Medicare, the program will first target the 180,000 physicians working in practices of 100 or more eligible professionals and then expand to include the 220,000 physicians working in practices of 10 or more. This first group of physicians has now declared whether they will participate in the PVBM or accept de facto penalties. Will this tectonic shift in CMS’s approach to physician payment set off a new wave of efforts to improve quality and cost performance? Examination of CMS’s path leading up to the PVBM, as compared with the parallel Hospital
Value-Based Purchasing (HVBP) program, offers some insight into the answer to this question (see timeline). In particular, the timeline highlights gaps in physicians’ preparedness for value-based purchasing relative to that of hospitals. Three major CMS programs have served as building blocks for HVBP: a quality-reporting program known as Hospital Inpatient Quality Reporting; Hospital Compare, which allows the public to view quality information; and a direct test of pay for performance in hospitals under the Premier Hospital Quality Incentive Demonstration (Premier). In terms of active involvement in quality measurement, CMS had achieved and maintained participation levels of over 90% among the roughly 3500 hospitals participating in the Hospital Inpatient Quality Reporting program for 9 years preceding the start of HVBP. By comparison, after 6 years, only one third of physicians participate in the comparable Physician Quality Reporting System. Whereas the Hospital Compare website had been presenting information on hospital quality for 9 years before the beginning of HVBP, CMS is not scheduled to debut
n engl j med 369;22 nejm.org november 28, 2013
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF EXETER on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved.
NEW ENGLA ND JOURNAL
of
MEDICINE
Perspective november 28, 2013
The Quest for an HIV-1 Vaccine — Moving Forward Dan H. Barouch, M.D., Ph.D.
Related article, p. 2083
V
accines have historically been the most effective biomedical interventions for controlling global infectious diseases. The development of a safe and effective vaccine against human immunodeficiency virus type 1 (HIV-1) is therefore a critical research priority. Although other HIV-1 prevention efforts based on behavioral risk reduction, male circumcision, topical microbicides, preexposure prophylaxis, and treatment as prevention have had substantial effects on HIV-1 transmission rates, it is likely that a vaccine will be required to end the global HIV-1 epidemic. The challenges in the development of a prophylactic HIV-1 vaccine, however, are unprecedented in the history of vaccinology. First, HIV-1 exhibits tremendous global genetic diversity as well as mutational capacity that can evade both humoral and cellular immune responses. The generation
of vaccine antigens that will elicit immunologically relevant and broadly cross-reactive immune responses thus represents a major challenge. Second, HIV-1 rapidly integrates into the host genome and establishes a latent reservoir that cannot be eliminated by conventional antiretroviral drugs or virus-specific immune responses. A vaccine will therefore most likely need to induce potent and functional virus-specific antibodies that block establishment of initial infection, in addition to high levels of T lymphocytes for virologic control. Third, there are no known examples of spontaneous immune-mediated clearance of HIV-1 infection indicative of natural immunity, and thus the pre-
cise types of immune responses that need to be induced by a vaccine are not well understood. Fourth, although a series of broad and potent neutralizing monoclonal antibodies have recently been discovered, such antibodies are induced only in a subgroup of HIV-1–infected persons after several years of infection and typically exhibit extensive somatic hypermutation. No method currently exists to induce such antibodies by vaccination. Over the past 30 years, only four HIV-1 vaccine concepts have been evaluated in clinical efficacy trials. The relative paucity of such trials speaks to the tremendous scientific and logistic challenges associated with HIV-1 vaccine development. The vaccine platforms that have been evaluated in efficacy studies have included purified HIV-1 envelope (Env) proteins, recombinant adenovirus and poxvirus vectors, and plasmid DNA
n engl j med 369;22 nejm.org november 28, 2013
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF EXETER on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved.
2073
PERS PE C T IV E
The Quest for an HIV-1 Vaccine
Env glycoprotein trimer Outer domain glycan site
Top view
Quaternary V1-V2 glycan site
CD4binding site Glycan shield
Membrane proximal external region
HIV-1
Structure of HIV-1 and Expanded View of the Envelope (Env) Glycoprotein Trimer. COLOR FIGURE Targets of virusspecific neutralizing antibodies are shown, including the quaternary Draft 5 11/13/13 V1V2 glycan site, the outer domain glycan site, the CD4binding site, and the mem Author Barouch brane proximal external region. From Nabel GJ. DesigningFigtomorrow’s vaccines. 1 # N Engl J Med 2013;368:55160. Title
vaccines. The first concept that was evaluated was the AIDSVAX Env gp120 protein vaccines, which were tested in two phase 3 efficacy studies in the United States and Thailand and were reported in 2003 to have no efficacy in the populations studied.1,2 The second concept that was evaluated was an adenovirus serotype 5 (Ad5) vector expressing the internal proteins Gag, Pol, and Nef. This vaccine was shown in a phase 2b efficacy study in North 2074
ME
and SouthDEAmerica in 2007 to Malina Artist Knoper have no efficacy and in fact may AUTHOR PLEASE NOTE: have increased the riskand type ofhasHIV-1 Figure has been redrawn been reset Please check carefully 3 acquisitionIssue indate certain subgroups. 11/28/13 A parallel study involving the same vaccine in South Africa was terminated shortly after initiation, and unblinded follow-up also showed increased rates of HIV-1 infection in vaccinees. The third concept that was evaluated was a prime–boost vaccine regimen that involved the canarypox ALVAC vector followed
n engl j med 369;22
nejm.org
by the AIDSVAX Env gp120 proteins. This was a phase 3 study (RV144) conducted in a low-risk population in Thailand that showed in 2009 a 31% reduction in the rate of HIV-1 acquisition.4 Vaccine-elicited antibodies against the first and second variable loops (V1-V2) of Env correlated with a reduced risk of HIV-1 infection,5 although the applicability of these findings to other vaccine platforms remains unclear. The fourth HIV-1 vaccine concept for which clinical efficacy testing has been completed is described in this issue of the Journal (see pages 2081–2090). This vaccine was produced by the National Institutes of Health (NIH) Vaccine Research Center and included priming with DNA vaccines and boosting with Ad5 vectors expressing Env, Gag, and Pol. The trial was a phase 2b efficacy study (HVTN 505) conducted in the United States in men or transgender women who have sex with men. Vaccinations were halted at the interim analysis in April 2013 because of lack of efficacy. Although the vaccine induced both humoral and cellular immune responses in the majority of recipients, the levels of neutralizing antibodies, nonneutralizing antibodies, and V2specific antibodies were low. There was, however, no evidence of increased rates of HIV-1 acquisition among vaccinees, although unblinded follow-up of participants is still ongoing. Despite the lack of efficacy, this study represents an important contribution to the HIV-1 vaccine field. It was a well-designed study that reached a clear conclusion on which future research can build. Future HIV-1 vaccine candidates will need to elicit im-
november 28, 2013
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF EXETER on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved.
PE R S PE C T IV E
The Quest for an HIV-1 Vaccine
mune responses that are either qualitatively different from or quantitatively superior to those induced by the DNA–Ad5 vaccine. It also appears that preclinical evaluation of future vaccine candidates should involve stringent challenge models, since the DNA– Ad5 vaccine afforded substantial protection against challenges with the easy-to-neutralize simian immunodeficiency virus (SIV) strain E660 (SIVsmE660) in rhesus monkeys but failed to protect against the more difficult-to-neutralize virus SIVmac251. In addition, despite the need to offer the best available HIV-1 prevention meth-
sibility that vaccination strategies could be developed to induce such antibodies. Emerging data on the structure of the HIV-1 Env glycoprotein and the ontogeny of Envspecific B-cell responses have led to the design of novel immunogens. The impressive virologic control achieved by virus-specific T lymphocytes in certain settings has also suggested important new strategies for improving cellular immune responses. Moreover, preclinical studies involving stringent challenge models have shown that several novel vaccine candidates have substantially better protective efficacy
There are clear reasons for optimism in the quest to develop an HIV-1 vaccine. The modest protection achieved in the RV144 study provides the proof of concept that an HIV-1 vaccine is in fact possible. ods to all participants, potentially including preexposure prophylaxis with antiretroviral drugs, it is still operationally feasible to conduct rigorous clinical efficacy trials of HIV-1 vaccines. There are clear reasons for optimism in the quest to develop an HIV-1 vaccine. The modest protection achieved in the RV144 study provides the proof of concept that an HIV-1 vaccine is in fact possible. There have also been major advances in our basic understanding of HIV-1 immunology and virology that inform vaccine design. The discovery of many new broad and potent neutralizing antibodies to the Env An interactive glycoprotein (see diagram graphic showing and interactive graphic, the structure of HIV-1 available with the full text and targets of neutralizing of this article at NEJM antibodies is available at NEJM.org .org) has raised the pos-
than previously tested vaccine regimens. The HIV-1 vaccine pipeline currently encompasses several concepts that are moving toward clinical efficacy trials. Vaccine candidates for which efficacy studies are planned include ALVAC– gp120 vaccines specifically designed for South Africa and Thailand, which build directly on the results of the RV144 study, as well as novel vaccine regimens that include poxvirus vectors with greater potency than ALVAC vectors, alternative serotype adenovirus vectors that are biologically different from and superior to Ad5 vectors, mosaic antigens that provide improved immunologic coverage of global HIV-1 diversity, improved Env protein immunogens, and adjuvants with increased potency. Additional concepts that
have shown considerable promise in preclinical studies include replicating vaccine vectors, such as cytomegalovirus vectors, and novel strategies for generating broadly neutralizing antibodies, including stabilized Env trimers that mimic the native viral spike, scaffolds that display specific antibody epitopes, and immunogens designed to stimulate particular B-cell lineages. Yet HIV-1 vaccine development remains slow and challenging. It is therefore critical to capitalize now on the wealth of basic scientific advances and the current pipeline of vaccine candidates to accelerate the development of an HIV-1 vaccine. One important lesson from the efficacy studies conducted to date is that the results of these studies are often surprising. Regardless, both positive and negative outcomes of clinical efficacy trials provide critically important feedback that affects preclinical and early-phase clinical studies and informs the development of the next generation of HIV-1 vaccine candidates. Testing only four HIV-1 vaccine concepts for clinical efficacy over the past three decades is insufficient given the scope of the global HIV-1 epidemic. We clearly need more “shots on goal.” We should therefore accelerate the advancement of a diverse series of novel and promising HIV-1 vaccine candidates into clinical efficacy trials over the next several years. Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; and the Ragon Institute of Massachusetts General Hospital, the Massachusetts Insti tute of Technology, and Harvard University, Cambridge, MA.
n engl j med 369;22 nejm.org november 28, 2013
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF EXETER on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved.
2075
PERS PE C T IV E
The Quest for an HIV-1 Vaccine
1. Flynn NM, Forthal DN, Harro CD, Judson FN, Mayer KH, Para MF. Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection. J In fect Dis 2005;191:654-65. 2. Pitisuttithum P, Gilbert P, Gurwith M, et al. Randomized, double-blind, placebo-con trolled efficacy trial of a bivalent recombi nant glycoprotein 120 HIV-1 vaccine among
injection drug users in Bangkok, Thailand. J Infect Dis 2006;194:1661-71. 3. Buchbinder SP, Mehrotra DV, Duerr A, et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-con trolled, test-of-concept trial. Lancet 2008;372: 1881-93. 4. Rerks-Ngarm S, Pitisuttithum P, Nita
yaphan S, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med 2009;361:2209-20. 5. Haynes BF, Gilbert PB, McElrath MJ, et al. Immune-correlates analysis of an HIV-1 vac cine efficacy trial. N Engl J Med 2012;366: 1275-86. DOI: 10.1056/NEJMp1312711 Copyright © 2013 Massachusetts Medical Society.
Medicare’s Physician Value-Based Payment Modifier — Will the Tectonic Shift Create Waves? Alyna T. Chien, M.D., and Meredith B. Rosenthal, Ph.D.
F
or at least two decades, the Centers for Medicare and Medicaid Services (CMS) has been transforming itself from a passive payer to an active purchaser of health care, a process that was accelerated by the passage of the 2010 Affordable Care Act (ACA). One ACA provision ushered in a new payment paradigm for physicians — the Physician ValueBased Payment Modifier (PVBM).1 The PVBM seeks to financially reward physicians who provide health care that is high value — both high in quality and low in cost.2 Although the PVBM is being rolled out to physicians in large groups first, the legislation requires that the PVBM be applied to all physicians and groups by January 1, 2017.1 The PVBM reward formula is a simple, relative system in which performance is assessed in two dimensions (quality and cost), with payments accruing to physicians who have above-average performance along both dimensions. Physicians who perform worse than average or choose not to be involved will be paid less; physicians with average performance will experience no change. The maximum bonus is about 2%
2076
of Medicare fees, and the maximum penalty is approximately 1%. For CMS, scoring physicians relative to one another achieves budget neutrality. For physicians, it eliminates the effects of common shocks to performance, such as an influenza epidemic or vaccine shortage. The key disadvantage of this incentive structure is the inherent uncertainty for physicians about the amount of improvement that will be necessary to receive a bonus or avoid a penalty. Although the PVBM will eventually affect all the approximately 600,000 physicians who currently bill Medicare, the program will first target the 180,000 physicians working in practices of 100 or more eligible professionals and then expand to include the 220,000 physicians working in practices of 10 or more. This first group of physicians has now declared whether they will participate in the PVBM or accept de facto penalties. Will this tectonic shift in CMS’s approach to physician payment set off a new wave of efforts to improve quality and cost performance? Examination of CMS’s path leading up to the PVBM, as compared with the parallel Hospital
Value-Based Purchasing (HVBP) program, offers some insight into the answer to this question (see timeline). In particular, the timeline highlights gaps in physicians’ preparedness for value-based purchasing relative to that of hospitals. Three major CMS programs have served as building blocks for HVBP: a quality-reporting program known as Hospital Inpatient Quality Reporting; Hospital Compare, which allows the public to view quality information; and a direct test of pay for performance in hospitals under the Premier Hospital Quality Incentive Demonstration (Premier). In terms of active involvement in quality measurement, CMS had achieved and maintained participation levels of over 90% among the roughly 3500 hospitals participating in the Hospital Inpatient Quality Reporting program for 9 years preceding the start of HVBP. By comparison, after 6 years, only one third of physicians participate in the comparable Physician Quality Reporting System. Whereas the Hospital Compare website had been presenting information on hospital quality for 9 years before the beginning of HVBP, CMS is not scheduled to debut
n engl j med 369;22 nejm.org november 28, 2013
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF EXETER on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved.
