l e r i etter from the ditor t 3 - thebody · 1:30 pm session 1: recap of ’99 meeting...

D E A R R E A D E R

Salvage is an ugly word. Saying it by itself, one thinks of a large yard with rusting heapsof old appliances or dismantled cars that once had use and purpose in our modernworld. Salvage can also refer to the rescue of a ship from a shipwreck, fire, or otherdestruction. So, how in the world could we have ever applied such a word to people liv-ing with HIV/AIDS? Perhaps it’s the meaning of salvage as a verb—to save from loss or

destruction. But is that any more appropriate?

Medical jargon is filled with examples of dehumanizing and insensitive terminology, created largely for pur-poses of convenience and, less convincingly, practicality. How many of us cringe when we hear about “can-cer patients” or “AIDS patients” instead of “patients with cancer” or “people living with AIDS,” as if one’sdisease defined a human being? Those are by far among some of the least offensive examples. Therefore,considerable burden or even stigma might be attached to the use of phrases like “salvage patients” or even“salvage therapy” to refer to the situation where cross-class viral drug resistance abounds and treatmentoptions to suppress virus and restore immune function are in desperate need.

But given one of its meanings is synonymous with “rescue,” the use of “salvage” might be justifiable. Whatare the alternatives? Highly antiretroviral treatment-experienced? Multi-drug resistant? Such lengthy ortechnical phrases do not impart the urgency associated with this condition. Language is a powerful tool, andthe ability to express such a profound concept in just one word can be very effective.

The reality of patients who need salvage or rescue therapy has been apparent from the very early days ofHIV therapy. These are patients who will experience disease progression and die unless something is done.With each enhancement in antiretroviral therapy over the past 15 years or so has come the acute reminderthat this virus presents a formidable challenge and will not easily be subdued or eradicated. Salvage thera-py represents our failures in HIV therapy thus far. Salvage patients remind us that we must not settle foranything short of a cure.

I write this letter in the midst of hearing about the loss of Charles Clifton, a colleague, a friend, and aninspiration. Charles was the Executive Director of Test Positive Aware Network (TPAN) in Chicago andEditor of its publications (www.tpan.com). He also served with me on the Steering Committee of the AIDSTreatment Activists Coalition (www.atac-usa.org). His presence in AIDS advocacy will be sorely missed;his humanity and service will not be forgotten. This issue is dedicated in Charles Clifton’s memory.Farewell, Charles.

Very truly yours,The Center for AIDS:Hope & Remembrance Project

Thomas Gegeny, MS, ELSSenior Editor

L E T T E R F R O M T H E E D I T O RR IT A 3

tableof contentsOVERVIEW 5

MEETING SUMMARY

The Salvage Therapy II Think Tank

By Jennifer Newcomb-Fernandez, PhD 8

ESSAYS

Integration of salvage research into existing networks and structures

(A personal take on Panel 1. Discussion leader: Daniel Kuritzkes)

By David Evans 22

Proof of concept studies/translational research; new hypotheses

(A personal take on Panel 2. Discussion leader: Kimberly Struble)

By Bob Huff 24

The future of salvage therapy: monitoring systems for patient outcomes

(A personal take on Panel 3. Discussion leader: Douglas Ward)

By Matt Sharp 26

Regulatory issues and challenges in salvage therapy

(A personal take on Panel 4. Discussion leader: Trip Gulick)

By Martin Delaney 29

BOARDS & STAFF 31

4R IT A

O V E R V I E W 5

S a l v a g e T h e r a p y I I T h i n k Ta n kApril 16–17, 2004Houston, Texas

Sponsored by

The Center for AIDS: Hope & Remembrance Project (Houston)

and

Forum for Collaborative HIV Research (Washington, DC)

with local planning partner

The Center for AIDS Research (CFAR) at Baylor College of Medicine and The University of Texas Health Science Center

Made possible with funding fromRD Foundation

TibotecTrimeris

Special Thanks

Steering CommitteeRoberto Arduino, Ben Cheng, Cal Cohen, Steve Deeks, Tom Gegeny, Gregg

Gonsalves, Trip Gulick, Dorothy Lewis, Veronica Miller, Jeff Murray, Lynn Smiley,Kim Struble

Forum StaffIpsita Das (Project Coordinator)

Paul Oh, Houtan Mova

Intern at The Center for AIDSSusan Davidson

Additional thanks to Betty Slagle and Dede Fox of Baylor College of Medicine.

This meeting was dedicated in memory of L. Joel Martinez, 1953–2003.

R IT A

O V E R V I E W

A t t e n d e e s

6

Roberto C. Arduino, MDUniversity of Texas–Houston Medical School

Rich ArenschieldtThe Center for AIDS

Ben Barnett, MDUniversity of Texas–Houston Medical School

Tanvir Bell, MDUniversity of Texas MedicalBranch–Galveston

Thomas Campbell, PhDUniversity of Colorado HealthSciences Center

Nancy Chang, PhDTanox, Inc.

Andrew Cheng, MD, PhDGilead

Ben ChengForum for Collaborative HIV Research

Calvin J. Cohen, MDHarvard Vanguard Medical Associates

Lynda DeeAIDS Action Baltimore

Steven G. Deeks, MDUniversity of California–San Francisco

Martin DelaneyProject Inform

Sarah DonovanBoehringer IngelheimPharmaceutical, Inc.

David EvansProject Inform

Courtney Fletcher, PharmDUniversity of Colorado Health Sciences Center

Joel Gallant, MDJohns Hopkins University School ofMedicine

Thomas Gegeny, MS, ELSThe Center for AIDS

Roy (Trip) Gulick, MD, MPHCornell University

George Hanna, MDBristol-Myers Squibb

Richard Haubrich, MDUniversity of California–San Diego

Bob HuffGay Men’s Health Crisis

Veronika Kohlbrenner, MDBoehringer IngelheimPharmaceutical, Inc.

Daniel Kuritzkes, MDBrigham & Women’s HospitalPartners AIDS Research Center

Eric Lefebvre, MDTibotec

Sandra Nusinoff Lehrman, MDNational Institutes of Health

Dorothy E. Lewis, PhDBaylor College of Medicine

Stanley Lewis, MDUniversity of Texas–Houston Health Science CenterTanox, Inc.

Jessica Mayer, RN, MSN, NPPfizer

Veronica Miller, PhDForum for Collaborative HIV Research

Nathalie MorgensztejnAgence Française de SécuritéSanitaire des Produits de Santé

Timothy MurphyPOZ Magazine

Jeffrey Murray, MD, MPHUS Food and Drug AdministrationDivision of Antiviral Drug Products

Jennifer Newcomb-Fernandez, PhDThe Center for AIDS

Richard Ogden, PhDPfizer

Neil Parkin, PhDViroLogic

Maria Rodriguez-Barradas, MDVeterans Administration MedicalCenter–Houston

Miklos Salgo, MD, PhDHoffman–La Roche, Inc.

Daniel Seekins, MDBristol-Myers Squibb

Matt SharpTest Positive Aware Network

Betty Slagle, PhDBaylor College of Medicine

Kimberly A. Struble, PharmDUS Food and Drug AdministrationDivision of Antiviral Drug Products

Nelson VergelProgram for Wellness Restoration

Douglas Ward, MDDupont Circle Physicians Group

A. Clinton White, Jr., MDBaylor College of Medicine

Marjorie D. Williams, MPHThe Center for AIDS

Mike Youle, MDRoyal Free Center for HIV Medicine

R IT A O V E R V I E W

O V E R V I E W 7

P r o g r a m i n b r i e f

R IT A

Saturday, April 17, 2004

8:00 am Breakfast

8:30 am Session 3: Clinical management issues in the salvage setting

Presentation by Joel GallantPanel discussion moderated by Thomas Campbell

10:00 am Break

10:15 am Session 4: Do we have new tools?Presentation by Richard OgdenPanel discussion moderated by Richard Haubrich

12:15 pm Lunch

1:00 pm Session 5: Novel strategiesPresentation by Steven DeeksPanel discussion moderated by Ben Cheng

2:30 pm Session 6: Adjourn to break-out panels

Panel 1: Integrating salvage research into existing networks/structures (clinical trial networks, observational cohorts, industry-sponsored programs).

Moderated by Daniel Kuritzkes

Panel 2:Proof of concept studies/translational research; new hypotheses.

Moderated by Kimberly Struble

Panel 3: Future of Salvage Therapy: Monitoring systems for patient outcomes. Will the needs change in the next decade?

Moderated by Doug Ward

Panel 4:Regulatory Issues and challenges in salvage therapy

Moderated by Trip Gulick

4:00 pm Final discussionModerated by Veronica Miller

5:30 pm Close of Day 2

7:00 pm Dinner; Departures

Friday, April 16, 2004

12:00 pm Registration/sign-in; Lunch

1:15 pm Welcome and introductionsThomas Gegeny

1:30 pm Session 1: Recap of ’99 meetingPresentation by Trip Gulick

2:30 pm Session 2: Clinical research in the salvage setting (I)

Presentation by Miklos Salgo

3:15 pm Break

3:30 pm Session 2: Clinical research in the salvage setting (II)

Panel discussion moderated by Trip Gulick

5:30 pm Close of Day 1

6:45 pm Dinner

8 M E E T I N G S U M M A R YR IT A

On April 16 and 17 of 2004, the “Salvage TherapyII Think Tank” was held at the Baylor College ofMedicine in Houston at the Texas Medical Center.This meeting was co-sponsored by The Center forAIDS (CFA) and the Forum for Collaborative HIVResearch. The Center for AIDS Research (CFAR) atBaylor College of Medicine and at The Universityof Texas Health Science Center at Houston was alocal planning partner. This meeting was dedicatedto the memory of L. Joel Martinez, the founder ofThe CFA, who passed away in November 2003. Thegoals of “Salvage Therapy II” were as follows:

■ To bring together relevant groups with the goalof establishing priorities and objectives forincreasing the effectiveness of medical care, thequality of life, and the survival of highly treatment-experienced (“salvage”) patients with HIV/AIDS.

■ To identify areas of basic science and clinical research that might translate into the develop-ment of treatments or the establishment of useful clinical care guidelines for the medical management of salvage patients.

■ To facilitate initiation of research collaborationsamong the various participants and to explore ways to build a national network of research collaborators for implementing these research priorities and objectives.

Participants at the meeting were from a variety of backgrounds and organizations, including HIV/AIDS community advocates; HIV-treating physi-cians; scientists working in the fields of HIV andimmunology; and representatives from pharma-

ceutical companies, the Food and DrugAdministration (FDA), the National Institutes ofHealth (NIH), and the European MedicinesAgency (EMEA). This gathering allowed an inter-disciplinary dialogue offering several different per-spectives on the state of salvage therapy. The meet-ing’s format comprised plenary presentations andpanel discussions, and participation from all atten-dees was encouraged.

1999: SALVAGE THERAPY MEETING

The Salvage Therapy II Think Tank was a follow-up to “The Challenges of Clinical TrialDesign in Assessing the Effects of Anti-HIVTherapy in Heavily Pre-treated Patients,” a meeting held in May 1999. A report from the 1999 meeting is available at the website of The Forum for Collaborative HIV Research (hivforum.org/publications/clinicaltrial_design.pdf).Roy (Trip) Gulick, MD, MPH, from CornellUniversity, chaired this first meeting and provideda recapitulation at the 2004 meeting. At the time ofthe first meeting, patients had access to 14approved antiretroviral drugs. As use of proteaseinhibitors (PIs) increased, the number of deathsattributable to HIV infection was decreasing dra-matically.1 Consequently, more people were livingwith HIV infection and taking combination anti-retroviral therapy. Dr. Gulick emphasized how “thereality of these therapies began to sink in” as largecohort studies across the US and Western Europebegan to report that, in contrast to data collected inclinical trials, about half of the patients seen at theseclinics were failing therapy despite taking state-of-the-art combination therapy.2-6 Clear and effectivestrategies were necessary to deal with this chal-

The Salvage Therapy II Think TankBy Jennifer Newcomb-Fernandez, PhD

M E E T I N G S U M M A R Y 9R IT A

lenge. The Department of Health and HumanServices (DHHS) released guidelines in 1999 rec-ommending that a patient’s regimen “be changedentirely to drugs that have not been taken previ-ously. . . . at least two and preferably three newdrugs should be selected that are not subject toanticipated cross-resistance.” This was obviously achallenge with only 3 classes of drugs available.These guidelines also failed to adequately accountfor variable cross-resistance such that new drugsdid not necessarily mean effective drugs.

Several studies began investigating possible salvageregimens with very disappointing results, with onlyabout 26% to 37% of patients able to suppress viralloads.7-10 This environment was the backdrop ofthe first meeting in 1999, the goals of which were asfollows:

■ To discuss the design and implementation of studies of salvage therapy regimens in heavily pre-treated patients.

■ To present needs, priorities, and challenges faced by industry, researchers, regulators, and patients.

■ To define treatment failure and success.

■ To understand and agree on what is necessary and feasible when designing studies of new drugs for salvage therapy.

Meeting participants discussed the numerousobstacles to developing successful salvage options.These barriers included a heterogeneous patientpopulation and a lack of 1) clinical studies address-ing salvage therapy, 2) standard of care guidelines(ie, when to change therapy) and definitions (eg,virologic failure), and 3) pharmacokinetic (PK) anddrug interaction data. Existing clinical trials had asmall likelihood of success and a potential for caus-ing increased drug resistance among participating

patients. Several challenges were identified con-cerning the complicated logistics of conductingmulti-agent studies. Much discussion centered onthe distinction between assessing individual agentsversus a combination regimen. Industry represen-tatives believed there was little incentive to partici-pate in multi-drug studies. Specifically, they wereconcerned about the effect of negative data on theapproval process and the maintenance of confiden-tiality between companies. Regardless of theseobstacles, Dr. Gulick noted, “the salvage setting isthe greatest challenge and the greatest need in ourclinics,” words he spoke at the first meeting in 1999and repeated again in 2004.

Participants agreed the best way to find effectivetherapies for this population was through moreclinical trials and data collection. Specifically, theconsensus was to utilize resistance testing and ther-apeutic drug monitoring (TDM), and to assess PKand drug interaction data early in the drug devel-opment process. Participants also discussed novelstudy designs that would allow examination of sev-eral new agents while patients still received thestandard of care. Recommendations includedshort-term studies to evaluate virologic response,specifically designing multi-stage nested studieswhereby patients would receive a single agent for 1to 2 weeks and then a combination regimen for 24to 48 weeks. In this type of design, virologicresponse to a particular agent could be assessedquickly over a matter of weeks while safety and effi-cacy of the combination regimen could be analyzedover several months or years. The idea of usingstructured treatment interruptions (STIs) in thispatient population was also considered.Importantly, the FDA representatives encouragedindustry representatives to evaluate their therapiesin different patient populations, including heavilypretreated patients, and acknowledged that therewas a different risk:benefit ratio in this type ofpatient compared with treatment-naïve patients.

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2004: SALVAGE THERAPY II THINK TANK

Fortunately, there have been some advances in thearea of salvage therapy since the 1999 meeting. InJanuary 2001, the FDA convened an Antiviral DrugProducts Advisory Committee meeting to specifical-ly address the challenges of designing salvage stud-ies and developing investigational agents for sal-vage therapy. On March 23, 2004, updated DHHSGuidelines (available at aidsinfo.nih.gov) werereleased supporting “the strategy of . . . designing anew regimen based on the treatment history andresistance testing results, and selecting active anti-retroviral agents for the new treatment regimen.”Joel Gallant, MD, from Johns Hopkins UniversitySchool of Medicine, explained that today, resistancetesting is wisely and commonly used in the settingof clinical failure. A benefit realized by all HIV-infected patients today is the increased number ofapproved antiretroviral agents and the number ofdrugs advancing through the drug developmentpipeline. (Though, if none of the drugs work intreatment-experienced patients, then such agentsoffer little advantage to these patients.) The use ofother agents, primarily ritonavir (Norvir), as a PKboosting agent in antiretroviral regimens is com-mon practice today. Clinical studies have been con-ducted in which short-term PK studies are nestedin longer-term studies (eg, ACTG 5143). In addi-tion, a few multi-agent studies have been conduct-ed (eg, ACTG 398, ACTG 5118). The two-parthybrid study design is also used in salvage therapystudies where a new agent is tested for 1 to 2 weeksand then combined with an “optimized back-ground” therapy (OBT).

Unfortunately, many of the challenges and obsta-cles facing the patient and physician in 1999 stillexist. With the exception of the studies discussedbelow, there have been few clinical trials focusedon regimens for highly treatment-experiencedpatients. Dr. Gulick summarized the situation bynoting that in 1999, patients had 2 chances to

achieve sustained viral suppression. Now theyhave 3. The lack of clearly defined study end-points and standard guidelines for patient careslows progress in this area. Though many agentsare in the drug development pipeline, it is not yetclear if they will benefit the highly treatment-experienced patient. Ensuring these patients haveaccess to multiple effective agents is absolutelycritical. For a variety of reasons, this access is fre-quently not available, forcing patients into anarchaic cycle of sequential monotherapy.

The TORO studies

The TORO1 and TORO2 trials are examples ofclinical trials specifically designed for salvagepatients. These trials led to the FDA approval ofenfuvirtide (Fuzeon or T-20), the first drug devel-oped specifically for use in salvage. Miklos Salgo,MD, PhD, from Hoffmann-La Roche, Inc.,explained that while designing these studies, heand his colleagues struggled with many of the issuesraised at the first salvage therapy meeting. In addi-tion, numerous consultations were made with HIVpatient advocates and experts in the field of HIVmedicine, as well as regulatory authorities. Dr.Salgo noted that to have clinical relevance, thestudy population had to reflect the patient popula-tion likely to use the drug in clinical practice. In thiscase, this was the treatment-experienced patient, atype of patient typically not included in clinical tri-als at that time.

Several challenges existed because of the complexneeds of this patient population. Conventional effi-cacy endpoints (eg, the proportion of patients withvirus below the level of detection) and common def-initions of treatment failure were not appropriatefor these advanced patients, forcing the researchersto construct novel criteria for this study. Moreover,patients received an individualized optimized back-ground (OB) because a standard fixed-drug back-ground might not be as effective. The use of geno-

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typic and phenotypic viral resistance testingensured that patients received the best possiblebackground regimen. Patients were permitted toinclude 2 investigational antiretrovirals,lopinavir/ritonavir (Kaletra) and tenofovir, whichwere available in expanded access programs at thestart of the trial, as part of their OB regimen. Studyparticipants were randomly assigned to an OB arm(control group) or OB plus T-20 arm, but were per-mitted to switch to the T-20 arm if they experiencedvirologic failure on the control arm. This “switchdesign” created challenges in the safety assessmentbecause the control arm dwindled as the study pro-gressed. Regardless of these complications, Dr.Salgo believes these studies were patient friendly,medically and scientifically sound, and statisticallyrobust. However, concerns were raised by othersthat studies of any new drug in patients with virusexhibiting multi-drug resistance (MDR)—a majorcharacteristic of patients in salvage situations—might force patients into sequential monotherapy.Dr. Salgo reasoned that the provision of viral resis-tance testing at screening and allowing use of 2other investigational agents as part of the OB regi-men were practical steps incorporated into theTORO studies to minimize the risks to patients.

Lack of standard of care guidelines and

definitions

A major hindrance to progress in salvage therapy isthe lack of standardization in patient care guide-lines and definitions of terminology. This patientpopulation is extremely heterogeneous with differ-ent treatment histories, resistance profiles, andafflictions—features that complicate the task ofdesigning clinical trials. As debated by several par-ticipants, the lack of universal definitions confusesthe salvage therapy arena, making comparisonsbetween trials difficult.

Indeed, Jeff Murray, MD, MPH, from the FDAcommented that there is still no clear and univer-

sal definition of “salvage patient,” a point alsonoted by Nathalie Morgensztejn from the EMEA.At the 2001 Antiviral Drug Products AdvisoryCommittee meeting, participants agreed thatpatients who experienced a loss or lack of virolog-ic response with at least 2 highly active antiretrovi-ral treatment regimens (HAART) and 3 classes ofdrugs were considered to be in salvage. However,with the introduction of a fourth class of antiretro-virals (entry inhibitors), this definition is now out-dated. In addition, there are still no clear defini-tions for treatment success or failure in the salvagepopulation. For example, is complete virologicsuppression a requirement for treatment success?Is study success synonymous with clinicalresponse? Matt Sharp from Test Positive AwareNetwork in Chicago, a long-term HIV-positive sur-vivor and TORO participant, pointed out thatwhile he “failed” treatment according to study def-initions, he experienced a clinical response on T-20and is a “salvage therapy success story.”

Further complicating this situation is that there areno standard guidelines on how to treat the salvagepatient population. While we now know thatpatients must switch to at least 2 effective drugs once their previous regimen fails, physicians do notfully understand if and when to switch patients.Unfortunately, some physicians may not have theclinical experience or education to recognize theimportance of cross-resistance. They fail to notethat new drugs do not always equate with newoptions in treatment-experienced patients withMDR. In the absence of efficacious therapeuticoptions, some clinicians will keep patients withMDR on a failing regimen that may provide somevirologic stability and decrease the loss of CD4 Tcells. Dr. Gallant pointed out the pros and cons ofthis approach (see Figure 1).

A patient management issue that is still underdebate is whether dual-boosted PI therapy is bene-ficial in the salvage population. This strategy could


be used in situations where patients have no ade-quate nucleoside/nucleotide reverse transcriptaseinhibitor (NRTI) or non-nucleoside reverse tran-scriptase inhibitor (NNRTI) options. Disadvantagesof this strategy include high pill burden and poten-tial for increased drug toxicity. Though thisapproach is used in many patients, physicians havelittle guidance. Steven Deeks, MD, from theUniversity of California at San Francisco, comment-ed that his patients did not want to participate inthis type of treatment regimen because of concernsover increased toxicity. It is still unclear whether adual-boosted PI approach at standard doses isadvantageous compared with higher-than-normaldoses of one boosted PI. Calvin Cohen, MD, fromHarvard Vanguard Medical Associates, commentedthat this issue is more complicated than comparinga single PI versus 2 PIs and requires an under-standing of the specific viral patterns suppressed bya dual-boosted approach versus those that are sup-pressed by one boosted PI. Further exploration is

required as these questions have not been answeredadequately. Unfortunately, pharmaceutical compa-nies have shown little interest in conducting thenecessary clinical trials.

Another potential approach to treating salvagepatients is intensification. The pivotal studies lead-ing to initial approval of tenofovir (Viread) wereintensification studies. In an intensification strate-gy, the addition of another active agent is used tobolster a patient’s existing regimen (eg, adding afourth drug to intensify a 3-drug regimen). Forsome patients, particularly those with modestviremia, this approach may lead to sustained viralsuppression and prevent or delay the develop-ment of drug resistance. The downside of thisstrategy is that it only exposes patients to a singlenew agent. If the viral load is not completely sup-pressed, this may result in rapid loss of efficacy ofthe newer drug. The meeting consensus was thatthis is not an ideal design.


Figure 1. The challenges of continued treatment in salvage patients as presented by Joel Gallant


Whether or not treatment interruptions could bebeneficial when switching salvage patients to a newregimen was also a point of discussion and wasreviewed by Dr. Gallant during his presentation.The concept of STIs in this patient populationstems from the hypothesis that interrupting treat-ment may allow a rebound of wild-type, drug-sus-ceptible virus. Temporary re-emergence of drug-susceptible viral strains, while transient, may pro-vide an opportunity for salvage therapy to workwith some increased efficacy. As pointed out by Dr.Gallant, the results of clinical trials assessing thisapproach are conflicting (see the Fall 2003 issue ofRITA! for more discussion: centerforaids.org/rita).Some smaller studies have reported positive effectsof STIs prior to initiating salvage therapy,11-13

while more recent data suggest that interruptingtreatment is associated with no benefit and may infact be harmful.14,15 Factors responsible for the dis-parate results include duration of interruption,intensity of salvage regimen, shift to wild-typevirus, and patient adherence. The OPTIMA trial(OPTions In Management with Antiretrovirals) is alarge, randomized, multi-center, controlled trialinvestigating the effects of interrupting treatmentin patients taking mega-HAART (comprised of 5 to9 antiretroviral drugs) or standard HAART. Thisstudy is currently enrolling patients in the US,United Kingdom, and Canada.16 By contrast, otherinvestigators felt that prior large, randomized STItrials have disproven the concept of viral reversionimproving the response to therapy. However, someimprovement in adherence may result from allow-ing patients a break prior to initiating highly com-plex regimens (eg, GigaHAART).

Challenges to conducting clinical trials

in the salvage population

The challenges of conducting studies in salvagepopulations were discussed at length throughoutthe conference. Few clinical trials are currentlyaddressing salvage therapy. As discussed above,the extreme heterogeneity of the patient popula-

tion introduces numerous complications that donot need to be addressed when studying treat-ment-naïve patients, most notably the need forindividualized OBT. In addition, if a “switch” tothe experimental arm is permitted (andresearchers believe this option should be availableto salvage patients), assessing safety is problematicbecause the control group is whittled away as thestudy progresses. Therefore, long-term safetycomparisons with the control arm are virtuallyimpossible. Whether clinical trials should focus ontesting drugs in treatment-naïve or salvagepatients before approval was also discussed.Because more salvage therapy options are desper-ately needed, should clinical trials initially focuson this patient population? There was obviousconcern by the industry representatives that iftesting is not successful in salvage patients, theapproval process could be jeopardized.

Much discussion centered on the timing of thesestudies. While participants agreed that drug activi-ty could be determined fairly quickly, with studiesas short as 12 weeks or less, confirmation of safetyrequires more time because serious adverse eventsand drug interactions may not be evident as quick-ly. Initially establishing the safety profile for anindividual drug is important before combining itwith other effective agents to understand whichdrug is causing a particular side effect. But for howlong should a drug be studied before it is consid-ered safe, even in the salvage population?Recommendations from meeting participantsranged from 24 weeks to 1 year. Finally, in this sce-nario, when does a company perform the necessaryPK studies? For patients to have access to newdrugs and make informed decisions about combin-ing antiretrovirals, PK data examining potentialdrug interactions with other antiretrovirals or com-mon concomitant drugs is crucial. As more drugsare developed, there will be more potential combi-nations and thus the number of desirable interac-tion studies will grow exponentially. Understand-ably, pharmaceutical companies do not want to

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conduct these interaction studies until an experi-mental drug is shown to be effective and safe,which could take many months. From their per-spective, until they know an agent has a goodchance of obtaining approval, there is no reason toconduct such studies.

A recurring discussion was the lack of multi-agentinvestigational trials. Because salvage patients arebest treated with at least 2 effective agents, studieswith multiple experimental agents would seemideal. However, as new agents are typically in dif-ferent stages of development, it is a formidablechallenge for a single pharmaceutical company toconduct a clinical trial with 2 new such agents. As aresult, studies with multiple experimental agentsmost likely will require the cooperation of 2 (ormore) pharmaceutical companies. For a variety ofreasons, companies are wary about working togeth-er and sharing confidential information. A majorconcern is that the toxicity of one drug will be gen-eralized to the entire regimen, deeming both inves-tigational agents as dangerous. Even potential situ-ations where one drug is shown to be “good” andthe other as “great” can cause anxiety for thesecompanies. The “good” drug may appear less thanoptimal, or even ineffective, but may provide thesupport to make the other drug “great.” The logis-tics of designing and conducting clinical trials with2 sponsors may seem daunting because of legal and

proprietary concerns on the part of industry.However, conducting such trials through a thirdparty (such as a research institution or clinical trialsnetwork) may be one potential solution.

The “modified” multi-factorial design (see Table 1)was discussed at length during the first salvagetherapy meeting, but has since been deemed unre-alistic by many researchers because of the chal-lenges associated with including multiple newagents in one study. While the chances of having 3investigational agents to include in one trial designare unlikely, the odds are better with 2 investiga-tional drugs. As with concerns about sequentialmonotherapy in patients with MDR virus (such aswith the TORO studies), most patients enrolledinto a modified factorial study design with 2 newagents only receive one new drug in addition toOBT. However, the opportunity for subjects toreceive 2 new agents may be possible if 3-class-experienced, T-20-naïve subjects are randomized toreceive Drug X + OBT vs Drug Y + OBT vs DrugX + Drug Y + OBT when OBT includes T-20.

Expanded access and

compassionate use

The HIV patient advocacy community is extreme-ly discouraged with the complexities involved inproviding experimental agents for compassionate

For 2 investigational drugs (X and Y) For 3 investigational drugs (X, Y, and Z)

Drug X + OBT Drug X + Drug Y + Drug Z + OBTDrug Y + OBT Drug X + Drug Y + OBTDrug X + Drug Y + OBT Drug X + Drug Z + OBT

Drug Y + Drug Z + OBTDrug X + Drug Y + Drug Z*

OBT = Optimized Background Therapy * May not be possible depending on drug classes, Standard of care (SOC) assumed. resistance, etc.


Table 1. Modified, multi-factorial clinical trials designs


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use and felt this issue was not adequatelyaddressed at the meeting. Because of the lack ofapproved and effective agents for salvage therapy,patients with no other options (and who areexcluded from most clinical trials of new agents)have no good means for accessing these drugsbefore FDA approval. Activists emphasized the dif-ferent risk:benefit ratio for these types of patientsand that the inability to obtain access to 2 newagents at the same time was perpetuating treat-ment failure (for instance, patients who areenrolled in a clinical trial of an experimental anti-retroviral agent are often prohibited from also tak-ing agents in expanded access, which are usually inlate-phase clinical investigation).

Participants debated over which information wasnecessary before drugs could be released intoexpanded access or compassionate use programs.As discussed above, are extensive PK and interac-tion data required for these patients as they will betaking the new drug in combination with otherantiretrovirals? Representatives from industrypointed out that access may necessarily be limitedearly in the drug development process, not onlybecause efficacy and safety data are lacking, butbecause drug dose may not be determined yet andlarge-scale manufacturing may not be available.Nevertheless, is the lack of extensive safety datalegitimate grounds for delaying access to patientswith no other options? Participants also discussedthe barriers that exist when trying to obtainexpanded access and compassionate use forpatients. HIV-treating physicians explained thatthe administration associated with expanded accessprograms is enormously time consuming and takesaway from funded clinical research. The FDA hasfew requirements other than the reporting of seri-ous adverse events. However, institutional reviewboards (IRBs) and pharmaceutical companiesrequire extensive data collection for each patient,resulting in large amounts of paperwork.

While patient safety was one of the main reasonscited for delaying drug access, Daniel Kuritzkes,MD, from Brigham and Women’s Hospital,described other risks and costs to research that canoccur when access is provided too early in the drugdevelopment process. For example, preclinical datasuggesting that a side effect may occur in a patientnecessitates comprehensive evaluations that com-plicate the study design and data collection. Otherdisadvantages include harming the investigators’and university or hospital’s reputations if a patientexperiences significant or fatal side effects. Thesetypes of situations can slow down the approvalprocess considerably. One industry representativepointed out that pre-approval access can interferewith the efficiency of enrolling patients in a PhaseIII program, as well as potentially delay theapproval process, because studies will have difficul-ty enrolling patients.

DRUGS IN THE PIPELINE:

SECOND-GENERATION HAART

NRTIs, NNRTIs, and PIs in the pipeline

As explained by Richard Ogden, PhD, fromAgouron/Pfizer, the decision for companies to workin the salvage setting is not to be taken lightlybecause of the numerous challenges discussedabove. However, he believes, as do other industryrepresentatives, that there is a compelling need andresponsibility to develop drugs for these patients.Several companies have compounds in develop-ment from existing drug classes (ie, NRTI, NNRTI,and PI), though the therapeutic advantage of theseagents is only of value to salvage patients if theyhave unique resistance profiles. Unless the drug isactive against common MDR strains, other benefitssuch as improved dosing or less serious side effectsare of limited benefit to salvage patients. However,some drugs in development may provide addition-al treatment options for this patient population


...continued from page 15because they have shown activity against drug-resistant HIV. Tipranavir, a PI being developed by Boehringer Ingelheim, is currently in Phase IIIstudies and, when boosted by ritonavir, is activeagainst HIV strains that are resistant to currentlyavailable PIs. However, the actual utility oftipranavir in some salvage patients with several (3 or more) major PI-resistance mutations is limit-ed without additional effective agents in the regi-men. Tibotec has 2 agents in the pipeline, TMC114and TMC125, a PI and an NNRTI, respectively.Both agents appear to have activity against drug-resistant viruses and are being studied in Phase IItrials. Potentially, both agents could be investigatedin combination in the same study sample.

Entry inhibitors in the pipeline

In addition to the agents already described, newclasses of drugs are also being developed. Theseinclude different types of entry inhibitors (see

Table 2) that may affect various steps or sites in theentry process (ie, attachment, fusion, or entry),such as the CCR5 (“R5”) and CXCR4 (“X4”) core-ceptor antagonists being developed by severalcompanies or the monoclonal CD4 antibody beinginvestigated by Tanox, a small company inHouston. George Hanna, MD, from Bristol-MyersSquibb, commented that in vitro testing has demon-strated synergy between different kinds of entryinhibitors, potentially creating a new HAART reg-imen for patients who have exhausted the tradi-tional options. While the development of any newclass of antiretrovirals can only benefit the HIV-infected population, these advances come withtheir own sets of challenges. Dr. Ogden discussedhow inhibition of a human protein such as CCR5may not necessarily have the same result as thedeletion of that protein, such as in patients withthe homozygous ∆ 32 CCR5 mutation. Likewise,these new drugs may require specific assays thatare currently unavailable. In particular, before

Drug Name Mechanism of Action Phase of Development Company

AMD-070* CXCR4 coreceptor antagonist Phase 1 AnormedAMD-887* CCR5 coreceptor antagonist Phase 1 AnormedPRO-140† CCR5 coreceptor antagonist Phase 1 ProgenicsBMS-488043* Attachment inhibitor Phase 1 Bristol-Myers SquibbUK 427,857* CCR5 antagonist Phase 1-2 PfizerSP-01A* Entry inhibitor (specific Phase 1-2 Samaritan

mechanism not yet defined) PharmaceuticalsSCH-D* CCR5 coreceptor antagonist Phase 2 (early) Schering PloughTNX-355† Attachment inhibitor Phase 2 (early) Tanox

(CD4-binding)GSK(GW)-873140* CCR5 coreceptor antagonist Phase 2 GlaxoSmithKlinePRO-542† Attachment inhibitor Phase 2 Progenics

(CD4-mimicking)

Table 2. HIV entry inhibitors in clinical development

Source (with some modifications): 2004 Antiviral Pipeline, by Rob Camp, prepared for Treatment Action Group.aidsinfonyc.org/tag/tx/pipeline2004.html*orally bioavailable†currently administered by injection or infusion

using the coreceptor antagonists, the significanceof a patient’s predominant viral population/tropism(R5 or X4 or mixed) must be assessed. How suchinformation will affect patient access remainsunclear, as does whether or not highly treatment-experienced patients, particularly those with mixedor dual tropic (R5/X4) virus, will benefit from thecoreceptor antagonists in the absence of other effec-tive drugs. Moreover, there is a potential risk ofaccelerating disease progression if a patient’s virusswitches from R5- to X4-tropic virus.

NEXT STEPS AND RECOMMENDATIONS

Much of the meeting focused on suggestions forwhat could be done to improve the landscape ofsalvage therapy from 2004 forward. Participantsagreed that routine resistance testing would beadvantageous in this patient population. Indeed,Stanley Lewis, MD, a general internist at TheUniversity of Texas Health Science Center atHouston, pointed out a common misperceptionamong patients and even some providers: thatprior exposure to an antiretroviral agent (evenwith an absence of detectable viremia) excludesfuture use of that agent because of drug resis-

tance. The adoption of resistance testing as astandard of patient care and in clinical trials is ofparticular use in salvage for guiding treatmentdecisions, establishing OBT, etc.

Dr. Deeks reviewed ongoing studies of patientswith MDR virus. He described several strategiesused to balance adverse effects, regimen com-plexity, and clinical efficacy. He noted that somepatients seem to sustain immunologic responseswith simplified regimens. In particular, patientsmaintain immunologic benefits despite discon-tinuing protease inhibitors and staying on onlyNRTIs (see Figure 2). The benefit of continuedNRTIs seems to result from decreased viralreplicative capacity. The utility of the replicativecapacity (RC) assay, which is being offered alongwith some resistance tests, was also discussed,though the clinical significance of this assay hasyet to be validated.

In addition, the utility of TDM was also consideredas a tool to help suppress virus and manage drugtoxicity. In Europe, performing TDM in salvagepatients is standard clinical practice and is actuallysupported by the drug manufacturers. However, in


continued...Figure 2. Data from pilot studies in salvage patients being followed by Steven Deeks and colleagues



the US, routine TDM is only performed in certainpatients, including pediatric patients, pregnantpatients, patients with HCV co-infection, and thosepatients taking a concomitant drug known to inter-act with antiretrovirals. Though it could benefit thedrug development process, Courtney Fletcher,PharmD, of the University of Colorado HealthSciences Center, explained that TDM is not used inthe US to facilitate the drug development process.Drawbacks of TDM are its expense, limited assayavailability (and no availability for some antiretrovi-rals), confusion over interpretation of results, lackof studies demonstrating widespread applicability,and the absence of any well-standardized, commer-cially-available assay to monitor drug levels. Onedebate centered on cost versus benefit of routineTDM, and some meeting participants questionedhow many patients would actually benefit from thistype of testing.

The risk of repeatedly failing regimens and poten-tially eliminating the benefit of new drugs is a com-mon reason why physicians do not want to enrolltheir salvage patients in some randomized clinicaltrials for fear of rapidly using up all availableoptions. While randomized, controlled studies areimperative to answering questions regarding drugefficacy, they should not be answered at theexpense of the patients in the control arm.Consider, for example, the patient who is naïve toT-20 and who has high levels of resistance to allavailable NRTIs, NNRTIs, and PIs. If such apatient enrolls in a study of a new agent plus opti-mized background (which would often include T-20), then randomization of that patient to the con-trol arm will result in the patient being essentiallytreated with T-20 monotherapy.

Typically, studies show differences between the con-trol arm and investigational arm quickly. Thus, one solution proposed by Dr. Cohen was to allow

patients in the control arm to receive the investiga-tional agent once activity has been demonstrated(prior to 8 weeks). This “staggered” approach mayallow patients to benefit before any T-20 resistancedevelops. An inherent limitation of this approach isthe lack of long-term safety comparison databetween the 2 patient groups. However, KimberlyStruble, PharmD, of the FDA put these concerns torest and explained that drug approval is grantedbased on the entire package submitted by the company, which will contain long-term safety comparison data in less-experienced patients.Nevertheless, Dr. Deeks felt this staggeredapproach was not practical given the fact that resis-tance to T-20 often emerges rapidly in the presenceof incomplete viral suppression.

An alternative salvage therapy study design sug-gested by Dr. Deeks was to randomly assign treat-ment-experienced patients (who are naïve to T-20)to receive OBT + immediate T-20 + new agent orOBT + delayed T-20 + delayed new agent. Datacollected from the TORO studies could be used forcomparison purposes to define a priori what kind ofresponse would be needed to prove that the newagent was effective and potentially avoid jeopardiz-ing a patient’s chance of responding to T-20. Theprecise antiretroviral activity of the agent could bedefined in concurrent studies of patients who aretreatment naïve or who are minimally pre-treated,an approach the FDA authorizes. The goal of thePhase III, randomized, clinical trial in the salvagesetting would largely be to establish safety and toprovide an estimate of the drug’s activity.Obviously, conducting multi-agent studies with thisapproach would require additional considerations.

Some potential and often overlooked strategieswere proposed by the FDA that could be imple-mented to help better design studies involving sal-vage patients: to collect real-time PK data, to dose-


adjust in a small cohort of patients before enrollinga larger cohort, and to use population PK to aid inthese dosage studies. Another recommendationwas to conduct preliminary PK studies in seroneg-ative volunteers. Dr. Kuritzkes explained thatobtaining approval with studies conducted in treat-ment-naïve patients may allow researchers to havemore flexibility in designing studies for the salvagepopulation because industry would not have thepressure of obtaining approval at that point.However, this strategy still introduces a delay inbringing new and effective agents to the salvagepatient. Others pointed out that small pilot studies,even case studies of single patients, are still helpfuland can provide important information on drugactivity, safety, PK, and interactions. A suggestionwas made that researchers submit concept sheets toindustry to conduct these small studies. In terms ofstudy endpoints, advocates suggested that mea-sures like quality of life, a reasonably healthyimmune system, and a lower (but not unde-tectable) viral load would be more appropriateendpoints for this type of patient.

During the meeting, Dr. Ogden reviewed specificgoals of the drug development process in the sal-vage setting. These included minimizing toxicities,treatment cost, pill count, and dosing frequency;developing drugs with activity against resistant viralstrains; discovering drugs that improve antiretrovi-ral drug levels without increasing toxicities (eg,CYP3A4 inhibitors like ritonavir); finding new mol-ecular therapeutic targets; and studying multipleinvestigational agents in combination. One strategyproposed by Dr. Fletcher was to “learn in a smallpopulation and confirm in a large population.”This approach may provide a means to answersome of these prevailing questions.

The need for multi-experimental agent trials withcooperation from multiple pharmaceutical compa-nies was discussed at length throughout the meet-ing. One recommendation appreciated by all was tohold a meeting between the FDA and regulatory

representatives from the pharmaceutical compa-nies so the FDA could address the regulatory representatives’ concerns and emphasize the feasibility of multi-drug/multi-company clinical tri-als. Dr. Murray explained that the FDA could pro-vide certain incentives to pharmaceutical compa-nies developing drugs for this patient populationsuch as accelerated approval, priority review, andfast-track status. Government networks andcohorts, such as the ACTG and CPCRA, may be thebest chance for the salvage community becausesuch research networks have the ability and where-withal to conduct these types of trials. Indeed, Dr.Gulick emphasized that a top goal of these net-works was the development of more effective treat-ments for highly treatment-experienced patients.Eric Lefebvre, MD, from Tibotec acknowledgedthat his company was considering this type ofdesign for studies investigating TMC114 andTMC125, which are currently in the same phase ofdevelopment at Tibotec.

Representatives from several community advocacyorganizations emphasized the need for HIVresearchers and pharmaceutical companies tothink “outside the box” and questioned if the HIVcommunity was at a point of diminishing return interms of the types of antiretroviral drugs beingdeveloped. Indeed, will the approval of 5 morePIs have a considerable impact on the HIV-posi-tive community? Throughout the meeting, advo-cates called on the pharmaceutical companies tocollaborate in studying multiple agents in combi-nation so that salvage patients could benefit.Another challenge in treating HIV-infectedpatients is diminished immune system function,even in the presence of a suppressed viral load.Incorporation of immune-based therapies, such asinterleukin-2 and therapeutic vaccines, may ame-liorate this situation and keep patients healthier,thus allowing them to benefit even more fromavailable antiretrovirals drugs. The question ofwhy humans get AIDS when other primate speciesdo not was also raised, and some participants felt

continued...


that exploration of this discrepancy could providesome answers on how to battle this virus. In addi-tion, the important role of advocacy organizationswas emphasized in the continued education ofpatients on topics such as the benefits of a healthylifestyle and medication adherence.

Finally, another issue identified was barriers (wait-ing time, paperwork, etc.) to expanded access andcompassionate use when patients have no otheroptions. One solution proposed by Veronica Miller,PhD, the executive director of the Forum forCollaborative HIV Research, was a 2-stage strategywhereby a drug is released for compassionate useafter the drug has been studied for a short time (12or 16 weeks) and then subjected to a wider expand-ed access after 24 weeks of study. Mike Youle, MD,an HIV-treating physician from the Royal FreeHospital in London, commented that tipranavirwas distributed in a similar manner in the UnitedKingdom. Another solution might be to provideadditional funding to clinics to run these types ofprograms. Unfortunately, in light of the recentfunding cutbacks, this recommendation may not berealistic.

CONCLUSION: THE EVOLVING SALVAGE

POPULATION

Further complicating any definition of salvage isthat the salvage population itself is evolving. Forexample, Dr. Kuritzkes explained that patients onsalvage therapy today are perhaps quite differentfrom those who are just starting salvage therapynow and in the near future. Earlier salvage

patients began NRTI mono-or dual therapy in the1980s or 1990s. As a result of the inadequatepotency of these regimens, they first developedNRTI resistance. When protease inhibitors becameavailable, early use was not always coupled witheffective NRTI backbones, such that patients arenow battling MDR virus. Today’s patients who ini-tiated and failed effective combination therapy willbe different in terms of the resistance profiles andtreatment requirements. Indeed, Dr. Youle com-mented that half of the salvage patients he seestoday in London initiated therapy after 1999, wellinto the “HAART era.”

But other factors also complicate matters. Firstand foremost, MDR virus is increasing in the US,with drug resistance concentrated in groups lesslikely to adhere to complex regimens (eg, patientswith psychiatric or substance abuse co-morbidi-ties). In addition, issues such as ease of adminis-tration and regimen “forgiveness” (ie, the numberof doses that can be missed without developingresistance) may be more important in the future.The introduction of entry inhibitors furtherchanges this scenario.

So, what does the future hold for all HIV-positivepatients? Will tomorrow’s salvage patients farebetter or worse than salvage patients today? Dr.Kuritzkes emphasized the need for collecting dataon these patients. As one AIDS activist proclaimedamong discussions of clinical trial logistics andappropriate study endpoints, researchers muststay focused on the ultimate goal—curing the dev-astating epidemic.


R IT A


References

1. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338(13):853-860.

2. Deeks SG, Hecht FM, Swanson M, et al. HIV RNA and CD4 cell count response to protease inhibitor therapy in an urban AIDS clinic: response to both initial and salvage therapy. AIDS. 1999;13(6):F35-F43.

3. Ledergerber B, Egger M, Opravil M, et al. Clinical progression and virological failure on highly active antiretro-viral therapy in HIV-1 patients: a prospective cohort study. Swiss HIV Cohort Study. Lancet. 1999;353(9156):863-868.

4. Lucas GM, Chaisson RE, Moore RD. Highly active antiretroviral therapy in a large urban clinic: risk factors for virologic failure and adverse drug reactions. Ann Intern Med. 1999;131(2):81-87.

5. Valdez H, Lederman MM, Woolley I, et al. Human immunodeficiency virus 1 protease inhibitors in clinical practice: predictors of virological outcome. Arch Intern Med. 1999;159(15):1771-1776.

6. Wit FW, van Leeuwen R, Weverling GJ, et al. Outcome and predictors of failure of highly active antiretroviral therapy: one-year follow-up of a cohort of human immunodeficiency virus type 1-infected persons. J Infect Dis.1999;179(4):790-798.

7. Falloon J, Ait-Khaled M, Thomas DA, et al. HIV-1 genotype and phenotype correlate with virological response toabacavir, amprenavir and efavirenz in treatment-experienced patients. AIDS. 2002;16(3):387-396.

8. Gulick RM, Hu XJ, Fiscus SA, et al. Randomized study of saquinavir with ritonavir or nelfinavir together with delavirdine, adefovir, or both in human immunodeficiency virus-infected adults with virologic failure on indi-navir: AIDS Clinical Trials Group Study 359. J Infect Dis. 2000;182(5):1375-1384.

9. Hammer SM, Bassett R, Squires KE, et al. A randomized trial of nelfinavir and abacavir in combination with efavirenz and adefovir dipivoxil in HIV-1-infected persons with virological failure receiving indinavir. Antivir Ther.2003;8(6):507-518.

10. Para MF, Glidden DV, Coombs RW, et al. Switching from long-term hard-capsule saquinavir to indinavir or soft-gel capsule saquinavir in AIDS Clinical Trials Group Protocol 333. J Infect Dis. 2000;182:733-743.

11. Deeks SG, Wrin T, Liegler T, et al. Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. N Engl J Med. 2001;344(7):472-480.

12. Deeks SG, Grant RM, Wrin T, et al. Persistence of drug-resistant HIV-1 after a structured treatment interruption and its impact on treatment response. AIDS. 2003;17(3):361-370.

13. Katlama C, Dominguez S, Duvivier C, et al. Long-term benefit of treatment interruption in salvage therapy (GIGHAART ANRS 097). 10th Conference on Retroviruses and Opportunistic Infections, 2003, abstract 68.

14. Lawrence J, Mayers DL, Hullsiek KH, et al. Structured treatment interruption in patients with multidrug-resistant human immunodeficiency virus. N Engl J Med. 2003;349(9):837-846.

15. Ruiz L, Ribera E, Bonjoch A, et al. Role of structured treatment interruption before a 5-drug salvage antiretrovi-ral regimen: the Retrogene Study. J Infect Dis. 2003;188(7):977-985.

16. Kyriakides TC, Babiker A, Singer J, et al. An open-label randomized clinical trial of novel therapeutic strategies for HIV-infected patients in whom antiretroviral therapy has failed: rationale and design of the OPTIMA Trial. Controlled Clinical Trials. 2003;24:481–500.

22 E S S A Y SR IT A

Panel 1 focused on ways to integrate salvage thera-py research into existing networks and structuresincluding government-sponsored clinical trials net-works, observational cohorts, and industry-spon-sored trials. Though the panel discussed a numberof environments in which salvage research is hin-dered, it concluded that a solution to most of theobstacles must involve greater communicationbetween all stakeholders at much earlier stages inthe drug development process.

Dr. Kuritzkes laid out 3 primary areas of focus forthe group, all of which demand greater collabora-tion between industry, the Food and DrugAdministration (FDA), academic researchers, andactivists:■ To better integrate salvage research into the

drug approval process and registration trials;

■ To explore new drugs in combination earlier inthe development process—even when the drugsare produced by different companies; and,

■ To identify ways for Expanded Access (EA) programs to collect more meaningful data with-out limiting access to treatment or overburden-ing physicians who participate in EA programs.

Regarding new drug development, industry repre-sentatives expressed those concerns most compa-nies have about doing any type of research thatcould jeopardize their chances for FDA approval.In cases where a company hoped to gain approvalfor first-line therapy, this often led them to delay

critical pharmacokinetic and drug interaction stud-ies that would allow salvage trials to move forwardearlier in the drug development process. Industryrepresentatives also noted that because the clinicalresearch staff at the largest companies are so inter-nally focused on attaining drug approval, they donot often interact with community or academiaearly enough to fully understand the needs andconsiderations of people living with HIV until wellafter plans are underway.

However, some in the activist community suspectthat industry researchers believe they are alreadysensitive to such concerns and are conducting theappropriate types of research. In addition, activistssuspect these representatives meet with the com-munity largely as a courtesy and because they con-sider it politically necessary. Getting input “afterthe fact” is largely a choice they make rather thanan accident.

Activists encounter the results of this poor commu-nication constantly. They are asked to give feedbackabout the plans for a clinical trial only to discoverthat the company has already submitted the trialdesign to the FDA and researchers, thereby ensur-ing that critical suggestions cannot be incorporated.Likewise, companies will claim that they cannotmake certain changes because the FDA will notallow them, but when contacted by activists, theFDA claims otherwise, leaving activists in the posi-tion of having to decide whom to believe. Early andopen communication among all parties would sig-nificantly improve this situation.

Integration of salvage research into existing networks and structures (A personal take on Panel 1. Discussion leader: Daniel Kuritzkes)

By David Evans

David Evans is the Information and Advocacy Associate with Project Inform (projectinform.org).

E S S A Y S 23R IT A

One researcher suggested that a meeting be heldto bring together industry, the FDA, and commu-nity (both researchers and activists) to identifyareas of common interest that could remove atleast some of the obstacles standing in the way of salvage research using new drugs. Most pan-elists agreed this was a good idea and asked theForum for Collaborative HIV Research toexplore hosting such a meeting. Granted, theissues described during this breakout session havepersisted for years despite previous meetings of this type. Nevertheless, pursuing the idea maystill be worthwhile.

A particular benefit of such a meeting would be thechance to identify those areas where existing clini-cal trial networks may be most ideally suited tocarry out necessary research. This is particularlycritical when studying 2 new drugs produced by different companies. A group formed in the mid-1990s called the Inter-Company Collaborative(ICC) sought to achieve such a goal, but initiatedlittle meaningful research. One major stumblingblock the ICC grappled with was anti-trust laws.The panel suggested that the government’s clinicaltrial networks could provide just the kind of neu-tral playing field necessary to minimize anti-trustconcerns. For this to be successful, however, com-panies would be required to work much more col-laboratively with community activists, the FDA,and government researchers to reduce bureaucra-cy and conflicting priorities. Still, companies arealso concerned that the side effects of one drugmight become associated with all the drugs used insuch trials. This issue leads some companies to fearthat such trials run the risk of damaging theirchances of approval.

Greater collaboration and coordination could alsoimprove the process by which meaningful data canbe collected from EA programs. However, ratherthan place additional reporting burdens on analready overwhelmed network of community physi-cians, the panel suggested that large existingcohorts could serve as a model for data collectionpurposes. Use of EA programs to collect consistentand reliable data could provide earlier safety anddrug interaction data and allow companies andresearchers to more quickly identify prospectiveparticipants for follow-up studies. But this will beimpossible to accomplish without resources goingdirectly to the physicians who must collect andreport the data.

Greater integration of salvage research into thedrug development process will not be easy. Theupcoming recompetition of government grants forAIDS research could significantly change existingclinical trials networks. Even changes for the bettercould delay new salvage research as all partiesadapt to new systems and structures. Moreover, theescalating crisis in healthcare and drug access in theUS is making treatment of people in salvage situa-tions more difficult. Increasing drug prices com-bined with shrinking public and private healthcareresources are leading to growing numbers of peo-ple living with HIV/AIDS who have neither expertcare nor access to new treatments. However, littlehas been easy in the fight against AIDS, and thepanel unanimously agreed that greater communi-cation and collaboration among industry, commu-nity, and government is a critical next step toincrease and enhance clinical trials for people whohave few treatment options.

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So you’ve developed a new drug that is designed toblock HIV at a novel point in its lifecycle. This isnot a “me-too” drug but a whole new approach.Your drug is nicely active against HIV in the testtube and didn’t raise any worries in tests in miceand dogs, so it’s time to move forward. You’ve got-ten your preclinical data together and the Food andDrug Administration (FDA) has agreed to let youtry it out in people without HIV to see if there isany overt toxicity. After a few studies in “healthies,”you’ve come up with what you think is the maxi-mum tolerated dose, and you now have someunderstanding about how quickly your drug isabsorbed and eliminated in humans. Yet severalyears and several million dollars later, one big ques-tion remains: will it actually lower viral load in peo-ple with HIV?

A “proof of concept” study is needed to answer thatcrucial question before the drug developmentprocess can move forward. But what does thatentail? This discussion explored some of the diffi-cult questions that are raised when using a newdrug for the first time in patients.

Typically, a proof of concept study for an HIVdrug might involve giving the experimental agentas monotherapy for 7 to 14 days to an individualwith detectable HIV. Another design is a virtual/functional monotherapy study where the investi-gational drug is added or substituted for anotherantiretroviral agent for 7 to 14 days in an individ-ual receiving therapy and with detectable HIV.The viral load drop at the end of that periodwould be the main endpoint of interest, and the

rapidity of the viral load reduction (or the steep-ness of the slope) could be a secondary indicator ofthe drug’s activity.

But these designs raise some ethical questions thatmust be carefully considered. The possibility existsthat resistance to the entire drug class could devel-op after exposure to a subtherapeutic dose, espe-cially when it is given as monotherapy. This risk isof particular concern because the FDA would liketo see some evidence of dose response from a proofof concept study. Seeing a dose response, wherethe higher dose produces a greater or steeper dropin viral load, gives reassuring evidence that thedrug is really doing something. Yet a volunteercould be harmed if drug resistance were to devel-op during that short time because the dosereceived was inadequate. Although establishing adose response from a proof of concept study isdesirable, subtherapeutic doses must be avoided.In vitro resistance and pharmacokinetic data canhelp with appropriate dose selection and durationto minimize the development of resistance fromsubtherapeutic doses.

Another ethical issue concerns the appropriate typeof patient to enroll. Risk:benefit issues are impor-tant considerations for early drug development.Some feel a treatment-naïve individual (one whostill has a full range of treatment options available)might be taking the least risk; however, others feelthat because there are many proven durable treat-ments available, there is a higher risk for treatment-naïve patients because a treatment may have unex-pected toxicities or might allow resistance to

Proof of concept studies/translationalresearch; new hypotheses(A personal take on Panel 2. Discussion leader: Kimberly Struble)

By Bob Huff


emerge that could confound future therapy choic-es. If a drug is expected to have activity againstmulti-drug-resistant virus, then the proof of con-cept study should determine the activity in thepatients mostly likely to use the drug, ie treatment-experienced patients. Because risk:benefit issuesmay be complex for investigational agents, the useof a data safety monitoring board and early treat-ment stopping rules can be used in protocols tominimize risk to patients.

Another issue concerns the expectations of patientsafter participating in a proof of concept study.Unfortunately, there is no guarantee that someonewho has experienced a good response after 14 dayscan continue to receive the drug after the briefstudy ends. Several months may be required toevaluate the results of the proof of concept studybefore a dose is selected and larger trials arebegun. Additional drug interaction studies may berequired before it is used in combination withother antiretroviral agents. This is especiallyimportant for treatment-experienced patientsreceiving numerous medications, a situation wherethe risk for drug interactions is large. Also, some-times a company decides not to continue develop-ing a drug past the proof of concept point. Finally,because so few people have received a drug at thisstage of development, vigilance for adverse eventsmust remain high—even after the 14-day exposurehas ended. One salvage-related issue for investiga-tors to consider is that highly treatment-experi-enced patients may be more vulnerable to adverseevents than treatment-naïve patients. Obviously,drug development at this stage is not for the faintof heart.

Although small numbers of patients are involved atthis stage of drug development, there are signifi-cant concerns associated with exposing salvage

patients to a potentially useful, albeit investigation-al, therapeutic agent. For one, exposure to subopti-mal doses of a single agent might allow resistance todevelop, thus eliminating any hope of using theagent in future therapy. Secondly, the agent mightnot be further available to such patients because ithas ceased being developed or because prior expo-sure becomes a criterion of exclusion in later clini-cal trials. Third, removing salvage patients fromstable therapy—even in the setting of virologic fail-ure—is risky and potentially harmful if not donewith the intention of beginning a new, active regi-men to resuppress virus.

So how do investigators and patients evaluate therisks versus the benefits of participating in thesevery early drug trials? As in any trial, this processbegins with a thorough discussion of the risks and acommitment to the principle of a patient informedconsent. Yet the conduct of these early trials israrely transparent or obvious to members of theHIV treatment community. Such trials may takeplace in foreign countries where people have fewertreatment options or may offer paid inducementsto participants to accept the risks. This presentsadditional ethical challenges. But these studies area necessary step that every trailblazing drug musttake. With proof of concept in hand, the investiga-tors can move forward with learning how to get themost out of this latest agent against HIV.

Translational research or new therapeuticapproaches are always likely to come with such risksto patients, especially at early but critical stages ofdevelopment. Patients in salvage situations areoften desperate for new therapeutics to treat HIV,and yet their decisions to participate in clinical tri-als must be made with careful consideration toavoid losing precious options down the road.

Bob Huff is Editor of Treatment Issues, a publication of Gay Men’s Health Crisis (gmhc.org).

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The future of salvage therapy: monitor-ing systems for patient outcomes (A personal take on Panel 3. Discussion leader: Douglas Ward)

By Matt Sharp

In looking to the future of salvage therapy, consid-eration must be given to what treatment strategieswill work best, what the salvage population will looklike, what types of patients will be available for tri-als of new drugs, and what resources will be avail-able to provide the new drugs. Will multi-drugresistance (MDR) of the virus occur with the treat-ment regimens used today? How can research pro-vide answers for how to circumvent MDR? Thesewere the topics discussed in Panel 3, which focusedon ways to define, monitor, and treat the currentsalvage population and the how the salvage popu-lation will prevail over time.

Doug Ward, MD, an HIV-treating physician,defined his salvage population as 2 groups: thosewho were treated with sequential monotherapy andare typically stable, and those who may be stable yethave MDR. Because of the availability of back-upregimens, Dr. Ward doesn’t believe he is creatingany new salvage patients today. Panelists noted thatit is difficult to determine the actual extent of thesalvage population. Are there new salvage patientsor just treatment-experienced patients who are sta-ble but have MDR regardless of CD4 T cell count?Also, why are there clinical differences betweenpatients who have similar viral loads? One observa-tion is that today’s patients seem to be doing betterwith lower T cells, and changes in viral pathogenic-ity may be the reason. Because Dr. Ward’s clinic isnot representative of the larger HIV-infected com-munity, how can we define this population?

The HIV epidemic in the US itself has changed,affecting many more women and minority popula-tions. In addition, the development (from nonad-herence and other factors) and transmission ofdrug resistance are affecting the epidemic inregions where antiretroviral treatments are widelyavailable, such as the US. To make matters worse,clinical trial enrollment is becoming more challeng-ing, perhaps because of the wide availability ofexisting treatments or issues of distrust concerningthe medical establishment. All of these issues makestudying and treating the salvage population aschallenging as ever.

Because health clinics may not be completely rep-resentative of the salvage population, one way todefine the salvage population is to utilize databasesfrom Virologic or other diagnostics companies.These databases contain information on the per-centage of people carrying specific resistance pat-terns, though such databases lack medical historyinformation. However, if the research communitycan accept the drawbacks, this type of database maybe useful for quantitative analysis. Nevertheless, itstill comes back to defining the salvage population.Clinical cohorts such as Johns Hopkins, the HIVOut-Patient Study (HOPS), and the University ofAlabama may provide some definition of the sal-vage population, though they may be collectinginformation on just treatment-experiencedpatients, therefore skewing their data collectiontoward patients with more resistance. Little preva-


lence data exist in nonacademic settings to helpdefine a population of salvage patients. One cohortstudy is being developed. Other data from MikeYoule, an HIV-treating physician attending theThink Tank, also exist from his clinic.

The activist community has been attempting tosolicit useful data from expanded access (EA) pro-grams that may provide some information on thesalvage population. Again, the caveat is that treat-ment history information is often not collected inthese programs. Extensive sampling techniquestudies that collect population-representative infor-mation may be another way to characterize the sal-vage population. The Centers for AIDS Research(CFARs) have the CFAR Network of IntegratedClinical Systems (CNICS), which is a large systemtrying to link existing CFAR site databases electron-ically, but there are apparently logistical complexi-ties with the linking of sites. While this system candefine the population, there is no sampling and noinformation on medical history. However, there is adenominator of patients, their regimens, and levelsof resistance. In any case, it may be the best way wehave at this point to assess the salvage population.

Another question is how can we best predict treat-ment failure? There is concern that quality of life(QOL) assessments in determining treatment fail-ure in the salvage population are not being ade-quately monitored and evaluated. Much attentionhas been placed on pharmacokinetics (PK) and efficacy, but is there a standard tool for QOL evaluations that could be adapted for use in clinicaltrials for drug development? The ACTG uses a QOL assessment tool that is accepted for manyclinical trials.

In addition, guidelines on how to treat thesepatients are still unclear. Is “mega-HAART”(HAART that employs more than 3 drugs, and as

many as 6 or 8 drugs, to treat HIV) still a usefulstrategy for salvage patients? Most panelists agreedthere is little evidence to support it. However, ifused today, mega-HAART would mean fewer pillssince many drugs have been reformulated or cofor-mulated. Have dual-boosted protease inhibitors(PIs) caught on for salvage therapy? An increase inpill burden and potential pharmacologic interac-tions may be reasons to not use dual-boosted PIs.What about enfuvirtide (Fuzeon or T-20) for thosewho are treatment experienced but fairly stablewith relatively low viral loads and a CD4 T cellcount above 200? Consideration must be given tosave future options in this population and to avoidusing novel therapies like T-20 too early, as it maybe more useful in a deeper salvage setting.Intermittent therapy and regularly switching regi-mens may become promising approaches as moredrugs are developed from new classes. Also, theremay be utility in alternating Kaletra monotherapyin such a setting, given recent promising data.Further, would the use of an intermittent strategybe beneficial in patients who start therapy early andgain viral control?

Newer drugs are selecting for different types ofresistance, especially in nucleoside reverse tran-scriptase inhibitors (NRTIs), so that there may notbe large numbers of thymidine analog mutations(TAMs) developing in patients who have startedtherapy in recent years. This changes the treatmentparadigm and the expectations for new drugs. Weknow about “type 2” or “second generation” nucle-osides, such as abacavir (Ziagen) or lamivudine(Epivir), which are distinguished by the 184 codonsusceptibility. So, there needs to be newer com-pounds in the older thymidine analog nucleosidegeneration—drugs such as Retrovir (zidovudine orAZT) and Zerit (stavudine or d4T)—without thetoxicities, which should be considered for any newdrugs being developed. Some panel members ques-

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tioned whether this would be applicable over timedepending on growing mutation patterns and thevariability of viruses with the 65 or 184 mutations.Other questions persist with newer drugs; forexample, whether tenofovir (Viread) is clinicallyeffective in those who are highly treatment experi-enced and for whom it is the only phenotypicallysusceptible NRTI.

Is there additional benefit for use of phenotypictesting in MDR patients? This type of testing maybe useful depending on the patient. Phenotypictesting provides a benefit when there is some sus-ceptibility to antiretroviral drugs. Questions stillexist concerning cost effectiveness and where theuse of phenotype and genotype tests is most prac-tical. A replicative capacity (RC) assay is currentlydone with a commercially available phenotypetest, and there is pressure to explore the idea ofrequiring a separate payment for RC tests.Obviously, the clinical utility of such a test shouldfirst be established through more studies in largenumbers of patients.

One of the biggest salvage research questions todayis where would the therapeutic drug monitoring(TDM) test be most useful in the salvage paradigm?Such testing is used widely in Europe. The panelistsagreed that TDM results are much simpler to readthan those of a resistance test. If TDM is being usedto choose drugs for patients with multi-PI resis-tance, then population-based information on PKand protein binding for the particular drug beingtested should be considered. However, drug PK

reports are not updated, especially in the currentera of boosted PIs. Also, TDM cannot be used fornucleosides because of their intracellular activity(blood plasma levels may not accurately be a reflec-tion of drug penetration and therapeutic activity).Therefore, the use of TDM will be best for deter-mining therapeutic doses for individual patients orin patients with hepatitis co-infection to look forliver toxicities.

In summary, resource allocation and access todrugs will continue to be an issue for patients in sal-vage situations. One panel participant suggestedthat the problem was the overall structure of thehealthcare system. At present, this is especiallyproblematic for indigent patients who cannot accessspecialty care. Such situations actually create sal-vage patients. Recent studies have shown thatadherence is actually improving in salvage patients,so treatment failure may get worse but resistancedata may improve. Some consider it far worse to behighly resistant to a bad regimen than nonadherentto a good regimen. As far as treatment guidelinesare concerned, the pendulum may swing in thedirection of starting antiretrovirals earlier as regi-mens become easier to take and have less toxicity.Starting treatment early may be advantageous forseveral reasons. While no one is advocating thatpatients be on therapy for the rest of their lives, abrief period of early therapy may be beneficial.Some believe that patients are easier to treat overallif they start therapy earlier. With more research,time will tell if this is true.

Matt Sharp is a person living with AIDS and is Director of Treatment Education with Test Positive Aware Network in Chicago (tpan.com).


R IT A


Regulatory issues and challenges in salvage therapy (A personal take on Panel 4. Discussion leader: Trip Gulick)

By Martin Delaney

Panel 4 focused on how regulatory issues werepresently affecting options for salvage patients.Initial discussion noted that the numerous changesand improvements made at the Food and DrugAdministration (FDA) over the last 20 years, oftenas a result of community input and pressure, haveeliminated most of the regulatory obstacles thatonce existed. In short, today the FDA is not per-ceived as a major roadblock to the development ofsalvage therapy.

Nevertheless, the participants of the group pointedout that this did not mean that people requiringtrue salvage therapy could always get what theyneeded. One of the biggest problems in the realmof salvage therapy is that it is seldom possible toobtain access to more than one new drug at anyparticular time. Yet we know that simply bringingin one effective drug, when a person is failing allavailable drugs and combinations, provides littlemore than short-term improvement. The additionof a single new drug in a salvage setting is basicallyequivalent to monotherapy and, with the drugspresently available, it is all but impossible to achievea lasting and powerful antiviral response with a sin-gle drug. The necessity of effective combinationtherapy is even more critical in the salvage settingthan it is for people initiating antiretroviral therapy.

Some of the clinicians in the discussion group com-mented that even “failing” drugs often provide a

degree of viral suppression. One reason for this isthat the drug-resistance mutations that developand cause a drug to “fail” also may cause it to repli-cate less effectively. New diagnostic tests that mea-sure the replicative capacity of a person’s virus arecurrently being studied to help quantify and char-acterize this effect. Nonetheless, the most desirablesituation is for the person in a salvage situation tohave access to at least 2 new active drugs at thesame time.

Several obstacles make this scenario difficult toachieve. One major factor is that multiple newdrugs rarely, if ever, come from the same company.If a single company is developing 2 antiretroviralagents, they are usually not in the same stage ofdevelopment because each drug moves forward atits own pace. Although different companies havehistorically shown little or no willingness to maketheir individual drugs available under a commontimeline, the FDA has stated that it does not opposestudy designs that include 2 or more investigation-al new drugs. Community pressure regarding theseissues therefore needs to be directed, not at theFDA, but at the individual companies developingthe drugs.

For example, Tibotec has 2 drugs in parallel devel-opment, a protease inhibitor (PI) with good activityagainst PI-resistant virus and a new non-nucleosidereverse transcriptase inhibitor (NNRTI) that over-

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R IT A

30R IT A

comes viral resistance to other drugs of this type.Both community advocates and scientists agreedthat the situation developing at Tibotec was espe-cially well suited to test an approach studying 2investigational agents in one study. Developing clin-ical trials that allow people access to these 2 newdrugs at the same time should be relatively simple.In addition, tipranavir, a protease inhibitor devel-oped by Boehringer Ingelheim, will be also accessi-ble in this time frame. Farther down the road, atleast 2 new entry inhibitor drugs will most likelybecome available at a similar time. Thus, theprospects for treating people in need of salvagetherapy with 2 or more new drugs at the same timeappear quite good.

This issue of multi-drug availability also pertainsto expanded access (EA) programs. Almost everydrug has an EA program that makes the drugavailable to people in need before formal FDAapproval. The challenge for salvage therapy is tocoordinate 2 or more such programs so that sal-vage patients have access to 2 or more new drugsat the same time. Again, this issue is not so mucha regulatory issue as it is a “collaboration” issuebetween pharmaceutical companies. Communitypressure must be placed on the individual compa-nies to coordinate their EA programs. While suchcoordination may be challenging, there is noinherent reason why this cannot be achieved.

Some advocacy representatives commented thateven if EA programs could be coordinated, and

some studies combined 2 or more new drugs, therewould still be patients who could not obtain accessto multiple new agents at the same time. Not allpeople are qualified for these clinical trials, nor dothey all live in locations served by the trials.Furthermore, there will always be people who needaccess to multiple new drugs prior to the launch ofEA programs. This highlights the dilemma of anumber of people in the salvage setting and asksthe question “how can we provide these patientswith the necessary access to multiple new drugs atthe same time?”

At the Salvage Therapy meeting, researchers andcommunity activists alike found this to be the mostchallenging situation. Fortunately, this dilemma isnot that common. One possible approach is the useof a mechanism that would provide access to theneeded new drugs on a “case by case” basis (some-times called “compassionate use”). Some of the clin-icians, however, feared it would require a great dealof paperwork on their part for each patient. Inresponse, community advocates pointed out thatthe monumental paperwork procedures were notnecessarily required and instead a bad habit of theFDA and pharmaceutical companies. Individualaccess should be achievable with minimal paper-work as long as the manufacturers and the FDA arecommitted to making it happen.

Martin Delaney is the founder of Project Inform (projectinform.org).


E S S A Y S

31B O A R D S & S T A F FR IT A

BOARD OF DIRECTORS

Margaret O’Donnell, LMSW-ACP, ChairSteve Loden, First Vice ChairGlen Fillmore, Second Vice ChairBill Patterson, CPA, TreasurerLynn T. Johnson, MDiv, Secretary

Polly A. AhrendtsNancy Pierce BrumbackPhillips K. Campbell, Jr.Julie GreenwoodRick HerrmanKevin LandryJoseph Murphy, MD

COMMUNITY & MEDICAL

ADVISORY BOARD

Wendy AdairCarlos Arreola, PhDK. Wayne Bockmon, MD J. Brad Bowden, MDJanet S. Butel, PhDCathy CampbellCarla M. Cooper, PhDDavid DonnellyJoseph C. Gathe, Jr., MDChris JimmersonRick KammererCele Keeper. MSWDorothy Lewis, PhDNeal S. ManneTom MathewsWesley E. ParkerJoanne C. PinkettAdan S. Rios, MDCarol RisleyShannon Schrader, MDP. Joe ShafferTeresa B. SouthwellStephen Tyring, MD, PhDLaurie Van Fleet, JD

STAFF

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Administrative DirectorSara W. Haynes

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l e r i etter from the ditor t 3 - thebody · 1:30 pm session 1: recap of ’99 meeting...

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