Transcript Presentation by Robert Caldwell, Ph.D.

MEDICAL PERSPECTIVE ON HIV AND
THE IMPORTANCE OF TREATMENT
ADAP ADVOCACY ASSOCIATION'S 6TH
ANNUAL CONFERENCE
ROBERT L. CALDWELL, PH.D.
RENEWING THE COMMITMENT
AGENDA
GENERAL OVERVIEW OF THE HIV
LIFECYCLE
CURRENT AND EMERGING HIV
THERAPEUTICS
THE CRITICALITY OF TREATMENT
OVERVIEW OF THE HIV
LIFECYCLE
DRUG CLASSES
ANTIRETROVIRAL (ARV) DRUGS ARE BROADLY CLASSIFIED BY THE PHASE OF
THE VIRUS LIFECYCLE THAT THE DRUG INHIBITS.
ENTRY (OR FUSION) INHIBITORS
NUCLEOSIDE AND NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTI)
NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTI)
INTEGRASE INHIBITORS
PROTEASE INHIBITORS
MATURATION INHIBITORS
CURRENT THERAPEUTIC
OPTIONS
NRTI
Brand Name
Generic Name
Pharmaceutical Company
Atripla
efavirenz + tenofovir + emtricitabine
Bristol-Myers Squibb and Gilead Sciences
Combivir
zidovudine + lamivudine
ViiV Healthcare
Complera
rilpivirine* + tenofovir + emtricitabine
Janssen Therapeutics and Gilead Sciences
Emtriva
emtricitabine
Gilead Sciences
Epivir
lamivudine
ViiV Healthcare
Epzicom
abacavir + lamivudine
ViiV Healthcare
Retrovir
zidovudine
ViiV Healthcare
Trizivir
abacavir + zidovudine + lamivudine
ViiV Healthcare
Truvada
tenofovir DF + emtricitabine
Gilead Sciences
Videx EC
didanosine
Bristol-Myers Squibb
Viread
tenofovir disoproxil fumarate (DF)
Gilead Sciences
Zerit
stavudine
Bristol-Myers Squibb
Ziagen
abacavir
ViiV Healthcare
CURRENT THERAPEUTIC
OPTIONS
NNRTI
Brand Name
Generic Name
Pharmaceutical Company
Atripla
efavirenz + tenofovir + emtricitabine
Bristol-Myers Squibb and Gilead Sciences
Complera
rilpivirine + tenofovir + emtricitabine
Gilead Sciences and Janssen Therapeutics
Edurant
rilpivirine
Janssen Therapeutics
Intelence
etravirine
Janssen Therapeutics
Rescriptor
delavirdine
ViiV Healthcare
Sustiva
efavirenz
Bristol-Myers Squibb
Viramune
nevirapine
Boehringer Ingelheim
CURRENT THERAPEUTIC
OPTIONS
PROTEASE INHIBITORS
Brand Name
Generic Name
Pharmaceutical Company
Aptivus
tipranavir
Boehringer Ingelheim
Crixivan
indinavir
Merck & Co
Invirase
saquinavir
Genentech
Kaletra
lopinavir + ritonavir
AbbVie
Lexiva
fosamprenavir
ViiV Healthcare
Norvir
ritonavir
AbbVie
Prezista
darunavir
Janssen Therapeutics
Reyataz
atazanavir
Bristol-Myers Squibb
Viracept
nelfinavir
ViiV Healthcare
CURRENT THERAPEUTIC
OPTIONS
INTEGRASE INHIBITORS
Brand Name
Generic Name
Pharmaceutical Company
Isentress
raltegravir
Merck & Co
Stribild
elvitegravir + cobicistat + tenofovir + emtri
Gilead Sciences
FUSION INHIBITORS
Brand Name
Generic Name
Pharmaceutical Company
Fuzeon
enfuvirtide
Genentech
Selzentry or Celsentri
maraviroc
ViiV Healthcare
The life cycle of HIV and HIV disease
December 2011
THERAPEUTIC DEBUTS
Timeline of drug development
Strikethrough = discontinued in US.
FUSION (OR ENTRY INHIBITORS)
INTERFERES WITH THE BINDING, FUSION AND ENTRY OF
AN HIV VIRION TO A HUMAN CELL. BY BLOCKING THIS
STEP IN HIV'S REPLICATION CYCLE, SUCH AGENTS SLOW
THE PROGRESSION FROM HIV INFECTION TO AIDS
SELZENTRY BINDS TO CCR5, PREVENTING AN INTERACTION
WITH GP120
FUZEON BINDS TO GP41 AND INTERFERES WITH ITS
ABILITY TO APPROXIMATE THE TWO MEMBRANES
FUSION (OR ENTRY) INHIBITORS
XX
REVERSE-TRANSCRIPTASE
INHIBITORS
REVERSE TRANSCRIPTASE INHIBITORS (RTIS) COME IN THREE FORMS:
NUCLEOSIDE AND NUCLEOTIDE REVERSE-TRANSCRIPTASE INHIBITORS (NRTIS)
NON-NUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITORS (NNRTIS)
REVERSE-TRANSCRIPTASE
INHIBITORS
XX
X
INTEGRASE INHIBITORS
INTEGRASE INHIBITORS ARE A CLASS OF ARV DESIGNED TO BLOCK THE ACTION
OF INTEGRASE, A VIRAL ENZYME THAT INSERTS, OR INTEGRATES, THE NEWLY
REVERSE-TRANSCRIBED VIRAL DNA INTO THE DNA OF THE HOST CELL.
INTEGRASE INHIBITORS
X
X
X
X
PROTEASE INHIBITORS
PROTEASE INHIBITORS WERE THE SECOND CLASS OF ARVS
DEVELOPED
PROTEASE IS INVOLVED IN FINAL ASSEMBLY OF VIRAL PROTEINS
PREVENT VIRAL REPLICATION BY INHIBITING THE ACTIVITY OF
PROTEASES
TYPICALLY ADMINISTERED IN COMBINATIONS AND +/- NNRTIS
PROTEASE INHIBITORS
X
X
X
X
X
HIGHLY ACTIVE
ANTIRETROVIRAL THERAPY
(HAART)
INTRODUCED IN 1996, FORMALIZED BY FDA IN 2001.
COMBINATION OF TWO NUCLEOSIDE ANALOGS WITH EITHER A PROTEASE
INHIBITOR OR AN NNRTI.
FIRST TREATMENT GIVEN TO PATIENTS, SHOULD KEEP VIRAL LOAD AT < 50
COPIES/ML, WHICH CAN PREVENT EMERGENCE OF DRUG-RESISTANT
MUTANTS.
IF FIRST HAART FAILS, SUBSEQUENT TREATMENT MUCH LESS LIKELY TO
SUCCEED (MUTANTS ACCUMULATE).
EMERGING THERAPEUTICS
MATURATION INHIBITORS
THERAPEUTIC VACCINES
“THE BEST THING ABOUT THE FUTURE IS THAT IT COMES ONE DAY AT A TIME.”
― ABRAHAM LINCOLN
MATURATION INHIBITOR
MATURATION INHIBITORS INHIBIT THE LAST STEP IN VIRUS PROCESSING IN WHICH THE
VIRAL ARCHITECTURAL PROTEINS ARE CLEAVED, THEREBY BLOCKING THE CONVERSION
OF THE POLYPROTEIN INTO THE MATURE INDEPENDENT PROTEINS. THESE VIRAL
PARTICLES HAVE A DEFECTIVE ARCHITECTURE, AND THE VIRIONS RELEASED CONSIST
MAINLY OF NON-INFECTIOUS PARTICLES.
ALPHA INTERFERON IS A CURRENTLY AVAILABLE AGENT IN THIS CLASS. TWO ADDITIONAL
ONES UNDER INVESTIGATION ARE BEVIRIMAT AND VIVECON.
MATURATION INHIBITORS
XX
X
X
X
X
THERAPEUTIC VACCINES
“SHOCK AND KILL”
TESTED IN PEOPLE WHO ARE ALREADY HIV-POSITIVE
BUT WHO HAVE HEALTHY IMMUNE SYSTEMS
CONTROLS INFECTION AND DELAYS PROGRESSION OF
HIV BY STIMULATING THE IMMUNE SYSTEM TO SEEK
AND DESTROY HIV-INFECTED CELLS
CONSIDERABLY LESS FREQUENT ADMINISTRATION
(EVERY 2-3 MONTHS)
THE MOVE TOWARD LOWER
PILL BURDENS
Regimen
Dosing
1996
Zerit/Epivir/Crixivan
10 pills, Q8H
1998
Retrovir/Epivir/Sustiva
5 pills, BID
2002
Combivir (AZT/3TC)/EFV
3 pills, BID
2003
Viread/ Emtriva/Sustiva
3 pills, QD
2004
Truvada/Sustiva
2 pills, QD
THE CRITICALITY OF TREATMENT
VIRAL LOAD
CD4 T-CELL COUNTS
BENEFITS OF HAART
ENGAGEMENT IN HIV CARE
“THE ONLY WAY TO KEEP YOUR HEALTH IS TO EAT WHAT YOU DON'T WANT,
DRINK WHAT YOU DON'T LIKE, AND DO WHAT YOU'D RATHER NOT.” MARK
TWAIN
MONITORING HIV DISEASE:
VIRAL LOAD
VIRAL LOAD TESTS REFLECT THE CURRENT REPLICATION RATE
OF HIV IN THE BLOOD.
CONCENTRATIONS OF HIV IN OTHER PARTS OF THE BODY
(SEMEN, VAGINAL FLUIDS, BREAST MILK) ARE NOT REFLECTED
VIRAL LOAD SHOULD BE KEPT AS MINIMAL AS POSSIBLE
OVER TIME, PREFERABLY UNDETECTABLE (<50 COPES/ML SERUM)
ASSAY LIMIT OF DETECTION WILL IMPROVE OVER TIME AND
WILL REDEFINE “UNDETECTABLE”
MONITORING HIV DISEASE: CD4
CELL COUNTS
OI = OPPORTUNISTIC
INFECTIONS
FEDERAL GUIDELINES, JANUARY 2011
BENEFITS OF VIRAL LOAD
REDUCTION
AN INCREASING NUMBER OF OBSERVATIONAL RESULTS AND EARLY STUDIES SUGGEST LOWER RATES OF
AIDS AND OTHER HEALTH RELATED CONDITIONS AND DEATH
CURRENT FIRST-LINE REGIMENS ARE MORE EFFECTIVE AND EASIER TO TAKE AND TOLERATE, WHICH
HELPS IMPROVE ADHERENCE
BETTER ABLE TO ACHIEVE AND MAINTAIN HIGHER CD4 LEVELS
EASIER TIME TOLERATING ANCILLARY MEDICINES
REDUCES THE RISK OF EARLY DAMAGE TO THE IMMUNE SYSTEM
REDUCES, BUT IT DOES NOT ELIMINATE, INFLAMMATION
REDUCES TRANSMISSION OF HIV BASED ON SEVERAL STUDIES OF MIXED HIV STATUS, HETEROSEXUAL
COUPLES
EARLY TREATMENT MAY DECREASE OVERALL COST OF HEALTHCARE BY AVOIDING MORE SERIOUS
CONDITIONS
WITH THE ADVENT OF HAART, MORE
PEOPLE ARE LIVING WITH HIV AS AIDSRELATED DEATHS DECLINE
ENGAGEMENT IN HIV CARE
LOW VIRAL LOAD IS ASSOCIATED WITH
DECREASED PRESENTATION OF HIV AND
THERAPEUTIC CO-MORBIDITIES
PERIPHERAL NEUROPATHY
NAUSEA
BACTERIAL INFECTIONS
PERIPHERAL NEUROPATHY
DEPRESSION AND ANXIETY
INSOMNIA
DIARRHEA
HYPERHIDROSIS
FUNGAL INFECTION
FATIGUE
PARKINSON’S DISEASE
DIABETES
PSYCHOSIS
OTHER VIRAL INFECTIONS
ACKNOWLEDGEMENTS
GREGORY PAPPAS, M.D.
HIV/AIDS, HEPATITIS, STD, AND TB ADMINISTRATION, D.C.
DEPARTMENT OF HEALTH
ROHIT TALWANI, M.D.
ASSISTANT PROFESSOR AT UNIVERSITY OF MARYLAND INSTITUTE OF HUMAN VIROLOGY
CONTACT INFORMATION:
ROBERT L. CALDWELL, PH.D.
[email protected]
ADDITIONAL SLIDES
www.hcvadvocate.org
Zidovudine(Azidothymidine, AZT)

AZT was the first approved treatment for HIV, sold under the names Retrovir and
Retrovis.

AZT use was a major breakthrough in AIDS therapy in the 1990s.

AZT slows HIV spread significantly, but does not stop it entirely.
Tenofovir

Tenofovir disoproxil fumarate (TDF or PMPA), marketed by Gilead Sciences under the
trade name Viread, belongs to a class of antiretroviral drugs known as nucleotide
analogue reverse transcriptase inhibitors (NRTIs), which block reverse transcriptase,
an enzyme crucial to viral production in HIV-infected people.
Raltegravir

Raltegravir (MK-0518, brand name Isentress)

Raltegravir targets integrase, an HIV enzyme that integrates the viral genetic material
into human chromosomes, a critical step in the pathogenesis of HIV. The drug is
metabolized away via glucuronidation
EFAVIRENZ

BRAND NAMES SUSTIVA AND STOCRIN

NNRTI

UNLIKE NRTIS, WHICH BIND AT THE ENZYME'S ACTIVE SITE, NNRTIS ACT
ALLOSTERICALLY BY BINDING TO A DISTINCT SITE AWAY FROM THE ACTIVE SITE
KNOWN AS THE NNRTI POCKET.
SAQUINAVIR

SAQUINAVIR WAS THE FIRST PROTEASE INHIBITOR (AND
SIXTH ANTIRETROVIRAL) APPROVED BY THE FDA.

HIV PROTEASE IS VITAL FOR BOTH VIRAL REPLICATION
WITHIN THE CELL AND RELEASE OF MATURE VIRAL
PARTICLES FROM AN INFECTED CELL. SAQUINAVIR INHIBITS
BOTH HIV-1 AND HIV-2 PROTEASES.
Nucleoside Analog

AZT: when abundant in cytoplasm, replaces thymidine, lacks the OH group-halts reverse
transcription

RTase irreversibly binds to AZT

Viral RTase prefers AZT, host polymerases prefer thymidine

Other examples: 3TC, ddC, ddI
Non-Nucleoside Analogs
•
React directly with RTase, termed NNRTIs. Most are structurally similar to
nucleotides
•
Problem – patients treated with NNRTIs tend to accumulate resistant mutants. 1
study: 29 patients on NNRTI-containing regimen, 83% had more than two NNRTIresistant forms. Mutants persisted 12 months after therapy stopped.