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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.
