Human Immunodeficiency Virus Infection A Modern Day Epidemic Frank Romanelli, PharmD, MPH, BCPS Assistant Dean and Associate Professor of Pharmacy Clinical Specialist in HIV/AIDS University of Kentucky Learning Objectives Formulate a pharmacologic treatment plan based on patient specific laboratory and psychosocial parameters. Describe advances in the treatment of HIV disease. List available antiretrovirals for the management of HIV disease. 1
HIV Positive (HIV +) High risk patient sent for testing Patient s tests are ELISA positive ELISA test is repeated and is positive Test is confirmed by western blot Patient is now said to be HIV positive Acquired Immunodeficiency Syndrome (AIDS) Patients have AIDS when: They are HIV+ with a CD4 cell count that is or ever has been less than 200 cells/mm 3 They are HIV+ and have had an AIDS defining illness such as PCP, toxoplasmosis, MAC, Kaposi s Sarcoma, etc. - regardless of CD4 cell count 2
Definitive etiology remains a mystery Multiple theories have been proposed: - sperm overload - antigenicity - advanced tech - genocide/biologic gi warfare - rare chimp likely source of human HIV Etiology Zoonosis Historical Perspective Early 1980s First clinical cases of HIV reported in the US [GRID]. CDC notes increased requests for pentamidine. 1982 GRID re-named AIDS. 1984 NIH Isolates HIV. 1985 Ryan White banned from classes. 3
Historical Perspective 1985 ELISA test approved and marketed. 1987 FDA approval of AZT heralded as HIV cure. 1990 Ryan White passes away @ 18 years of age. 1991 Looped red ribbon becomes Intl symbol of HIV. Historical Perspective 1996 Introduction of the PIs Adherence and marked declines in mortality. 2000 SA Pres. HIV not the cause of AIDS. New side effects and emphasis on QOL. 2003 First injectable anti-hiv drug (Fuzeon ) launched - cost : $1,200/month. 2004 First CLIA-waived HIV screening test (OraQuick ) approved. 4
Historical Perspective 2007 CDC: HIV testing is routine. Introduction of two new drug classes. (IIs; co-receptor blockers) 2008 Second Generation NNRTIs The search for new targets 25 + Years of HIV and AIDS Morbidity and Mortality Weekly Report June 5, 1981 PCP in 5 otherwise Healthy PCP in 5 otherwise Healthy Homosexual Males in Los Angeles. 5
Transmission Primary route of transmission in the US is through sexual contact Blood Semen/vaginal fluids (including oral sex) Perinatal/breast milk Precautions Safer Sex anal vaginal receptive oral sex Latex condoms Standard d precautions Barrier techniques (dental dams) Abstinence 6
Perinatal Precautions Intrauterine - ACTG protocol 076 Begin AZT 100mg PO 5X/day at 14-34 weeks of gestation IV AZT during labor - load with 2mg/kg then 1mg/kg/h until birth AZT 2mg/kg q6h for the 1st 6 weeks of newborn s life 67.5% reduction in perinatal transmission PREVENTION The simplest and most effective preventative measure remains EDUCATION 7
Epidemiology Worldwide (2006) 40 million infected persons 4.9 million new infections in 2005 50% of infected individuals are female More then 20 million deaths Very serious in African continent particularly Sub-Saharan (30-40% of pregnant women) 75% of infections from heterosexual contact Vertical transmission responsible for 95% of childhood cases 8
Epidemiology United States (2006) > 1,000,000 cases of HIV New surveillance methodologies: 56,300 new cases (AA 45% of new infections) 12% decline in AIDS cases reported since 96 17% decline in deaths since 1996 23% of all cases are females 30% white, 49% AA (disproportionate representation), 18% Hispanic Shift: minorities, women, rural, heterosexuals 9
Trends in Annual Rates of Death from Leading Causes of Death Among Persons 25-44 Years Old, USA, 1982-1998 Deaths per 100,000 Popula ation 40 35 30 25 20 15 10 5 0 82 84 86 88 90 92 94 96 98* National Center for Health Statistics National Vital Statistics System *Preliminary 1998 data Unintentional injury Cancer Heart disease Suicide HIV infection Homicide Chronic liver disease Stroke Year Diabetes 10
US Transmission, 2006 MSM 53% Heterosexual 31% IDU 12% MSM-IDU 4% 11
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Epidemiology Kentucky (12/2007) AIDS Cases: 201 Low prevalence compared to other states 37 (4.9/100K; national average: 12.7/100K) Cases mainly concentrated in Louisville, Lexington, and Northern Kentucky Male: 84%; Female 15%; 1% Children 65% white; 31% AA, 3% Hispanic Risk factors: MSM (55%), IDU(13%), heterosexual sex (15%), undetermined (10%) Cumulative Kentucky HIV/AIDS Cases as of December 2007 Case Type Number of Cases Cases living with AIDS 2,802 Cases of AIDS living and deceased 4,764 14
Who Should Be Tested? One-Quarter of all HIV-infected persons are unaware of their status High risk populations only? Men having sex with men (MSM) Promiscuous sex: hetero- or homosexual Injection drug use (IDU) CDC: A routine component of care 13 to 64 YOA HIV ELISA Initial screening test Highly sensitive but not specific High incidence of false positives Positive tests should be repeated and confirmed by a western blot Negative tests should be repeated in 6 months 15
Western Blot Confirmatory test DNA finger printing New Testing Technology OraQuick Advantage HIV-1/2 - CLIA-waived 20 minute fingerstick/oral fluid ELISA test. - Confirmation testing still required. - May capture patients who do not report for initial test results. 16
OraQuick Advance HIV-1/2 Obtain fingerstick specimen 17
Insert loop into vial and stir Collect oral fluid specimens by swabbing gums with test device. Gloves optional; waste not biohazardous 18
Insert device; test develops in 20 minutes Positive HIV-1/2 Reactive Control Positive Negative Read results in 20 40 minutes 19
Antiretrovirals Traditional Model of HIV Inhibition 20
New Model of HIV Replication Target-cell membrane Coreceptor gp120 gp41 CD4 CD4-induced gp120 conformational change Viral membrane Coreceptor binding Six-helix bundle formation Extended coiled-coil drives insertion of fusion peptide into target membrane Membrane fusion Therapeutic Arsenal Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Protease Inhibitors (PIs) Nucleotide Reverse Transcriptase Inhibitors Fusion Inhibitors Co-receptor antagonists Integrase Inhibitors 21
Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Inhibit reverse transcriptase enzyme Plagued with drug resistance and intraclass resistance Multiple newer combination drug products Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Zidovudine AZT (Retrovir ) Marrow suppression Didanosine ddi (Videx EC ) Peripheral neuropathy Stavudine d4t (Zerit ) Peripheral neuropathy Lamivudine 3TC (Epivir ) Headache, Nausea Emtricitabine FTC (Emtriva ) Headache, Nausea Abacavir ABC (Ziagen ) Hypersensitivity Combivir Tii Trizivir i Truvada Epzicom AZT/3TC AZT/3TC/ABC FTC/TF 3TC/ABC 22
Atripla Emtricitabine 200 mg + Tenofovir 300 mg + Efavirenz 600 mg First triple therapy single pill option Gold standard? Unprecedented manufacturer cooperation Cost comparable Single co-pay? 1 PO Qhs The Ideal Antiretroviral Potent. Easily administered. Low cost. High resistance barrier. Effective as monotherapy. Few adverse effects. Few drug interactions. Disturb latent HIV reservoirs. 23
Nucleotide Reverse Transcriptase Inhibitors Inhibit reverse transcriptase enzyme Requires less intracellular phosphorylation and activation Less amenable to resistance Salvage therapy Nucleotide Reverse Transcriptase Inhibitors Tenofovir (Viread ) 300mg PO QD Efficacy against Hep B Nausea/vomiting 24
Non-nucleoside Reverse Transcriptase Inhibitors Structurally distinct i from the NRTIs Resistance remains a problem as does cross-resistance Non-nucleoside Reverse Transcriptase Inhibitors Nevirapine (Viramune ) Rash, Diarrhea Delavirdine (Rescriptor ) Rash, Headache Efavirenz (Sustiva ) Rash, CNS Disengagement 200 mg qd x 2 weeks then 200 mg BID 400 mg TID 600 mg Qhs 25
The First Arrival of 2008 Etravirine (Intelence ) Formerly TMC125 Second generation NNRTI Higher resistance ceiling [K103N] [Y181C] 200 mg PO BID Salvage therapy Rash, diarrhea D/I: (several) Tip, famp, ATA Protease Inhibitors Among the most potent of the antiviral medications Resistance develops quickly, especially in cases of non-adherence Wide intra-class resistance Boosting 26
Protease Inhibitors Saquinavir (Invirase ) Nausea, vomiting, diarrhea Ritonavir (Norvir ) D/I, GI distress, perioral tingling Indinavir (Crixivan ) Nephrolithiasis, increased bilirubin Nelfinavir (Viracept ) Diarrhea, nausea 500 mg BID 600 mg BID 800 mg q8h 1250 mg BID Protease Inhibitors Lopinavir/Ritonavir (Kaletra ) Nausea, HyperTG, diarrhea Fosamprenavir (Lexiva ) Nausea, diarrhea Atazanavir (Reyataz ) Increased bilirubin 2 Caps BID 700 mg BID (variable) 400 mg QD Tipranavir i (Aptivus ) 500 mg BID (boosted) Nausea, diarrhea Darunavir (Prezista ) Nausea, diarrhea 600 mg BID (boosted) 27
Fusion Inhibitors Enfurvitide (Fuzeon ) 90mg SQ BID $$ Injection site reactions Salvage therapy Co-Receptor Antagonists AKA chemokine receptor blockers Block either CCR5 or CXCR4 Concern regarding trophism [CXCR4 associated with increased virulence] Theoretical concerns: malignancy, infection, others? 28
Maraviroc (Selzentry ; Celsentri ) Father of the class CCR5 antagnoist Indicated for tx experienced patients only Requires trophic assay before use - $$$ [TroFile TM ] Dose: 150 mg PO BID varies with concurrent drug use [interactions] i Pneumonia? Malignancy? Cardiovascular complications? Trophic conversion? Integrase Inhibitors Raltegravir (Isentress ) Newest anti-hiv class Years of research Tx experienced patients only 400 mg PO BID HA, NV, CPK UGT1A1 Glucuronidation D/Is: Tip/Rit, Rif Cost: $27.00/day ($2.00/d less than MAR) 29
Treatment Resistance testing recommended for all patients entering care. All symptomatic patients Asymptomatic patients: CD4 + cell count < 350 cells/mm 3 All patients: Pregnant, HIV-nephropathy, Hep B co-infected (where Hep B tx is indicated) Treatment Regimens Typical backbones: 2 NRTIs + 1 NNRTI 2 NRTIs + 1 PI Initial Regimens: Downgrades: AZT/3TC; D4T/3TC; NFV Upgrades: 3TC/ABC (HLA-B*5701); Saq/rit 30
Goal of Therapy Primary Goal To reduce and maintain plasma HIV RNA levels (viral load) below the point of detection <48 COPIES/ML Secondary Goal Preservation of the CD4 + cell count Drug Toxicity or Adverse Effects Doses of drugs should not be decreased in response to an adverse effect or toxicity Clinicians should D/C the drug and substitute another drug from the same class 31
Antiretroviral Resistance Testing Technique Advantage Limitation Genotyping Phenotyping - Availability - Days to results - Less technical - Direct measure of susceptibility - More familiar reporting results (IC 50, IC 90 ) - Indirect measure - Expert interpretation required - Minor species not tested -Costly - Weeks to results - More technical - Minor species not detected - Breakpoints undefined 32
Opportunistic Infection Prophylaxis and Treatment Pneumocystic jiroveci formerly Pneumocystic carinii (PCP) Prophylaxis (CD4 + cell count <200): Bactrim DS 1 PO QD Treatment: Bactrim IV 15 mg/kg/d x 21 d Toxoplasmosis gondii Prophylaxis (CD4 + cell count <100): Bactrim DS 1 PO QD Treatment: Sulfadiazine and Pyrimethamine Opportunistic Infection Prophylaxis and Treatment Mycobacterium avium Complex Prophyalxis (CD4 + cell count <50): Azithromycin 1200 mg PO Qweek Treatment: Clairithromycin and Ethambutol Candida albicans Prophylaxis (Frequent, recurrent, or severe infection): Fluconazole Treatment: Fluconazole High Dose or IV 33
Medication Burden HIV treatment only marginally better than HIV disease itself. Zidovudine I have no energy. Nelfinavir I m having 10-12 BM per day! Stavudine I need methadone for the pain! PIs Look what has happened to my face! Ritonavir I can t stop throwing up! Atazanavir I m yellow! Efavirenz I m too scared to go to sleep! Indinavir I have a horrible pain in my side! Financial Burden Clinic visits q3 months Consults q12 months Eye, dental Lab Monitoring q3 months CMP, CBC, VL, CD4 + cell count, lipids, LFTs Antiretroviral therapy ~ $1,200/month OI Medications 34
Unresolved Issues In patients with long term undetectable viral loads, is it ever possible to D/C medications? Why do certain subsets of patients who have definite exposures to HIV not seroconvert? Are medications the answer? Vaccine Obstacles No approved vaccine to date Can a natural protective state against HIV exist? No human disease model Long term survivors/slow progressors offer best models Lack of animal models also poses a challenge 35
Ticking Clock " Let us today set a new national goal for science in the age of biology. Today, let us commit ourselves to developing an AIDS vaccine within the next decade... If America commits to find an AIDS vaccine and we enlist others in our cause, we will do it. I am prepared to do all I can to make it happen. Pres. Bill Clinton, 1997 Lessons Learned 36
Historical Perspective 2008 Elvitegravir (Another II) X4 blockers Oral fusion inhibitors Why not start therapy earlier? No novel class ARVs in Phase III trials. 37
HIV and AIDS 38