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A CLINICAL UPDATE ON HIV/AIDS 27 August 2003

A CLINICAL UPDATE ON HIV/AIDS 27 August 2003. The Very Rev. Drew A. Kovach, M.D., M.Div., Director of HIV Services, Hawaii Permanente Hawaii dkovach@hawaii.rr.com (808) 432-2383. WHAT I WANT TO TALK ABOUT…. Work up of newly diagnosed patients Current Therapy Future Therapies

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A CLINICAL UPDATE ON HIV/AIDS 27 August 2003

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  1. A CLINICAL UPDATE ON HIV/AIDS27 August 2003 The Very Rev. Drew A. Kovach, M.D., M.Div., Director of HIV Services, Hawaii Permanente Hawaii dkovach@hawaii.rr.com (808) 432-2383

  2. WHAT I WANT TO TALK ABOUT… • Work up of newly diagnosed patients • Current Therapy • Future Therapies • Comprehensive care of HIV/AIDS patients

  3. EARLY DECTECTION OF HIV • Kaiser National HIV Research Consortium • Klein D, et al. J Acquir Immune Defic Syndr (JADIDS) 2003:32:143-152 • All HIV positive patients in 1998 (n=416) • Look back 5 years

  4. AT TIME OF FIRST POSTIVE HIV TEST • 44% Cases had AIDS (<200 CD4) • 19% Cases were <50 CD4

  5. 8 HIV ASSOCIATED CLINCAL EVENTS • Oral infection • Pneumonia • Unexplained fever • Herpes zoster • Seborrheic dermatitis • Night sweats • Unexplained weight loss • Lymphadenopathy ≥1 site

  6. CONCLUSIONS OF STUDY • Nearly half of the cases had AIDS at diagnosis • Although 80% of the patients were in a classic risk group for HIV only 31% were noted to have such risk prior to diagnosis • Improved risk assessment and attention to clinical conditions may prompt earlier testing

  7. HIV DIAGNOSIS • THINK OF HIV • SCREEN FOR HIV

  8. WHAT CHANGED THE EPIDEMIC IN THE USA? • The ability to measure HIV viral load in the blood • Highly Active Anti-Retroviral Therapy (HAART)

  9. VIRAL LOAD • HIV PCR RNA Method • bDNA (branched DNA) Method • 1st Generation <400 copies/ml to >750,000 copies/ml • Ultra-Sensative (2nd generation) <50 copies/ml to >75,000 copies/ml

  10. BASELINE TESTS 1 • HIV Serology -baseline • Total CD4 count -every 3 months • HIV-RNA (Viral Load) -every 3 months • CBC, LFT’s, -every 3 months • Renal function -every 3 months • VDRL(RPR) -yearly • PPD -yearly

  11. BASELINE TESTS 2 • Hepatitis A, B, C -baseline • Fasting lipids -baseline • FBS, Hgb-A1C -baseline • Toxoplasma IgG -baseline • CMV IgG -baseline • Retinal screen -baseline

  12. ACUTE HIV INFECTION • “Mono” like illness with or without rash • Weight loss and fatigue • Chronic respiratory infections • Population “at risk” • Think of it and test for it! • Very Aggressive Treatment Early!

  13. GOALS OF THERAPY • Maximal and durable suppression of viral load • Restoration or preservation of immunologic function • Improvement in quality of life • Reduction of HIV-related morbidity and mortality

  14. TOOLS TO ACHIEVE GOALS OF THERAPY • Maximize adherence to the antiretroviral regimen • Rational sequencing of drugs • Preservation of future treatment options • Use of drug-resistance testing in selected clinical settings

  15. NUCLEOSIDE & NUECLEOTIDE ANALOGUES • Act by incorporating themselves into DNA of the virus, stopping the building process. The resulting DNA is incomplete and stops replication.

  16. NUCLEOSIDE & NUCLECOTIDE ANALOGUES • AZT (Retrovir, ZDV, zidovudine) • 3TC (Epivir, lamivudine) • D4T (Zerit, stavudine) • DDI (Videx, didanosine) • DDC (Hivid, zalcitabine) • ABC (Ziagen, abacavir) • TNF (Viread, tenofovir) {nucleotide} • FTC (Emtriva, emtricitabine)

  17. NUCLEOSIDE & NUCLECOTIDE ANALOGUES SIDE EFFECTS • Fatigue • Anemia • Peripheral neuropathy • Pancreatitis • Lactic acidosis • Lipoatrophy • GI side effects

  18. PROTEASE INHIBITORS • Potent antiretroviral medications • Inhibit protease enzyme resulting in immature HIV particles • Activity of the PIs dependent on potency, bioavailability, plasma protein binding and resistance • Lipodystrophy and blood sugar metabolism problems

  19. PROTEASE INHIBITORS • Saquinavir (Inverase and Fortovase) • Ritonavir (Norvir) • Indinavir (Crixivan) • Nelfinavir (Viracept) • Amprenavir (Agenerase) • Lopinavir/retonivir (Kaletra) • Atazanavir (Reyataz)

  20. PROTEASE INHIBITORS SIDE EFFECTS • GI side effects • Lipid abnormalities • Fat accumulation • Osteoporosis • Kidney stones • Blood sugar abnormalities

  21. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS • Act by binding directly onto reverse transcriptase and prevent the conversion of RNA to DNA by a different mechanism than the nucleoside/nucleotide analogs

  22. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS • Nevirapine (Viramune) • Delavirdine (Rescriptor) • Efavirenz (Sustiva)

  23. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS SIDE EFFECTS • Rash • CNS side effects

  24. FUSION INHIBITORS • Unique mechanism of action by inhibiting the attachment of the virus to the CD4 cell

  25. ENFUVIRTIDE (T-20) “FUZEON” • Introduced March 2003 • Limited quantities available (9,000 doses in the US) on a first come, first serve basis • Sub-Q injections bid • Injection site reactions • Cost $1700/month

  26. COMBINATION MEDICATIONS • Combivir = AZT + 3TC; Introduced 1998 • Trizivir = AZT + 3TC + ABC; Introduced 2000

  27. HIGHLY ACTIVE ANTI-RETROVIRAL THERAPY (HAART) • Goal is to reduce viral load to undetectable levels • Measure viral load when starting HAART and then 4 weeks after • Effective HAART = significant reduction in viral load and ­in CD4s

  28. DHHS GUIDELINES 7-14-03 www.aidsinfo.nih.gov/guidelines

  29. WHEN TO START THERAPY • If symptomatic any value CD4 or VL Treat • If asymptomatic CD4<200; any VL Treat • If asymptomatic CD4 201-350; any VL Generally Offer Therapy (controversy exists)

  30. WHEN TO START THERAPY • If asymptomatic CD4 >350 & VL >55,000 Consider Therapy • If asymptomatic CD4 >350 & VL <55,000 Observe • If asymptomatic CD4<350 & VL >55,000 BEGIN TREATMENT

  31. NNRTI BASED REGIMENS • Preferred: EFV + 3TC + TFV or D4T (except in pregnancy) • Alternate: EFV + 3TC + DDI (except in pregnancy) • Alternate: NVP + 3TC + (AZT or D4T or DDI)

  32. PI BASED REGIMENS • Preferred: LPV/r + 3TC + (AZT or D4T) • Alternate: AMP + RTV + 3TC + (AZT or D4T) • Alternate: IND + 3TC + (AZT or D4T) • Alternate: IND + RTV + 3TC + (AZT or D4T) • Alternate: NFV + 3TC + (AZT or D4T) • Alternate: SQV + RTV + 3TC + (AZT or D4T)

  33. TRIPLE NRTI REGIMENS • Alternate: ABC + 3TC + AZT • Alternate: ABC + 3TC + D4T

  34. DO NOT USE • Monotherapy • Two drug therapy • D4T + DDI in pregnancy • EFV in pregnancy • D4T + AZT; DDC + D4T; DDC + DDI • Hydroxyurea

  35. MEGA-HAART THERAPY • 5-9 HIV drugs ! • 2-3 NRTI’s • 2-3 PI’s • 2 NNRTI’s • Worked 43% of the time in rescue therapy but discontinued 38% of the time due to toxicity

  36. MONITORING • Check CD4s and viral load and routine labs every 3 month and more often if clinically indicated • Undetectable viral load may take up to 12 weeks or longer to achieve • Genotypic and Phenotypic resistance testing • Viral “fitness”

  37. WHEN TO ASK FOR HELP? • Anytime you or the the patient wishes • Inability to attain clinical goals (¯ viral loads or ­ CD4s) • Recommendations on drug management and adherence • Evaluating resistance testing

  38. HIV RESISTANCE TESTING ASSAYS • Genotypic Assays • Detect mutations in RT & Protease genome • Generally require >500 copies/ml • Phenotypic Assays • Determine amount of drug required to suppress HIV replication in vitro • Generally require > 500 copies/ml • Viral replication capacity (“fitness”)

  39. HIV PRIMARY RESISTANT ISOLATES(N=280 pts. genotypic data in San Francisco)

  40. Virologic failure Sub-optimal suppression Acute HIV Initiation of Tx HIV Viral load <500 Recommended Recommended Consider Consider Not Recommended USE OF RESISTANCE TESTING

  41. NEW ANTIVIRAL AGENTS 1 • NRTI’s • DAPD • Capravirine • Dupont 961 • TMC 120 • Emivrine (MKC442)

  42. NEW ANTIVIRAL AGENTS 2 • PI’s • Tipranavir • MK944A • AG1776 • PD178390 • DPC 681 & 684 • GW433908/VX175

  43. FUSION INHIBITORS • T-1249 • binds with the CD4 cell surface to prevent invasion of the virus; particle needs to be given by sub-q injection; in clinical trials for rescue therapy; difficult to manufacture • TAK-779 • AOP-Rantes • PRO-140

  44. INTEGRASE INHIBITORS • L-731,988 • L-708,906 • None ready for clinical trials • 2-4 years ?

  45. CHEMOKINERECEPTORS • CCR-5: Schering Plough SCH-C; CXCR-4: SDF-1a • Years?

  46. ZINC-FINGER NUCLEOCAPSID PROTEINS • ?? • ?? • ??

  47. LONG TERM COMPLICATIONS 1 • Hyperglycemia/Diabetes • Lipid Disorders • High Cholesterol (↓HDL & ↑LDL) • High Triglycerides • Abnormal Fat Distribution • Fat accumulation • Fat loss • Lactic Acidosis • Bone Abnormalities

  48. LONG TERM COMPLICATIONS 2 • Liver dysfunction • Pancreatitis • Peripheral Neuropathy • Depression

  49. ADJUNCTIVE MEDICAL THERAPY • PCP Prophylaxis if CD4< 200 (Saved the most lives!) • Herpes Prophylaxis • Testosterone/anabolic therapy • Vitamin B12 therapy • Human Growth Hormone • Interluken 2 • MAC Prophylaxis

  50. ADJUCTIVE MEDICAL THERAPY 2 • Fungal Prophylaxis • CMV Prophylaxis • Nutrition, Diet and Exercise (monitor BIA) • Lifestyle Changes (Sexual, Alcohol, Tobacco, Street Drugs) • Treat Concurrent Chronic Diseases • Treat Depression • Offer Hope

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