Human Immunodeficiency Virus Presentation
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Human Immunodeficiency Virus Presentation Human Immunodeficiency Virus Presentation Presentation Transcript

  • Human Immunodeficiency Virus Deanne Tabb, PharmD, MT (ASCP) Infectious Disease Specialist
  • Objectives
    • Review epidemiology and transmission of HIV
    • Describe the clinical presentation of HIV infection
    • Discuss diagnostics for HIV identification
    • Interpret surrogate markers commonly utilized in HIV care
    • Construct the lifecycle of HIV
    • Identify criteria for initiating antiretroviral therapy
  • Objectives
    • Discuss goals of therapy
    • Review recommendations for initial antiretroviral selection
    • Highlight agents used for PEP
    • Review pharmacologic therapy
    • Review newer agents in the pipeline
    • Examine opportunistic infection prophylaxis and treatment
  • Adult and Children estimated to be living with HIV/AIDS WHO UNAIDS AIDS epidemic update, December 2005
  • AIDS Rates 2004
  • Modes of Transmission Risk of transmission after single exposure to HIV infected source Needle Sharing Percutaneous (occupational exposure) Receptive anal intercourse Insertive anal intercourse Receptive vaginal intercourse Insertive vaginal intercourse Exposure 0.67% 0.3 – 0.4% 0.1 – 3% 0.03% 0.08 – 0.2% 0.03 – 0.09% Risk/ 10,000 exposures Am J Med 1999; 106:323. MMWR 1998; 47(RR17);1-14.
  • Virus Characteristics
    • Retrovirus
    • > 10 9 to 10 10 virus particles produced on a daily basis
      • Half-life of infected cell approximately 1-2 days
      • 1/3 to ½ of circulating virus replaced each day
    • HIV lacks 3’-5’ exonuclease proofreading capability
      • Cannot repair defects in genetic code
      • Estimated 1 error per viral genome transcribed
  • Goals of Therapy
    • Reduce HIV-related morbidity/mortality
    • Improve quality of life
    • Restore and preserve immunologic function
    • Maximally and durably suppress viral load
      • Goal < 50 copies HIV RNA/ mL (undetectable)
      • Prevention of viral resistance
    Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. (DHHS) Updated October 2006.
  • Definition of Failure
    • Virologic failure:
      • Confirmed HIV RNA level > 50 c/mL after 48-weeks HAART (ultra-sensitive assay)
      • HIV RNA level > 400 c/mL after 24-weeks of HAART
    • Immunologic failure: failure to increase CD4 count by 25-50 cells/mm 3 above baseline over the first year of therapy
    • Clinical failure: occurrence of HIV related events > 3 months after starting ART
    An Update and Review of Antiretroviral Therapy Pharmacotherapy 2006;26(8):1111-33
  • Natural History/Time Course
    • Acute retroviral syndrome symptoms present in 40-90%
    • Typically occur within 5-30 days of exposure
    • Typically resolves within 14 days of onset
    • Severity ranges from mild to severe
    • Symptoms
      • Malaise, myalgia (54%), night sweats, fever (96%), headache (32%), N/V/D (~30%), neurologic (12%)
    • Signs
      • Cervical lymphadenopathy (74%), mucocutaneous ulceration, rash (70%), weight loss (13%), oral candidiasis (12%)
  • Natural History/Time Course
    • Approximately 2.6 days from initial cellular infection to release of formed virus particles from target cell
    • After primary infection , plasma viremia (HIV RNA) markedly increases
      • Peaks within 30 days of exposure
    • Latency of virus in lymph nodes
      • Asymptomatic for years
      • Median time from initial infection to an AIDS diagnosis 8 years
  • Surrogate Markers
    • Plasma RNA (PCR)
    • CD4 cell counts
    CD4 Cell count % CD4 > 500/mm 3 > 29 200 – 500/mm 3 14-28 < 200/mm 3 <14
  • Natural History in Patient Without HAART Ann Intern Med 1996;124:654
  • Immune Defense
    • The major target of HIV is the CD4 cell
    • High variability in CD4 rate of decline
      • Rampant loss to < 200 within 2 years
      • CD4 > 500 at > 8yrs (chronic nonprogressors)
      • Average decline CD4 50 mm 3 /yr
      • Rate of decline is inversely proportional to viral clearance by cytotoxic T cells (CD8)
  • Diagnosis
    • Enzyme-linked Immunosorbent Assay (EIA)
      • Detects antibodies against HIV-1
      • >99 % sensitive and >98% specific
      • Optimal time to perform 2 months post-exposure
      • Positive EIA repeated
    • Confirmatory Western Blot
      • Positive confirmatory test with EIA +
      • Negative confirmatory test, most likely not infection
        • Repeat confirmatory test
        • Re-test in 3-6 months
        • Perform viral load assay
  • Factors That Influence Rate of Progression
    • Cytotoxic T-lymphocyte response
    • Defective virus
    • Genetic susceptibility of receptor sites
    • Age - Duration of survival is inversely correlated with age
    • Major Histocompatibility genes
    • Plasma HIV RNA level (set point)
  • Prognosis Progression to AIDS or Death
    • 0 - 49 cells/mm 3
    • 50 - 99 cells/mm 3
    • 100 - 199 cells/mm 3
    • 200 - 349 cells/mm 3
    • > 350 cells/mm 3
    • 16 % 20%
    • 12% 16%
    • 9.3% 12%
    • 4.7% 6.1%
    • 3.4% 4.4%
    CD4 T cell count 3 yr-probability VL <10 5 VL >10 5
  • HIV Life Cycle and Drug Targets Reverse Transcriptase Inhibitors Integrase Inhibitors Protease Inhibitors Entry Inhibitors
  • MOA
    • NRTIs
      • interfere with reverse transcriptase thus inhibiting viral replication
    • NNRTIs
      • bind directly to reverse transcriptase halting the addition of DNA to the growing chain
    • PIs
      • interfere with the enzyme protease which is responsible for cleaving viral precursors necessary for new viral replication
  • MOA
    • Entry and Fusion Inhibitors
      • bind to gp41 subunit of the viral envelope glycoprotein preventing conformational changes required for fusion of viral and cellular membranes (blocking HIV from entering human cells)
    • Integrase Inhibitors
      • Inhibit viral integration into host DNA
    • CCR5 coreceptor antagonists
      • block viral entry
    • Maturation Inhibitors
      • block HIV maturation by inhibiting the final step in the processing of the HIV Gag protein
  • Pretreatment Evaluation
    • Complete medical history, physical examination, lab evaluation
      • Presence of co-infection
      • Assess overall health status
    • Optional tests:
      • GC/Chlamydia
      • x-ray if indicated
    • Laboratory evaluation
      • HIV antibody test
      • CD4 T cell count
      • Plasma HIV RNA
      • CBC, BMP, LFT’s, U/A, RPR or VDRL, PPD, Toxo IgG, Hepatitis panel, PAP smear for women, fasting glucose and lipids, viral genotype
  • Utilization of Drug Resistance Testing in Clinical Practice
    • Persons with acute HIV infection
    • Persons with chronic HIV infection
    • Genotypic analysis preferred for naïve
    • Suboptimal viral load reduction
    • In cases of virologic failure
      • Should perform while patient on failing regimen (or within 4 weeks of discontinuation)
      • Viral load > 1,000 copies/mL
  • Methods to Achieve Readiness to Start HAART
    • Patient-related:
      • Negotiate plan/regimen
      • >2 visits ensure readiness
      • Recruit family/friends
      • Use memory aids
      • Address drug/ETOH abuse mental illness
    • Provider/Team-related:
      • Educate: goals, pills, food effects, side effects
      • Assess adherence
      • Ensure off-hour access
      • Utilize full health care team – ensure medication refills
    • Provider/Team-related cont:
      • Consider impact of new diagnosis on adherence
      • Provide team training updates
      • Monitor adherence and intensify when needed
    • Regimen-related:
      • Avoid drug interactions
      • Simplify regimen
      • Inform patient about SE
      • Anticipate and treat SE
    Pocket Guide Adult HIV/AIDS Treatment January 2006; The Johns Hopkins AIDS Service
  • When to Start HAART Defer therapy < 100,000 CD4 T cells > 350/mm 3 Asymptomatic Most clinicians recommend deferring therapy, but some will treat > 100,000 CD4 T cells > 350/mm 3 Asymptomatic Treatment should be offered following full discussion of pros/cons Any value CD4 T cells > 200/mm 3 but < 350/mm 3 Asymptomatic Treat Any value CD4 T cells < 200/mm 3 Asymptomatic Treat Any value Any value AIDS-defining illness or severe symptoms Recommendation Plasma HIV RNA CD4T Cell Count Clinical Category
  • Considerations for Selecting an Initial Regimen
    • Factors to consider include
      • Comorbidities
        • Liver/renal disease
        • Depression
        • Cardiovascular disease
        • Diabetes mellitus
      • Pregnancy status
      • Adherence
        • Pill burden
        • Dosing regimens
        • ADEs
        • Food restrictions
    • Drug interactions
    • Resistance mutations
    Pharmacotherapy 2006;26(8):1111-33. JAMA , August 16, 2006 – vol 296, No. 7.
  • HAART
    • Highly Active Antiretroviral Therapy
    • Triple drug regimen, combining agents from different classes
      • 2 Nucleoside Reverse Transcriptase Inhibitors (NRTI)
      • PLUS
      • Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)
      • OR
      • Proteus Inhibitor (PI)
  • Currently Available Antiretroviral Therapy
    • Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
      • Efavirenz (EFV)
      • Nevirapine (NVP)
      • Delavirdine (DLV)
    • NucleoSIDE Reverse Transcriptase Inhibitors (NRTIs)
      • Zidovudine (AZT)
      • Lamivudine (3TC)
      • Abacavir (ABC)
      • Didanosine (ddI)
      • Stavudine (D4T)
      • Zalcitabine (ddC)
      • Emtricitabine (FTC)
    • NucleoTIDE Reverse Transcriptase Inhibitors (NRTI)
      • Tenofovir (TDF)
    • Protease Inhibitors (PIs)
      • Ritonavir (RTV)
      • Amprinavir (APV)
      • Indinavir (IDV)
      • Nelfinavir (NFV)
      • Saquinavir (SQV)
      • Lopinavir/Ritonavir (LPV/r)
      • Atazanavir (ATV)
      • Fosamprenavir (fAPV)
      • Tipranavir (TPV)
      • Darunavir (DRV)
    • Fusion Inhibitors
      • Enfuvertide (T-20)
  • Starting Recommendations Treatment- naive Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. (DHHS) Updated October 2006. Abacavir/lamivudine (BII) Didanosine + lamivudine (BII) Nevirapine Atazanavir (unboosted) (BII) (BII) Fosamprenavir (unboosted) (BII) Fosamprenavir +ritonavir q Day (AII) Lopinavir/ritonavir q Day (BII) Alternative (  order) Tenofavir/emtracitabine (AII) Zidovudine/lamivudine (AII) Efavirenz Atazanavir + ritonavir (AIII) (AII) Fosamprenavir +ritonavir BID (AII) Lopinavir/ritonavir BID (AII) Preferred (  order) 2-NRTI NNRTI PI Column B Column A
  • Special Considerations
  • Hepatitis Co-infection
    • HBV
      • Tenofovir, Lamivudine, Emtricitabine
      • Hepatocellular inflammation “Flares”
      • LMV or FTC add entecavir
      • In early HIV, If treating HBV only: adefovir or entecavir
    • HCV
      • ART excluding ddI with ribavirin (↑LA/PA)
  • Pregnancy
    • Avoid ART during 1 st trimester
    • Preferred:
      • AZT + 3TC or FTC (nRTIs) +
      • NFV 1,250 mg po bid or SQV/r 800/100 (PI)
    • Do not use
      • Efavirenz – teratogenic
      • Nevirapine - ↑ hepatotoxicity in CD4 > 250 - caution
    • Prevention of perinatal transfer
      • Intra-partum: AZT 2 mg/kg; 1 mg/kg/h until delivery
      • Post-partum: (Infant) AZT syrup 2 mg/kg po q6h or 1.5 mg/kg IV q6h x 6 wks
    Pocket Guide Adult HIV/AIDS Treatment January 2006; The Johns Hopkins AIDS Service
  • HCW PEP
    • Initiate as soon as possible
    • 2-drug regimens
      • Basic: 3TC or FTC plus AZT, d4T or TDF
      • Expanded: basic + LPV/r (alt: ATV, FPV, IDV/r, SQV/r or NFV
      • SE management and counseling sheets
    • Expert consultation
    • HCW serology: Baseline, 6 wk, 12 wk, 6 mo +/- 12 mo
  • NucleoSIDE Reverse Transcriptase Inhibitors
  • Zidovudine (AZT, ZDV)/Retrovir ® FDA approved 1987 Formulations Normal dose Food Requirements Dose adjust T ½ Intracellular T1/2 Caps 100 mg Tabs 300 mg IV 10 mg/mL Syrup 10 mg/mL 300 mg PO bid or 200 mg PO tid None Crcl < 10 and HD: 300 mg Q Day 1.1 hrs 7 hours
    • Unique AE: BM suppression ( ↑ MVC anemia or neutropenia)
    • Class AE: GI intolerance, HA, LA, hepatic steatosis
    • Combinations: Combivir (AZT+3TC); Trizivir (AZT+3TC+ ABC)
  • Didanosine (ddI)/ Videx EC ® FDA approved 1991 Formulations Normal dose Food Requirements Dose adjust T ½ Intracellular T1/2 > 60 kg 400 mg PO/day Take ½ hr before or 2 hr after meal (food ↓ bioavial 55%) < 60 kg 250 mg PO/day With TDF 200 mg/day 1.1 hrs 7 hours
    • Unique AE: pancreatitis, peripheral neuropathy
    • Class AE: Lactic acidosis (LA), hepatic steatosis
    • Avoid combinations: with stavudine (d4T) due to ↑ AE
    Capsules 125, 200, 250, 400
  • Zalcitabine (ddC)/ Hivid ® Formulations Normal dose Food Requirements Dose adjust T ½ Intracellular T1/2 0.75 mg po tid None Crcl < 50; 0.75 bid; <10 and HD 0.75/day 1.2 hr
    • Unique AE: Peripheral neuropathy, stomatitis
    • Class AE: Lactic acidosis (LA), hepatic steatosis, pancreatitis
    • Not routinely used due to TID dosing/peripheral neuropathy
    • Avoid combination with d4T ( ↑ peripheral neuropathy)
    Tabs: 0.375, 0.75 mg
  • Stavudine (d4T) Zerit ® Formulations Normal dose Food Requirements Dose adjust T ½ Intracellular T1/2 > 60 kg 40 mg po bid;< 60kg 30 mg po bid None Crcl < 50 adjust dose based on weight 1.0 hr 7.5 hr
    • Unique AE: ↑ LA and hepatic steatosis , or lypodystrophy
    • Class AE: peripheral neuropathy, pancreatitis
    • Avoid combination wit ddI, antagonistic with AZT
    Capsules 15,20,30, 40 1mg/ml oral solution
  • Lamivudine (3TC)/ Epivir ® Formulations Normal dose Food Requirements Resistance T ½ Intracellular T1/2 150 mg po bid or 300 mg po/day None 5-7 hr 18 hr
    • Class AE: LA with hepatic steatosis
    • Approved for treatment of HepB; dose 100 mg po/day
    • Combinations:
      • Combivir 3TC + ZDV Epzicom 3TC + ABC
      • Trizivir 3TC + ZDV + ABC
    Tabs: 150, 300 10 mg/ml oral solution Combivir M184V
  • Abacavir (ABC)/ Ziagen ® Formulations Normal dose Food Requirements Dose adjust T ½ Intracellular T1/2 300 mg po bid or 600 mg po/day None ETOH ↑ ABC 41% 1.5 hr 12-26 hr
    • Unique AE: hypersensitivity (fever, rash, N/V/D, fatigue, malaise, dyspnea, cough)
      • STOP taking immediately; do not re-challenge, fatal anaphylaxis
    • Class AE: GI intolerance, HA, LA, hepatic steatosis, lipodystrophy
    Tabs: 300 mg 20 mg/ml oral solution
  • Emtricitabine (FTC) Emtriva ® FDA approved 2003 Formulations Normal dose Food Requirements Dose adjust T ½ Intracellular T1/2 200 mg po/day or 240 mg po/day solution None 10 hr >20 hr
    • Unique AE: hyperpigmentation of palms and soles
    • Approved for HepB
    • Combinations:
      • Truvada FTC + TDF (one tablet/day)
      • Atripla EFV + FTC + TDF (FDA approved first once-a-day 3-drug combination tablet – July 2006)
    Caps: 200 mg 10 mg/ml oral solution Crcl < 50: 200 mg/48h; <30 200 mg/72h; < 15 or HD 200 mg/96h Truvada
  • NucleoTIDE Reverse Transcriptase Inhibitor
  • Tenofovir (TDF)/ Viread ® FDA approved 2001 Formulations Normal dose Food Requirements Dose adjust T ½ Intracellular T1/2 300 mg po/day None 17 hr >60 hr
    • Unique AE: RI, ARF
    • Class AE: LA, hepatic steatosis, HA, D/N/V
    • Combinations:
      • Truvada FTC + TDF (one tablet/day)
      • Atripla EFV + FTC + TDF (FDA approves first once-a-day 3-drug combination tablet – July 2006)
    Tabs: 300 mg Crcl < 50: 300 mg/48h; <30 300 mg/2 x wk; HD 300 mg/ wk Viread
  • Non-Nucleoside Reverse Transcriptase Inhibitors
  • Efavirenz (EFV)/ Sustiva ® FDA approved 1998 Formulations Normal dose Food Requirements Dose adjust T ½ Intracellular T1/2 600 mg po qhs Empty stomach preferred; high fat meal ↑ by 39 and 79% 40-55 hrs
    • Unique AE: Rash, morbilliform (15-27%) – discontinuation not required unless blistering and desquamation present (1.7%). Onset ~ 11 days, duration ~ 14 days. CNS AE: confusion, dizziness, insomnia, abnormal dreams, hallucinations, nightmares, depersonalization (transient usually subside 2-4 weeks following initiation); False-positive cannabinoid test
    • Class AE: GI intolerance, HA, ↑LFTs
    • Do not use in pregnancy; teratogenic
    • Combination: Atripla TM – with FTC + TDF
    Caps: 50, 100, 200 mg Tabs: 600 mg CYP 3A4 inducer/inhibitor; Hepatic metabolism, renal and hepatic excretion Efavirenz
  • Nevirapine (NVP)/ Viramune ® Formulations Normal dose Food Requirements Dose adjust T ½ Intracellular T1/2 200 mg po/day x 14 days then 200 mg po/bid None 25-30 hr
    • Unique AE: Maculopapular red rash on face, trunk, limbs (17%), and fatal hepatotoxicity ( ↓ incidence by titrating dose)
      • ↑ incidence hepatotoxicity in women with CD4 count >250
      • 7% require discontinuation
    • Class AE: GI intolerance and HA
    Tabs: 200 mg 10 mg/ml oral suspension CYP 3A4 inducer (autoinduction) Nevirapine
  • Delavirdine (DLV) Rescriptor ® Formulations Normal dose Food Requirements Dose adjust T ½ Intracellular T1/2 400 mg po tid None; separate from antacids by 1 hour 5.8 hrs
    • Unique AE: Rash (18%), maculopapular, red on trunk and arms. Usual duration = 2 weeks, discontinuation not required unless accompanied by fever, swelling, mucous membrane involvement or arthralgias.
    • Class AE: GI intolerance, HA, ↑LFTs
    • Dose adjustments required when used with PIs
    • Not routinely used in clinical practice
    Tabs: 100, 200 mg 100 mg tabs in > 3oz water to make slurry CYP 3A4 inhibitor; Hepatic metabolism, renal and hepatic excretion
  • Protease Inhibitors
  • PI Considerations
    • 10 PIs
    • Factors: dosing frequency, food and fluid requirements, pill burden, drug interaction potential, baseline hepatic function, toxicity profile, propensity to cause metabolic abnormalities
    • Ritonavir: potent CYP450 3A4 inhibitor
      • Exploited for PK properties w/other PIs
      • Increased level of AE when used as single PI
  • PI Class Considerations
    • Class AE
      • Significant GI intolerance
      • HA
      • ↑ Tg & TChol
      • Hyperglycemia
      • Lipodystrophy
      • Hepatotoxicity, ↑LFTs
    • Contraindications
      • Rifampin
      • Midazolam, triazolam
      • Simvastatin, lovastatin
      • St. John’s wart
  • Amprenavir (APV)/ Agenerase ® Formulations Normal dose Food Requirements Dose adjust Half-life 1400 mg bid oral solution w/ or without food; avoid high fat meal ( ↓AUC 21%) 7.1-10.6 hrs
    • Unique AE: GI intolerance, hepatotoxicity, oral parethesias, rash – APV is a sulfonamide; watch for sulfa allergies
    • Oral solution contains propylene glycol: contraindicated in pregnant women, children < 4 years old, patients with hepatic or renal failure, and patients treated with disulfuram or metronidazole
    • Caution: anticonvulsants, methadone
    Caps: 50 mg 15 mg/mL oral solution (not interchangeable) Not recommended in patients with hepatic or renal failure
  • Fosamprenavir (fAPV) Lexiva TM FDA approved 2003 Formulations Normal dose Food Requirements Dose adjust 1,400 mg bid None H2 blockers and PPIs may ↓ absorption
    • Adverse effects: GI intolerance, rash (17%), HA, hyperlipidemia, ↑LFTs, hyperglycemia, fat maldistribution, possible increased bleeding episodes in patients with hemophilia
    • 700 mg fosamprinavir = 600 amprenavir
    • Coadministration with EFV use fAPV boosted regimen only
    • PI-experienced patient (q day dosing not recommended)
    • Caution: see amprenavir
    Tabs: 700 mg CYP 3A4 inh/sub/ind Boosted should not be used w/ hepatic impairment; not recommended in severe liver disease Boosted dose 1,400 mg + 200 mg RTV q day, fAPV 700 mg + 100 mg RTV bid
  • Atazanavir (ATV)/ Reyataz TM Formulations Normal dose Food Requirements Dose adjust 400 mg q day Take w/ food ↑ AUC Avoid use w/ H2 blockers, PPIs
    • Unique AE: ↑ indirect hyperbilirubinemia, jaundice, GI intolerance, rash, ↑ PR interval -1 st degree heart block
    • Possible increased bleeding episodes in patients with hemophilia
    • Neutral effects on lipids and blood glucose compared with other PIs
    • Caution: indinavir, irinotecan
    Caps: 100, 150, 200 mg CYP 3A4 inhibitor/substrate 300 mg Q day in liver disease Boosted dose 300 mg + 100 mg RTV (w/ TDF or EFV)
  • Indinavir (IDV)/ Crixivan ® Formulations Normal dose Food Requirements Dose adjust 800 mg q 8h Unboosted: take 1h before or 2h after; may take w/ skim milk or low-fat meal
    • Unique AE: nephrolithiasis (ADV crystals); drink > 48 oz. water/day, ↑ indirect bilirubin, dry skin, mouth, eyes, alopecia, metallic taste, hemolytic anemia
    • Class AE: GI intolerance, hyperlipidemia, hyperglycemia, fat maldistribution
    • Caution: azoles, clarithromycin, oral contraceptives, anticonvulsants
    Caps: 200, 333, 400 mg None in renal Mild/moderate hepatic insufficiency 600 mg q8h Boosted dose 800 mg + RTV 100 or 200 mg q12h
  • Lopinavir + Ritonavir (LPV/r)/ Kaletra ® Formulations Normal dose Food Requirements Dose adjust Two tablets or 5mL bid Four tablets or 10 mL q day (naïve pts) Tabs: None Oral solution: take with food
    • Unique AE: GI intolerance, esp. diarrhea with once daily, ↑ LFT’s
    • Class AE: Hyperlipidemia (esp. hypertriglyceridemia), hyperglycemia, fat maldistribution, ↑ bleeding episodes in patients with hemophilia
    • Caution: rifampin, oral contraceptives, atorvastatin AUC ↑ 6x, pravastatin levels ↑ 33% (no dose change), azoles (max dose 200 mg ketoconazole/day), anticonvulsants, atovaquone
    Tabs: 200/50 mg 400/100 mg/5mL (42% alcohol) No dose adjustments Dosing Modifications For tx experienced: w/ EFV or NVP three tablets bid
  • Saquinavir (SQV), Invirase® Hard gel capsules Formulations Normal dose Food Requirements T ½ serum 1000 mg + 100 mg RTV bid Take within 2 hours of a meal
    • Adverse Events: GI intolerance (N/D), HA, ↑ LFTs
    • Class AE: Hyperlipidemia (esp. hypertriglyceridemia), hyperglycemia, fat maldistribution, ↑ bleeding episodes in patients with hemophilia
    • Note: Boosted Invirase better tolerated than Fortavase (no longer available)
    • Caution: Dexamethasone, anticonvulsants, methadone, ketoconazole, grapefruit juice, clarithromycin
    Tabs: 500 mg Caps: 200 mg hard gel 1-2 hours Dosing Modifications CYP3A4 inhibitor
  • Nelfinavir (NFV)/ Viracept ® Formulations Normal dose Food Requirements T ½ serum 1,250 mg bid or 750 mg tid Take with meal or snack
    • Adverse Events: diarrhea/loose stools 10-30% (can treat with Psyllium or loperamide), ↑ LFTs
    • Class AE: Hyperlipidemia (esp. hypertriglyceridemia), hyperglycemia, fat maldistribution, ↑ bleeding episodes in patients with hemophilia
    • Caution: atorvastatin ↑ 74%, rifampin, methadone, anticonvulsants, oral contraceptives
    • Note: safe in pregnancy
    Tabs: 250 mg or 625 mg Powder: 50 mg/mL 3.5 – 5 hours Dosing Modifications CYP3A4 inhibitor and substrate
  • Tipranavir (TPV)/ Aptivus ® FDA approved 2005 Formulations Normal dose Food Requirements Storage 500 mg + 200 mg RTV bid Take with food
    • Adverse Events: Hepatotoxicity, skin rash (TPV has a sulfonamide moiety), Rare cases of fatal and nonfatal intracranial hemorrhages
    • Caution: atorvastatin ↑ 9-fold, rifampin, methadone, anticonvulsants, oral contraceptives, no data with azoles – do not exceed 200 mg daily of azole, TPV contains alcohol avoid use of flagyl/disulfuram
    • Miscellaneous drug interactions: Abacavir, AZT, loperamide, antacids
    • Note: new option for treatment experienced patients
    Caps: 250 mg Refrigerated Room temp: 60 days Dosing Modifications CYP3A4 inhibitor and substrate
  • Darunavir (DRV) Prezista TM Formulations Normal dose Food Requirements T ½ serum 600 mg + 100 mg RTV bid Take with food
    • Adverse Events: Skin rash (7%) – DRV has a sulfonamide moiety (SJS/erythema multiforme), GI intolerance N/D, HA, ↑ LFTs,
    • Caution: atorvastatin use lowest possible dose, rifampin, methadone, anticonvulsants, oral contraceptives, no data with azoles – do not exceed 200 mg daily of azole, Paroxetine & setraline AUC ↓
    • Note: new option for treatment experienced patients
    Tabs: 300 mg 15 hours Dosing Modifications CYP3A4 inhibitor and substrate
  • Entry Inhibitors
  • Enfuvirtide (T20)/ Fuzeon TM
    • Dose: 90 mg (1mL) SC bid to upper arm, abdomen, anterior thigh
    • Storage: reconstituted solution should be refrigerated and used within 24-hours
    • Adverse Events:
      • local injection site reactions in all patient (~3% require discontinuation) – pain, erythema, induration, nodules, cysts, pruritus, ecchymosis
      • ↑ rate of bacterial pneumonia
      • Hypersensitivity reaction (<1%); do not rechallenge
  • Maraviroc (Selzentry) FDA approved August 2007
    • Treatment experienced CCR5-tropic MDR-HIV-1 strains
    • Considerations: tropism testing, not recommended in dual/mixed CXCR4-tropic HIV-1, pediatrics, and treatment naïve
    • Dosing:
      • 300 mg bid
      • 150 mg bid if given with PIs except tipranivir/ritonavir, delavirdine, ketoconazole, itraconazole, clarithromycin, and telithromycin
      • 600 mg bid if given with efavirenze, rifampin, carbamazepine, phenobarbital, and phenytoin
    • Adverse Events:
      • Cough, fever, rash, abdominal pain, respiratory infections, rhinitis, dizziness, edema, sleep disorder
      • Serious events < 2%: hepatic cirrhosis or failure, viral meningitis, osteonecrosis, rhabdomyolitis
      • Lab abnormalities: ↑ bilirubin, amylase/lipase, AST/ALT
  • Newer Agents Coming to Market
  • Investigational Agents
    • Nucleoside Reverse Transcriptase Inhibitors
      • AVX754 (apricitabine)
      • Elvucitabine
      • KP-1461
      • Racivir
      • Fozivudine tidoxil
    • Non-nucleoside Reverse Transcriptase Inhibitors
      • TMC125 (etravirine)
      • TMC278 (rilpivirene)
    aidsinfo.nih.gov
  • Investigational Agents
    • Entry and Fusion Inhibitors
      • AMDO70
      • PRO 140
      • Peptide T
      • SCH-D (vicriviroc)
      • TNX-355
      • BMS-488043
      • PRO 542
    • Integrase Inhibitors
      • GS 9137
      • MK-0518 (raltegravir)
    • CCR5 coreceptor antagonists (Phase I)
    • Maturation Inhibitors (Phase II)
    aidsinfo.nih.gov
  • Agents not Recommended as Initial Therapy Inferior virologic efficacy, ↑ AE than alt Zalcitabine-AZT Lack of data in treatment-naïve Tipranavir (boosted) ↑ pill burden, Inferior virologic efficacy Saquinavir (unboosted) High pill burden, GI intolerance Ritonavir mono PI High incidence of nephrolithiases Indinavir (boosted) Tid with meals; fluid requirements Indinavir (unboosted) No trial experience in naïve, SC bid Enfuvirtide ↑ rate of virologic failure, rapid selection of resistance, potential for CD4 decline ddI + tenofovir Inferior virologic efficacy; tid dosing Delavirdine Lack of data in treatment-naïve Darunavir (boosted) Reasons for not recommending Drug
  • Agents not Recommended at Any Time Antagonistic effect on HIV-1 D4T + AZT Additive peripheral neuropathy D4T + Zalcitabine In vitro antagonism 3TC + Zalcitabine Similar resistance profile Emtricitabine + 3TC Teratogenic Efavirenz in pregnancy ↑ LA with hepatic steatosis +/- pancreatitis in pregnancy (fatal) DDI + stavudine Additive hyperbilirubinemia Atazanavir +Indinavir ↑ early virologic non-response Triple NRTI Rapid development of resistance Dual-NRTI Rapid development of resistance Monotherapy NRTI or NNRTI Reasons for not recommending Drug
  • Changing Therapy
    • Toxicity/intolerance
      • Single-substitution naïve patients
      • Stop all
      • Symptomatic management
      • Lipid lowering agents
      • Structured treatment interruptions
    • Inconvenience
    • First regimen failure
      • Ensure 2 preferably 3 active agents
    • Multiple regimen failure
      • If 2 active agents not available continue current regimen
      • Investigational agents
      • Lamivudine/emtricitabine retain some activity even when resistant (M184V or L44I substitution)
    Pharmacotherapy 2006;26(8):1111-33. JAMA , August 16, 2006 – vol 296, No. 7.
  • Activity of ART with Mutations An Update and Review of Antiretroviral Therapy Pharmacotherapy 2006;26(8):1111-33 Class resistance K103N NNRTIs Primary mutations, ↑ mutations = MDR L90M, L10I, 154V, M46I, 184V PI Resistant Decreased activity with ↑ number of mutations Activity may be resensitized with M184V Resistant Activity may be resensitized to tenofovir, AZT, D4T L74V TAMs Tams + M184V K65R K65R + M184V Abacavir Tenofovir Decreased activity with increased number of mutations TAMs = M41L, D67N, K70R/Q/N, T215F/Y Stavudine- zidovudine Resistant Sensitive M184V TAMs Lamivudine-emtricitabine Multiple drug resistance, sensitive to LMV and tenofovir May be sensitive to only tenofovir Multidrug resitance likely May have activity against tenofovir Q151M Q151M + M184V T69S insertion + TAMs T69S + M184V NRTIs Result Mutation ART
  • Salvage Therapy
    • Structured treatment interruptions
    • Multi-drug Rescue
      • Drug selection based on past exposure and resistance
      • Give as many as possible
      • Foscarnet induction
    • Mega-HAART
      • Typically 5-9 drugs
        • Boosted PI (not 3)
        • 1-2 NNRTIs
        • Several NRTIs
        • hydroxyurea
    • Adherence > 95% required
    3 rd International Workshop on Salvage Therapy for HIV infection HIV/AIDS eJournal 6(3),2000
  • Opportunistic Infections in HIV
  • Frequency of Initial AIDS-Defining Diagnosis Pneumocystis Jirvoveci 42 75-85 HIV wasting syndrome 11 70-90 Candida esophagitis 15 20-30 Kaposi’s sarcoma 11 15-25 HIV-associated dementia 4 40-70 Disseminated CMV 4 80-90 Toxoplasmosis encephalitis 3 5-15 Disseminated MAC 5 30-40 Lymphoma 4 3-5 Chronic mucocutaneous herpes simplex 1 10-25 Cryptococcus meningitis - 8-12 Cryptosporidiosis 2 5-10 Tuberculosis 5 4-20 % among all without proph 1997 %
  • Prevention of OI TB (latent) PPD + (> 5mm) INH 300 mg/day + pyridoxin 50 mg/day PCP CD4 < 200/mm 3 TMP-SMX 1 DS or SS/day or CD4% <14, thrush Toxoplasmosis CD4 < 100/mm 3 TMP-SMX 1 DS/day + anti-Tox IgG MAC CD4 < 50/mm 3 Azithromycin 1200 mg/wk Clarithromycin 500 mg bid Varicella Exposure to VZIG 6.25 mL IM < 96 hr chickenpox/zoster Disease Indication Preferred Regimen Pocket Guide Adult HIV/AIDS Treatment January 2006; The Johns Hopkins AIDS Service
  • OI Treatment OI Preferred Treating OI Among HIV-Infected Adults and Adolescents MMWR Dec 17,2004 CS for focal lesion edema Secondary prophylaxis can be discontinued ss of TE are gone and CD4 > 200 cells/uL for > 6 months Pyrimethamine (leucovorin) + CD 600 mg IV or PO q6h Acute therapy Pyrimethamine 200 mg PO x1, then 50 mg (< 60 kg) q/day + sulfadiazine 1,000 (<60 kg) PO q6h + leucovorin 10-20 mg PO q/day TE Other Issues Indications for CS PaO2 <70 mm/Hg Prednisone 40 mg PO bid days 1-5, then q day days 6-10, then 20 mg q day days 11-21 Secondary prophylaxis can be discontinued when CD4 > 200 cells/uL for > 3 months Alternatives For severe PCP : Pentamidine 4mg/kg IV q/day Mild-mod: Dapsone 100 mg PO q/day + TMP 15 mg/kg/day PO (divided tid) Primaquine 15-30 mg PO q/day + CD 600-900 mg IV q6-8h or CD 300-450 mg PO q6-8h Acute therapy TMP-SMX 15-20 mg TMP/kg/day IV divided q6-8h or same dose PO x 21 days Chronic maintenance therapy TMP-SMX 1-DS or SS PO/day Alt: Dapsone 100 mg/day Dapsone 50 mg/day + pyrimethamine 50 mg and leukovorin 25 mg PO q/wk Dapsone 200 mg + pyremethamine 75 mg + leukovorin 25 mg PO/wk Pentamidine aerosole 300 mg/mo Atovaquone 1,500 mg PO/day TMP-SMX 1-DS TIW PCP
  • OI Treatment OI Preferred Treating OI Among HIV-Infected Adults and Adolescents MMWR Dec 17,2004 Therapeutic CSF punctures to ↓ ICP Secondary prophylaxis can be discontinued if asymptomatic and CD4 > 100-200 cells/uL for > 6 months Amphotericin or fluconazole 400 -800 po or IV mg/day for less severe disease Fluconazole + flucytosine Acute therapy Ampho B 0.7 mg/kg IV q/day+ flucytosine 25 mg/kg po qid x 2 weeks followed by fluconazole 400 mg po q/day for 8 weeks or until CSF sterile Chronic maintenance therapy Fuconazole 200 mg po q/day Crypto Other Issues NSAIDS or CS if IRS Secondary prophylaxis can be discontinued in patients who completed 12 mo/tx remain asymptomatic CD4 > 100 for > 6 mo Alternatives Azithromycin 500-600 mg po q/day Alt: 3-4 th drug in pts with more severe disseminated disease Ciprofloxacin 500-750 po bid or Levo 500 mg po/day or Amikacin 10-15 mg/kg IV q/day At least 2 drugs as initial therapy Clarithromycin 500 mg PO bid + ETH 15 mg/kg PO q day Consider adding a 3 rd agent for CD4 < 50, high mycobacterial load, or in absence of ART; Rifabutin 300 mg po/day Chronic maintenance therapy Clarithromycin 500 mg PO bid + ETH 15 mg/kg/day +/- Rifabutin 300 mg po/day lifelong until sustained immunity MAC
  • Immune Reconstitution Syndrome
    • Occurs with CD4 T cell recovery and improved response to antigens
    • Presentation: paradoxical worsening
    • Onset: <1 week to several months
    • Incidence: 10-25% of patients on ART
    • Implicating pathogens: Mycobacterial (33%), C. neoformans , CMV, HBV, HCV, HIV – severe demyelinating leucoencephalopathy in CNS, BK virus – hemorrhagic cystitis
    • Management: treat PCP/TB defer ART 1-3 wks depending on CD4 count or use CS
    CID 2004;38:1159-66
  • Final Considerations
    • Review all HAART regimens carefully
      • Right combinations
      • Doses
      • drug-drug/food interactions
      • adherence
    • Consider antiretroviral SE and patient CC
    • Identify needs for OI prophylaxis
    • Individualize patients counseling needs
    • Refer patients to HIV clinic