Review of HIV Therapy

1
Review of HIV Therapy

• Ronald D. Wilcox MD FAAP
• Project Director / Principal Investigator, DAETC
• Assistant Professor of Internal Medicine and
  Pediatrics, LSUHSC

2
Disclaimer

• The speaker receives funding for research from
  the following companies
• Tibotec
• Pfizer
• Boeringer-Ingelheim
• GlaxoSmithKline
• Bristol-Myers-Squibb
• Merck

3
Objectives

• Review the life cycle of the HIV virus
• Review the current medications for treatment of
  HIV
• Review the current recommendations for initiation
  of HAART
• Review appropriate prophylaxis for OIs

4
Question

• How familiar are you with the different classes
  of HIV medications?
• 1. Very familiar know all 7 classes and most
  of the agents
• 2. Can name at least 5 classes
• 3. Can name at least 3 classes
• 4. Can name at least 1 class
• 5. Know none of the classes of medications

5
HIV Life Cycle

• Attaches at CD4 marker with help of CXCR4 and
  CCR5
• Injects RNA into the cytoplasm
• cDNA is made using reverse transcriptase
• cDNA is integrated into the cell DNA using
  integrase and replication occurs
• Protease cleaves the subsequent RNA and proteins
  into individual segments
• Buds off or disrupts cell membrane for release

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HAART Therapy

• 4 major targets
• Fusion inhibition
• CD4 receptor inhibitor
• CCR5-Inhibitor
• Reverse transcriptase enzyme
• Nucleoside Reverse Transcriptase Inhibitors
• Nucleotide Reverse Transcriptase Inhibitors
• Non-Nucleoside Reverse Transcriptase Inhibitors
• Integrase
• Integrase Inhibitor
• Protease enzyme
• Protease inhibitors

8
Nucleoside RT Inhibitors

• Abacavir (ABC) (1998)
• Didanosine (ddI) (1991)
• Emtricitabine (FTC) (2003)
• Lamivudine (3TC) (1995)
• Stavudine (d4T) (1994)
• Zalcitabine (ddC) (1992)
• Zidovudine (AZT, ZDV) (1987)

9
Case 1

• 28 year old obese patient is being seen by one of
  your colleagues. His current (second) HAART is
  d4T Efavirenz ddI and his viral load last
  month was lt 400 on this regimen. He is also on
  dapsone for PcP prophylaxis.
• The patient comes to your office complaining of
  some abdominal cramping over the past week that
  has steadily increased along with some nausea
  with one episode of emesis. No hematochezia,
  hematemesis, melena, diarrhaea, or constipation.
  He has also had lower extremity pain for 2 months.

10
Case 1

• Laboratory work-up reveals a WBC 8.2 with diff 66
  s and 30 l. His H/H and platelets are within
  normal limits. His chemistry reveals a Na 128, K
  3.4, Cl 98, CO2 14, BUN/Creat 22/1.4, glucose 88,
  and his AST and ALT are elevated at 2x the upper
  limits of normal. Lipase was 34.

11
Question

• Which of the following is the most likely cause
  of the patients symptoms?
• Methemoglobinemia from the dapsone
• Pancreatitis from the ddI
• Hepatitis from the efavirenz
• Lactic acidosis from the d4T
• Cryptosporidiosis of the gallbladder

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Adverse Side Effect of Class

• Lactic Acidosis / - hepatic steatosis

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Hepatic Steatosis / Lactic Acidosis

• Mechanism
• Inhibitor of DNA polymerase gamma
• (mitochondrial DNA synthesis)
• Incidence Low but with high fatality rate
• Risk Factors
• Female sex, Obesity, Prolonged Use, Pregnancy
• Presentation
• Non-specific GI (nausea, anorexia, pain,
  diarrhea), weakness, dyspnea, hepatomegaly,
  increased lactate, mild increase in
  transaminases, increased anion gap
• Highest risk with d4T, esp when paired with ddI

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Hepatic Steatosis
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Hepatic Steatosis / Lactic Acidosis

• CT SOME pts have enlarged, fatty liver
• Screening Do NOT stop RTI in every pt with
  lactate or transaminase elevation
• Therapy Stop RT if pt is symptomatic,
  acidotic, or lactate gt 5 ? Riboflavin,
  Carnitine, Thiamine, Coenzyme Q
• Rechallenge Are any nucleosides safe?

16
Question

• All of the following are considered examples of
  mitochondrial toxicity effects of nRTIs EXCEPT
• 1. cardiomyopathy
• 2. pancreatitis
• 3. lipoatrophy
• 4. peripheral neuropathy
• 5. insulin resistance

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Abacavir (ABC, Ziagen)

• Pregnancy Risk Factor C
• Dosing
• 8 mg/kg BID up to 300 mg po BID
• May give as 600 mg po daily
• HYPERSENSITIVITY REACTION
• 2-8 presents as anaphylaxis, fever, rash,
  fatigue, malaise, diarrhea, abdominal pain, N/V,
  respiratory symptoms, headache,
  myalgias/arthralgias
• Screen with assay for HLA-B5701
• Other ADEs depression, dizziness, anxiety,
  thrombocytopenia, increased transaminases,
  myocardial infarction (90 increase)

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Didanosine (ddI, Videx, Videx EC)

• Pregnancy Risk Class B
• Comes as EC capsule or chewable tablets or liquid
• Dosing
• Peds 180-240 mg / m2 / day divided q12
• Adults gt 60 kg 200 BID or 400 daily lt
  60 kg 125 mg BID or 250 daily
• MUST be on an EMPTY stomach (except when given
  with tenofovir)
• Adverse side effect Pancreatitis (2-3),
  peripheral neuropathy (17-20), retinal changes
  and optic neuritis, GI disturbances, increased
  transaminases and alkaline phosphatase,
  myocardial infarction (49 increase)

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Emtricitabine (FTC, Emtriva)

• Pregnancy Risk Class B
• Dosing
• Children gt 33 kg and older 200 mg daily with or
  without food
• Children lt 33 kg 6 mg/kg/day (liquid)
• Adverse Drug Effects
• Rash Headache, dizziness, insomnia, diarrhea,
  nausea, weakness with increased CK, cough,
  abnormal dreams.

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Lamivudine (3TC, Epivir)

• Pregnancy Risk Class C
• Dosing 150 mg bid or 300 mg daily
• lt50 kg 2 mg/kg bid (liquid)
• Adverse drug effects
• Well tolerated
• Headache and fatigue gt 10, pancreatitis (higher
  in peds), peripheral neuropathy, neutropenia

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Stavudine (d4T, Zerit)

• Pregnancy Risk Class C
• Dosing
• Peds 1 mg/kg bid (liquid)
• Adults lt60 kg 30 mg bid gt60 kg
  40 mg bid
• Adverse effects
• Peripheral neuropathy
• Increased transaminases, triglycerides
• Increased risk of lactic acidosis
• Lipo-atrophy
• Severe motor weakness

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Zidovudine (AZT, ZDV, Retrovir)

• Pregnancy Risk Class C
• Dosing
• 200 mg tid or 300 mg bid
• Peds 480 mg/m2 divided q6-q12 (liquid)
• Postnatal 2 mg/kg q6 x 6 weeks
• Adverse drug effects
• Bone Marrow Suppression (23 anemia, 39
  granulocytopenia in children) Myopathies
• Headache (42) GI Upset
• Macrocytosis Bluish-brown Nails
• Hair texture change in African-Americans

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Combined Forms

• Combivir AZT 3TC (1997)
• Trizivir AZT 3TC ABC (2000)
• Truvada TDF FTC (2004)
• Epzicom ABC 3TC (2004)

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Nucleotide RT Inhibitors

• Adefovir
• Tenofovir (TDF) (2001)

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Adefovir

• No longer used in HIV care secondary to renal
  impairment

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Tenofovir (TDF, Viread)

• Pregnancy Risk Class C
• Dosing
• 300 mg daily
• No peds dosing
• Adverse drug effects (equal to placebo)
• Fanconi syndrome, renal insufficiency
• Must change dosing with ClCr lt 50
• 30-49 every 48 hours
• 10-29 twice weekly
• Hemodialysis once weekly

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Non-Nucleoside RT Inhibitors

• Delavirdine (DLV) (1997)
• Nevirapine (NVP) (1996)
• Efavirenz (EFV) (1998)
• Etravirine (ETV) (2008)

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Delavirdine (DLV, Rescriptor)

• Pregnancy Risk Class C
• Avoid use in lactating women
• Dosing (no peds dosing)
• 400 mg tid or
• 600 mg bid
• Adverse drug effects
• Rash Elevated transaminases
• Headache
• Booster effect on some PIs lopinavir,
  ritonavir, saquinavir

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Nevirapine (NVP, Viramune)

• Pregnancy Risk Class B
• Dosing
• 200 mg daily x 14 days then bid
• (May give as 400 mg daily)
• Peds 120 mg/m2 bid (liquid)
• Adverse Drug Effects
• RASH (15-20)
• Elevated transaminases especially when used in
  PEP
• Initiate cautiously with women with CD4 gt 250 or
  men with CD4 gt 400
• Neutropenia, diarrhea

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Efavirenz (EFV, Sustiva)

• Pregnancy Risk Class D
• Dosing 600 mg qHS
• Peds based on weight gt10 kg
• Adverse Drug Effects
• CNS Stimulation nightmares/abnormal dreams,
  dizziness, depression, anxiety, insomnia,
  jitteriness, daytime somnolence, psychosis,
  problems with memory and concentration
• Rash (up to 46 in pediatrics)
• Increased transaminases
• Hyperlipidemia

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Etravirine (TMC-125, Intelence)

• Approved January 18, 2008
• Dosing 100 mg (2) po BID
• ADEs rash (16.9) and nausea (13.9)
• Salvage medication must be used with a boosted
  protease inhibitor in the regimen

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Protease Inhibitors

• Amprenavir (1999) / fos-Amprenavir (fAMP) (2003)
• Atazanavir (ATV) (2003)
• Darunavir (DRV) (2006)
• Indinavir (IND) (1996)
• Lopinavir / rtv (LPV/r) (2000)
• Nelfinavir (NLF) (1997)
• Ritonavir (RTV) (1996)
• Saquinavir (SQV) (1997)
• Tipranavir (TPV) (2005)

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Case 2

• 33 year old male patient presents to you office
  after being on d4T ddI Indinavir for 2 years
  with new complaints of increased urinary
  frequency and increasing fatigue. The patient
  reports that his shirt collar and pants are
  getting more tight and he reports concern about
  possible breast development.

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Question

• All of the following are metabolic side effects
  of the protease inhibitors EXCEPT
• Lipoatrophy
• Lipodystrophy
• Osteopenia
• Insulin resistance
• Hyperlipidemias

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Case 2

• Laboratory work-up reveals
• Glucose 273
• UA with gt1000 glucose
• TG 875 with a total cholesterol of 266
• HDL 25

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Insulin resistance

• New onset DM or worsening of current DM
• Insulin resistance
• Impairment of glucose tolerance
• Hyperglycemia
• Frank diabetes rare

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Lipid metabolism

• Increase in triglycerides
• Increase in cholesterol

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Morphologic changes

• Fat accumulation
• Abdominal obesity
• Buffalo Hump
• Lipomatosis
• Breast enlargement

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Lipoatrophy - nRTIs

• Fat loss
• Appendices
• Face
• Buttocks

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Osteopenia

• Highest incidence
• Femoral head osteonecrosis
• Screen with DEXA scans

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fos-Amprenavir (fAMP, Lexiva)

• Pregnancy Risk Class C
• Dosing
• Unboosted 1400 mg BID
• Boosted Lexiva 1400 mg with 100 mg Norvir daily
  (naive) OR 700 mg with 100 mg Norvir BID
• Pediatric Dosing (50 mg/ml) (2 years and older)
• Unboosted 30 mg/kg BID
• Boosted 18 mg/kg Ritonavir 3 mg/kg BID
• Adverse Drug Effects
• GI upset (N/V, diarrhea, taste disorders)
• Rash
• Circumoral paresthesias

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Atazanavir (ATV, Reyataz)

• Pregnancy Risk Class B
• Dosing
• PI-naïve patients 200 mg (2) daily or
  ritonavir-boosted
• PI-experienced patients 300 mg daily with 100
  mg Norvir
• Adverse Drug Effects hyperbilirubinemia,
  jaundice (5)
• Recent reports of kidney stones
• PPI use only in treatment-naïve patients on
  boosted atazanavir and given 12 hours apart
• Cannot give with nevirapine

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Darunavir (TMC-114, Prezista)

• Pregnancy Risk Class B
• Dosing
• PI-experienced patients 300 mg (2) or 600 mg
  (1) with 100 mg Norvir BID
• Adverse Drug Effects
• Diarrhea, nausea vomiting, headache, rash (7
  and included all severities including
  Stevens-Johnson)
• Elevated liver enzymes/hepatitis
• Also perioral paresthesia, hepatitis, fat
  redistribution, hyperlipidemia, Type 2 diabetes
  are possible
• Must take with food

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Indinavir (IND, Crixivan)

• Pregnancy Risk Class C
• Taken on empty stomach if given alone
• Dosing
• Forms 333 mg, 400 mg capsules
• 800 mg q8
• Boosted 800 mg bid with Norvir 100 mg with food
• Peds 500 mg/m2 q8
• Adverse Drug Effects
• Nephrolithiasis Hyperbilirubinemia
• GI intolerance
• 42-64 oz of fluids per day required
• Best PI for CNS penetration studied

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Lopinavir/RTV (LPV/r, Kaletra)

• Pregnancy Risk Class C
• Dosing
• 400 mg/100 mg bid
• 800 mg/200 mg po daily naïve pts
• 3 forms tablets 200 mg/50 mg tablets
  100mg/25 mg liquid 5 cc
• Adverse Drug Effects
• GI intolerance
• Hyperlipidemias

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Nelfinavir (NLF, Viracept)

• Pregnancy Risk Class B
• Must be taken after meals (500 kcal / 30 fat)
• Dosing
• 250 mg or 625 mg tablets 50 mg scoops
• 750 mg tid OR 1250 mg bid
• Peds 20-30 mg/kg tid OR 50-55 mg/kg bid (mix
  with formula but avoid acidic juices)
• Adverse Drug Effects
• Diarrhea Rash
• Weakness

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Ritonavir (RTV, Norvir)

• Pregnancy Risk Class B
• Dosing
• 600 mg bid
• Booster effect 100-200 mg bid
• Taken with food
• Store in refrigerator
• Adverse drug effects
• GI Intolerance Taste Perversion
• Circumoral, peripheral paresthesia
• Elevated transaminases Fatigue

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Saquinavir (SQV, Fortovase, Invirase)

• Pregnancy Risk Class B
• Dosing 500 mg tablets of Invirase
• 1000 mg with Norvir 100 mg BID
• 2000 mg with Norvir 100 mg Daily
• No peds dosing
• Adverse drug effects
• GI intolerance
• Headaches
• Elevated transaminases

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Tipranavir (TPV, Aptivus)

• Pregnancy Risk Class B
• Dosing 250 mg tablets
• 500 mg with Norvir 200 mg BID
• No peds dosing
• Cannot give with other PIs
• Adverse drug effects
• GI intolerance Headaches
• Elevated transaminases
• Intracranial hemorrhages

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Fusion Inhibitors

• Enfuvirtide (T-20) (2003)
• Maraviroc (MRV) (2007)

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Enfuvirtide (T-20, Fuzeon)

• Pregnancy Risk Class B
• Dosing
• 90 mg SQ bid
• Adverse Drug Reactions
• Injection site reactions, diarrhea, nausea,
  fatigue, peripheral neuropathy, decreased
  appetite, pneumonia?

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Maraviroc (MRV, Selzentry)

• Pregnancy Risk Class B
• Mechanism of Action CCR5 inhibition
• Dosing
• 150 600 mg po BID, dependent on concomitant
  meds
• no data yet in patients lt 16 y/o
• Adverse Drug Reactions
• Infections (50.2 versus 38.3) Candida, URI,
  and HSV similar to placebo for hypotension a
  case of possible MRV-induced hepatotoxicity with
  allergic features has been reported in a study of
  healthy volunteers

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Raltegravir (Isentress)

• First integrase inhibitor approved by FDA (2007)
• Pregnancy risk class C
• 400 mg po bid
• Side effects rare reports of weakness and CK
  elevation
• Recent (8-08) reports of liver toxicity when
  co-administered with tipranavir (3 patients)

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Atripla

• Combination of Tenofovir Emtricitabine
  Efavirenz (2006) given once daily

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Question

• Which of the following patients would probably
  NOT need HAART therapy?
• 1. 42 y/o with treated pulmonary TB, CD4 count
  220, and viral load 42,000
• 2. 35 year old with PcP and CD4 count 20
• 3. 24 year old 16 weeks pregnant patient with CD4
  count 525 and viral load 10,000
• 4. 68 year old with night sweats, LAD, fever, and
  CD4 count 367 with viral load 55,000
• 5. 52 year old otherwise healthy with CD4 count
  370 and viral load 85,000

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Guidelines for Initiation

• General guidelines
• Consider
• Viral load gt 100,000 and CD4 count gt 350
• Offer
• CD4 lt 350
• Pregnancy
• Chronic hepatitis B
• HIV-Associated Nephropathy
• Exceptions
• Symptomatic HIV disease
• Acute Retroviral Syndrome

58
Question

• Patient newly diagnosed with HIV. Initial CD4
  count is 94 (8.2) with HIV viral load of 125,000
  copies/ml. Toxo serology is 1.2 and CMV IgG is
  10.0. PPD shows 3 mm induration. The patient
  would need prophylaxis for which of the following
  diseases (more than one answer may be correct)?
• 1. Pneumocystis jiroveci (PcP) only
• 2. PcP Toxoplasmosis
• 3. PcP Cytomegalovirus
• 4. MAC PcP Tuberculosis toxoplasmosis
• 5. MAC PcP Toxoplasmosis Tb CMV

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Prophylaxis

• Pneumocystis jiroveci pneumonia (PcP)
• Adults / Adolescents
• CD4 lt 200 or lt 14
• AIDS-defining OI
• Oropharyngeal candidiasis
• Pediatrics
• lt 12 months begin at 4-6 weeks of age if
  exposed
• 1-5 years CD4 lt 500 or lt15
• 6-12 years same as adolescent

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Prophylaxis

• PcP
• Medications
• TMP/SMX SS or DS daily or DS TIW
• Peds TMP/SMX 10 mg/kg/day divided BID qMTW
  begin at 4-6 weeks of age
• Dapsone 50 to 100 mg daily
• Peds Dapsone 2 mg/kg daily or 4 mg/kg weekly

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Prophylaxis

• PcP
• Medications cont.
• Atovaquone 1500 mg po daily
• Peds 1-3 gt 24 months 30 mg/kg daily
• 4-24 months 45 mg/kg daily
• Aerosolized pentamidine 300 mg monthly for adults
  or children

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Prophylaxis

• Toxoplasmosis
• Adults / Adolescents
• CD4 count lt 100 and serology (IgG) positive
• Pediatrics
• Age gt 12 months qualify for PcP prophylaxis and
  are seropositive

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Prophylaxis

• Toxoplasmosis
• Medications
• TMP/ SMX DS or SS daily
• Peds 10 mg/kg divided BID qMTW
• Atovaquone 1500 mg daily
• Peds 1-3 gt 24 months 30 mg/kg daily
  4-24 months 45 mg/kg daily
• Pyrimethamine 50 mg leucovorin 25 mg weekly

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Prophylaxis

• MAC
• Adults / Adolescents
• CD4 count lt 50
• Pediatrics
• lt1 year CD4 count lt 750
• 1-2 years CD4 count lt 500
• 2-6 years CD4 count lt75
• 6-12 years CD4 count lt50

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Prophylaxis

• MAC
• Azithromycin 1200 mg qWeek
• Peds 20 mg/kg Weekly (max 1200) OR 5 mg/kg
  daily
• Clarithromycin 500 mg BID
• Peds 7.5 mg/kg BID (max 500 mg)
• Rifabutin 300 mg daily
• Peds only in children gt 6 years of age
  150-450 mg daily

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Discontinuation Criteria

• PcP Prophylaxis
• Primary and Secondary
• CD4 count gt 200 (and above 14) for at least 3
  months
• Toxoplasma prophylaxis
• Primary
• Same criteria as PcP prophylaxis discontinuation
• Secondary
• Treatment for gt 12 months and CD4 gt 200 for at
  least 3 months
• MAC
• Primary prophylaxis
• CD4 count gt 100 for 6 months
• Secondary prophylaxis
• Treatment for gt 12 months and CD4 gt 100 for 6
  months

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Question

• How familiar are you NOW with the different
  classes of HIV medications?
• 1. I could identify the seven major classes and
  the most common side effects from the classes
• 2. I could identify 5 of the classes and many of
  the side effects
• 3. I could identify 3 of the classes and some
  side effects
• 4. I could identify 2 of the classes but almost
  none of the side effects
• 5. There are medications to treat HIV?

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Tha-tha-tha-thats all, folks!