delta region aids education and training center deltaaetc.org review of hiv therapy ronald d. wilcox...

DELTA REGION AIDS EDUCATION AND TRAINING CENTER • deltaaetc.org

Review of HIV Therapy

Ronald D. Wilcox MD FAAPProject Director / Principal

Investigator, DAETCAssistant Professor of Internal

Medicine and Pediatrics, LSUHSC


Disclaimer

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


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


Question

• How familiar are you with the different classes of HIV medications?1. Very familiar – know all 7 classes and most of the agents2. Can name at least 5 classes3. Can name at least 3 classes4. Can name at least 1 class5. Know none of the classes of medications


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


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


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)


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 < 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.


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.


Question

• Which of the following is the most likely cause of the patient’s symptoms?

1. Methemoglobinemia from the dapsone2. Pancreatitis from the ddI3. Hepatitis from the efavirenz4. Lactic acidosis from the d4T5. Cryptosporidiosis of the gallbladder


Adverse Side Effect of Class

• Lactic Acidosis + / - hepatic steatosis


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


Hepatic Steatosis


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 > 5

? Riboflavin, Carnitine, Thiamine, Coenzyme Q

• Rechallenge: Are any nucleosides safe?


Question

• All of the following are considered examples of mitochondrial toxicity effects of nRTIs EXCEPT:1. cardiomyopathy2. pancreatitis3. lipoatrophy4. peripheral neuropathy5. insulin resistance


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-B*5701• Other ADEs: depression, dizziness, anxiety,

thrombocytopenia, increased transaminases, myocardial infarction (90% increase)


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: > 60 kg: 200 BID or 400 daily

< 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)


Emtricitabine (FTC, Emtriva)• Pregnancy Risk Class: B

• Dosing:– Children > 33 kg and older: 200 mg daily

with or without food– Children < 33 kg: 6 mg/kg/day (liquid)

• Adverse Drug Effects:– Rash; Headache, dizziness, insomnia,

diarrhea, nausea, weakness with increased CK, cough, abnormal dreams.


Lamivudine (3TC, Epivir)

• Pregnancy Risk Class: C• Dosing: 150 mg bid or 300 mg daily– <50 kg: 2 mg/kg bid (liquid)

• Adverse drug effects:– Well tolerated– Headache and fatigue > 10%, pancreatitis (higher in

peds), peripheral neuropathy, neutropenia


Stavudine (d4T, Zerit)• Pregnancy Risk Class: C• Dosing:– Peds: 1 mg/kg bid (liquid)– Adults: <60 kg: 30 mg bid >60 kg:

40 mg bid• Adverse effects:– Peripheral neuropathy– Increased transaminases, triglycerides– Increased risk of lactic acidosis– Lipo-atrophy– Severe motor weakness


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


Combined Forms• Combivir: AZT + 3TC (1997)

• Trizivir: AZT + 3TC + ABC (2000)

• Truvada TDF + FTC (2004)

• Epzicom ABC + 3TC (2004)


Nucleotide RT Inhibitors

• Adefovir

• Tenofovir (TDF) (2001)


Adefovir

• No longer used in HIV care secondary to renal impairment


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 < 50– 30-49: every 48 hours– 10-29: twice weekly– Hemodialysis: once weekly


Non-Nucleoside RT Inhibitors

• Delavirdine (DLV) (1997)

• Nevirapine (NVP) (1996)

• Efavirenz (EFV) (1998)

• Etravirine (ETV) (2008)


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


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 > 250 or men

with CD4 > 400– Neutropenia, diarrhea


Efavirenz (EFV, Sustiva)• Pregnancy Risk Class: D• Dosing: 600 mg qHS– Peds: based on weight {>10 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


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


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)


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.


Question

• All of the following are metabolic side effects of the protease inhibitors EXCEPT:

1. Lipoatrophy2. Lipodystrophy3. Osteopenia4. Insulin resistance5. Hyperlipidemias


Case 2

• Laboratory work-up reveals:– Glucose 273– UA with >1000 glucose– TG 875 with a total cholesterol of 266– HDL 25


Insulin resistance

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


Lipid metabolism

• Increase in triglycerides

• Increase in cholesterol


Morphologic changes

• Fat accumulation:– Abdominal obesity– Buffalo Hump– Lipomatosis

– Breast enlargement


Lipoatrophy - nRTIs

• Fat loss

– Appendices

– Face

– Buttocks


Osteopenia• Highest incidence– Femoral head – osteonecrosis

• Screen with DEXA scans


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


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


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


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


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


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


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


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


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


Fusion Inhibitors

• Enfuvirtide (T-20) (2003)

• Maraviroc (MRV) (2007)


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?


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 < 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


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)


Atripla

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


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


Guidelines for Initiation• General guidelines:

– Consider:• Viral load > 100,000 and CD4 count > 350

– Offer:• CD4 < 350• Pregnancy• Chronic hepatitis B• HIV-Associated Nephropathy

• Exceptions:– Symptomatic HIV disease– Acute Retroviral Syndrome


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


Prophylaxis

• Pneumocystis jiroveci pneumonia (PcP)– Adults / Adolescents:• CD4 < 200 or < 14%• AIDS-defining OI• Oropharyngeal candidiasis

– Pediatrics• < 12 months: begin at 4-6 weeks of age if exposed• 1-5 years: CD4 < 500 or <15%• 6-12 years: same as adolescent


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


Prophylaxis

• PcP:– Medications cont.:• Atovaquone 1500 mg po daily– Peds: 1-3 & > 24 months: 30 mg/kg daily

4-24 months: 45 mg/kg daily• Aerosolized pentamidine 300 mg monthly for adults

or children


Prophylaxis

• Toxoplasmosis– Adults / Adolescents:• CD4 count < 100 and serology (IgG) positive

– Pediatrics:• Age > 12 months: qualify for PcP prophylaxis and are

seropositive


Prophylaxis

• Toxoplasmosis– Medications:• TMP/ SMX DS or SS daily– Peds: 10 mg/kg divided BID qMTW

• Atovaquone 1500 mg daily– Peds: 1-3 & > 24 months: 30 mg/kg daily

4-24 months: 45 mg/kg daily• Pyrimethamine 50 mg + leucovorin 25 mg weekly


Prophylaxis

• MAC:– Adults / Adolescents:• CD4 count < 50

– Pediatrics:• <1 year: CD4 count < 750• 1-2 years: CD4 count < 500• 2-6 years: CD4 count <75• 6-12 years: CD4 count <50


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 > 6 years of age: 150-450

mg daily


Discontinuation Criteria• PcP Prophylaxis– Primary and Secondary:

• CD4 count > 200 (and above 14%) for at least 3 months

• Toxoplasma prophylaxis– Primary:

• Same criteria as PcP prophylaxis discontinuation– Secondary:

• Treatment for > 12 months and CD4 > 200 for at least 3 months

• MAC– Primary prophylaxis:

• CD4 count > 100 for 6 months– Secondary prophylaxis:

• Treatment for > 12 months and CD4 > 100 for 6 months


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 classes2. I could identify 5 of the classes and many of the side effects3. I could identify 3 of the classes and some side effects4. I could identify 2 of the classes but almost none of the side effects5. There are medications to treat HIV?


Tha-tha-tha-that’s all, folks!

delta region aids education and training center deltaaetc.org review of hiv therapy ronald d. wilcox...

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