Highly Active Antiretroviral Therapy Associated Adverse Events

Jacqueline Gabbay, B.S., Pharm.D.Bellevue Hospital Center

Overview

• Differentiating between common and severe adverse drug events

• Exploring the fine line between HIV disease and drug toxicities

• Monitoring for the presence of ADE’s• Management of HAART related ADE’s• Long term effects of HAART as a result of

increased survival

Antiretroviral Agents • NRTI

– Abacavir (Ziagen)– Didanosine (Videx)– Emtricitabine (Emtriva)– Lamivudine (Epivir)– Stavudine (Zerit)– Tenofovir (Viread)– Zidovudine (Retrovir)

• NNRTI– Delaviridine (Rescriptor)– Efavirenz (Sustiva)– Nevirapine (Viramune)– Etravirine (Intelence)

• PI– Amprenavir (Agenerase) or

fosamprenavir (Lexiva)– Atazanavir (Reyataz)– Darunavir (Prezista)– Indinavir (Crixivan)– Lopinavir (+ ritonavir = Kaletra)– Nelfinavir (Viracept)– Ritonavir (Norvir)– Saquinavir (Invirase)– Tiprinavir (Aptivus)

• Entry inhibitor: Enfuviritide (Fuzeon)

• Integrase inhibitor: Raltegravir • CCR5-r inhibitor: Maraviroc

HAART Associated Events

Hypersensitivity Reactions

• Incidence with all major classes of antiretroviral agents

• Most common during induction phase with non-nucleoside reverse-transcriptase analogs

• Spectrum of reactions– Mild self limiting maculopapular rash – Severe life threatening reactions

Hypersensitivity Reactions: Viramune® (nevirapine)

• Skin reactions- [US Boxed Warning]: Severe life-threatening skin reactions– Stevens-Johnson syndrome– Toxic epidermal necrolysis– Hypersensitivity reactions with rash and organ

dysfunction• Incidence

– Grade 1 & 2: 13%– Grade 3 & 4: 2%

Hypersensitivity Reactions: Viramune® (nevirapine)

• Greatest risk of reactions is within the initial 6 weeks of treatment

• Intensive monitoring during initial 18 weeks• Baseline liver function test• Periodic serum transaminases

• Management: permanently discontinue therapy

Hypersensitivity Reactions: Viramune® (nevirapine)

• Fourteen day lead-in period– 200 mg once daily x 14 days 200 mg BID– Do not increase dose until rash resolves – Not to exceed 28 days– If therapy interrupted > 7 days restart at daily dosing

• Avoid in high risk patients– Males CD4 > 400 cells/mm3

– Females CD4 > 250 cells/mm3

– Moderate to severe hepatic impairment

Hypersensitivity Reactions: NNRTI’s

• Rescriptor® (delaviridine)– Incidence 16 – 32%– Lasts < 2 weeks– May rechallenge

• Intelence® (etravirine)– Incidence 10%– May rechallenge

• Sustiva® (efavirenz)– Grade 1 & 2 rash: 5 –

26%– Grade 3 & 4 rash: < 1%

(46% in children)– Prophylactic

antihistamines – Discontinue if severe

Hypersensitivity Reactions: Ziagen® (abacavir)

• [U.S. Boxed Warning]: serious and fatal hypersensitivity reactions

• Incidence 5%• Screening for HLA-B 5701• Reaction worsens with each subsequent dose• Symptoms with two or more of the following

warrant discontinuation:– Fever, skin rash, constitutional symptoms, respiratory

symptoms, GI symptoms

Gastrointestinal Effects

• Most common adverse effect associated with ART– Nausea, vomiting, anorexia– Diarrhea

• Multiple potential etiologies– Advanced HIV disease– Opportunistic infections – Medication induced

• Mostly associated with NRTI’s and PI’s

Metabolic Effects

• Mitochondrial dysfunction• Lactic acidosis• Dyslipidemia • Lipodystrophy• Abnormal glucose utilization

NRTI’s

PI’s

• Role of mitochondria– Oxidative phosphorylation– Fatty acids and pyruvate used to produce energy as ATP– Generation of reactive oxygen species

NRTI Induced Mitochondrial Dysfunction

• Triphosphorylated intracellularly nucleotides incorporated into viral DNA via viral reverse transcriptase enzyme

• Prevent viral DNA elongation and replication• May function as substrates for other enzymes

capable of DNA formation– Human polymerase g

NRTI Induced Mitochondrial Dysfunction

NRTI Induced Mitochondrial Dysfunction

• Videx® (didanosine) > Zerit® (stavudine) >= Retrovir® (zidovudine) >>> Viread® (tenofovir) = Emtriva® (emtricitabine) = Ziagen® (abacavir)= Epivir® (lamivudine)

• Onset may vary depending on individual’s cell type– Variations in copies and numbers of mtDNA

• Organelle dysfunction and impairment of oxidative phosphorylation

NRTI Induced Mitochondrial Dysfunction

Clinical Manifestations of Mitochondrial Toxicity

Clinical Symptoms NRTILactic acidosis Videx® (didanosine) , Retrovir®

(zidovudine) , and Zerit® (stavudine) Proximal tubular dysfunction Viread® (tenofovir)

Pancreatitis Videx® (didanosine) and Zerit® (stavudine)

Hepatic steatosis Videx® (didanosine), Retrovir® (zidovudine), and Zerit® (stavudine)

Polyneuropathy Videx® (didanosine) and Zerit® (stavudine)

Myopathy Retrovir® (zidovudine) Pancytopenia Retrovir® (zidovudine) Lipodystrophy Viread® (tenofovir) and Zerit®

(stavudine)

Mechanism of NRTI Induced Lactic Acidosis

NRTI Lactic Acidosis

• Hyperlactitemia (lactate > 5 mEq/L)– Chronic hyperlactitemia vs. severe lactic acidosis

• Usually occurs after 6 months of treatment• Symptoms: Nausea, vomiting, abdominal pain, weight loss,

severe fatigue, hyperventilation • Risk factors

– Obesity– Nutritional depletion of cofactors and vitamins– HIV infection

• Most common NRTI’s: Videx® (didanosine) , Viread® (tenofovir), Zerit® (stavudine)

Management of Lactic Acidosis

L > 5 mmol/L

Renal Toxicity: Viread® (tenofovir) • Forms of renal toxicity

– Renal impairment– Acute renal failure– Fanconi syndrome– Interstitial nephritis– Nephrogenic DI– Case reports of acute tubular necrosis

• Manifests after 5 weeks or more of therapy– Resolution of proximal tubular dysfunction within 1 – 10

weeks after discontinuation • Mechanism: accumulation in proximal tubular cells

– Impaired tubular reabsorption– Renal tubular acidosis– Defects in vitamin D hydroxylation

Dominik et atl., AIDS 2005; 19: 1329 - 40

Renal Toxicity: Viread® (tenofovir)

• Risk factors– Age, sex, race– Underlying renal impairment – Concomitant nephrotoxic agents– Coadministration with PI’s: inhibition of Viread® (tenofovir)

efflux from tubule cells – Coadministration with Videx® (didanosine)

• Dose adjustments:– CrCl> 50 mL/min: 300 mg PO daily– 30 – 49 mL/min: 300 mg Q48H– 10 – 29 mL/min: 300 mg Q72-86H– <10 mL/min: not recommended without HD

Renal Safety of Viread® (tenofovir) in HIV-Infected Patients

• Systematic review and meta-analysis• Included 17 studies (9 RCT)• Results

– Significantly greater loss of kidney function with the use of Viread® (tenofovir) (CrCl difference of 3.92 mL/min, 95% CI, 2.13 – 5.7 mL/min)

– Significantly higher risk of acute renal failure (risk difference 0.7%, 95% CI, 0.2 – 1.2)

– No evidence of increased risk of severe proteinuria, hypophosphatemia, or fractures

Cooper et al., CID 2010; 51(5), 496 - 505

Nephrolithiasis: Crixivan® (indinavir)

• Incidence– Adults: 12%– Pediatrics: 29%

• Calculi composed of unmetabolized Crixivan® (indinavir)

• Dose dependent effect• Onset 4 weeks – 6 months • Symptoms:

– Acute flank pain/renal colic– Hematuria– Urgency and dysuria– Asymptomatic crystalluria

Nephrolithiasis: Crixivan® (indinavir)

• Risk factors: low body weight, low CD4 count, changes in kidney function, liver disease, high urinary pH

• Management:– Fluids– Acidification of urine– Pain control – NSAID’s not recommended

• Monitoring: renal function and urinalysis

• Prevention: 48 oz water daily

Pancreatitis • Implicating agents:

– NRTI’s: Videx® (didanosine) , Zerit® (stavudine), and Epivir® (lamivudine) (pediatrics)

– PI’s: associated with severe increases in triglycerides• Occurs within 1 – 6 months after induction • Resolves 1 – 3 weeks after discontinuation • Suggested mechanisms: mitochondrial toxicity• Risk factors

– Alcohol use, hyperlipidemia, cholelithiasis, h/o pancreatitis, advanced HIV disease, CD4 < 50 cells/mm3

• Clinical manifestations– Abdominal pain, nausea, and vomiting– Elevated triglycerides and glucose prior to onset

Hepatic Steatosis

• 1993 – eight cases of severe hepatomegaly with diffuse steatosis were reported in HIV infected patients taking Retrovir® (zidovudine)

• NRTI’s: Videx® (didanosine) , Zerit® (stavudine), and Retrovir® (zidovudine)

• Mechanism: esterification of TG and decreased egress from the liver accumulation of small lipid droplets

• Management: cessation of offending NRTI and supportive care

Peripheral Neuropathy

• Implicating agents:– NRTI’s: Videx® (didanosine), Zerit® (stavudine), Epivir® (lamivudine) (peds)– NNRTI’s: Viramune® (nevirapine)

• Appear to be dose related • Incidence is higher than other mitochondrial toxicity related

adverse events • Clinical manifestations: Bilateral tingling, burning, or aching sensation in

the hands and lower extremities • Risk factors:

– Advanced HIV, aging, diabetes, nutritional deficiencies, concomitant isoniazid

• Management: discontinue when neuropathic pain is severe due to possible irreversible nerve damage

Myopathy: Retrovir® (zidovudine)

• Incidence of 9% • Onset after months of therapy • Clinically resembles idiopathic polymyositis and HIV myopathy

– Muscle tenderness– Proximal muscle weakness– Muscle atrophy– Elevations in CK (10x ULN)

• Mechanism: affects muscle mitochondrial DNA polymerase g• Treatment

– May consider discontinuing Retrovir® (zidovudine) – NSAIDs– Muscle strength usually returns within months of discontinuation

Hematologic toxicity: Retrovir® (zidovudine)

• [US Boxed Warning]: associated with hematologic toxicity -granulocytopenia, severe anemia requiring transfusions, and rarely, pancytopenia

• Incidence– Granulocytopenia 2 %; onset 6 – 8 weeks– Anemia 1%; onset 2 – 4 weeks

• Mechanisms: direct bone marrow toxicity via inhibition of heme/globin synthesis and effect on iron supply

• Management: – Dose interruption for significant anemia (HgB< 7.5 mg/dL

or > 25% reduction from baseline) until recovery of bone marrow is evident

– Epoetin alfa and neupogen

Lipodystrophy

• Onset within 2 – 12 months after induction• Implicating agents:

– PI – NRTI: Zerit® (stavudine)

• Clinical features– Lipoatrophy - peripheral fat loss in the face, limbs, buttocks– Fat accumulation in the abdomen, breasts, and dosocervical

spine (“buffalo hump”) • Risk factors: longer duration of treatment, increasing age,

advanced HIV disease • Management: protease-sparing regimen, resistance training,

aerobic exercise

Lipidystrophy

Dyslipidemia • Features of dyslipidemia

– Elevated triglycerides ( > 150 mg/dL)– Elevated LDL (> 130 mg/dL)– Low levels of HDL (< 40 mg/dL)– Obtain baseline lipid panel

• Incidence highest with PI’s– Highest with lopinavir/ritonavor combination– Lowest with Reyataz® (atazanavir)– PI sparing regimens containing Zerit® (stavudine), Retrovir®

(zidovudine), or efavirenz– Viramune® (nevirapine) may have beneficial effect

• Pathogenesis unclear– Disruption of lipid metabolism

• SQV/RTV– atorvastatin 347% AUC– simvastatin 3059% AUC– pravastatin 50% AUC

• NFV– atorvastatin 74% AUC– simvastatin 505% AUC

• LPV/r– atorvastatin 588% AUC– pravastatin 30% AUC

fibratesfluvastatin

pravastatinrosuvastatin

statin-fibratesatorvastatin

lovastatinsimvastatin

Low interactionpotential

Use cautiously

Contraindicated

Lipid Lowering Agents and Protease Inhibitors

Antimicrob Agents Chemother 2001; 45: 3445-3450. AIDS 2002; 16: 569-577 40th ICAAC 2000; abstract 1644

Altered Glucose Metabolism

• 1997 – FDA issued a public health advisory concerning reports of hyperglycemia and new-onset diabetes mellitus related to PI’s

• Incidence with PI’s is 1 – 6%• Mechanism of insulin resistance unknown

– Increased concentration of insulin, C- peptide, proinsulin, and glucagon

– Peripheral insulin resistance– Elevated endogenous glucocorticoid levels

• Obtain baseline and follow-up blood glucose concentration

• Increased doses of antidiabetic agents may be indicated

Hepatotxicity

• Transaminitis and hepatotoxicity associated with most antiretroviral agents– PI’s: Norvir® (ritonavir) (full dose – < 2 %)– NRTI’s: Videx® (didanosine) and Zerit® (stavudine) – NNRTI’s: Viramune® (nevirapine)

• Risk factors: coinfection with viral hepatitis, other hepatotoxic agents, and baseline abnormalities of aninotransferases

Hyperbilirubinemia: Reyataz® (atazanavir)

• Most common side effect of atazanavir– Usually asymptomatic elevations– Incidence of increase > 2.6x ULN is 35 – 49%

• Mechanism– Inhibition of enzyme that conjugates bilirubin – Correlates with serum concentrations

• Management: – Discontinue if bilirubin is 5x ULN– Evaluate alternative etiology if transaminases

concomitantly elevated

Central Nervous System Effects: Sustiva® (efavirenz)

• Manifestations– CNS depression – impaired concentration (8%),

dizziness (28%), drowsiness (7%), insomnia (16%)– Psychiatric – severe depression (1 – 2%), suicide,

paranoia, mania, vivid dreams (6%)– Overall incidence as high as 50% with 3% severe

enough to cause discontinuation • Associated with higher serum concentrations• Onset within a few days to weeks of initiation

– Resolution within a four weeks of therapy

QT Prolongation: Invirase® (saquinavir)

• Recent labeling updates 2010: potential for prolonged QT or PR intervals when saquinavir is administered with Norvir® (ritonavir)

• Dose dependent effect• Contraindications: patients with congenital or

acquired QT prolongation, refractory hypokalemia, concomitant use of medication that increase saquinavir concentrations or prolong QT interval, or AV block

• Obtain baseline ECG • Management: if QT prolongation exceeds

pretreatment value by 20 msec discontinue

Overall Cardiovascular Risk

• Significantly higher rates of CHD and MI when compared to the general population

• HOPS – HIV Outpatient Study– Nine year follow-up study including 5500 patients with HIV– Increased frequency of MI after initiation of PI’s– Controlled for hypertension, smoking, diabetes, age, sex, and

dyslipidemia

• Risks– Hyperlipidemia– Altered glucose metabolism– Direct cytotoxic effects on myocardium

Schiller D. Am j Health SystPharm 2004; 61 (23)

Clinical Relevance of HAART ADE’s

• Decreased mortality with the use of HAART• Increased risk for long term effects• Important to monitor and identify common vs.

severe adverse drug events• Management of HAART related adverse events

Questions