Antiretroviral Therapy: Pharmacology Cristina Gruta, PharmD, Asst. Clinical Professor of Clinical Pharmacy and FCM San Francisco AIDS Education and Training Center

HIV Life Cycle Step 1: Fusion Step 2: Transcription reverse transcriptase Step 3: Integration Step 4: Cleavage Step 5: Packaging and Budding HIV

Nucleoside Analogues (NA’s) or NRTI’s

Nucleoside Analogues: Food Constraints ddI (didanosine/Videx) only one that requires an empty stomach, i.e. at least one hour before or two hours after a meal – For buffered tablets, need at least two tabs/dose for adequate buffering capacity – Enteric-coated still requires empty stomach All other “NRTI’s” can be taken with food– best for GI tolerability

Nucleotide Analogues Tenofovir (Viread TM ), TFV Dose: 300 mg once daily Take with food for optimal absorption

Nucleoside/Nucleotide Analogues: Common Adverse Effects AZT: HA’s, n/v, fatigue, bone marrow suppression ddI, ddC, d4T: peripheral neuropathy, pancreatitis 3TC: HA’s, nausea (generally well-tolerated) Abacavir (ABC): n/v/d, perioral paresthesias, hypersensitivity rxn in 4-5% (FEVER, malaise, myalgia, arthralgia, GI sx’s, rash)  not advise re-challenge Tenofovir (TFV): Nausea, vomiting, flatulence (generally well-tolerated)

Case: 44 yo male recently diagnosed with HIV, VL=75,000 copies/mL, CD4=230 /mm 3. After several discussions of HAART therapy, side effects and adherence, AZT/3TC/ABC was started one week ago. Today he calls your clinic complaining of a rash.

Abacavir hypersensitity Occurs in up to 5% of patients Most common symptoms: – Fever, rash, nausea, malaise/fatigue, GI symptoms – Respiratory symptoms may occur Onset usually first two weeks of therapy Symptoms worsen with each dose Can be fatal if continued or restarted NEVER re-challenge Patient counseling and follow-up mandatory

HIV/HAART Toxicities: Lactic Acidosis Rare but potentially fatal syndrome Linked to prolonged use of NRTIs Symptoms include lethargy, fatigue, abdominal pain, respiratory distress Etiology: ?mitochondrial dysfunction, possibly due to inhibition of key mitochondrial replication enzyme by antiretroviral agents

Lactic Acidosis- Potential Lab Findings Anion gap,  lactate,  AST/ALT, CPK, LDH, lipase, amylase,  HCO3, liver bx: steatosis, necrosis, and inflammation Venous lactate level > 2.5 nmol/L (normal mmol/L) and normal pH Lactic acidosis: arterial pH 2.0 plus HCO3 < 20 mmol/L Mild: mmol/L Severe: > 5-10 mmol/L

Lactic Acidosis: Management Draw serum lactate levels if suspected If serum lactate >2 and symptomatic, d/c antiretrovirals until Sx resolve and lactate levels normalize (may take months) Anecdotal reports of help from supplemental L- carnitine, riboflavin, coenzyme Q Consider NRTI-sparing regimen if resumption of HAART indicated

NRTI Mitochondrial Toxicity MOA: Inhibition of mitochondial DNA polymerase- ,  oxidative metabolism,  ATP generation Implicated in lactic acidosis with hepatic steatosis Other possible manifestations: – Myopathy (AZT) – Neuropathy (d4T, ddI, ddC), – Lipoatrophy (d4T) – Pancreatitis (ddI)

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI’s)

NNRTI’s: Adverse Effects RASH!!  LFT’s EFV: CNS effects (e.g. sedation, insomnia, vivid dreams, dizziness, confusion, feeling of “disengagement”)

Nevirapine– New Data September 2000 two instances of life- threatening HEPATOTOXICITY in health-care workers taking NVP for PEP reported to CDC One of the two HCW’s required a liver transplantation for fulminant hepatic failure Serious adverse effects associated with NVP- containing PEP regimens reported in 22 cases (16 occupational expsures)

ARV Complications-- Case 33 y.o. male with CD4+= 539 and viral load= 44,000. Pt is HCV+ with chronically elevated LFT’s. Current LFT’s AST=588; ALT= 860. ARV regimen is d4T/ 3TC/NVP. What should be done about ARV regimen in light of LFT’s?

Protease Inhibitors (PI’s)

Dual Protease Inhibitor Combinations Exploits the enzyme inhibition properties of PI’s, specifically RTV Lessens pill burden Theoretical ability to suppress resistant HIV strains by enhancement of PI plasma levels

Basic Pharmacology Principles IC90 IC50 C min C max Time DrugLevel Dosing Interval Area of Potential HIV Replication Dose

Time Postdose (hours) ,000 10,000 IDV/RTV q12h: 800/200 High-fat Meal 800/100 High-fat Meal 400/400 High-fat Meal IDV q8h: 800 mg Fasted Indinavir Plasma Concentration (nM) 6th Conference on Retroviruses and Opportunistic Infections; Abstract 362. Indinavir/Ritonavir Pharmacokinetics

Dual Protease Inhibitor Combinations-- Dosing RTV 400 mg + SQV 400 mg BID RTV 400 mg + IDV 400 mg BID RTV 200 mg + IDV 800 mg BID RTV mg + APV 600 mg BID Kaletra 3 pills BID Not as common…. RTV 400 mg + NFV 750 mg BID NFV 1250 BID + SQV 1600 mg BID

Protease Inhibitors: Adverse Effects

PI Class-Wide Effects Hepatotoxicities Lipodystrophy Lipid abnormalities (  T chol,  triglycerides) Hyperglycemia, insulin resistance

Hepatotoxicity RTV use linked to increased risk of severe hepatotoxicity (Sulkowski, JAMA 2000; 283:74) Increased LFT’s observed with all PI’s More common in pts with chronic viral hepatitis (HBV, HCV) Data do not support witholding PI’s from pts co-infected with HBV or HCV

ARV Complications-- Case 34 y.o. female with CD4+ = 545 (nadir 150) with undetectable VL presents as a new pt with ARV regimen of d4T/3TC/SQV/RTV and c/o intermittent loose stools, abdominal cramping; negative stool w/u. Primary MD denotes prominent central obesity, enlarged breasts, and peripheral wasting. Total cholesterol = triglycerides= 1230

HAART Toxicities: Lipodystrophy Body habitus changes – central fat accumulation – peripheral fat wasting Risk factors – female gender (maybe get it worse) – older age – HAART – Protease Inhibitor use

Dorsocervical fat pad (“buffalo hump’) in HAART-treated patient

Dorsocervical fat pad and gynecomastia in patient on HAART

Peripheral Lipoatrophy

Facial Lipoatrophy

Lipodystrophy: Unclear Etiology Mitochondrial toxicity? Interference w/ adipocyte differentiation? Pro-inflammatory activation of the immune system during reconstitution?

Lipodystrophy: Treatment Options Switching Protease Inhibitors out of HAART regimen: inconsistent results Metformin? Thiazolidinediones? Growth hormone?

HIV/HAART Toxicities: Lipid Abnormalities Hypertriglyceridemia; risk of pancreatitis Low HDL, high LDL Increased CAD not yet documented Generally treated w/ fibrates and/or statins Inconsistent results from switch studies Beware of drug interactions, risk of myositis

HIV/HAART Toxicities: Insulin Resistance Progression to frank diabetes mellitus possible Monitor with fasting glucose values Improvement often seen with switching out of PI-based regimens Some success w/ metformin (Glucophage™)

Case T.C. is a24 y.o. male diagnosed with HIV infection 2 years ago. Back then, CD4 count= 565, viral load 13,500. Pt chose to defer therapy. Pt was lost to follow-up until 6 months ago. CD4 count= 349 and viral load 60,000. He admits to not always practicing safe sex. He seeks your advice about antiretrovirals– how would you counsel him?

Considerations in Initiating Therapy HIV Asymptomatic Theoretical benefit No proven long-term clinical benefit for CD4 >200 cells/ml 3 Expert opinion advises initiation of therapy for CD4 <350 cells/ml 3 at any viral load – Consider the viral load when > 350 cells/ml 3 CD4+ T cell The “downside” of antiretroviral regimens –  QOL – Short- and long-term toxicities

Considerations in Initiating Therapy HIV Asymptomatic Willingness of patient to begin and the likelihood of adherence Degree of immunodeficiency Plasma HIV RNA Risk of disease progression Potential risks and benefits

Prognosis without HAART 3-year probability of AIDS in 1604 men enrolled in the Multicenter AIDS Cohort Study (MACS) from Mellors Ann Int Med 1997 Viral load >60, , , ,000 <1000

Goals of Therapy & Tools to Achieve Goals Goals Maximal and durable suppression of viral load Restoration and/or preservation of immunologic function Improvement of quality of life Reduction of HIV-related morbidity and mortality Tools Maximize adherence Rational sequencing of therapy Preservation of future treatment options Use of resistance testing in selected clinical settings

ARV Therapy in the Chronically HIV Infected Patient CLINICAL CATEGORY Symptomatic (AIDS, severe symptoms) Any CD4+ T cell Any Plasma HIV RNA Asymptomatic, AIDS CD4+T cells Asymptomatic CD4+ Count Any <200/mm 3 >200/mm 3 but <350/mm 3 >350 Plasma HIV RNA Any >55,000 (RT- PCR or bDNA)) <55,000 (RT- PCR or bDNA) RECOMMENDATION Treat Offer treatment but controversy exists Clinical experts differ in their recommendations; many experts would treat Many experts defer therapy and observe

Indications for ART in the Chronically HIV-Infected Patient TREAT ALL (regardless of viral load) Symptomatic (AIDS, severe symptoms) Asymptomatic, CD4+ <200 cells/mm 3 Asymptomatic, CD4+ >200/mm 3 but <350 cells/ mm 3 * * Treatment should generally be offered, though controversy exists

Indications for ART in the Chronically HIV-Infected Patient TREAT Asymptomatic, CD4+ >350/mm 3 and HIV RNA>55,000(RT-PCR or bDNA)* * Some experts would recommend initiating therapy, recognizing that the 3 year risk of developing AIDS in untreated patients is >30%. In the absence of very high levels of plasma HIV RNA, some would defer therapy and monitor the CD4+ and level of plasma HIV RNA more frequently. Clinical outcomes data after initiating therapy are lacking.

Indications for ART in the Chronically HIV-Infected Patient DEFER TREATMENT Asymptomatic CD4+ cells > 350/mm 3 HIV RNA <55,000(RT-PCR or bDNA)* * Many experts would defer therapy and observe, recognizing that the 3 year risk of developing AIDS in untreated patients is <15%.

Initial Treatment Strongly Recommended Column A Efavirenz Indinavir Nelfinavir Ritonavir + Saquinavir (SGC or HGC)* Ritonavir + Lopinavir** Ritonavir + Indinavir*** Column B Didanosine+ Lamivudine Stavudine + Lamivudine Stavudine + Didanosine Zidovudine + Lamivudine Zidovudine + Didanosine One Choice Each From Column A and B * Saquinavir-SGC, soft-gel capsule (Fortovase): Saquinavir-HGC, hard-gel capsule (Invirase) ** Co-formulated as Kaletra *** Based largely on expert opinion

Initial Treatment Alternative Recommendation Column A Abacavir Amprenavir Delavirdine Nelfinavir + Saquinavir-SGC Nevirapine Ritonavir Saquinavir-SGC Column B Zidovudine + Zalcitabine One Choice Each From Column A and B CONTRAINDICATED ART monotherapy* Zidovudine and Stavudine * exception for prevention of perinatal transmission (see ACOG guidelines)

The Advantage of Sequencing Drugs To extend the overall long-term effectiveness of the available therapy options Delay the risk of certain side effects uniquely associated with a single class of drugs Anticipates up to 50% of failure rate and preserves future treatment options

Case T.C. is a24 y.o. male diagnosed with HIV infection 2 years ago. Back then, CD4 count= 565, viral load 13,500. Pt chose to defer therapy. Pt was lost to follow-up until 6 months ago. CD4 count= 349 and viral load 60,000. He admits to not always practicing safe sex. He seeks your advice about antiretrovirals– how would you counsel him?