YOU CAN NOW DOWNLOAD MISPLACED LESSONS FROM OUR WEBSITE (

Transcription

1 W-F Professional Associates, Inc. 400 Lake Cook Rd., Suite 207 Deerfield, IL June 2002 HIV/AIDS Update Part H02 YOU CAN NOW DOWNLOAD MISPLACED LESSONS FROM OUR WEBSITE ( THIS LESSON, COMBINED WITH THE MAY Y 2002 LESSON, HAS BEEN APPROVED BY THE FLORIDA BOARD OF PHARMACY FOR THEIR HIV/AIDS CE REQUIREMENT SPECIAL ID #PSA THIS MONTH HIV/AIDS 2002 UPDATE PART 2 SEND US AN AT info@wfprofessional.com.. WE CAN RESPOND MUCH FASTER TO YOUR NEEDS. REGARDING QUIZZES, PLEASE KEEP A COPY FOR YOUR RECORDS. HAVE YOU RECENTLY MOVED? PLEASE NOTIFY US. Welcome to Part 2 of our special program on HIV/AIDS. This is an up to date review, with special emphasis on background issues and drug therapy. Our goal is to present the most current information on this subject. This lesson provides 1.5 hours of credit (0.15 CEUs), and is intended for pharmacists in all practice settings. The program ID # for this lesson is H02.Pharmacists completing this lesson by June 30, 2005 may receive full credit. (June 30, 2004 for California.) To obtain continuing education credit for this lesson, you must answer the questions on the quiz (70% correct required), and return the quiz. Should you score less than 70%, you will be asked to repeat the quiz. Computerized records are maintained for each participant. Upcoming topics for continuous participants: Childhood Immunizations; Pain Management; Medication Errors. If you have any comments, suggestions or questions, contact us at the above address, or call toll free (In Alaska and Hawaii phone ). Please write your ID Number (the number that is on the top of the mailing label) in the indicated space on the quiz page (for continuous participants only). The objectives of this lesson are such that upon completion the participant will be able to: 1. Describe the indications for initiating antiretroviral therapy. 2. Differentiate between four different classes of antiretroviral agents currently approved for treatment of HIV infection in the U.S. 3. List currently approved antiretroviral agents, describe pharmacology, recognize major adverse effects or toxicities, and identify significant drug-drug interactions associated with each. 4. List preferred first-line and alternative combination therapies for HIV. 5. Discuss antiretroviral therapy in pregnancy to prevent perinatal transmission All opinions expressed by the author/authors are strictly their own and are not necessarily approved or endorsed by W-F Professional Associates, Inc. Consult full prescribing information on any drugs or devices discussed.

2 HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) Antiretroviral therapy has been one of the major advances in the fight against Human Immunodeficiency Virus (HIV), the virus that leads to acquired immunodeficiency syndrome (AIDS). The field of antiretroviral therapy has seen more dramatic changes than any other antimicrobial development in the past decade. Viral eradication is ambiguous in chronically infected patients. Clinical evidence shows that viral replication continues in the face of undetectable viral load. In other words, the infection may remain hidden but virulent. Therefore, two primary goals of antiretroviral therapy remain to be virologic control (measured as in reduced HIV RNA level) and immune restoration (measured as in increased CD4 count). Once these are achieved, clinicians are able to delay the progression of the disease, minimize opportunistic infections & malignancies, prolong survival, and improve quality of life. HAART has significantly improved morbidity and mortality by decreasing the risk of disease progression and prolonging life in HIV-infected patients. ADHERENCE Adherence is an important factor that determines degree and duration of virologic response. The ability of the patient to adhere to the prescribed regimen is critical for success of HAART and prevention of resistance. At least 90%-95% adherence is required to achieve undetectable viral load in 80% of patients. If adherence drops to 70-80%, only 25% of patients will likely achieve undetectable viral load. In short, less than perfect adherence leads to the development of drug resistance, limiting the effectiveness of therapy (1). Poor adherence has been shown to increase the likelihood of virologic failure and has been associated with increased morbidity and mortality. Due to increasing success of HAART, HIV/AIDS has become a chronic disease. It has become very difficult for patients to show perfect adherence to the regimens chronically. Reasons for the lack of adherence include complicated regimen, multiple daily doses, increased pill burden, and medication toxicities (1,2). For more predictable success of HAART, the pharmacist can prepare the patient for potential adverse effects, simplify regimens, avoid multiple drugdrug & drug-food interactions, reduce pill burden, explain goals of therapy and need for adherence, and most importantly, establish readiness to take medication before initiation of HAART (2). ANTIRETROVIRAL AGENTS Currently, four different classes of antiretroviral agents are available for the management of HIV disease: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and most recently nucleotide reverse transcriptase inhibitors Nucleotide RTIs). This lesson reviews the current treatment options for HIV infection (1,3,4,5). Nucleoside Reverse Transcriptase Inhibitors (NRTIs) These were the first antiretroviral agents to be used for the treatment of HIV. These agents chemically mimic naturally occurring nucleosides used for viral DNA proliferation. Their mechanism of action involves inhibition of the viral enzyme, reverse transcriptase, which is responsible for the transcription of viral RNA to DNA within the host cell (3,5,6). Thus, these agents inhibit viral replication in early stages of the viral life cycle. There are currently six NRTIs approved for HIV treatment in the U.S.: zidovudine (AZT, Retrovir ), didanosine (ddi, Videx ), zalcitabine (ddc, Hivid ), stavudine (d4t, Zerit ), lamivudine (3TC, Epivir ), and abacavir (ABC, Ziagen ) (1,3). All of these agents require intracellular metabolism to their triphosphate form before activation. Once activated, NRTIs competitively inhibit HIV reverse transcriptase, insert themselves into the growing viral DNA as a false nucleotide, block DNA synthesis, lead to chain termination, and subsequently inhibit viral replication (3, 6). Thymidine derivatives (AZT and d4t) control the viral replication in an actively dividing cell, while nonthymidine derivatives (ddi, ddc, 3TC, and ABC) control viral replication in a resting cell. Didanosine was recently formulated in 400 mg enteric-coated tablets to facilitate single tablet dosing and minimize food and other drug interactions with this agent. Two NRTI combination products are available to help improve adherence to HIV therapy by decreasing overall pill burden. Zidovudine and lamivudine are formulated together under the brand CE PRN (ISSN ) is owned and published by W-F Professional Associates, Inc. 400 Lake Cook Road, Suite 207, Deerfield, Illinois William J. Feinberg, President CE PRN is published eleven times per year, monthly, January through November. Subscription rate is $85.00 per year. Second-Class Postage paid at Deerfield, Illinois and at additional mailing offices by W-F Professional Associates, Inc. All rights reserved. None of the contents of this publication may be reproduced in any form without the written permission of the publisher. POSTMASTER: Send all address changes to W-F Professional Associates, Inc., 400 Lake Cook Road, Suite 207, Deerfield, IL June,

3 name Combivir, and Trizivir is a combination product containing zidovudine, lamivudine, and abacavir (3). These formulations are based on clinical data demonstrating the efficacy of these NRTIs in combination. Table 1 below summarizes the dosing and food effects for the NRTIs while Table 4 elaborates on adverse drug reactions with these agents (1,3,6,7,8,9,13). Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Like NRTIs, these drugs inhibit viral enzyme reverse transcriptase. However, they structurally bind to reverse transcriptase through a noncompetitive mechanism, making conformational change; rendering the reverse transcriptase enzyme less available for making proviral DNA (3,6). Unlike NRTIs, these drugs do not require intracellular metabolism for activation. Theoretically, drug resistance towards NRTIs would not affect NNRTIs or vice versa due to different site of action on reverse transcriptase. However, significant cross-resistance exists among NNRTIs within their class. There are three NNRTIs available: nevirapine (NVP, Viramune ), delavirdine (DLV, Rescriptor ), and efavirenz (EFV, Sustiva ). Recently, a 600 mg strength of efavirenz has been released to reduce the number of pills from three 200 mg capsules QHS to one 600 mg tablet QHS. Usual adult doses and food effects for these agents are summarized in Table #1 while adverse effect data are listed in Table #5 (1,3,6,7,9,13). Protease Inhibitors The third class of antiretrovirals, HIV protease inhibitors (PIs), was designed to inhibit viral replication during late stage in the life cycle of HIV. Protease is a viral enzyme responsible for cleaving complex viral polypeptide precursors into functional proteins that are essential for the maturation and assembly of virions. Activity of this enzyme is critical for the completion of HIV viral replication (3,6). PIs resemble the amino acid sequence where HIV protease binds or cleaves. Thus, PIs competitively inhibit HIV protease by binding to the active site of the enzyme. In other words, they inhibit production of new virions from chronically infected cells. There are currently six PIs approved by the FDA for HIV treatment in the U.S.: saquinavir (SQV) (Fortovase and Invirase ); ritonavir (RTV, Norvir ); indinavir (IDV, Crixivan ); nelfinavir (NFV, Viracept ); amprenavir (APV, Agenerase ); Lopinavir/ritonavir (LPV/RTV, Kaletra). Furthermore, saquinavir is available in two forms: a hard gelatin capsule (HGC; Invirase) and a soft gelatin capsule (SGC; Fortovase). Due to poor bioavailability, the HGC form of saquinavir is only recommended in combination with ritonavir. In all other cases, saquinavir-sgc is preferred. Lopinavir/ritonavir is the latest addition to the PI class of antiretrovirals in the U.S. Ritonavir inhibits CYP3A4 metabolism of lopinavir and increases lopinavir blood levels. Low dose ritonavir is clinically used in combination with multiple other PIs to help boost the pharmacokinetic levels of these agents to attain better viral suppression. See Table #1 for dosing and food effects and Table #7 for adverse effects and their prevalence with different protease inhibitors (1,3,6,7,9,10,13). Nucleotide Reverse Transcriptase Inhibitors (Nucleotide RTIs) Tenofovir disproxil fumerate is the newest antiretroviral agent approved by the Food and Drug Administration for the treatment of HIV infection in combination with other antiretroviral agents. This is the first nucleotide analogue reverse transcriptase inhibitor approved in the U.S (11). Nucleotide analogues are monophosphorylated nucleoside analogues, and they block HIV replication in the same manner as NRTIs. Therefore, tenofovir is classified in several sources under NRTIs. Tenofovir is an acyclic nucleoside phosphonate (nucleotide) with structure and actions similar to adefovir (the first nucleotide reverse transcriptase inhibitor developed that was denied FDA approval due to high incidence of nephrotoxicity) (5,11). In contrast to NRTIs, tenofovir and adefovir do not require initial intracellular phosphorylation, a limiting factor in resting cells; they are rapidly converted to their corresponding active diphosphate forms, which are potent intracellular inhibitors of retroviral reverse transcriptase. Clinical data are too limited to assess the role of tenofovir in the treatment of HIV infection. There are no data on tenofovir s effect on clinical progression of HIV or in antiretroviral naive patients. The oral prodrug may prove to be useful for initial therapy with other antiretrovirals to delay the use of protease inhibitors. Tenofovir is available in 300 mg tablets to be taken once daily by mouth (see Table #1) (5,11). Since this is the most recently approved antiretroviral agent, clinical experience and data on adverse effects is limited at this time (see Table #6) (11). NEW DRUGS IN THE RESEARCH Numerous agents from the above four classes (NRTIs, NNRTIs, PIs, and nucleotide RTIs) and from several new classes are being investigated and are in Phase I, II, or III of development. Tipranavir is the first non-peptidic protease inhibitor (NPPI) in development for addition to the antiretroviral family (5). It is presently entering Phase IIb clinical studies. This agent has a different chemical structure than currently available PIs that are actually peptidic protease inhibitors. T-20, an investigational anti-hiv compound, is the first in a new class of drugs called fusion inhibitors. These agents block fusion of HIV with the host cell before the virus enters the cell and begins the replication process (5). 3

4 Table #1 Generic Name, Brand Name Class Usual Adult Dose Food Effect Abacavir (ABC), Ziagen NRTI 300 mg BID ; alcohol increases ABC levels 41%; no affect on alcohol Didanosine (ddi), Videx Videx EC NRTI >60kg 200mg BID or 400mg QHS<60kg 125mg BID or 300 mg QHS 400mg QHS (EC) Levels decrease 55%, take half hour before or 1 hour after meals Lamivudine (3TC), Epivir NRTI 150 mg BID Stavudine (d4t), Zerit NRTI >60kg = 40 mg BID <60 kg = 30 mg BID Zalcitabine (ddc), Hivid NRTI 0.75 mg TID Zidovudine (AZT), Retrovir NRTI 300 mg BID Zidovudine/ Lamivudine: 300 mg / 150 mg, Combivir NRTIs 1 Tablet BID Zidovudine/Lamivudine/Abacavir 300mg/150mg/300mg, Trizivir NRTIs 1 Tablet BID Delavirdine (DLV), Rescriptor NNRTI 400 mg TID Efavirenz (EFV), Sustiva NNRTI 600 mg QHS Avoid taking after high fat meals, levels increase 50% Nevirapine (NVP) NNRTI 200 mg QD x 14days then 200mg BID Amprenavir (APV), Agenerase PI 1200 mg BID High fat meal reduces AUC 21%; with or without food but avoid high fat meal. Each 150mg capsule contain 109 IU vitamin E & oral solution has 46 IU/ml vitamin E, avoid vitamin supplement. Indinavir (IDV), Crixivan PI 800 mg TID Levels decrease 77%, take 1 hour before or 2 hours after meals; drink plenty of fluids Lopinavir/Ritonavir 133.3mg/33.3 mg, Kaletra PI 3 Capsules BID Take with food Nelfinavir (NFV),Viracept PI 750 mg TID or 1250 mg BID Levels increase 2-3 fold, take with meal or snack Saquinavir (SQV)-SGC, Fortovase PI 1200 mg TID Levels increase 6-fold, take with large meal Saquinavir (SQV)-HGC, Invirase PI 600 mg TID No food effect when taken with ritonavir Tenofovir,Viread Nucleotide RTI 300 mg QD Bioavailability improved from 25% (without food) to 40% (with food). Take with a meal 4

5 INDICATIONS FOR ANTIRETROVIRAL AGENTS Patients with established HIV infection are classified into one of the two clinical categories: asymptomatic infection or symptomatic disease (wasting, thrush, or unexplained fever) including AIDS as defined according to 1993 CDC classification. In February 2001 the Department of Health and Human Services (DHHS) published its revised Guidelines for the use of antiretroviral agents in HIV-infected patients (12). According to these guidelines, all patients with advanced HIV disease (AIDS) and symptomatic patients without AIDS should be treated with HAART regardless of their plasma RNA levels or CD4 cell count (12,13). Considerations for initiating antiretroviral therapy in asymptomatic patients are complex and depend upon virologic (viral load) and immunologic (CD4 count) factors. For asymptomatic patients with CD cell/mm 3, treatment should usually be offered. For patients with CD4 exceeding 350 cells/ mm 3, viral load level helps predict the risk for AIDS defining complication within 3 years (see Table #2) (12,13). Advance stage patients being maintained on an antiretroviral regimen should not have the HAART therapy discontinued during an acute opportunistic infection or other HIV complication, unless there are significant concerns regarding drug toxicity, intolerance, or drug interactions (12,13). Clinical Category CD4 T-Cell Count Table #2 HIV RNA level Recommendation Symptomatic (AIDS, thrush, weight loss, unexplained fever) Any Value Any Value Treat Asymptomatic, AIDS Any Value Any Value Treat Asymptomatic CD Any Value Offer treatment, controversial Asymptomatic CD4>350 >30,000 (bdna) or>55,000 (RT-PCR) Controversial, 3-year risk for developing AIDS in untreated patients >30% Asymptomatic CD4>350 <30,000(bDNA)<55,000(RT- PCR) Defer therapy & observe3- year risk for developing AIDS in untreated pts <15% DEVELOPING THE REGIMEN Combination of three or more antiretroviral agents has become the standard of care, when it comes to treatment of HIV infection. These therapies achieve goals of more effectively than previous one or two drug combinations. The first antiretroviral regimen used has the greatest chance of success; subsequent regimens are often more complicated and have higher failure rate (12). Table #3 provides a guide to the use of available treatment regimens for individuals with no prior or with limited experience to HIV therapy (1,9,12,14). Table #3 Recommended Antiretroviral Agents for Initial Treatment Strongly Recommended Column A Efavirenz Indinavir Nelfinavir Ritonavir + Indinavir Ritonavir + lopinavir Ritonavir + Saquinavir SGC/HGC Alternatives Column A Abacavir Amprenavir Delavirdine Nelfinavir + saquinavir (SGC) Nevirapine Saquinavir (SGC) Column B Zidovudine + lamivudine Zidovudine + didanosine Stavudine + amivudine Stavudine + didanosine Column B Didanosine + lamivudine Zalcitabine + zidovudine 5

6 Antiretroviral drug regimens are formulated by using 1 selection each from columns A and B (12). Priority is given to regimens in which clinical data supports sustained viral suppression, sustained increase in CD4 cell count, and favorable clinical outcome. There is a strong evidence of clinical benefit and/or sustained suppression of plasma viral load for regimens titled above as strongly recommended. On the other hand, regimens titled as alternatives are less likely to provide sustained viral suppression, or available data is inadequate. Several drugs or combinations are not recommended, as current clinical data is insufficient to allow a recommendation for or against their use (1,2,12). These include hydroxyurea in combination with other antiretroviral agents, and ritonavir in combination with amprenavir or nelfinavir. Certain combinations are not recommended and should not be offered due to less than optimal efficacy or overlapping toxicities (1,2,12). DHHS suggests that all monotherapies should be avoided except zidovudine monotherapy in HIV-infected pregnant woman with high CD4 cell count and low viral load (12). The hard gel formulation of saquinavir (Invirase ) should be avoided due to poor bioavailability, except in combination with ritonavir. Combinations of zalcitabine + didanosine, zalcitabine + lamivudine, or zalcitabine + stavudine should be avoided due to overlapping toxicity of peripheral neuropathy (7,12,14). Zidovudine and stavudine should not be taken concurrently due to pharmacologic antagonism. The combination of ddi and d4t should be avoided in pregnant women due to the risk of lactic acidosis and hepatotoxicity (12). INDICATIONS FOR CHANGING THERAPY Therapeutic goals of HAART include maximum viral suppression, optimum immunologic response, minimum adverse effects of antiretroviral medications, and the highest adherence. Change in therapy is warranted when any of these goals are not achieved (1,12). Common reasons for altering therapy include drug intolerance, non-adherence, emergence of resistance, or failure to achieve sustained viral suppression. Changes based on inadequate virologic response should be confirmed using at least two measurements of viral loads. Such changes should be prompted by one of the following: sub-optimal reduction in viremia (less than log reduction in viral load at 4 weeks or less than 1 log reduction at 8 weeks after initiating or changing therapy), failure to suppress viral load to undetectable levels at 4-6 months after initiating or changing therapy, re-appearance of viremia after suppression to undetectable, significant increases in viremia from the nadir of suppression, or persistently declining CD4 cell count (1,12). Testing for antiretroviral resistance may be helpful in selecting alternative therapy in case of virologic failure. As per DHHS guidelines, it is recommended not to change a single drug or add a single drug to a failing regimen; rather, at least two new drugs, preferably an entirely new regimen with at least three new drugs, should be utilized for best response. Furthermore, changing between drugs/classes with documented cross-resistance is not recommended. Single agent substitution is only recommended in case of drug toxicity. Based on the above recommendations, decision to change therapy must be carefully evaluated, as premature switch in therapy may severely limit future therapeutic options due to factors such as resistance and cross- resistance (12). ADVERSE DRUG REACTIONS It used to be that AIDS complications were mostly life threatening opportunistic infections (OIs). With successful viral control and immune repair in patients taking HAART, complications due to therapy have become more prevalent than OIs and malignancies (3,7). Most frequent adverse effects reported with all antiretrovirals remain to be GI related including nausea, vomiting, and flatulence. Several class-related adverse events have been recognized with antiretroviral drugs during the post-marketing period. Lactic acidosis with hepatomegaly and hepatic steatosis including fatal cases have been reported with the use of NRTIs alone or in combination with other antiretroviral agents. Hyperglycemia/diabetes mellitus, insulin resistance, increased bleeding episodes in patients with hemophilia, and lipodystrophy with and without serum lipid abnormalities have been associated with PI use with variable frequency 12. Rash and skin reactions are relatively common events encountered during use of NNRTIs. A significant minority of these rashes are severe; potentially fatal cases of Stevens-Johnson s syndrome have been reported. Average time of onset is 1-3 weeks. The frequency is 15%-20% with nevirapine and delavirdine, and 8%-10% with efavirenz. Severity sufficient to require discontinuation is 7% with nevirapine and 2% with efavirenz (7,12). Tables 4-7 review the incidence of common adverse drug reactions (ADRs) with different classes of antiretroviral agents (3,6,7,8,10,11). The most significant reactions are printed in bold and class effects are italicized. 6

7 Table 4. Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Name of Drug Zidovudine Ritonavir Lamivudine Epivir Didanosine Videx Zalcitabine Hivid Stavudine Zerit Abacavir Ziagen Type of Toxicity Hematologic Other Hematologic Hematologic Other Hematologic Characteristics Headache (62%), malaise (53%) Nausea (50%), vomiting (17%), anorexia (20%) Nail discoloration Myelosuppression (45%), agranulocytosis (39%), anemia (24%), thrombocytopenia (12%) LFTs (alk. phos, AST, ALT, total bilirubin) Lactic acidosis Severe myopathy (17%) [muscle weakness, pain, and CPK], nail discoloration (42%) Depression (9%), insomnia (11%), dizziness (10%), neuropathy (12%), headache (35%), malaise/fatigue (27%) Nausea (35%), vomiting (12%), diarrhea (18%) Neutropenia (7%), anemia (3%), thrombocytopenia (2%) Rash, pruritus LFTsLactic acidosis Peripheral neuropathy (20%), headache (7%) Nausea & vomiting, diarrhea (38%), pancreatitis (6%) Leukopenia (16%) LFTs (13%) Lactic acidosis Fever (12%) Peripheral neuropathy (35%), headache Pancreatitis (1%), oral ulcers Neutropenia (17%), anemia (8%), leukopenia (13%), thrombocytopenia (1%) LFTs (8%) Lactic acidosis Peripheral Neuropathy (20%) Nausea & vomiting (6%), diarrhea (4%), pancreatitis (1%) Rash (3%) Elevated LFTs (5-10%) Life-threatening hypersensitivity reaction (5%) [Fever, skin rash, fatigue, nausea, vomiting, diarrhea, abdominal pain, and respiratory signs & symptoms including shortness of breath, cough, & other flu-like symptoms] Nausea, vomiting, diarrhea, anorexia Lactic acidosis 7

8 Table #5: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Name of Drug Type of Toxicity Characteristics Nevirapine Viramune Drowsiness headache (11%), fatigue Diarrhea (2%), nausea (9%) Rash (37%), Steven-Johnson reaction LFTs (10%) Other Drug fever (10%) Delavirdine Rescriptor Efavirenz Sustiva Headache (6%), fatigue (4%) Nausea & vomiting (7%), diarrhea (4%), dyspepsia Rash (18%) LFTs (4-6%) Dizziness, confusion, insomnia Rash Table #6: Nucleotide Reverse Transcriptase Inhibitors Name of Drug Type of Toxicity Characteristics Tenofovir Viread Asthenia (8%), headache (6%), Nausea (11%), diarrhea (9%), flatulence (4%), anorexia (3%), abdominal pain (3%) LFTs/ALT (2%) Name of Drug Table #7: Protease Inhibitors Type of Toxicity Characteristics Ritonavir Norvir Indinavir Crixivan Nelfinavir Viracept Saquinavir SGC Fortovase HGC Invirase Nephrotoxicity General weakness (13%), peripheral paresthesia (5%), circumoral paresthesia (5%) Nausea (26%), vomiting (15%), diarrhea (17%) LFTs (4-13%) Blood glucose, cholesterol, elevated triglycerides, Lipodystrophy Headache (6%) Nausea (12%), vomiting (4%), diarrhea (5%), abdominal pain (9%) LFTs (2-3%), hyperbilirubinemia (10%), amylase Nephrolithiasis (4%) Blood glucose, cholesterol, elevated triglycerides, Lipodystrophy Diarrhea / loose stools Blood glucose, cholesterol, elevated triglycerides, Lipodystrophy Peripheral neuropathy (3%), headache (2%) Diarrhea (5%), nausea (2%) Rash (2%) LFTs (2%) Blood glucose, cholesterol, elevated triglycerides, Lipodystrophy 8

9 Name of Drug Type of Toxicity Characteristics Amprenavir Agenerase Lopinavir/ Ritonavir Kaletra Headache, fatigue, paresthesia (abnormal burning, tickling, or tingling sensation) Nausea, vomiting, diarrhea Skin rash, Stevens-Johnson syndrome. Blood glucose, cholesterol, elevated triglycerides, Lipodystrophy Headache, asthenia Diarrhea, nausea, abdominal pain, and vomiting Lipid elevations and pancreatitis New onset diabetes or exacerbation of pre-existing diabetes, An increased risk of bleeding in patients with hemophilia type A and B Redistribution or accumulation of body fat (central obesity, buffalo hump, peripheral wasting, breast enlargement, etc) DRUG INTERACTIONS Antiretroviral therapy has become increasingly more complex due to the propensity for drug-drug interactions with these medications. Drug(s) affecting plasma concentrations of concurrent medication(s) may result in reduced efficacy or increased toxicity. Most interactions with antiretroviral agents revolve around the hepatic enzyme system, cytochrome P450 (CYP450). NRTIs, including nucleotide RTIs, do not undergo extensive CYP450 metabolism. They are eliminated predominantly through renal mechanisms. Therefore, drug interactions are less common with these two classes. Nonetheless, there are a few clinically significant drug interactions involving the NRTIs (2,3,8,11,14). Zidovudine and stavudine appear to compete for phosphorylation; therefore, they are not recommended in combination with each other (1). Probenecid increases zidovudine levels by 2-fold, requiring a 50% dose reduction of AZT, when these drugs are given concurrently. Concurrent use of lamivudine with trimethoprim/sulfamethoxazole may result in increased AUC of lamivudine by about 40% (2,3). Didanosine immediate release impairs absorption of other medications, thus administration of several antiretrovirals and some antibiotics should be separated from ddi by 1-2 hours (2,3). Unlike NRTIs, protease inhibitors are extensively metabolized by CYP450. All protease inhibitors are competitive inhibitors of cytochrome P-450, predominantly the CYP3A4 isoform. PIs increase plasma drug levels of concurrent medications metabolized by this enzyme system (3). Of the protease inhibitors, ritonavir is the most potent enzyme inhibitor; saquinavir is the least potent inhibitor, while indinavir, nelfinavir, and amprenavir fall in between those two. In fact, ritonavir has been utilized extensively with other PIs to increase blood levels of the concurrent agent (3,15). Drugs that should not be used in combination with PIs include simvastatin, lovastatin, cisapride, rifampin, midazolam, triazolam, estemizole, terfinadine, dihydroergotamine & other ergotamines, and St. John s wort (2,3,10,15). Additionally, rifabutin should be avoided with saquinavir. Furthermore, concurrent use of amiodarone, flecainide, propafenone, quinidine, bepridil, meperidine, rifabutin, diazepam, and bupropion should be avoided with ritonavir. Like protease inhibitors, NNRTIs are associated with several significant drug interactions (2, 3). Delavirdine inhibits, nevirapine induces, while efavirenz both induces and inhibits CYP450 (3A4 and 2D6 isoforms). Nevirapine and efavirenz both induce their own metabolism, while delavirdine may inhibit its own metabolism (3). Due to their effects on CYP450, NNRTIs have potential to alter plasma concentrations of concurrent drugs metabolized by some isoforms of CYP450. Drugs that should not be used with efavirenz include estemizole, terfenadine, cisapride, midazolam, triazolam, DHE & other ergotamine derivatives (2,3). In addition to these agents, rifampin, rifabutin, simvastatin, lovastatin, H-2 blockers, and proton pump inhibitors should also be avoided along with delavirdine. Tables #8 a-g review significant drug interactions with specific antiretrovirals (2,3,8,9,10,11,14,15,16). Ritonavir: Table #8a + azoles = azole levels doses >200 of ketoconazole or itraconazole not recommended + rifabutin = rifabutin by (4-fold) rifabutin to 150mg QOD + rifampin = RTV 35% RTV dose not established + methadone = methadone 37% adjust methadone dose if needed + oral contraceptives = contraceptive efficacy additional / alternative form of contraception recommended + sildenafil = sildenafil (11-fold) do not exceed >25 mg within 48-hour period + anticonvulsants* = RTV (theoretical) avoid concomitant use, monitor anticonvulsant levels * = carbamazepine, phenytoin, and phenobarbital 9

10 Indinavir: June 2002 HIV/AIDS Update Part 2 Volume 24 Number 6 Table #8b + ketoconazole = IDV level by 68% IDV 600mg Q8H + delavirdine = IDV IDV 600mg Q8H + efavirenz = IDV IDV to 1000mg Q8H + indinavir = IDV IDV to 800m mg Q12H + RTV mg BID + rifabutin = rifabutin level rifabutin to 150mg QOD or alt. IDV efficacy IDV to 1000mg Q8H + sildenafil = sildenafil (4-fold) do not exceed >25 mg within 48-hour period Nelfinavir/ Amprenavir/ Lopinavir: Table #8c + rifabutin = rifabutin level rifabutin to 150mg QOD or alt. NFV efficacy NFV to 1000 mg TID + delavirdine = NFV AUC 113% NFV dose not established + nevirapine/efavirenz = APV level by 30-40% avoid unless with ritonavir, dose APV 1200mg BID + oral contraceptives = contraceptive efficacy additional /alternative form of contraception recommended + sildenafil = sildenafil (theoretical) do not exceed >25 mg within 48-hour period + ritonavir = NFV NFV mg BID + RTV 400 mg BID, APV APV 600 mg BID + RTV mg BID or APV 1200 mg QD + RTV 200 mg QD Saquinavir: Table #8d + rifabutin = SQV level 40% contraindicated unless combined with ritonavir & rifabutin ß to times/week + rifampin = SQV level by 80% contraindicated unless combined with ritonavir + delavirdine = SQV (5-fold) SQV-SGC to 800mg TID + ritonavir = SQV SQV-SGC 800 mg BID + RTV 200 mg BID or SQV-SGC 1600 mg QD + RTV 100 mg QD or SQV-HGC/SGC 400 mg BID + RTV 400 mg BID + sildenafil = sildenafil AUC (3-fold) do not exceed >25 mg within a 48-hour period Delaviridine: Table #8e + indinavir = IDV level by 40% IDV to 600mg Q8H + fluoxetine, ketoconazole = DLV level by 50% DLV to 300mg QAM, 200mg noon, & 300mg QPM + sildenafil = sildenafil (theoretical) do not exceed >25 mg within 48-hour period + warfarin = warfarin (theoretical) monitor INR + clarithromycin = clarithromycin by 100% dose adj. recommended in renal insufficiency + saquinavir = SQV SQV-SGC 1400 mg BID + DLV 600 mg BID or SQV-SGC 800 mg TID + DLV 400 mg TID Table #8f Efavirenz: + methadone = methadone level methadone dose + rifampin = EFV level 26% EFV dose to 800mg QD + rifabutin = rifabutin level 35% rifabutin to mg QD + saquinavir = SAQ level 60% avoid unless used w/ ritonavir + ritonavir = RTV level 20% RTV toxicity & LFTs + amprenavir = APV level 60%; APV dose 1200mg BID with ritonavir + anticonvulsants* = EFV (theoretical) avoid concomitant use, monitor anticonvulsant levels * = carbamazepine, phenytoin, and phenobarbital 10

11 Table #8g Nevirapine: + methadone = methadone level; methadone dose + oral contraceptives = contraceptive efficacy; additional /alternative form of contraception recommended + rifabutin= NVP level 16%, no dose adjustment + anticonvulsants* = NVP (theoretical) avoid concomitant use, monitor anticonvulsant levels * = carbamazepine, phenytoin, and phenobarbital In short, with the knowledge of current nomenclature of drug interactions with the CYP450 system, clinicians should be able to predict most of these interactions. TREATMENT DURING PREGNANCY Treatment guidelines during pregnancy have also been developed for HIV-infected pregnant women and prevention of vertical transmission (1,12). If these women satisfy criteria for therapy, DHHS guidelines should be followed for treatment like any other HIV infected patient. Pregnant women should be offered the standard therapy with HAART as well as therapy to prevent perinatal transmission (1,12). The most significant data on prevention for perinatal transmission comes from the Pediatric AIDS Clinical Trial Group Protocol 076 (PACTG 076). This pivotal trial demonstrated that AZT reduced the rate of perinatal transmission from 22.6% to 7.6% (1,2,12). Multiple uncontrolled studies have confirmed the benefit of AZT in reducing perinatal transmission. As per AZT 076 protocol, zidovudine chemoprophylaxis is a three part regimen consisting of maternal AZT therapy from week 14 to delivery, followed by intrapartum IV AZT administration, which is then followed by 6 weeks of AZT for the newborn (1,2,9,12). Nevirapine is the other antiretroviral agent with proven efficacy in preventing vertical transmission, given as a single dose to the mother during labor and as a single dose to the infant hours after delivery (1,12). Oral AZT+3TC combination during labor and one week of therapy with AZT + 3TC to the infant may be more effective than AZT alone (1,2). Not much is known about the use of antiretroviral agent in pregnant women and their effect on the developing fetus. The data, to date, supports the safety of antiretroviral agents in pregnancy except for ddi + d4t, efavirenz, and hydroxyurea (1). Use of zidovudine during pregnancy has not been associated with fetal abnormalities, but mitochondrial dysfunction has been reported in children exposed to zidovudine alone or in combination with lamivudine (1,2). The pregnant HIV infected women should be extensively counseled on the risks and benefits of antiretroviral therapy for the mother and the newborn infant. Some authorities recommend HAART therapy be delayed or interrupted during the first trimester, as safety of these agents is sometimes questioned during this, the most vulnerable, part of the pregnancy. This involves a risk-benefit decision, and recommendations should be based on theoretical concerns as well as on clinical findings (CD4 count, viral load, symptoms, etc.) (1,2,12). 11

12 REFERENCES 1. Bartlett JG. and Gallant JE. Antiretroviral therapy. IN: Medical Management of HIV Infection, Johns Hopkins University. Baltimore, MD: H&N Printing and Graphics, : Pharmacist s Letter/ Prescriber s Letter: HIV/AIDS Drug Therapy Update Drug Facts and Comparisons Update Monthly (3/02). Antiretroviral Agents Fletcher CV, Kakunda TN, and Collier AC. Human Immunodeficiency Virus Infection. In Pharmacotherapy: A pathophysiologic approach. 4 th ed. Dipiro JT, Talbert RL, Hayes PE, et al. eds. Appleton & Lange. 1999; Zambrano CH. Antiretroviral Therapy 2002 / AIDS Positively Aware. Jan/Feb 2002;13(1): Beach JW. Chemotherapeutic agents for human immunodeficiency virus infection; mechanism of action, pharmacokinetics, metabolism, and adverse reactions. Clin Ther.1998; 20(1): Anonymous. Suggested definition and relationship among medication misadventures, medication errors, adverse drug events, and adverse drug reaction. AM J Health-Syst Pharm. 1998;55: Ziagen package insert. GlaxoSmithKline; 1999 Feb. 9. Sande MA, Gilbert DN, and Moellering RC Jr. The Sanford Guide to HIV/AIDS Therapy: Ninth Edition Agenerase package insert. GlaxoSmithKline; 1999 Apr. 11. Viread package insert. Gilead Sciences, Inc Oct. 12. Department of Health and Human Services, Guidelines for Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents; February 2001 Update. 13. Hetherington S, Powell WS, and Thornton C (eds.). Hypersensitivity to Antiretroviral Medications. Postgraduate Institute of Medicine. Feb. 2001; Etzel J and Dreitlein W. Current treatment strategies in the management of human immunodeficiency virus infection in adults. Clin. Phar. News Watch. 1998;5(5): Kaletra package insert. Abbott Laboratories; 2000 Sep. 16. Rathbun RC and Stephens JR. Human Immunodeficiency Virus Infection. In Pharmacotherapy Self-Assessment Program, 4 th ed.. American College of Clinical Pharmacy. 2001;1-45. THIS CONCLUDES THE 2-PART DISCUSSION OF HIV/AIDS. THESE (2) LESSONS (COMBINED) SATISFY THE FLORIDA HIV/AIDS CE REQUIREMENT. FLORIDA ID #PSA

13 Fill in the information below, answer questions and return Quiz Only for certification of participation to: CE PRN, 400 Lake Cook Road, Suite 207, Deerfield, IL NAME I.D.#(1st line on label) ADDRESS CITY STATE ZIP CHECK IF NEW ADDRESS COMPANY WHERE EMPLOYED LESSON EVALUA ALUATION Please fill-out this section as a means of evaluating this lesson. The information will aid us in improving future efforts. Please rate each of the following from 1 to 7. Circle your choices. (1 is the lowest rating; 7 is the highest). Poor Average Excellent 1. Relevance of topic to practice Author s ability to communicate Author s knowledge of topic Appropriateness of topic Do you have any further comments about this lesson? Please Select the Most Correct Answer 1. What is/are the goal(s) of 6.Which of these may increase levels antiretroviral therapy? of concomitant drug therapy by inhibiting A.Reduce HIV RNA levels to undetectable the cytochrome P-450 system? B. Minimize opportunistic infections A. Nevirapine & malignancies B. Abacavir C.Prolong survival C. Ritonavir D. Improve quality of life D. All of these E. All of these E. None of these 2. Which of the following may result 7. abnormalities, including lactic in poor adherence? acidosis, have been associated with A.Increasing pill burden which of these agents? B. Once or twice daily regimens A. Lamivudine C.Fewer side effects B. Nevirapine D. All of these C. Indinavir D. Lopinavir/ritonavir 2. All of the following are protease inhibitors, except: 8.Which statement regarding HIV-infected A.Abacavir pregnant women is true? B. Indinavir A. Zidovudine monotherapy is C.Nelfinavir recommended for all patients D. Saquinavir B. Nevirapine single dose is more effective than combination of 4. Which of the following statements lamivudine + zidovudine is correct? C. Recommendations of DHHS should A.ddI levels increase by 55% with be followed, usually with food; therefore, it should be taken AZT-containing regimen on a full stomach D. None of these B. Amprenavir increases alcohol levels by 41%, & should be avoided in 9.As per data from ACTG 076, which agent alcoholic patients should be included in the combination C.Ritonavir should be taken with food of HIV-infected pregnant to improve tolerability women? D. Saquinavir SGC should be taken on an A. Nevirapine empty stomach to improve bioavailability B. Zidovudine C. Indinavir 5. The following combinations are not D. Hydroxyurea recommended, except: A.Stavudine + ddi 10. Successful treatment with HAART B. Stavudine + zidovudine results in total eradication of the virus C.Stavudine + ddc from host cells. Zidovudine + lamivudine A. True B. F 13

14 Radhan B. Gopalani, PharmD Clinical Specialist Special Immunology Department of Veterans Affairs VA Medical Center Miami, Florida Contributing Author Deborah Kuhlman Healthcare/Medical Writer/Editor Park Ridge, Illinois David Brushwood, BS Pharm, JD Professor of Pharmacy Health Care Administration College of Pharmacy University of Florida Gainseville, Florida CE PRN is a publication of W-F Professional Associates, Inc. This program is in printed format. W-F Professional Associates, Inc. is approved by the American Council on Pharmaceutical Education (ACPE) as a provider of continuing pharmaceutical education. Providers who are approved by ACPE are recognized by the following states: Alaska, Arizona, Arkansas, California, Connecticut, Delaware, District of Columbia, Florida, Georgia, Idaho, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Maine, Maryland, Massachusetts, Michigan, Minnesota, Mississippi, Missouri, Montana, Nebraska, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Carolina, North Dakota, Ohio, Oregon, Pennsylvania, Puerto Rico, Rhode Island, South Carolina, South Dakota, Tennessee, Texas, Utah, Vermont, Virginia, Washington, West Virginia, Wisconsin and Wyoming. Pharmacists completing this course by June 30, 2005 may receive full credit. This program has been approved by the State Boards of Pharmacy in Alabama and Oklahoma. This lesson furnishes 1.5 hours (0.15 CEUs) of credit. Program ID # H02. This lesson, combined with the May 2002 lesson, has been approved by the Florida Board of Pharmacy for their HIV/AIDS CE requirement - Special ID # PSA