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Infectious diseases Board Review Manual Statement of Editorial Purpose The Hospital Physician Infectious Diseases Board Review Manual is a study guide for fellows and practicing physicians preparing for board examinations in infectious diseases. Each manual reviews a topic essential to current practice in the subspecialty of infectious diseases. PUBLISHING STAFF PRESIDENT, Group PUBLISHER Bruce M. White Senior EDITOR Robert Litchkofski executive vice president Barbara T. White Antiretroviral Therapy in HIV Infection Series Editor: Varsha Moudgal, MD Infectious Diseases Fellowship Program Director, St. Joseph Mercy Hospital, Ann Arbor, MI; and Assistant Professor of Medicine, Wayne State University School of Medicine, Detroit, MI Contributors: Christopher T. Miller, MD Infectious Diseases Fellow, Department of Infectious Diseases, Thomas Jefferson University Hospital, Philadelphia, PA Jason Schafer, PharmD, BCPS, AAHIVP Assistant Professor, Department of Pharmacy Practice, Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia, PA executive director of operations Jean M. Gaul NOTE FROM THE PUBLISHER: This publication has been developed without involvement of or review by the American Board of Internal Medicine. Table of Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 HIV Replication Cycle . . . . . . . . . . . . . . . . . . . . . 1 HIV Antiretroviral Drug Classifications. . . . . . . . 3 Use of Antiretroviral Therapy . . . . . . . . . . . . . . 14 Postexposure Prophylaxis. . . . . . . . . . . . . . . . . .24 Immune Reconstitution Inflammatory Syndrome.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Board Review Questions. . . . . . . . . . . . . . . . . . . 27 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Antiretroviral Therapy in HIV Infection Infectious Diseases Board Review Manual Antiretroviral Therapy in HIV Infection Christopher T. Miller, MD, and Jason Schafer, PharmD, BCPS, AAHIVP INTRODUCTION The first cases of HIV infection were described in the early 1980s, prompting an aggressive search for a cure for this deadly infection. In 1987, zidovudine became the first medication approved for the treatment of HIV infection, ushering in a new age in HIV management. As our understanding of HIV evolved through the 1990s, new therapies gradually emerged, as did hope that a curative medication regimen may be discovered. Single-drug nucleoside reverse transcriptase inhibitor therapy initially conferred only 6 to 12 months of benefit to patients before viral resistance rendered this approach ineffective. Therapeutic strategy then evolved into dual-drug therapy, which extended benefit to 2 to 3 years. In the mid-1990s, a 3-drug regimen (ie, highly active antiretroviral therapy, or HAART) became the predominant regimen and remains the standard of care today. Along with these drug developments came new frustrations, manifested as mutated and resistant HIV strains, high pill burdens, and significant toxicities. These multidrug regimens have been refined over the past 10 years, to the point where many patients are able to maintain an intact immune system with no detectable virus on single-pill, triple-drug co-formulated, minimally toxic antiretroviral therapy (ART) regimens. While the goal of HIV eradication has remained elusive, the modern age of ART has commonly rendered HIV disease a chronic condition in which infected patients have a reasonable life expectancy when the disease is ideally managed. This article provides a brief overview of HIV replication along with a more detailed review of the currently approved ART medications and classes, including their indications and combinations. Use of ART in the setting of a variety of host and viral characteristics, monitoring, and the immune reconstitution inflammatory syndrome are discussed as well. Note that most recommendations in this article apply only to HIV-1 virus. HIV REPLICATION CYCLE A better understanding of the HIV replication cycle has led to the development of antiretroviral medications targeted against viral enzymes and even host proteins. A visualization of this replication cycle is essential to understanding how these medications function. Current ART Copyright 2013, Turner White Communications, Inc., Strafford Avenue, Suite 220, Wayne, PA 19087-3391, www.turner-white.com. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of Turner White Communications. The preparation and distribution of this publication are supported by sponsorship subject to written agreements that stipulate and ensure the editorial independence of Turner White Communications. Turner White Communications retains full control over the design and production of all published materials, including selection of topics and preparation of editorial content. The authors are solely responsible for substantive content. Statements expressed reflect the views of the authors and not necessarily the opinions or policies of Turner White Communications. Turner White Communications accepts no responsibility for statements made by authors and will not be liable for any errors of omission or inaccuracies. Information contained within this publication should not be used as a substitute for clinical judgment. www.turner-white.com Infectious Diseases Volume 14, Part 3 1 Antiretroviral Therapy in HIV Infection Figure 1. HIV replication cycle. (Adapted with permission from Tsibris AMN, Hirsch MS. Antiretroviral therapy for human immunodeficiency virus infection. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. 7th ed. Philadelphia (PA): Elsevier; 2010:1834.) Figure 2. Fusion of HIV and host cell membranes. (Adapted with permission from Tsibris AMN, Hirsch MS. Antiretroviral therapy for human immunodeficiency virus infection. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. 7th ed. Philadelphia (PA): Elsevier; 2010:1843.) medications inhibit entry of virus into host cells, reverse-transcription of viral DNA from an RNA template, integration of this viral DNA into the host genome, and processing of newly transcribed viral proteins. Fusion of HIV with the host cell membrane with subsequent viral RNA entry into the host cell is the first step of HIV viral replication (Figure 1). Viral glycoproteins 120 and 41 group together and interact with host cell CD4 receptors and CCR5 or CXCR4 co-receptors, causing fusion of the viral and host membranes and entry of viral factors (Figure 2). After fusion, viral RNA is released into the host cell along with essential viral enzymes, including the viral reverse transcriptase enzyme 2 Hospital Physician Board Review Manual (RT). RT then uses host cell nucleosides and nucleotides to construct a double-stranded viral complementary DNA (cDNA).1 Viral cDNA interacts with the viral integrase protein in the host cell cytoplasm. It is then transported into the nucleus of the host cell, where integrase incorporates viral cDNA into the host DNA genome.1 Once incorporated into the host genome, viral DNA is transcribed and translated into polyproteins by host enzymes and ribosomes. Viral proteases then cleave these polyproteins into functional and mature viral proteins. Full HIV virions are constructed. These new virions then bud from the host cell surface, detach, and infect new host cells, repeating the cycle (Figure 1).1 www.turner-white.com Antiretroviral Therapy in HIV Infection Table 1. Summary of Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) Agent Analogue Metabolism Dosing Zidovudine (AZT, ZDV) [Retrovir] Thymidine Hepatic glucuronidation Renal excretion 300 mg orally every TAM1, TAM2 Headache, malaise, 12 hr or anorexia, nausea, vomiting, anemia, 200 mg orally every granulocytopenia, 8 hr lactic acidosis, hepatic 100 mg orally every steatosis, peripheral 8 hr for dialysis paneuropathy, lipotients dystrophy, myopathy Stavudine (d4T) [Zerit] Thymidine Didanosine (ddI) [Videx] Adenosine Adverse Effects Comments Alternative NRTI in combination with 3TC First antiretroviral First-line therapy in combination with 3TC for pregnant patients with HIV Antagonizes d4T and should not be coadministered Antagonizes AZT and Renal excretion 60 kg: 40 mg orally TAM1, TAM2 Peripheral neuropathy, every 12 hr hyperlactatemia, lactic should not be coacidosis, hepatic administered <60 kg: 30 mg orally steatosis, lipoatrophy, Risk of fatal lactic acievery 12 hr pancreatitis, hyperdosis in combination lipidemia with ddl and should not be co-administered Peripheral neuropathy, Should not co-adminCellular metabolism 60 kg: 400 mg orally L74V, 69 pancreatitis, myocardial ister with d4T (see daily insertion, infarction (possible), above) <60 kg: 250 mg orally Q151M mitochondrial toxicity Concentration increase daily (worst of all NRTIs) in combination with Decrease dose with ganciclovir, allopurinol, renal dysfunction TDF Poor absorption with Concentration decrease food with methadone (continued on page 4) HIV ANTIRETROVIRAL DRUG CLASSIFICATIONS Nucleoside and Nucleotide Reverse Transcriptase Inhibitors Viral RT uses a pool of available host cellular nucleosides and nucleotides to construct viral cDNA from a viral RNA template. Nucleoside/ nucleotide reverse transcriptase inhibitors (NRTIs) are designed to mimic the structure of these natural nucleosides and nucleotides. When viral RT www.turner-white.com Resistance erroneously incorporates an NRTI into the growing viral cDNA chain, the chain is prematurely terminated. NRTIs block further chain elongation in the 3’ direction.1 Table 1 presents a summary of the drugs in the NRTI class. With few exceptions, in a modern ART regimen 2 NRTI agents are combined to form an NRTI backbone that comprises 2 of the 3 active drugs. A third active agent is then added to this NRTI backbone. Emtricitabine (FTC) and lamivudine (3TC) are similar, roughly equivalent cytosine Infectious Diseases Volume 14, Part 3 3 Antiretroviral Therapy in HIV Infection Table 1. Summary of Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (continued) Agent Analogue Abacavir (ABC) Guanosine [Ziagen] Tenofovir (TDF) Adenosine [Viread] Metabolism Dosing Resistance Adverse Effects Comments Hepatic glucuronida- 300 mg orally every tion 12 hr or 600 mg orally daily 200 mg orally every 12 hr with mild hepatic dysfunction Contraindicated with moderate-severe hepatic dysfunction Renal excretion 300 mg orally daily (as prodrug tenofovir disoproxil fumarate) K65R, L74V, Hypersensitivity synCurrent preferred alterY115F, drome (possibly fatal), native NRTI in combination with 3TC M184V, 69 in- myocardial infarction (possible) sertion, Screen patients for HLA-B5701 allele to Q151M assess risk for hypersensitivity K65R, TAM1, 69 insertion Lamivudine (3TC) [Epivir] Cytosine Renal excretion 300 mg orally daily or 150 mg orally every 12 hr M184V Emtricitabine (FTC) [Emtriva] Cytosine Renal excretion 200 mg orally daily M184V Possible decline in GFR, Current preferred NRTI decrease in bone min- in combination with eral density, Fanconi FTC syndrome Active against HBV Decrease dose with renal dysfunction, (GFR <50 mL/min), discontinue with GFR <30 mL/min Headache, fatigue, Current preferred alternaneutropenia tive NRTI in combination with ABC Similar to FTC Active against HBV Often continued in face of M184V mutation, as this mutation leads to decrease in viral load and hypersensitivity of HIV to AZT, even in presence of TAMs Headache, fatigue, Current preferred NRTI in neutropenia combination with TDF Similar to 3TC Active against HBV M184V mutation exploited in same manner as with 3TC Note: Drug trade names are listed in brackets. GFR = glomerular filtration rate; HBV = hepatitis B virus. analogs, and are both very well tolerated. One of these 2 medications is typically combined with a second preferred or alternative agent of this class to form most front-line NRTI backbones. Tenofovir (TDF) is currently the preferred NRTI 4 Hospital Physician Board Review Manual in combination with FTC. Abacavir (ABC) is the main alternative NRTI and is generally combined with 3TC. Resistance to NRTIs generally occurs due to RT mutations. Mutations resulting in resistance to www.turner-white.com Antiretroviral Therapy in HIV Infection NRTIs and to the other classes of ART medications occur most commonly in the setting of noncompliance or incomplete adherence to a full ART regimen. Prolonged viremia is often necessary for the development of such mutations. With the exception of the M184V and K65R mutations, significant resistance to a drug may take several serial mutations, which may require several months of viremia. Table 1 lists specific mutations conferring resistance to each drug in the NRTI class, but there are several major mutations of notable importance. Thymidine analogue mutations (TAMs) were commonly seen prior to the use of triple-drug therapy, especially in patients taking zidovudine (AZT) or stavudine (d4T). They allow for excision of NRTIs from the growing viral cDNA strand. TAM1 mutations occur at positions 41, 210, and 215 on RT and can confer resistance to multiple drugs across the NRTI class (eg, TAMs can decrease TDF activity by a factor of 4).1–4 TAM2 mutations cluster at RT positions 67, 70, and 219 and do not confer class resistance to the extent that TAM1 mutations do.1 Insertion mutations can be significant as well, with an insertion at position 69 conferring classwide resistance.5 Important substitution mutations include the K65R mutation, which can decrease TDF activity as well as activity of other NRTIs,1 and the M184V substitution mutation, which may reduce FTC and 3TC activity by a factor of 1000. However, M184V also confers a fitness disadvantage to the HIV virus and reduces the viral load6,7 and renders HIV highly sensitive to AZT, even in the face of TAM mutations.8 Therefore, FTC or 3TC therapy may be continued in patients with known M184V mutation as an inactive drug to exploit such secondary advantages. This strategy may prove especially useful in patients with multidrug-resistant (MDR) HIV strains. www.turner-white.com Certain toxicities of this drug class can be attributed to the mechanism of action of NRTIs. In addition to terminating viral DNA transcription, they can also inhibit host DNA transcription enzymes. Mitochondrial DNA polymerase-g is particularly susceptible to these drugs, and lactic acidosis, peripheral neuropathy, hepatic steatosis, myopathy, and lipoatrophy can all result from inhibition of this enzyme.1 Insulin resistance and diabetes may also be potential adverse effects. The first-line NRTIs have minimal overlapping interaction with mitochondrial DNA polymerase-g, and therefore are much better tolerated than their predecessors. Care must be taken with TDF regimens in patients with renal dysfunction or osteoporosis. ABC regimens should be avoided in patients with the HLA-B5701 allele (severe hypersensitivity reaction may occur) or HIV viral loads >100,000 copies/mL. Non-nucleoside Reverse Transcriptase Inhibitors Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are allosteric RT inhibitors that bind to a dedicated site that lies apart from the enzyme’s active functional site. The result of NNRTI binding is a change to the enzyme’s conformation, rendering it ineffective at viral DNA transcription. Table 2 presents a summary of the drugs in the NNRTI class. First-generation NNRTIs include nevirapine (NVP) and efavirenz (EFV). EFV is considered the preferred medication of this class. It has demonstrated superior virologic suppression compared to triple-NRTI regimens or protease inhibitor–based regimens with nelfinavir (NFV), indinavir (IDV), and ritonavir-boosted lopinavir (LPV/r; a 3-letter antiretroviral abbreviation followed by “/r” indicates that the antiretroviral is “boosted” with the protease inhibitor ritonavir.)9–13 and noninferior suppression Infectious Diseases Volume 14, Part 3 5 Antiretroviral Therapy in HIV Infection Table 2. Summary of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Agent Metabolism Dosing Resistance Adverse Effects Delavirdine (DLV) [Rescriptor] Etravirine (ETR) [Intelence] Hepatic CYP3A4 400 mg orally every 8 hr Hepatic CYP3A4, CYP2C9, CYP2C19 200 mg orally every 12 hr Absorption decreased with food 50% Nevirapine (NVP) [Viramune] Hepatic CYP3A4, CYP2B6 200 mg orally daily for K103N, V106A/M, Rash, including Y181C, Y188L, Stevens-Johnson 2 weeks, then 400 mg orally daily G190A/S syndrome; hepatic necrosis Adjustment needed for dialysis patients Efavirenz (EFV) [Sustiva] Hepatic CYP3A4, CYP2B6 Rilpivirine (RPV) [Edurant] Hepatic CYP3A4 Comments Rarely used due to frequent dosing and paucity of data Y181C, G190A, multiple other mutations Rash, nausea Only medication of this class that cannot be inactivated by a single point mutation Current alternative NNRTI Contraindicated in women with CD4 >250 cells/μL and men with CD4 >400 cells/μL due to risk of hepatic toxicity Can precipitate acute methadone withdrawal Current preferred NNRTI 600 mg orally daily on K103N, 100, 106, Rash, hepatotoxicity, empty stomach 181, 188, 190, vivid dreams, insom- Must be taken on empty stomach 225 nia, dizziness, poor (usually before bed) concentration, terato- Can precipitate acute methadone genicity (Pregnancy withdrawal Category D) 25 mg orally every day, V90I, K101E/P/T, Depression, insomnia, Current alternative NNRTI taken with minimum E138K/G, headache, rash, QT Take with minimum 400-kcal meal 400-kcal meal V179I/L, Y181I/C, prolongation H2Bs must be taken 12 hr before Caution in severe renal V189I, H221I, or 4 hr after RPV F227C/L, M230L impairment Antacids should be taken 2 hr beContraindicated with fore or 4 hr after RPV PPIs, anticonvulsants, Caution with combination with rifampin/rifabutin/ rifamedications that prolong QT pentine, dexamethainterval sone, St. John’s wort ddl should be given 2 hr before or (all decrease RPV 4 hr after levels) Contraindicated when initial HIV viral load >100,000 copies/mL (more virologic failure than EFV) Note: Drug trade names are listed in brackets. H2Bs = histamine2-receptor blockers; PPI = proton-pump inhibitor. compared to atazanavir-based (ATV) therapy.14 EFV should be taken on an empty stomach. Neuropsychiatric side effects have been described in approximately 50% of patients, but are generally 6 Hospital Physician Board Review Manual mild and self-limited (within 2–6 weeks). EFV is the only FDA pregnancy category D antiretroviral and should not be initiated during pregnancy. NVP should not be administered to men with a CD4 www.turner-white.com Antiretroviral Therapy in HIV Infection count >400 cells/μL and women with a CD4 count >250 cells/μL, as usage in these groups has been associated with hepatic necrosis. Second-generation NNRTIs include etravirine (ETR) and rilpivirine (RPV). These NNRTIs have been chemically altered from their predecessors with the theoretical goal of rendering them more effective against drug-resistant HIV. RPV, the newest drug from the NNRTI class, has been demonstrated to have a higher rate of virologic failure compared to EFV in patients with higher HIV viral loads. The E138K mutation is commonly seen in the setting of RPV virologic failure, and the M184V/I and K65R/N mutations are seen with greater frequency in this setting than with EFV.15,16 Administration of RPV in patients with a viral load >100,000 copies/mL should be avoided, and its use is only approved in treatment-naïve patients. RPV must also be taken with a high-calorie meal. Its absorption requires an acidic environment, so care must be taken to avoid direct co-administration with antacids and H2-blocking medications. Proton pump inhibitors should be avoided altogether in patients on RPV. RPV may cause an artifactual rise in creatinine and decrease in glomerular filtration rate (GFR). ETR has been studied only in treatment-experienced patients and is approved only in this setting (see ART Selection in Multidrug-Resistant HIV, page 19). Unfortunately, since it is not directly involved in the action of the RT enzyme, the conformation of the dedicated NNRTI binding site is not important for RT functionality.1 Therefore, mutations at this site may block NNRTIs from binding, but generally do not affect RT functionality. Simple single-point mutations to the enzyme can render every first-generation NNRTI ineffective (hence the development of second-generation NNRTIs). Currently, ETR is the only NNRTI that is approved in the setting of NNRTI mutations. The low barrier www.turner-white.com to resistance with the NNRTIs may limit the use of these medications in patients with a history of noncompliance to ART. NNRTIs are hepatically metabolized by cytochrome P450 (CYP) enzymes, making drug-drug interactions a concern. Particular care must be taken when combining these medications with anticonvulsant, antimycobacterial, and certain antifungal therapies. Protease inhibitors (PI) may have strong interactions with NNRTIs as well, and their combination should generally be avoided, except in special cases. Protease Inhibitors PIs inhibit HIV aspartyl protease, an enzyme used by the virus to cleave and construct gag and pol proteins. Gag proteins form structural aspects of the virus, while pol proteins comprise the vital viral enzymes RT, protease, and integrase. PIs are primarily metabolized by hepatic CYP enzymes, especially CYP3A4. They may also induce or inhibit these enzymes. Drug-drug interactions are therefore significant, especially in the setting of co-administration with immunosuppressants, antiarrhythmics, antibiotics, statins, opiates, oral contraceptives, benzodiazepines, or other ART medications. For example, acute withdrawal may occur when PIs are administered to patients taking chronic opiates like methadone. Efficacy of contraceptives may be reduced significantly. Table 3 presents a summary of the drugs in the PI class. The metabolism of PIs by CYP3A4 is exploited with the relatively recent concept of “boosting.” The PI ritonavir (RTV) is an especially powerful inhibitor of CYP3A4. Owing to pill burden, toxicity, and a host of potential drug-drug interactions via its effect on other CYP enzymes, RTV is no longer considered a preferred stand-alone PI. However, when RTV is given at subtherapeutic doses in combiInfectious Diseases Volume 14, Part 3 7 Antiretroviral Therapy in HIV Infection Table 3. Summary of Protease Inhibitors (PIs) Agent Metabolism Dosing Resistance Adverse Effects Comments Ritonavir (RTV) Hepatic CYP3A4, CYP2D6 [Norvir] For boosting, M46L, V82A, I84V; minor mu- Diarrhea, nausea/vom100–200 mg orally tations at 10, 20, 24, 32, 36, iting, altered taste, every 12 hr 54, 71, 73, 76, 77, 90 paresthesias, dyslipidemia Stand-alone, 300 mg orally every 12 hr, increase to 600 mg orally every 12 hr over 5 days Indinavir (IDV) Hepatic CYP3A4 [Crixivan] 800 mg orally every M46L, V82A, I84V; minor mu- Nephrolithiasis, uncon12 hr boosted with tations at 10, 20, 24, 32, 36, jugated hyperbilirubiRTV 100 mg orally 54, 71, 73, 76, 77, 90 nemia (no jaundice), every 12 hr abdominal pain, nausea, dry skin Saquinavir (SQV) [Invirase] May prolong PR/QT intervals One randomized trial showed non-inferiority to atazanavir and better side effect profile* Poor efficacy compared to other PIs RTV does not boost levels Should not be used in treatmentexperienced patients 700 mg orally every I50V, I84V; minor mutations at Diarrhea, rash, hyperlip- Prodrug of amprenavir idemia, may increase Sulfonamide compo12 hr boosted with 10, 32, 46, 47, 54, 73, 76, RTV 100 mg orally 82, 90 risk for cardiovascular nent may cause reacevery 12 hr disease tion in sulfa-allergic patients 400 mg orally every V82A, V32I, I47A; minor muta- Diarrhea, nausea/vomit- Current alternative PI 12 hr boosted with tions at 10, 20, 24, 33, 46, 50, ing, hyperlipidemia, Often compared with RTV 100 mg orally 53, 54, 63, 71, 73, 76, 84, 90 may increase risk for newer PIs for nonevery 12 hr cardiovascular disease inferiority Concurrent V32I, I47A, and position 46 mutation confers Generally 6 or more high resistance mutations required for significant drug resistance (continued on page 9) Nelfinavir (NFV) [Viracept] Hepatic CYP3A4 1000 mg orally every L90M, G48V; minor mutations Nausea/vomiting, diar12 hr boosted with at 10, 24, 54, 62, 71, 73, 77, rhea, abdominal pain, RTV 100 mg orally 82, 84 hyperlipidemia every 12 hr Take within 2 hr of high-calorie/fat meal Hepatic CYP2C19, 1250 mg orally every D30N, L90M; minor mutations Diarrhea, hyperlipidemia CYP3A4, CYP2D6 12 hr at 10, 36, 46, 71, 77, 82, 84, 88 Take with meals Fosamprenavir Hepatic CYP3A4, (FPV) biliary excretion [Lexiva/Telzir] Lopinavir (LPV) [Kaletra (lopinavir/r combination pill)] Powerful CYP3A4 inhibition exploited at low doses to boost levels of other PIs Rarely used as stand-alone agent due to toxicity Also inhibits CYP2D6 Induces CYP3A, CYP1A2, CYP2C9, CYP2C19, CYP2B6 Must increase water intake to avoid nephrolithiasis Infrequently used due to toxicity Hepatic CYP3A4 8 Hospital Physician Board Review Manual www.turner-white.com Antiretroviral Therapy in HIV Infection Table 3. Summary of Protease Inhibitors (continued) Agent Metabolism Dosing Resistance Adverse Effects Comments Tipranavir (TPV) [Aptivus] Hepatic CYP3A4 500 mg orally every 12 hr boosted with RTV 200 mg orally every 12 hr Take with high-fat meal Atazanavir (ATV) [Reyataz] Hepatic CYP3A4 300 mg orally daily boosted with 100 mg RTV orally daily 400 mg orally daily unboosted if not given with TDF/ FTC Take with food Absorption requires low pH, avoid H2Bs and PPIs Darunavir (DRV) [Prezista] Hepatic CYP3A4 800 mg orally daily boosted with 100 mg RTV orally daily in treatmentnaïve patients 600 mg orally every 12 hr boosted with RTV 100 mg orally every 12 hr in treatmentexperienced patients Hepatotoxicity, intracra- Used in treatmentnial hemorrhage, nauexperienced sea, diarrhea; GI side patients with resiseffects largely due to tance to other PIs; higher dose of ritonavir efficacy demonused strated in RESIST-1 and -2 trials for this population Contraindicated in patients at risk for serious bleeding Sulfonamide component may cause reaction in sulfaallergic patients Current preferred PI I50L, I84V; minor mutations at Nausea, hyperbilirubinemia with jaundice/ 10, 16, 20, 24, 32, 33, 34, Should not be used scleral icterus, nephro- in treatment-expe36, 46, 48, 53, 54, 60, 62, lithiasis, hyperlipidemia rienced patients on 64, 71, 73, 85, 90, 93 renal dialysis Does not affect methadone levels Should not be used in combo with ddl/FTC due to inferiority Can prolong PR interval PI with least effect on lipids Only PI shown to be non-inferior to EFV† I50V, V11I, I54L, G73S, L89V, Diarrhea, nausea, head- Current preferred PI V32I, L33F, I47V, I54M, I76V, ache, nasopharyngitis, Sulfonamide compoI84V acute hepatitis, hypernent may cause reaclipidemia tion in sulfa-allergic patients Should be taken with food Note: Drug trade names are listed in brackets. H2Bs = histamine2-receptor blocker; PPI = proton-pump inhibitor. *Vrouenraets SM, Wit FW, Fernandez Garcia E, et al; BASIC Study Group. Randomized comparison of metabolic and renal effects of saquinavir/r or atazanavir/r plus tenofovir/emtricitabine in treatment-naive HIV-1-infected patients. HIV Med 2011;12:620–31. †Daar ES, Tierney C, Fischl MA, et al; AIDS Clinical Trials Group Study A5202 Team. Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1. Ann Intern Med 2011;154:445–55. www.turner-white.com Infectious Diseases Volume 14, Part 3 9 Antiretroviral Therapy in HIV Infection nation with another “primary” active PI, CYP3A4 metabolism becomes saturated, allowing plasma concentrations of the primary PI to become higher (“boosted”) and more stable (increased half-life) with less frequent dosing. The newer primary PIs ATV and darunavir (DRV) have less toxicity than their predecessors (eg, nausea, diarrhea, hyperlipidemia). The overall effect of this strategy is that fewer pills are required to be taken on a less frequent basis with less toxicity to the patient. This boosting effect also minimizes viral mutations to the active PI. Before boosting was employed, the shorter half-life of primary PIs would cause plasma concentrations to drop quickly. If a dose of medication was accidentally missed, the plasma concentration might drop even further to the point that the HIV virus was able to begin replicating in the presence of subtherapeutic drug, thereby allowing the virus to mutate in a selectively resistant manner. With the extended half-life and stable plasma concentrations now seen with boosted PIs, mutations are much less common. However, while boosting does allow for higher-fidelity concentrations of less toxic drugs, adverse effects and drug-drug interactions that still do exist with the primary PIs may become accentuated as well. RTV toxicity is also limited at this subtherapeutic dose, yet some effects such as nausea and vomiting may become clinically relevant. Currently, DRV and ATV are the preferred medications of this class, both boosted by RTV. ATV was found to be noninferior with respect to virologic response compared to EFV.14 Boosting with RTV was clearly shown to be effective when RTV-boosted ATV (ATV/r) was compared to unboosted ATV17 and to LPV/r.18 Once-daily DRV/r was demonstrated to be noninferior to LPV/r in treatment-naïve patients (once-daily DRV/r is only approved in treatment-naïve patients; otherwise it 10 Hospital Physician Board Review Manual should be used twice daily).19 DRV is an effective choice in treatment-experienced patients and in MDR HIV (see Selection of PI and ART Selection in Multidrug-Resistant HIV, pages 18 and 19, respectively). Dyslipidemia is a toxicity seen with drugs from this class (ATV having the least effect in this regard1). Propensity toward insulin resistance and diabetes may potentially occur as well. Gastrointestinal symptoms are well documented, including abdominal pain, nausea, vomiting, and diarrhea. With regard to the primary preferred PIs, ATV has the notable effect of reversibly causing increased indirect bilirubin levels due to inhibition of UDPglucuronosyltransferase.20 Jaundice or scleral icterus may even become evident in patients taking ATV, and a change to an alternative agent should be considered if cosmetic concerns exist. While isolated hyperbilirubinemia itself does not constitute hepatic failure in this setting, the presence of elevated transaminases should raise concern for alternative pathology. As mentioned previously, newer boosted PIs have a high barrier to viral resistance. Several mutations to viral protease are usually required for resistance, and generally one or more mutations must be major.1 DRV is especially robust in the setting of multiple PI mutations. Entry Inhibitors Entry inhibitors are drugs targeted at inhibition of HIV fusion and entry into host cells. The primary drugs of this class are enfuvirtide (ENF) and maraviroc (MVC). Neither of these medications is included in current recommendations for preferred ART regimens. ENF is an amino acid polypeptide fusion inhibitor and is used primarily as a salvage drug for patients who have prior experience with ART and multiple resistance mutations to primary www.turner-white.com Antiretroviral Therapy in HIV Infection ART medications. Two randomized trials with median patient CD4 count <100 cells/μL demonstrated significantly improved viral suppression when ENF was added to an optimized ART regimen.21,22 ENF is dosed as a 90-mg subcutaneous injection administered twice daily. Advantages of this drug include no need to adjust dose for renal or hepatic function and no known drug interactions. There is also no evidence of teratogenicity in animal models (although experience in pregnant humans is lacking). A major disadvantage, however, is the need for twice daily injections to avoid gastrointestinal denaturation of the medication. Not only is this a potential barrier to home use among patients, but there is also additional risk of local injection reactions, which occur in 98% of patients.1 Injections must be administered away from recent previous injection sites or areas of reactive skin, and care must also be taken to avoid blood vessels, large nerves, injured skin, and tattoos. Nausea, vomiting, diarrhea, fatigue, and insomnia are additional adverse effects that have been described. Viral resistance can occur with amino acid substitutions on viral glycoprotein 41, usually at position 36, 38, 40, and 43.23 MVC is a CCR5 allosteric antagonist. It is the only approved ART medication that targets a host, not a viral, receptor. It is designed to prevent interaction of viral gp120 with host CCR5, thereby inhibiting viral attachment. It has been demonstrated to effectively lower viral load and raise CD4 counts in 2 randomized, double-blind, placebo-controlled trials.24,25 Patients must be screened with a tropism test prior to initiation to ensure their specific HIV strain does not use CXCR4 for entry, either in lieu of or in conjunction with reliance on CCR5, as MVC has not been shown to be of benefit in this patient population. MVC was shown to be most effective in these 2 studies when combined with at least www.turner-white.com 2 other effective antiretrovirals. If used in combination with ENF, patients responded best when there was no ENF resistance and when ENF was being administered to the patient for the first time. The 48-week MERIT study in which MVC plus AZT/3TC was compared with EFV plus AZT/3TC (a standard primary initial HAART regimen at the time of that study) failed to demonstrate that the MVC regimen conferred as much viral suppression as the EFV regimen.26 However, re-analysis of this data in the MERIT-ES study with a newer Trofile test demonstrated improved efficacy, and MVC may now be considered in treatment-naïve patients in special cases.26 MVC is generally dosed at 300 mg twice daily. There is little data to date to suggest dose adjustment in patients with renal or hepatic dysfunction. MVC is metabolized by CYP3A, and therefore dose adjustment is necessary with CYP3A inducers or inhibitors. Concurrent medications that inhibit CYP3A that may be encountered in the HIV population include PIs and clarithromycin, while common inducers encountered in this population include EFV, NVP, and anticonvulsants. Dosing should be decreased to 150 mg twice daily in the presence of an inhibitor, and increased to 600 mg twice daily with an inducer. Side effects of MVC include dizziness, cough, rash, upper respiratory tract infection, and fever.1 There are 2 major pathways of viral resistance to MVC. The first occurs with an amino acid substitution on viral gp120.1 The second, and much more common, pattern is seen when selection of CXCR4-binding virus occurs (patients initially screened for CXCR4-using virus may have low levels present that are undetectable by the lab assay), as was demonstrated in the MOTIVATE trials.24 Aside from drug resistance, selection of CXCR4 virus in patients prescribed MVC may have adInfectious Diseases Volume 14, Part 3 11 Antiretroviral Therapy in HIV Infection ditional consequences. Patients with CXCR4predominate virus may develop a faster drop in CD4 cell count and more aggressive progression to AIDS.5,27–29 Discontinuation of MVC in patients who develop CXCR4 tropism may lead to a resurgence of CCR5-predominate infection in such patients (however, MVC should not be reconsidered as a viable therapeutic option in the future). Integrase Strand Transfer Inhibitors Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral medications designed to block HIV integrase–mediated incorporation of HIV cDNA into the host DNA genome. Raltegravir (RAL) was the first drug of this class, and elvitegravir (EVG) has just received FDA approval (see New and Investigational Medications). RAL has been demonstrated to be noninferior and better tolerated compared to EFV-containing primary ART regimens30 for treatment-naïve patients. RAL was also shown to decrease the viral load faster within 24 weeks compared to these EFV-based regimens.30 The clinical significance of this class-wide INSTI effect is unknown. RAL also has demonstrated efficacy in treatment-experienced patients. It showed greater suppression of HIV viral load at 48 weeks compared to placebo when added to an optimal ART backbone in 2 randomized, double-blinded phase III studies.31 Of note, in one of these studies patients with resistant virus concurrently started on DRV and ENF for the first time had even greater response, although the study was not powered to assess this effect.32 In another investigation of RAL use in treatment-experienced patients, substituting RAL for ENF maintained virologic suppression.33 RAL is administered orally at 400 mg twice daily. Dose adjustment is not necessary in renal or hepatic insufficiency, unless hepatic insufficiency is severe. It is metabolized by glucuronidation. 12 Hospital Physician Board Review Manual Primary resistance mutations to the viral integrase protein exist as substitutions at Y143, Q148, and N155 on the integrase enzyme.34 Fixed-dose Combination Pills The emergence of several commercial fixeddose combination (FDC) pills has made the administration of several ART regimens a more practical venture. These combination pills lead to increased adherence by limiting the number of pills patients must consume. Some of these formulations have the advantage of offering a complete ART regimen in 1 pill taken once daily. Toxicities and drug-drug interactions must still be considered for each individual component of these FDCs (Table 4). New and Investigational Medications EVG is an INSTI that received FDA approval in August 2012. It is currently approved only for HIV therapy in treatment-naïve patients as part of a 4-drug combination pill trade-named Stribild (EVG/ COB/TDF/FTC). This regimen contains 150 mg of the investigational drug cobicistat (COB) for boosting (discussed below), as well as 150 mg EVG + 200 mg FTC + 300 mg TDF. This combination is 1 pill administered once daily. Phase II and III clinical trials comparing the EVG/COB/TDF/FTC pill to Atripla (EFV/TDF/FTC) (see Table 4) have demonstrated non-inferiority with regard to viral suppression.35 An ongoing study comparing EVG/COB/TDF/FTC to ATV/r plus TDF/FTC is demonstrating the same result.36 EVG is also under investigation as therapy for treatment-experienced patients in combination with PIs. RTV is being used as the boosting medication in these studies. EVG is primarily metabolized by CYP3A4. The dose should be decreased to 85 mg once daily when used in combination with ATV/r or LPV/r. When EVG is used in combination with MVC, the www.turner-white.com Antiretroviral Therapy in HIV Infection Table 4. Fixed-Dose Combination Pills Combination (Trade Name) Components Dosing Atripla* Combivir Complera* Epzicom Trizivir Truvada Stribild* 600 mg EFV + 200 mg FTC + 300 mg TDF 300 mg AZT + 150 mg 3TC 25 mg RPV + 200 mg FTC + 300 mg TDF 300 mg 3TC + 600 mg ABC 300 mg AZT + 150 mg 3TC + 300 mg ABC 200 mg FTC + 300 mg TDF 150 mg EVG + 150 mg COB + 200 mg FTC + 300 mg TDF 1 tablet once daily before bed on empty stomach 1 tablet twice daily 1 tablet once daily with a meal 1 tablet once daily 1 tablet twice daily 1 tablet once daily 1 tablet once daily *Complete antiretroviral regimen. dose of MVC should be reduced to 150 mg twice daily. Gastrointestinal side effects (nausea) were significantly notable with the EVG/COB/TDF/FTC combination, although these side effects might be most attributable to the COB portion of the new pill. Primary viral integrase substitution mutations demonstrated to confer resistance to EVG include E92Q, H51Y, S147G, and E157Q.37 COB is a pharmacoenhancer medication that strongly inhibits CYP3A4 and is used as a dedicated boosting agent. It was approved by the FDA as part of the EVG/COB/TDF/FTC regimen in August 2012. It was designed with the intent to replace RTV for boosting. COB has the theoretical benefit of interacting with fewer CYP enzymes compared to RTV. The hope that COB may have fewer side effects when used as a booster has not yet bore fruit, however, as a study comparing EVG/COB/ TDF/FTC to ATV/r plus TDF/FTC did not show any difference in this regard.38 Thus far, COB has only been approved as a booster for EVG (as part of EVG/COB/TDF/FTC) in treatment-naïve patients. It is also currently being studied as a booster for ATV in a head-to-head trial with an ATV/r-boosted regimen. COB may replace RTV where boosting is indicated in the near future. www.turner-white.com The most common toxicity associated with COB is gastrointestinal side effects. Cobicistat also competes with creatinine excretion in the kidney, causing an increase in serum creatinine levels that does not represent a true reduction in GFR. This asymptomatic elevation in serum creatinine seen in approximately 7% of patients studied on EVG/ COB/TDF/FTC was sustained at 48 weeks of therapy. A rise in serum creatinine above 0.4 mg/dL should prompt consideration of alternative therapy. Stribild should also not be initiated in patients with baseline serum creatinine clearance of less than 70 mL/min.39 Dolutegravir (DTG) is an investigational INSTI. It does not require boosting. Phase III clinical trials are currently underway involving patients with established resistance to other INSTIs. Eligible patients must be older than age 18, should avoid pregnancy, have documented HIV-1 with a viral load of at least 400 copies/mL 3 months prior to DTG initiation, have documented RAL or EVG resistance, and be unable to use a full viable ART regimen due to resistance. Exclusion criteria included GFR <30 mL/min, pregnancy/breastfeeding, allergy to another integrase inhibitor, alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN), ALT >3 times Infectious Diseases Volume 14, Part 3 13 Antiretroviral Therapy in HIV Infection ULN with total bilirubin >1.5 ULN, and severe hepatic impairment.40 DTG is administered once daily, but in the presence of resistance to other INSTIs it is administered twice daily.16 The presence of Q148 or G140 mutations may indicate limited viral response to DTG therapy.41 USE OF Antiretroviral THERAPY Guidelines for ART Initiation Expert consensus continues to evolve with regard to criteria for initiation of ART. When ART first became available, consensus was initially to push for early therapy for every patient. It soon became clear, however, that the toxicities of these early regimens were not benign, the high pill burden made compliance difficult, and resistance quickly developed if adherence was not strict. As the pendulum swung back toward delayed therapy, however, obvious detriments arose such as increased progression to AIDS or death, increased risk of opportunistic infection (OI) and of HIV-associated organ dysfunction (such as HIV-associated nephropathy), and decline in absolute ability to regain maximal CD4 counts and full viral suppression. However, the newer ART regimens are better tolerated and pill burdens have lessened as a result of boosting, more potent formulations, and fixed-dose combinations. The potential for greater patient compliance and improved mortality has experts once again recommending earlier initiation of these newer ART regimens. While HIV cure has never been achieved with any current regimen, there are 4 other major goals of ART treatment: (1) to reduce HIV-associated morbidity and to extend and improve patient life; (2) to restore and maintain a patient’s immune system; (3) to suppress the HIV viral load to undetectable levels; and (4) to prevent HIV 14 Hospital Physician Board Review Manual transmission. Because evidence indicating that these goals are increasingly achievable with current treatment regimens, HIV treatment guidelines now recommend initiating ART for any HIV-infected patient, regardless of their CD4 cell count. The strength of the recommendation increases with lower CD4 counts. Other compelling indications for ART initiation and strength of recommendation are listed in Table 5.16 These most recent recommendations to start ART in all HIV patients are backed by several studies. The HIV-CAUSAL study demonstrated a 38% increase in AIDS or death in patients initiated on ART at a CD4 count ≤350 cells/μL compared to a group in which ART was initiated at CD4 count ≤500 cells/μL.42 The CASCADE and COHERE trials confirmed these results in patients with CD4 ≤500 cells/μL.43,44 Expert consensus, rather than randomized trials, have extended the recommendation to start ART at CD4 counts >500 cells/μL. Benefit seen from administering ART to HIVpositive patients who were sexually active with HIV-negative partners is yet another compelling reason to extend the universal ART treatment recommendation (not mentioned in Table 5). The HPTN 052 trial demonstrated a 96% reduction in HIV transmission to a noninfected partner when the HIV-positive partner was on ART therapy.45 This effect was demonstrated in HIV-positive partners with CD4 counts of 350 to 500 cells/μL, and these results have been extrapolated to higher CD4 counts. Any of the approved ART regimens can be used to achieve the specific benefit of minimizing transmission. Ideally, maximum viral suppression should be achieved before onset of sexual activity (or attempts at conception begin in HIV-discordant couples desiring natural pregnancy). Patients should be advised that even use of ART cannot prevent HIV transmission with absolute certainty. It also cannot www.turner-white.com Antiretroviral Therapy in HIV Infection Table 5. Indications for Antiretroviral Therapy Initiation Condition Level of Evidence CD4 ≤500 cells/μL AIa Pregnancy AIa Opportunistic infection (within 2 weeks)* AIa † Active tuberculosis infection with CD4 count <50 cells/μL (within 2 weeks of anti-tuberculosis therapy) AIa † Active tuberculosis infection with CD4 count ≥50 cells/μL (within 8–12 weeks of anti-tuberculosis therapy) AIa Chronic hepatitis B virus co-infection AIIa HIV-associated nephropathy AIIa Age >60 years BIIa CD4 count >500 cells/μL BIII Acute primary HIV infection BIII Tuberculosis meningitis (within 2–8 weeks of anti-tuberculosis therapy) BIII Chronic hepatitis C virus co-infection CIII Strength of Recommendations A Strong support B Moderate support C Limited support Quality of Recommendations Ia Evidence from 1 or more randomized controlled clinical trials published in the peer-reviewed literature Ib Evidence from 1 or more randomized controlled clinical trials presented in abstract form at peer-reviewed scientific meetings IIa Evidence from nonrandomized clinical trials or cohort or case-control studies published in the peer-reviewed literature IIb Evidence from nonrandomized clinical trials or cohort or case-control studies presented in abstract form at peer-reviewed scientific meetings III Recommendation based on the panel’s analysis of the accumulated available evidence *Antiretroviral therapy should be used with caution in patients with cryptococcal meningitis; this is discussed in the section on immune reconstitution inflammatory syndrome. †Does not include tuberculosis meningitis. prevent the transmission of other sexually transmitted infections. Therefore, condom use should still be encouraged. Pre-exposure prophylaxis therapy may be considered for HIV-negative patients who engage in sexual contact with patients who have confirmed HIV or who have high risk for HIV infection (see Preexposure Prophylaxis, page 25). www.turner-white.com Selection of Regimen Selection of an antiretroviral regimen is based upon multiple considerations. Since noncompliance can lead to ART resistance, barriers to compliance must be addressed prior to ART initiation. Specifically, untreated mental illness such as depression, untreated chemical dependency, homelessness, and a chaotic life circumstance are all potential Infectious Diseases Volume 14, Part 3 15 Antiretroviral Therapy in HIV Infection Table 6. Antiretroviral Regimens for Treatment-Naive Patients Preferred NNRTI-based PI-based INSTI-based Alternative EFV + TDF/FTC ATV/r + TDF/FTC DRV/r + TDF/FTC RAL + TDF/FTC NNRTI-based EFV + ABC/3TC* RPV† + TDF/FTC RPV† + ABC/3TC* NVP + TDF/FTC NVP + ABC/3TC * PI-based DRV/r + ABC/3TC* LPV/r + TDF/FTC ATV/r + ABC/3TC* LPV/r + ABC/3TC* INSTI-based RAL + ABC/3TC* EVG/COB + TDF/FTC Third-line for use in special circumstances Entry inhibitor–based MVC + TDF/FTC MVC + ABC/3TC * NRTI-sparing‡ DRV/r + RAL LPV/r + RAL INSTI = integrase strand transfer inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor. *ABC-based NRTI combination should be avoided in patients with HIV viral load >100,000 copies/mL and/or presence of HLA-B5701 allele. †RPV-based regimens should be avoided in patients with HIV viral load >100,000 copies/mL. ‡Limited data exists examining the use of such regimens. barriers to compliance. A patient’s additional medical conditions must be taken into account as well, as should interactions with any medications the patient is taking for these conditions. Pregnancy status or desire to become pregnant should be assessed with female patients. Medication cost and access to coverage or assistance may become a factor. Prior exposure to ART and a patient’s HIV genotype are additional factors. All of the preferred regimens for treatment-naïve patients contain 2 NRTI medications (an “NRTI backbone”) combined with an additional anchoring agent. The preferred additional agent can either be an NNRTI, a boosted PI, or an INSTI. See Table 6 for listings of preferred, alternative, and third-line NRTI-backbones. NRTI Backbone Three NRTI combination formulations are currently available (Table 4): TDF/FTC, ABC/3TC, and www.turner-white.com AZT/3TC. Currently the TDF/FTC backbone is preferred, and ABC/3TC is considered the primary alternative. A 48-week head-to-head comparison study of TDF/FTC and AZT/3TC (each combination combined with EFV) demonstrated that TDF/FTC therapy resulted in noninferior viral load suppression (primary endpoint) as well as better CD4 improvement and less drug resistance and side effects.46 At 96 weeks, patients in the TDF/FTC arm had less lipodystrophy and better serum triglyceride levels. TDF/FTC has the additional advantage of being administered as 1 pill once daily, as opposed to AZT/3TC, which is administered as 1 pill twice daily. A 48-week study comparing ABC/3TC to AZT/3TC (each combined with EFV) also demonstrated that ABC/3TC is noninferior to AZT/3TC with respect to viral suppression.47 Again, ABC/3TC offers the advantage of being administered as 1 pill once daily. Two important studies have compared TDF/FTC and ABC/3TC. The HEAT trial compared each Infectious Diseases Volume 14, Part 3 17 Antiretroviral Therapy in HIV Infection backbone in combination with LPV/r and demonstrated equal efficacy with respect to viral load suppression.48 The ACTG 5202 compared each of these NRTI backbones head-to-head in combination with both EFV and ATV/r (each separately). The ABC/3TC arm demonstrated higher cholesterol levels, more adverse effects (most likely from ABC hypersensitivity in the setting of HLA-B5701 positivity), and, most importantly, significantly higher virologic failure in patients with high initial viral loads (>100,000 copies/mL) compared to the TDF/ FTC arm.49 The rate of virologic failure was so significant that this group of patients was unblinded and offered TDF/FTC as alternative therapy. This increased rate of virologic failure was not observed in a second randomized trial.48 As mentioned, ABC-based backbones have been associated with concerning adverse reactions. A severe, life-threatening hypersensitivity reaction is possible in patients positive for the HLAB5701 allele. Also, a large cohort review trial did show increased risk of myocardial infarction in patients using ABC over the prior 6 months, although follow-up studies have not clearly supported this finding.50 Caution is therefore generally recommended in patients at risk for vascular disease, and ABC/3TC is only considered a viable NRTI combination in the setting of an HIV viral load of <100,000 copies/mL and a negative HLA-B5701 allele test. Selection of NNRTI NNRTI-based regimens are frequently employed in treatment-naïve patients. EFV is generally considered the first-line medication in this class, with RPV and NVP being alternatives.16 As mentioned above, EFV is a Pregnancy Category D agent and should not be initiated in pregnant patients. EFV has generally demonstrated better efficacy and less 18 Hospital Physician Board Review Manual toxicity compared to NVP. EFV is available in a single-pill, once-daily fixed-dose combination as EFV/TDF/FTC (Atripla). RPV is also a popular choice since it has been made available in the single-pill combination RPV/FTC/TDF (Complera; see Table 4 for complete formulation). However, it is considered less effective than EFV in patients with high viral loads and is contraindicated in patients requiring proton-pump inhibitors for stomach acid suppression. ETR is not approved for treatment-naïve patients. Selection of PI PI-based regimens all generally make use of RTV boosting, as discussed above. ATV and DRV are considered first-line agents of this class because of their toxicity profiles, although LPV, fosamprenavir (FPV), and saquinavir (SQV) have all demonstrated noninferiority with respect to efficacy. DRV is the most robust agent in the face of multiple viral mutations. ATV has the least effect on lipids, although DRV is almost equivalent. As mentioned, COB may replace RTV as the boosting agent of choice in these regimens, although hopes it would have less adverse reactions compared to RTV have not necessarily been seen to date. If virologic failure occurs on an initial first-line regimen, a switch to a boosted PI-based regimen is often recommended. Again, the boosted PI is usually combined with 2 NRTIs. If PI mutations occur in addition to resistance to other classes, a boosted DRV- or TPV-based regimen is especially recommended.16 Selection of INSTI RAL is currently the preferred medication of this class. The new COB-boosted EVG (as part of Stribild) is an alternative regimen for treatmentnaïve patients. www.turner-white.com Antiretroviral Therapy in HIV Infection ART Selection in MultiDrug-Resistant HIV MDR-HIV can frequently be seen in patients who have failed 2 or more standard ART regimens and occasionally in patients newly diagnosed with HIV. Treatment in these settings often requires a nonstandard regimen. At least 2 active drugs, and ideally 3 active drugs, should be administered, and potency of the drugs is considered a more important factor than the number of drugs administered. Typically, a boosted PI should be selected based on genotypic resistance testing (data exists that DRV/r or TPV/r are most effective in this setting51,52). ETR has been studied in the setting of known NNRTI resistance in combination with DRV/r and NRTIs and was found to confer benefit.53 In settings where no documented RAL resistance exists, it should be added as well because there is evidence for significant efficacy in this setting31 (although special resistance testing to RAL may be needed, especially if RAL has been used in the past, as resistance attenuates benefit54). MVC has shown effect in CCR5-tropic infections.25 NRTIs may continue to provide partial efficacy, even in the face of known mutations.55 ENF can be considered for salvage therapy, although it is poorly tolerated because of the need for injections and significant injection site reactions. The presence of certain mutations to particular drugs may lend credence to their addition when these mutations decrease the fitness of the HIV virus. For instance, the M184V mutation may significantly reduce the action of FTC and 3TC, but this particular mutation confers a fitness disadvantage to the HIV virus and makes AZT highly effective, even in the presence of TAM mutations. Therefore, FTC or 3TC may be continued in the face of such a mutation. For patients with highly resistant virus, including resistance to RAL or EVG, registration for the experimental INSTI DTG may be considered. www.turner-white.com ART Selection in Patients with Comorbidities Cardiovascular Disease ABC, LPV/r, and FPV/r have been associated with some increased risk of cardiovascular disease, and alternatives should be considered in patients at high risk. Renal Disease TDF, ATV/r, and LPV/r have been associated with decline in renal function in some cases. Renal function should be monitored while using these agents, and they should be avoided, if possible, in patients with baseline renal dysfunction. As mentioned previously, COB as well as RPV may cause an artifactual increase in serum creatinine and GFR that is not associated with true renal failure. Since COB is frequently administered with TDF, it may be difficult to distinguish true renal failure from this artifact in patients who are co-administered the 2 drugs. Osteoporosis HIV infection alone is considered an independent risk factor for bone loss. Decreased bone mineral density can generally be expected with all ART regimens during the first year of therapy. In particular, TDF has been shown to be a strong independent risk factor for bone density loss and fracture,56 and should potentially be avoided in postmenopausal women or those at high risk for osteoporosis.57 Pregnancy Pregnancy is a level AIa indication for initiation of ART. Prevention of vertical transmission of HIV from mother to fetus is the primary goal. HIV testing should be performed on all pregnant female patients, and ART should be initiated as soon as Infectious Diseases Volume 14, Part 3 19 Antiretroviral Therapy in HIV Infection Table 7. Pregnancy Categories of Antiretroviral Medications Drug NRTI 3TC AZT FTC TDF ABC ddI d4T NNRTI NVP EFV ETR RVP PIs LPV RTV ATV DRV SQV IDV NFV FPV TPV INSTIs RAL Entry Inhibitors ENF MVC Recommendation Preferred Preferred Alternative Alternative Alternative Third-line Third-line Preferred Pregnancy category D, generally not recommended Insufficient data Insufficient data Preferred Preferred for boosting Alternative Alternative Alternative Third-line Third-line Insufficient data Insufficient data Third-line Insufficient data Insufficient data Information from AIDS Info. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. aidsinfo.nih.gov/ guidelines/html/1/adult-and-adolescent-arv-guidelines/0/ Updated Mar 27, 2012. Accessed December 20, 2012. INSTI = integrase strand transfer inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor. possible, even if diagnosis is made immediately before delivery. Pregnant patients with HIV should be started on ART regardless of CD4 count. As with 20 Hospital Physician Board Review Manual traditional ART, a 2-drug NRTI backbone should generally be used in combination with a third active medication. Current guidelines list LPV/r plus AZT/3TC as the preferred regimen in pregnancy, given that it has the most historical data regarding use in pregnant patients. However, the known toxicities associated with AZT compared with newer agents make its choice less attractive, and in clinical practice less toxic regimens with newer ART medications are frequently employed (Table 7). Generally, all approved NRTI backbones can be considered in pregnancy. Most boosted PI-based regimens are considered to be reasonably safe during pregnancy. With regard to NNRTI-based regimens, EFV is the only Pregnancy Category D ART medication and is generally avoided. Neural tube defects have been reported with the use of EFV during pregnancy, especially in the first trimester. However, the Antiretroviral Pregnancy Registry has recorded no increase in the rate of these congenital defects compared to the general population with EFV or any other ART medications (even with first-trimester exposure).58 There are insufficient data to recommend use of INSTI-based regimens. The PACTG 076 trial demonstrated the benefit of intravenous AZT infusion starting 3 hours before delivery in HIV-positive mothers with CD4 count greater than 400 cells/μL,59 regardless of use of antenatal ART. Intravenous AZT should also be administered to all mothers newly diagnosed with HIV immediately prior to delivery. Infants of mothers who did not receive ART during the antenatal period should be administered a 2- or 3-drug AZTcontaining regimen for 6 weeks after birth.60 A regimen consisting of 6 weeks of AZT 8 to 12 mg twice daily plus 3 doses of NVP 8 to 12 mg within the first 96 hours post-birth resulted in the best combination of efficacy and safety. www.turner-white.com Antiretroviral Therapy in HIV Infection Mycobacterial Infections Patients concurrently taking rifamycin antibiotics for mycobacterial infections are particularly susceptible to drug-drug interactions. There are guidelines for dose adjustments in such cases. An EFV-based regimen is generally preferred in patients taking a rifampin-based antimycobacterial regimen. Despite concern for a reduction in EFV levels in this setting, this result is not felt to be clinically significant.61–64 While package recommendations suggest the EFV dose should be increased to 800 mg per day in patients weighing more than 50 kg taking rifampin, the fixed-dose formulation of 600 mg of EFV in Atripla has been shown to produce reliable treatment of HIV regardless of weight.61,62,64,65 If EFV cannot be used, rifampin should be switched to rifabutin and a PIbased regimen should be considered. PI-based regimens have been shown to increase the drug concentration of rifabutin, and therefore the dose of rifabutin should be adjusted to 150 mg once daily.66 RAL-based regimens have not been extensively studied in the setting of antimycobacterial treatment. RAL levels are decreased in the setting of rifampin, so either the dose of RAL should be increased to 800 mg twice daily, or rifabutin should be substituted for rifampin. A recently approved 3-month, once-weekly regimen of isoniazid and rifapentine for the treatment of latent tuberculosis infection should not be used in patients on ART, and generally should be avoided in patients with HIV.67 Liver Disease All ART medications have some degree of hepatic metabolism, and caution should be exercised with their use in patients with liver disease or cirrhosis (although patients with Pugh score A can www.turner-white.com still tolerate most medications). The NNRTI NVP is especially concerning with regard to hepatic failure and should be avoided if possible in this patient population. Chronic Hepatitis B Interferon-based hepatitis B–treatment regimens have not been extensively studied in the setting of HIV. Therefore, an NRTI-based approach is generally employed. Usually, a typical 3-drug HIV ART regimen is selected that includes an NRTI backbone with 2 active NRTIs against hepatitis B virus (HBV) and 2 active NRTIs against HIV. TDF and either FTC or 3TC are recommend, as all of these agents are active against both HBV and HIV. NRTI backbones where FTC or 3TC is the only active medication against HBV are not recommended.68,69 Therefore, in cases where significant contraindications to TDF exist, entecavir can be used for HBV treatment. Since entecavir is only partially active against HIV, adding another fully active anti-HIV NRTI, such as ABC, is required, or selection of the M184V HIV RT mutation might result.70 Since 3TC has full activity against both HIV and HBV, its use counts towards each virus. Chronic Hepatitis C Peginterferon alfa and ribavirin have typically been used for treatment of hepatitis C virus (HCV) infection in patients co-infected with HCV and HIV. Co-administration of the NRTIs ddl or AZT should be avoided with ribavirin. The addition of the PIs telaprevir and boceprevir to peginterferon alfa and ribavirin has been demonstrated to improve treatment response in patients with lone HCV genotype 1 infection.71,72 Phase II and III trials suggest similar efficacy in patients with HCV/HIV co-infection as well. Limited data exists regarding drug-drug interactions between telaprevir or boceprevir with Infectious Diseases Volume 14, Part 3 21 Antiretroviral Therapy in HIV Infection current ART medications, but it is currently felt that RAL-based regimens may be safely used in combination with either telaprevir and boceprevir, and that ATV/r- and EFV-based regimens may additionally be used with telaprevir. Telaprevir and boceprevir are not considered to be acceptable therapies for HIV. Laboratory Testing With the expanded role of ART in patients with less-advanced disease, a new diagnosis of HIV in any patient should prompt a panel of blood tests to evaluate the appropriateness of offering such therapy. Similarly, patients with a known diagnosis of HIV who are not taking ART should have studies performed at regular intervals to continuously reevaluate disease status. If not performed recently, lab testing should be performed immediately prior to therapy initiation. Testing should continue at regular intervals during treatment to monitor for virologic failure, HIV-related or unrelated organ dysfunction, and medication side effects. Relevant lab tests to be performed before and after initiation of ART are listed in Table 8; this list does not include additional tests that may also be indicated to screen for chronic coinfections or malignancy (eg, syphilis serology, cervical cancer screening, tuberculin skin test). In general, a follow-up lab panel consisting of CD4 count, HIV viral load, complete blood count with differential, and complete metabolic panel should be performed every 3 months from the time of diagnosis, with or without therapy. For a patient with reliable adherence to an ART regimen with CD4 ≥350 cells/μL and undetectable viral load for greater than 1 year, it may be reasonable to extend this monitoring interval to every 6 months.16 Fasting lipids and urinalysis should be repeated every 12 months (unless significant abnormalities exist or there is concern for HIV22 Hospital Physician Board Review Manual associated nephropathy, where biannual testing may be appropriate). CD4 count and HIV viral load should also be reassessed 2 to 8 weeks after initiation of a new ART regimen. CD4 counts estimate an HIV patient’s immune status. These counts are monitored prior to initiation of ART to ascertain the need to begin therapy and/or prophylaxis for OIs. They are also monitored after therapy initiation to roughly assess the immune response to ART and to reevaluate need for prophylaxis for OIs. Generally, the CD4 count should increase by at least 50 to 150 cells/μL in the first year of therapy and an additional 50 to 100 cells/ μL in the second year.73,74 A lower CD4 count at the time of therapy initiation correlates to a lower potential CD4 count ceiling once therapy stability has been achieved. Patients with CD4 counts less than 200 cells/μL at ART initiation rarely achieve counts greater than 500 cells/μL after 4 years of therapy.73 Immunologic failure is the inability to appropriately mount a CD4 response to ART treatment. There is currently no known benefit to changing therapy based on immunologic failure, however.36,75–77 The HIV viral load is the gold-standard measurement of ART effectiveness. An undetectable HIV viral load is the major goal of treatment. The viral load should be expected to drop by a factor of log10 copies/mL 4 weeks after therapy initiation. The viral load should then be reasonably expected to become undetectable by 16 to 24 weeks of therapy.1 During this initial time frame, it is advisable to monitor HIV viral load every 4 to 8 weeks (instead of the usual 3- to 6-month follow-up interval) to assess for virologic failure. Virologic failure is the inability to achieve an appropriately undetectable viral load despite administration of ART. Once a patient has achieved an undetectable viral load, an elevation in the viral load during repeat testing could represent 1 of 2 scenarios. A www.turner-white.com Antiretroviral Therapy in HIV Infection Table 8. Relevant Laboratory Studies Before and After Initiation of Antiretroviral Therapy in HIV Patients Test At Diagnosis Before ART Initiation At ART Initiation ART Follow-up Virologic Failure CD4 Count HIV viral load + + + (3-mo intervals) + (3-mo intervals) + (and 2-–8 wk later) + (and 2–8 wk later) + + HIV genotype* , † Complete blood count/ differential Complete metabolic panel Fasting lipid panel Pregnancy test Serologies for HAV, HBV, HCV Electrocardiogram + + – + (3-mo intervals) + + + (3-mo intervals) + (every 4–8 wk until undetectable, then at 3-mo intervals) – + (3-mo intervals) + + (3-mo intervals) + + (3-mo intervals) – + – + + (12-mo intervals) – – + + – + (12-mo intervals) – – – – – – – – – HLA-B5701‡ – – – – Urinalysis + + (12-mo intervals) +/– (if considering SQV or ATV) +/– (if considering ABC) + + (12-mo intervals) – + – HAV = hepatitis A virus; HBV = hepatitis B virus; HCV = hepatitis C virus. * In patients with virologic failure, genotypic testing preferably should be performed while the patient is still taking the failing ART regimen. † A minimum viral load of 1000 copies/mL is recommended to ensure accuracy of genotypic testing. ‡ Patients positive for the HLA-B5701 allele should not be started on ABC therapy due to concern regarding severe hypersensitivity reaction. temporary increase in the viral load from undetectable to 50 to 1000 copies/mL likely represents a “blip.” Blips do not represent virologic failure, and the patient should be continued on the current regimen without changes.78,79 Blips should prompt an assessment of patient compliance with ART, as omitted therapy may sometimes account for a blip. A blip should also be confirmed with repeat viral load testing in 2 to 4 weeks.16 Virologic failure represents a sustained elevation in the viral load in previously undetectable patients, or the inability to fully suppress the viral load at 24 to 48 weeks of ART treatment. Virologic failure should prompt HIV resistance testing and consideration of a different ART regimen. www.turner-white.com Viral load monitoring should always be the true metric of ART treatment success. Judging the success of an ART regimen by CD4 count or clinical outcome alone may mask subclinical incomplete viral suppression. This incomplete viral suppression can lead to significant viral resistance, as this implies that the virus may be replicating in the presence of drug. Clinicians who administer ART should be especially mindful of viral resistance in patients who were previously treated in the developing world, where frequent viral load monitoring may be unavailable or unaffordable. A recommendation to check a patient’s coreceptor status (CCR5 or CXCR4) with a tropism assay is not included in Table 8. In general, this Infectious Diseases Volume 14, Part 3 23 Antiretroviral Therapy in HIV Infection Table 9. Occupational Postexposure Prophylaxis (PEP) Recommendations Exposure Severity HIV-Negative Source Percutaneous Injuries Mild * Severe† No PEP No PEP Mucous Membrane and Open Skin Exposures Small-volume§ No PEP Large-volume¶ No PEP HIV-Positive Source, VL <1500 Copies/mL HIV-Positive Source, VL ≥1500 Copies/mL HIV Source Status Unknown 2-drug PEP 3-drug PEP 3-drug PEP 3-drug PEP Consider 2-drug PEP‡ Consider 2-drug PEP‡ Consider 2-drug PEP 2-drug PEP 2-drug PEP 3-drug PEP No PEP Consider 2-drug PEP# Information from Panlilio AL, Cardo DM, Grohskopf LA; U.S. Public Health Service. Updated U.S. Public Health Service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep 2005;54 (RR-9):1–17. Available at aidsinfo.nih.gov/contentfiles/HealthCareOccupExpoGL.pdf. Accessed December 20, 2012. VL = viral load. * Superficial injury, solid needles. † Deep injuries, large-bore hollow needles, visible blood on penetrating object, use of object in patient’s vein or artery. ‡ Based on patient preference after careful discussion with treating physician. § A few drops. ¶ A large splash. # Based on patient preference after careful discussion with treating physician. test should only be performed when MVC therapy is being considered. As mentioned above, MVC is generally not a medication that is used to construct an ART regimen for treatment-naïve patients. There is little utility to performing this tropism assay at the time of HIV diagnosis, as a patient’s co-receptor status can change over time. If MVC is being considered, an HIV viral load of at least 1000 copies/mL is recommended to ensure accuracy of most available tropism assays. Most patients will develop at least a small subpopulation of CXCR4-using viruses 5 years after initial diagnosis.29,59,80,81 As mentioned previously, MVC has not been shown to confer benefit to patients with CXCR4 viral populations. POSTEXPOSURE PROPHYLAXIS Percutaneous or mucous membrane exposure to HIV-contaminated bodily fluids does confer a 24 Hospital Physician Board Review Manual respective 0.3% to 0.09% risk of infection.82,83 Exposures in the health care workplace are generally related to blood and are often caused by contact with sharp objects or accidental splashes to the facial area. Nonoccupational exposures generally occur through voluntary or forced sexual contact and intravenous drug use. Expert consensus guides the usage of antiretroviral therapy for postexposure prophylaxis (PEP), as no randomized prospective trials have been conducted in this area. For occupational exposures, the HIV status of the reference patient and the severity of the exposure must be considered (Table 9 and Table 10). When treatment is indicated, it should ideally be initiated within 4 hours of exposure. Duration of therapy should be 28 days.83 PEP is generally not indicated beyond 72 hours of exposure. PEP in the setting of a nonoccupational exposure (nPEP) is recommended within 72 hours of www.turner-white.com Antiretroviral Therapy in HIV Infection exposure to bodily fluids such as blood, semen, vaginal or rectal secretions, or breast milk from a known HIV-positive contact. It may also be indicated on a case-by-case basis when the HIV status of the assailant is unknown, such as for victims of sexual assault. Again, treatment should begin promptly and continue for a 28-day course. A 3-drug regimen is used for nPEP. See Table 11 for recommended regimens for nPEP. PREEXPOSURE PROPHYLAXIS Preexposure prophylaxis (PrEP) is the administration of ART to an HIV-negative patient who is sexually active with a known HIV-positive partner or with partners at high risk for HIV disease. While minimizing the viral load in the HIV-positive patient is protective, patients with undetectable plasma HIV RNA levels may still harbor viral RNA in significant quantity in the genital region.84 Compared to the plasma viral load, the genital viral RNA concentration is a more important risk factor for transmission, yet testing for this metric is not widely available. Therefore, PrEP has been considered as an adjunct to condom use to minimize HIV transmission to the uninfected patient who partakes in high-risk sexual situations. Several clinical trials to assess use of PrEP are either currently underway or in the preliminary stages.85–88 In general, these studies employ daily single-drug TDF or a TDF/FTC oral combination and/or the use of a topical TDF gel. The data have been mixed, and current guidelines suggest that the cautious use of PrEP may be a reasonable consideration. Strict adherence must be stressed, as data suggests that failure of PrEP is most likely related to noncompliance. Major concerns do exist, especially with regard to possible acquisition of a new undetected HIV infection by a previously uninfected patient taking www.turner-white.com Table 10. Recommendations for Two-Drug and Three-Drug Occupational Postexposure Prophylaxis Regimens Recommendation Two-Drug Regimen Preferred Preferred Preferred Preferred Alternative Alternative Alternative Alternative Recommendation Preferred Alternative Alternative Alternative Alternative Alternative Alternative AZT/3TC AZT/FTC TDF/3TC TDF/FTC d4T/3TC d4T/FTC ddI/3TC ddI/FTC Three-Drug Regimen* LPV/r ATV/r FPV/r IDV/r SQV/r NFV EFV Information from Panlilio AL, Cardo DM, Grohskopf LA; U.S. Public Health Service. Updated U.S. Public Health Service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep 2005;54 (RR-9):1–17. Available at aidsinfo.nih.gov/contentfiles/HealthCareOccupExpoGL.pdf. Accessed December 20, 2012. *In addition to a 2-drug regimen. PrEP. As mentioned, the PrEP regimen is not a full 3-drug ART regimen, and viral resistance may quickly develop in this setting should a new infection go undetected. The HIV status of uninfected patients must therefore be confirmed prior to PrEP initiation and should be monitored frequently throughout therapy, as a new positive result should prompt full 3-drug ART therapy. The potential for developing an undetected new HIV infection with subsequent resistance while taking an inadequate regimen is a major drawback of PrEP, both to the patient and to the community in general (if the patient were to infect others in the community with their resistant strain). Infectious Diseases Volume 14, Part 3 25 Antiretroviral Therapy in HIV Infection Table 11. Recommendations for Nonoccupational Exposure Prophylaxis Regimens Recommendation Preferred Preferred Alternative Alternative Alternative Alternative Alternative Alternative Alternative Alternative Third-line Regimen EFV + (TDF or AZT)/ (FTC or 3TC) LPV/r + AZT/(FTC or 3TC) EFV + (ABC or ddI or d4T) + (FTC or 3TC) ATV + (FTC or 3TC) + [(AZT or d4T or ABC) or (TDF/r)] FPV + (FTC or 3TC) + [(AZT or d4T) or (ABC or TDF or ddI)] FPV/r + (FTC or 3TC) + (TDF or ABC or ddI or d4T) IDV/r + (FTC or 3TC) + (TDF or ABC or ddI or d4T) LPV/r + (FTC or 3TC) + (TDF or ABC or ddI or d4T) NFV + (FTC or 3TC) + (TDF or AZT or ddI or d4T) SQV/r + (FTC or 3TC) + (TDF or ABC or AZT or ddI or d4T) ABC + 3TC + AZT Information from Panlilio AL, Cardo DM, Grohskopf LA; U.S. Public Health Service. Updated U.S. Public Health Service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep 2005;54 (RR-9):1–17. Available at aidsinfo.nih.gov/contentfiles/HealthCareOccupExpoGL.pdf. Accessed December 20, 2012. Other considerations should be made as well. A patient’s HBV status should be assessed. Patients who are unwilling to undergo frequent lab testing probably should not be offered PrEP. Females taking PrEP who may become or recently became pregnant should have risks and benefits to the fetus clearly discussed. Ideally, uninfected females taking PrEP who become pregnant should abstain from further high-risk sexual contact to fully minimize their risk of contracting HIV during their pregnancy. Since TDF is a primary medication in this regimen, PrEP should not be offered to 26 Hospital Physician Board Review Manual patients with renal dysfunction. There are no data available for the use of PrEP in the setting where a monogamous HIV-positive partner is currently taking ART therapy. IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME HIV-positive patients who are initiated on ART at a low baseline CD4 count may be at risk for immune reconstitution inflammatory syndrome (IRIS; often when the initial baseline CD4 count is less than 100 cells/μL). In this patient population, OIs may exist subclinically, as the host is unable to mount an appropriate immune inflammatory defense response due to a virally impaired immune system. As the immune system is restored with ART treatment, these subclinical infections can stimulate an aggressive inflammatory reaction. This reaction usually involves infected organ systems, and is generally more common and profound in patients with disseminated OIs and high titers of pathogen. Autoimmune IRIS reactions that are unrelated to a known OI have also been described.1 IRIS is a clinical diagnosis that may be difficult to discern from a true new infection or drug reaction. Once IRIS is considered the most likely possibility, nonsteroidal anti-inflammatory or corticosteroid medications may be considered depending on severity. Some controversy exists with regard to the timing of ART initiation in newly diagnosed AIDS patients with active OIs. A concern has been that starting ART in the setting of a known OI might provoke an IRIS response that could compromise the health of the patient. Limited data suggests that ART therapy should be initiated earlier rather than later in these patients1 (Table 5), although www.turner-white.com Antiretroviral Therapy in HIV Infection care should be taken in certain special situations. For example, caution should be taken with patients with cryptococcal meningitis. A randomized clinical trial from Zimbabwe in patients with cryptococcal meningitis compared ART administration in a group 72 hours after diagnosis and in a second group after 10 weeks of fluconazole administration. The early-treatment group had over 2.5 times the risk of death.89 Therefore, the general recommendation is to delay ART for patients with cryptococcal meningitis until they have received at least 2 to 10 weeks of antifungal therapy.1 Patients with most OIs or active tuberculosis and CD4 count <50 cells/μL should be started on ART within 2 weeks of OI diagnosis or initiation of anti-tuberculosis treatment. Patients with active tuberculosis infection and CD4 count ≥50 cells/μL should be started on ART within 8 to 10 weeks of anti-tuberculosis treatment initiation. Timing of ART initiation in patients with tuberculosis meningitis is less certain. A Vietnamese study demonstrated no significant outcome improvement and more adverse effects in patients started on immediate ART in this setting versus patients started on 2-month delayed ART (tuberculosis treatment was started immediately in both groups).90 However, because of better patient monitoring in the United States, a grade CIII recommendation exists to initiate patients with tuberculosis meningitis and HIV on ART immediately. BOARD REVIEW QUESTIONS Test your knowledge of this topic. Go to www.turner-white.com and select Infectious Diseases from the drop-down menu of specialties. REFERENCES 1. Tsibris AMN, Hirsch MS. Antiretroviral therapy for human immunodeficiency virus infection. In: Mandell GL, Bennett www.turner-white.com JE, Dolin R, eds. Principles and practice of infectious diseases. 7th ed. Philadelphia (PA): Elsevier; 2010;1833–53. 2. Barrios A, de Mendoza C, Martin-Carbonero L, et al. 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Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatmentexperienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multidrug resistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomized openlabel trials. Lancet 2006;368(9534):466–75. 53. Katlama C, Haubrich R, Lalezari J, et al. Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled 48 week analysis of two randomized, controlled trials. AIDS 2009;23:2289–300. 54. Wirden M, Simon A, Schneider L, et al. Raltegravir has no residual antiviral activity in vivo against HIV-1 with resistance-associated mutations to this drug. J Antimicrob Chemother 2009;64:1087–90. 55. Deeks SG, Hoh R, Neilands TB, et al. Interruption of treatment with individual therapeutic drug classes in adults with multidrug-resistant HIV-1 infection. 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Abdool Karim S, Naidoo K, Padayatchi N, et al. Optimal Infectious Diseases Volume 14, Part 3 29 Antiretroviral Therapy in HIV Infection timing of ART during TB therapy: findings of the SAPiT trial. Abstract presented at: 18th Conference on Retroviruses and Opportunistic Infections; February 27–March 2, 2011; Boston (MA). 62. Blanc FX, Sok T, Laureillard D, et al; CAMELIA (ANRS 1295–CIPRA KH001) Study Team. Earlier vs later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med 2011;365:1471–81. 63. Friedland G, Khoo S, Jack C, Lalloo U. Administration of efavirenz (600 mg/day) with rifampicin results in highly variable levels but excellent clinical outcomes in patients treated for tuberculosis and HIV. J Antimicrob Chemother 2006;58:1299–1302. 64. Havlir DV, Kendall MA, Ive P, et al; AIDS Clinical Trials Group Study A5221. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med 2011;365:1482–91. 65. Boulle A, Van Cutsem G, Cohen K, et al. Outcomes of nevirapine- and efavirenz-based antiretroviral therapy when coadministered with rifampicin-based antitubercular therapy. JAMA 2008;300:530–9. 66. Naiker S, Conolly C, Weisner L, et al. Pharmacokinetic evaluation of different rifabutin dosing strategies in African TB patients on lopinavir/ritonavir-based ART. Abstract presented at: 18th Conference on Retroviruses and Opportunistic Infections; February 27–March 2, 2011; Boston (MA). 67. Centers for Disease Control and Prevention. Recommendations for use of an isoniazid-rifapentine regimen with direct observation to treat latent Mycobacterium tuberculosis infection. MMWR Morb Mortal Wkly Rep 2011;60:1650–3. 68. Matthews GV, Manzini P, Hu Z, et al; PHIDISA II Study Team. Impact of lamivudine on HIV and hepatitis B virusrelated outcomes in HIV/hepatitis B virus individuals in a randomized clinical trial of antiretroviral therapy in southern Africa. AIDS 2011;25:1727–35. 69. Thio CL. 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