Principles of Antiretroviral Therapy Christopher Behrens, MD Northwest AIDS Education & Training Center University of Washington CBB/2002

Current Treatment Strategies DHHS Guidelines regarding when to initiate antiretroviral therapy Adherence Strategic antiretroviral combinations Popular regimens Follow-up monitoring CBB/2002

HIV: Case History  A 29-year old woman comes to the clinic for routine HIV care; she has been HIV-infected for about 4 years, and has never received antiretroviral treatment. Her most recent CD4 count is 330 and her viral load is 88,000.  You explain the meaning of her CD4 count and viral load  She asks you if you would recommend antiretroviral therapy CBB/2002

Initiation of Antiretroviral Therapy Advantages –decrease viral load, increase CD4 count –prevent further damage to immune system –immune reconstitution –reduced morbidity & mortality (if effective) –prevent viral heterogeneity –decrease infectivity Disadvantages –toxicities, both short- & long-term –pill burden, lifestyle changes –potential for developing resistance –may limit future options –potential for transmission of resistant virus –cost CBB/2002

Initiation of Antiretroviral Therapy: Key Considerations Symptoms & Opportunistic Infections CD4 count Viral Load Anticipated Adherence - patient ‘readiness’ CBB/2002

Indications for Initiation of Antiretroviral Therapy for HIV DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, February 5, 2001, Table 6. CBB/2002

Indications for Initiation of Antiretroviral Therapy for HIV DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, February 5, 2001, Table 6. CBB/2002

Baseline CD4 Count and Survival after initation of HAART: prospective cohort of 715 patients Survival in Years Chen RY et al, 8th CROI, Chicago 2001 proportion surviving CD4 Count when Initiate HAART < >

CD4 > 200 CD CD4 < 50 Baseline CD4 Count and Survival after Initiation of HAART Probability of Survival (%) Time From Start of HAART (months) Cumulative Mortality by Baseline CD4 Count JAMA. 2001;286: N = 1219 therapy- naïve individuals initiating HAART in British Columbia ==================== CBB/2002

Indications for Initiation of Antiretroviral Therapy for HIV DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, February 5, 2001, Table 6. CBB/2002

Time from initation of HAART (mos) Probability of Survival (%) JAMA. 2001;286: N = 1219 therapy- naïve individuals initiating HAART in British Columbia Survival after Initiation of HAART by Baseline CD4 Count and Viral Load ===================

Impact of CD4 and Viral Load on Initiation of HAART: Summary The optimal time to initiate therapy is: –unclear –before CD4 drops below 200 –probably when CD4 between 200 and 350 –determined more by CD4 count than viral load Viral Load –predicts the slope of CD4 decline –may help determine whether to start closer to CD4 count of 200 or 350 CBB/2002

HIV: Case History  A 29-year old woman comes to the clinic for routine HIV care; she has been HIV-infected for about 4 years, and has never received antiretroviral treatment. Her most recent CD4 count is 330 and her viral load is 88,000.  Would you suggest she start antiretroviral therapy? CBB/2002

Initiation of Antiretroviral Therapy: Key Considerations Symptoms & Opportunistic Infections CD4 count Viral Load Anticipated Adherence - patient ‘readiness’ CBB/2002

Adherence “Drugs don’t work if people don’t take them.” - C. Everett Koop CBB/2002

Patients with HIV RNA <400 copies/mL, % PI adherence, % (electronic bottle caps) Paterson, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago, IL. Abstract 92. Virologic Control falls sharply with diminished adherence CBB/2002

10% Adherence difference = 21% reduction in risk of AIDS Adherence and AIDS-Free Survival Bangsberg D, et al. AIDS. 2001:15:1181 Proportion AIDS-Free Months from entry P = Adherence O 90–100% O 50–89% O 0–49%

Reasons for Non-Adherence: Clinician vs Patient Views Chesney M. Adherence to antiretroviral therapy. 12th World AIDS Conference, 1998; Geneva. Lecture 281 CBB/2002

Predictors of Poor Adherence active alcohol 1 or substance 2 abuse work outside the home for pay 1 depressed mood 1 lack of perceived efficacy of HAART 3 lack of advanced disease 4 concern over side effects 4 1. Chesney MA. 37th ICAAC, 1997; Toronto. Abstract Cheever LW, Curr Infect Dis Rep 1999 Oct;1(4): Horne R, et al. 39th ICAAC, 1999; San Francisco. Abstract Wenger N, et al. 6th Conference on Retroviruses and Opportunistic Infections, 1999; Chicago. Abstract 98. CBB/2002

Predictors of Poor Adherence, continued inability to fit medications into daily schedule tid dosing, food requirements 1 1. Stone VE, et al. JAIDS 2001; 28: CBB/2002

Factors Associated with Higher Levels of Adherence twice-daily or once-daily regimens 1,4 belief in own ability to adhere to regimen 1 not living alone 2 dependent on a significant other for support 2 history of Opportunistic Infection or Advanced HIV disease 3 1. Eldred L, et al, J Acquir Immune Defic Syndr Hum Retrovirol 1998;18: Morse EV et al, Soc Sci Med 1991;32: Singh N, et al, AIDS Care 1996;8: Stone VE, et al. JAIDS 2001; 28: CBB/2002

Factors Associated with Higher Levels of Adherence Belief in efficacy of antiretroviral therapy Belief that non-adherence will lead to viral resistance Wenger N, et al. 6th Conference on Retroviruses and Opportunistic Infections, 1999; Chicago. Abstract 98.

Interventions Shown to Improve Adherence to Antiretrovirals medication alarms 1 education & counseling sessions 2,3 Directly Observed Therapy (DOT) 4,5 1. Samet JH, et al. Am J Med. 1992;92: Malow RW, et al. Alcohol Drug Abuse 1998;49: Tuldra A, et al. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999; Abstract Sorensen JL, et al. AIDS Care. 1998;10: Wall TL, et al. Drug Alcohol Depend. 1995;37:

Self-Adminstered vs Directly Observed Therapy During Incarceration Fischl et al 8 th CROI, 2001 abstract 528 p < 0.01 N = 50 in each group

Putting it all Together Practical Strategies to Improve Adherence

Improving Adherence: before Initiation of Therapy  Assess patient's understanding and acceptance of the regimens  Determine other medical barriers to adherence  Manage or refer for management of adherence- limiting co-morbid conditions Adapted from: Miller et al., The AIDS Reader 10(3): , 2000.

Improving Adherence: before Initiation of Therapy Try to use simple regimens –bid or better –avoid food requirements if possible Clear & simple instructions Negotiated treatment plan

Improving Adherence: After Initiation of Therapy Close follow-up Ask patient to verbalize treatment regimen Education about adherence –re-emphasize importance of adherence at each visit, even in patients with good virologic control –review incidence & management of adverse effects often

Improving Adherence: After Initiation of Therapy consider cues to remind patients of dosing other reminders: alarms, watches, pagers consider recruiting family/friends as support referral to community support groups involve other members of the health care team Adapted from: Miller et al., The AIDS Reader 10(3): , 2000.

Back to the case You confirm her viral load and CD4 count; she keeps her follow-up appointments and appears to understand the importance of adherence. She has no significant co- morbid conditions or medications. What regimen would you recommend?

Highly Active Antiretroviral Therapy (HAART) Combination of at least 3 drugs, usually: –2 NRTIs (the “NRTI backbone”), plus: – 1 NNRTI or 1-2 PIs Therapy with only one or two agents allows HIV to overcome therapy through resistance mutations

Adapted from: Walker B. IDSA 1998 Classes of Antiretroviral Agents RNA DNA HIV Nucleus Host Cell Nucleoside Analogues Non-NucleosidesProtease Inhibitors RT

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Nucleoside analogues that block translation of HIV RNA into DNA by inhibiting HIV Reverse Transcriptase enzyme –AZT (zidovudine; Retrovir) –3TC (lamivudine; Epivir) –d4T (stavudine; Zerit) –ddI (didanosine; Videx) –Abacavir (Ziagen) –ddC (zalcitabine; Hivid)

Tenofovir: a new NRTI Nucleotide Reverse Transcriptase Inhibitor one 300mg tablet daily with food well-tolerated and effective in clinical trials to date effective against many strains of HIV with NRTI resistance also active against hepatitis B generally being reserved for salvage therapy

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Also inhibit HIV Reverse Transcriptase, but at a different site than NRTIs –Efavirenz (Sustiva) –Nevirapine (Viramune) –Delavirdine (Rescriptor)

Protease Inhibitors (PIs) Block release of the assembled HIV virus particles from infected cells –Ritonavir (Norvir) –Saquinavir (Fortavase; Invirase) –Nelfinavir (Viracept) –Indinavir (Crixivan) –Amprenavir (Agenerase) –Lopinavir (co-formulated w/ ritonavir as Kaletra)

Ritonavir intensification of other Protease Inhibitors (PIs) Protease Inhibitors, like many medications, are metabolized in the liver by the cytochrome P450 enzyme complex Ritonavir inhibits this complex, thereby boosting serum levels of co-administered protease inhibitors

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

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

Ritonavir intensification of other Protease Inhibitors (PIs) This can be used to ease pill burden, dosing intervals, and potentially overcome HIV resistance among protease inhibitors This can also lead to potentially dangerous or fatal interactions with other medications and recreational drugs

So What to Start With? PI - based regimens (2 NRTIs PIs) NNRTI - based regimens (2 NRTIs + 1 NNRTI) NRTI - based regimens (3 NRTIs)

Protease Inhibitor -based regimens  The most clinical outcome data available for PI-based regimens  Allow deferral of NNRTIs  High genetic barrier to resistance (multiple mutations required)  high pharmacologic barrier to resistance for pharmaco-kinetically boosted PIs  Short-term side effects (esp. gastrointestinal)  Long-term metabolic/morphologic side effects  Inconvenience & adherence (schedule, pill burden, food requirements)  Drug-drug interactions Advantages Disadvantages

NNRTI - based regimens Simpler regimens Fewer long-term toxicities Potent at high viral loads/low CD4+ cell counts (efavirenz) Allow deferral of PIs Fewer drug-drug interactions NNRTIs vary in potency; some may be less effective at high viral loads/low CD4+ counts (nevirapine, delavirdine) Low genetic barrier to resistance Extensive NNRTI cross- resistance toxicities: CNS, hyperlipidemia (efavirenz); rash (all); hepatotoxicity (NVP > EFV) Advantages Disadvantages

NRTI - based regimens (AZT + 3TC + Abacavir) Allows deferral of PIs and NNRTIs Simple, low pill burden Well tolerated minimal long-term toxicity virtually no drug interactions Limited data, no clinical endpoint data Relative potency and durability not established Efficacy at high viral loads questionable Abacavir hypersensitivity Advantages Disadvantages

Recommended Antiretroviral Combinations for Initial Therapy Choose one from Column A and one from Column B DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, August 13, 2001, Table 12.

Effect of Baseline Viral Load on Efficacy Inverse Association –Nelfinavir –Indinavir –Nevirapine –Delavirdine –triple NRTI No Association –Efavirenz –Lopinavir/ritonavir (Kaletra) Unknown Association –dual PI combination

Choice of initial regimen by baseline Viral Load VL > 100,000 Proven –LPV/RTV + 2 NRTIs –Efavirenz + 2 NRTIs Unproven –Boosted PI + 2 NRTIs –3 NRTIs + PI –3 NRTIs + Nevirapine –NRTI/NNRTI/PI VL < 100,000 –LPV/RTV + 2 NRTIs –Efavirenz + 2 NRTIs –Nevirapine + 2 NRTIs –1-2 PIs + 2 NRTIs –AZT/3TC/Abacavir

Popular Initial HAART Regimens: Efavirenz + 2 NRTIs d4T/3TC/Efavirenz –highly potent –generally well tolerated –CNS side effects from efavirenz AZT/3TC/Efavirenz (or Combivir/Efavirenz) –low pill burden –more side effects from AZT

DHS/ARV Rx /PP Efavirenz: Study 006 From: Staszewski S. N Engl J Med 1999;341:  Patients (N=450) - CD4 > 50 cells/mm 3 - HIV RNA > 10,000 copies/ml - Naive to PI, non-nucleoside, and 3TC  Regimens - AZT + 3TC + IDV - EFV + IDV - AZT + 3TC + EFV AZT/3TC/EFV AZT/3TC/IDV EFV/IDV 90 Undetectable VL at 48 Weeks 64

AIDS 2001 December 7;15(18): Kaplan–Meier plot showing the percentage of patients with virological failure by time from start of the non-nucleoside reverse transcriptase inhibitor (NNRTI) regimen, according to use of nevirapine or efavirenz.

Popular Initial HAART Regimens d4T/3TC/Nevirapine, AZT/3TC/Nevirapine –fewer CNS side effects –more hepatotoxic –Nevirapine may be less potent than efavirenz d4T/3TC/Nelfinavir, AZT/3TC/Nelfinavir –more experience with PIs as third agent –Nelfinavir preserves future PI options –higher pill burden; diarrhea common

Popular Initial HAART Regimens d4T/3TC/Kaletra, AZT/3TC/Kaletra –Kaletra a potent and well-tolerated PI –maintains high efficacy even in patients with baseline VL > 100,000 –many clinicians prefer to save Kaletra for salvage therapy

Other Initial HAART Regimens Trizivir (AZT/3TC/ABC) –simplest regimen available with lowest pill count –not considered first-line option –efficacy not well established –consider for patients with low VL who need very simple regimen –beware of ABC hypersensitivity

Abacavir: Study 3005 AZT + 3TC + ABC vs AZT + 3TC + IDV Patients (N = 562) –therapy-naïve adults –HIV VL > 10,000 –CD4 > 100 Regimens –AZT + 3TC + Abacavir –AZT + 3TC + Indinavir VL > 100,000 % of patients with VL < week data: HIV VL < 50 Staszewski, S. JAMA 2001;285:

Abacavir (Ziagen) Hypersensitivity  Incidence and Timing - Incidence < 3% - Onset typically within 4 weeks  Symptoms - Rash - Fever - Nausea - Throat/mouth lesions - Conjunctivitis/respiratory symptoms  Re-challenge can be fatal! DHS/ARV Rx/PP From: Hetherington S, et al. 12th World AIDS Conference, Geneva, 1998: Abstract 12353

HIV Case continued  You decide to start her on d4T (stavudine) plus 3TC (lamivudine) plus Efavirenz.  What are your goals of therapy?  What follow up labs do you arrange, and when?

DHS/ARV Rx/PP Antiretroviral Therapy: Optimal Response Medications Started 50

Several trials indicate the need to achieve better viral suppression, i.e. < 50 cps/ml AVANTI-2 (AZT/3TC/IDV)INCAS (AZT/ddI/NVP) All trials combined Weeks AVANTI-3 (AZT/3TC/NFV) Weeks Proportion of subjects with sustained virologic success* (%) Viral load Nadir 20 copies/ml 21–400 copies/ml >400 copies/ml *HIV-1 RNA <1000 copies/ml Montaner J. 12th World AIDS Conference Geneva 1998 AETC NRC Training Slide

Follow-up Laboratory Testing Viral load & CD4 counts, initially q month after starting therapy; can space out to q3mo if doing well Goals are undetectable viral load (<50 copies/mL) and rise in CD4 count CBC, electrolytes, LFTs at regular intervals to monitor for toxicity, also when signs or symptoms develop

Initial Antiretroviral Therapy: Summary When to initiate therapy is controversial, but probably best to start while CD4 > 200 HAART consists of at least 3 drugs, generally from 2 or more classes consider adherence and baseline viral load when designing initial regimen goal is undetectable viral load (< 50 copies/mL) and rise in CD4 count monitor closely after initiation of therapy

Back to the Case She does well on her regimen of d4T, 3TC and Kaletra Her viral load rapidly drops to undetectable within 4 months At the same time, her CD4 count rises to 390

Antiretroviral Therapy: Intermittent Viremia (“blips”) Medications Started 50

Case continued At her next blood draw, her viral load is 100 copies/mL what do you do?

Medications Started 50

Antiretroviral Therapy: Intermittent Viremia (“blips”) Medications Started 50

Predictive Value of Intermittent Viremia Methods –N=241 adults on ARV Rx* –HIV VL<50 at start of study –“viral blip” defined as transient VL>50 –virologic failure = VL>200 on 2 consecutive values Follow-up at 6 months –96 (40%) of 241 had “blips” –145 (60%) had no “blips” * AZT + 3TC + Indinavir (ACTG 343) Havlir DV et al. JAMA 2001;276:171.

Antiretroviral Therapy: Low-level Viremia Medications Started 50

Predictive Value of Low-Level Viremia Methods –N=1858 adults on HAART –HIV VL <50 copies/mL x 2 at outset –low level rebound: VL = –blip: rebound followed by VL < 50 –virologic failure: VL > 500 x 2 Follow-up at 6 months –604 (33%) with low-level rebound Greubl G et al. 8th CROI, 2001: Abstract 522 Virologic Failure

Salvage Antiretroviral Therapy Guiding Principles, Strategies and the Role of Resistance Testing

DHS/ HIV/PP HIV: Case History  A 26-year-old man with an HIV RNA level of 106,000 and a CD4 count of 121 cells/mm 3 is started on a regimen of AZT (zidovudine) plus 3TC (lamivudine) plus Nevirapine. He has an initial excellent response: HIV viral load < 50 at months 3, 6, and 9, and his CD4 count rises to 247. At the 12 month visit, he admits to missing some doses in the past month.  What would you do?  Would you change his regimen?

Salvage Antiretroviral Therapy: Indications Virologic breakthrough on previously successful regimen (viral failure) Failure to ever achieve desired level of virologic suppression immune deterioration (falling CD4 count) despite viral suppression adherence or intolerance problems with initial regimen

DHS/ARV Rx/PP Antiretroviral Therapy: Viral Failure Medications Started 50

DHS/ARV Rx/PP Antiretroviral Therapy: Failure to Suppress Medications Started 50

Salvage Antiretroviral Therapy: Guiding Principles Always confirm viral failure with repeat viral load measurements Re-visit adherence issues Try to correct adherence problems before starting a salvage regimen

Salvage Antiretroviral Therapy: Guiding Principles for adherence or intolerance problems, can change single agent in the regimen as long as resistance is not suspected for cases of viral failure or failure to achieve sustained virologic suppression, must change at least two of the agents; an entirely new regimen is best though not always feasible beware of cross-resistance within a class

Salvage Antiretroviral Therapy: Guiding Principles trials have demonstrated the clinical benefit of resistance testing in designing salvage regimens, but resistance testing can miss minor resistant variants of HIV trials have also demonstrated the clinical benefit of expert assistance in designing salvage regimens

Salvage Antiretroviral Therapy: Guiding Principles Many patients have limited salvage options; it is sometimes rational to continue a ‘failing’ regimen in order to maintain partial viral suppression discontinuation of HAART should be considered for patients experiencing return to viral baseline and declining CD4 count who do not have rational salvage options

DHS/ HIV/PP HIV: Case History  A 26-year-old man with an HIV RNA level of 106,000 and a CD4 count of 121 cells/mm 3 starts on a regimen of Zidovudine (AZT) plus Lamivudine (3TC) plus Nevirapine and has an initial excellent response (HIV RNA < 50 at months 3, 6, and 9; CD4 count rises to 247). At the 12 month visit, he admits to missing some doses in the past month  What would you do?  Would you change his regimen?

DHS/ HIV/PP HIV: Case History  You re-address his adherence problems  You continue his current regimen but order a viral load and CD4 count.  His 12 month HIV RNA level comes back at 624 copies/mL; CD4 count is essentially unchanged.  What would you do?

HIV Case continued The viral load is repeated 2 weeks later and returns at 822 copies/ml. Would you change his regimen? Would you order a resistance test?

DHS/ARV Rx/PP HIV Case continued Medications Started 50

Antiretroviral Resistance Testing due to HIV’s high transcription error rate and high level of replication, mutant HIV variants constantly generated these variants often contain mutations that confer variable levels of resistance to antiretroviral agents poor adherence or suboptimal regimens can lead to resistance and ‘viral breakthrough’

HIV Case continued Wild-type HIV Resistant HIV Pre-treatment: wild-type On Treatment: resistance Poor Adherence

Antiretroviral Resistance Testing Goal of resistance testing is to identify these resistance-conferring mutations in order to more intelligently design a ‘salvage’ regimen Studies have documented clinical benefit of resistance testing Expert advice on interpretation of the genotype carries a similar and additive benefit as well

Summary of Randomized Controlled Trials of Resistance Testing

Antiretroviral Resistance Testing: Guidelines for Implementation

DHS/ARV Rx/PP Antiretroviral Therapy: Viral Failure Medications Started 50

DHS/ARV Rx/PP Antiretroviral Therapy: Failure to Suppress Medications Started 50

DHS/HIV/Resistance /PP HIV Primary Infection Isolates From: Little SJ. JAMA 1999;282: Little SJ. 8th Conf Retrovirus. Abstract 756 N = 108 Patients Newly HIV-Infected Phenotypic Data: 10-fold Resistance

Resistance Testing: Acute vs. Chronic HIV Infection Wild-type HIV Resistant HIV Acute HIV Chronic HIV No Therapy

Resistance Testing: On (Failing) Therapy vs Off Therapy Wild-type HIV Resistant HIV On Therapy Off Therapy ARV Rx stopped

Resistance Testing: Genotypic Assays  Reports mutations in Reverse Transcriptase & Protease genes  Generally require > 1,000 copies/mL  Turn-around time of approximately two weeks  cost: around $400  several trials have demonstrated clinical benefit

Resistance Testing: Phenotypic Assays  Determine amount of drug required to suppress HIV replication in vitro  intuitively simpler but less clinical experience, less data demonstrating benefit  Generally require > 1,000 copies/mL  turn-around time of approximately four weeks  cost: close to $1,000

Genotyping vs Phenotyping discordance common between the two assays genotypic assays suffer from complexity of interpretation, potentially unknown interactions between various mutations phenotypic assays suffer from lack of consensus on susceptibility cut-offs for most agents, inability to delineate mutation patterns underlying resistance, high cost, and lengthy turn-around time

HIV Resistance Testing Virtual Phenotype Genotype Proteas e RTHIV Access Data Genotype & Phenotype Data Virtual Phenotype Wild-type HIV Resistant HIV

HIV Case continued You obtain a genotype which shows the K103N mutation in the Reverse Transcriptase Gene Would you change the nevirapine in his regimen to efavirenz?

Salvage Regimens & Resistance Testing: Key Points Consider salvage regimens for virologic failure, failure to suppress, immune deterioration, or inadherence/toxicity resistance testing is indicated for virologic failure, failure to suppress, and acute HIV infection expert advice has proven clinical benefit in interpreting resistance tests and designing salvage regimens

Consultation Services for Clinicians Caring for Patients with HIV/AIDS Northwest AETC –(206) pager, (206) VM University of Washington MEDCON –(800) National HIV Telephone Consultation Service (Warmline) –(800) National Clinicians’ Post-Exposure Prophylaxis Hotline (PEPline) –(888) HIV-4911