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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 Clinical Category CD4 count Viral Load Recommendation Symptomatic (AIDS, severe Sx) Any value Any value Treat Asymptomatic, AIDS < 200/mm3 Any value Treat Asymptomatic > 200/mm3 Any value but < 350 Treatment should generally be offered Asymptomatic > 350/mm3 >30,000 bDNA or >55,000 PCR 3 > 350/mm <30,000 bDNA or <55,000 PCR Some experts would recommend initiating treatment Many experts would defer therapy and observe Asymptomatic 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 Clinical Category CD4 count Viral Load Recommendation Symptomatic (AIDS, severe Sx) Any value Any value Treat Asymptomatic, AIDS < 200/mm3 Any value Treat Asymptomatic > 200/mm3 Any value but < 350 Treatment should generally be offered Asymptomatic > 350/mm3 >30,000 bDNA or >55,000 PCR 3 > 350/mm <30,000 bDNA or <55,000 PCR Some experts would recommend initiating treatment Many experts would defer therapy and observe Asymptomatic 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 proportion surviving 1.0 0.5 CD4 Count when Initiate HAART < 50 51 - 200 201 - 350 > 350 0.0 0 1 2 3 4 5 Survival in Years Chen RY et al, 8th CROI, Chicago 2001 Cumulative Mortality by Baseline CD4 Count ==================== N = 1219 therapynaïve individuals initiating HAART in British Columbia 1996 - 1999 CD4 > 200 Probability of Survival (%) Baseline CD4 Count and Survival after Initiation of HAART CD4 50-199 CD4 < 50 Time From Start of HAART (months) JAMA. 2001;286:2568-2577 CBB/2002 Indications for Initiation of Antiretroviral Therapy for HIV Clinical Category CD4 count Viral Load Recommendation Symptomatic (AIDS, severe Sx) Any value Any value Treat Asymptomatic, AIDS < 200/mm3 Any value Treat Asymptomatic > 200/mm3 Any value but < 350 Treatment should generally be offered Asymptomatic > 350/mm3 >30,000 bDNA or >55,000 PCR 3 > 350/mm <30,000 bDNA or <55,000 PCR Some experts would recommend initiating treatment Many experts would defer therapy and observe Asymptomatic DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, February 5, 2001, Table 6. CBB/2002 =================== N = 1219 therapynaïve individuals initiating HAART in British Columbia 1996 - 1999 Probability of Survival (%) Survival after Initiation of HAART by Baseline CD4 Count and Viral Load JAMA. 2001;286:2568-2577 Time from initation of HAART (mos) 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 Virologic Control falls sharply with diminished adherence Patients with HIV RNA <400 copies/mL, % 100 80 60 40 20 0 >95 90-95 80–90 70-80 <70 PI adherence, % (electronic bottle caps) Paterson, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago, IL. Abstract 92. CBB/2002 Adherence and AIDS-Free Survival 10% Adherence difference = 21% reduction in risk of AIDS Proportion AIDS-Free 1.00 0.75 0.50 0.25 P = .0012 0.00 0 5 10 15 20 Months from entry Bangsberg D, et al. AIDS. 2001:15:1181 25 30 Adherence O 90–100% O 50–89% O 0–49% Reasons for Non-Adherence: Clinician vs Patient Views 60 Clinican Patient value, % 50 40 30 20 10 0 No. of doses or pills Side Effects Meal Instructions Schedule complexity Other Chesney M. Adherence to antiretroviral therapy. 12th World AIDS Conference, 1998; Geneva. Lecture 281 CBB/2002 Predictors of Poor Adherence • • • • • • active alcohol1 or substance2 abuse work outside the home for pay1 depressed mood1 lack of perceived efficacy of HAART3 lack of advanced disease4 concern over side effects4 1. Chesney MA. 37th ICAAC, 1997; Toronto. Abstract 281. 2. Cheever LW, Curr Infect Dis Rep 1999 Oct;1(4):401-407. CBB/2002 3. Horne R, et al. 39th ICAAC, 1999; San Francisco. Abstract 588. 4. Wenger N, et al. 6th Conference on Retroviruses and Opportunistic Infections, 1999; Chicago. Abstract 98. Predictors of Poor Adherence, continued • inability to fit medications into daily schedule • tid dosing, food requirements1 1. Stone VE, et al. JAIDS 2001; 28:124-131 CBB/2002 Factors Associated with Higher Levels of Adherence • • • • • twice-daily or once-daily regimens1,4 belief in own ability to adhere to regimen1 not living alone2 dependent on a significant other for support2 history of Opportunistic Infection or Advanced HIV disease3 1. Eldred L, et al, J Acquir Immune Defic Syndr Hum Retrovirol 1998;18:117-125. 2. Morse EV et al, Soc Sci Med 1991;32:1161-1167. 3. Singh N, et al, AIDS Care 1996;8:261-269. 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 alarms1 • education & counseling sessions2,3 • Directly Observed Therapy (DOT)4,5 1. Samet JH, et al. Am J Med. 1992;92:495-502. 2. Malow RW, et al. Alcohol Drug Abuse 1998;49:1021-4. 3. Tuldra A, et al. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999; Abstract 595. 4. Sorensen JL, et al. AIDS Care. 1998;10:297-312. 5. Wall TL, et al. Drug Alcohol Depend. 1995;37:261-269. Self-Adminstered vs Directly Observed Therapy During Incarceration % with VL < 50 copies/mL N = 50 in each group 100 90 80 70 60 50 40 30 20 10 0 DOT <50 SAT <50 w4 w8 w16 w24 w48 w64 w72 w80 w88 p < 0.01 Fischl et al 8th CROI, 2001 abstract 528 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 adherencelimiting co-morbid conditions Adapted from: Miller et al., The AIDS Reader 10(3):177-185, 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):177-185, 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 comorbid 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 Classes of Antiretroviral Agents HIV Nucleoside Analogues RT RNA DNA Nucleus Host Cell Non-Nucleosides Adapted from: Walker B. IDSA 1998 Protease Inhibitors 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 Cmax Cmax Cmin IC90 Area of Potential HIV Replication IC50 Dosing Interval Cmin Time Dose Dose An Example of Ritonavir Boosting: Indinavir/Ritonavir BID PK Study 10,000 IDV/RTV q12h: 800/200 High-fat Meal Indinavir Plasma Concentration (nM) 800/100 High-fat Meal 1,000 400/400 High-fat Meal IDV q8h: 800 mg Fasted 100 0 2 4 6 8 Time Postdose (hours) 10 12 6th Conference on Retroviruses and Opportunistic Infections; 1999. 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 + 1-2 PIs) • NNRTI - based regimens (2 NRTIs + 1 NNRTI) • NRTI - based regimens (3 NRTIs) Protease Inhibitor -based regimens Advantages 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 Disadvantages Short-term side effects (esp. gastrointestinal) Long-term metabolic/morphologic side effects Inconvenience & adherence (schedule, pill burden, food requirements) Drug-drug interactions NNRTI - based regimens Advantages • Simpler regimens • Fewer long-term toxicities • Potent at high viral loads/low CD4+ cell counts (efavirenz) • Allow deferral of PIs • Fewer drug-drug interactions Disadvantages • 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 crossresistance • toxicities: CNS, hyperlipidemia (efavirenz); rash (all); hepatotoxicity (NVP > EFV) NRTI - based regimens (AZT + 3TC + Abacavir) Advantages Disadvantages • Allows deferral of PIs and NNRTIs • Limited data, no clinical endpoint data • Simple, low pill burden • Well tolerated • Relative potency and durability not established • minimal long-term toxicity • Efficacy at high viral loads questionable • virtually no drug interactions • Abacavir hypersensitivity Recommended Antiretroviral Combinations for Initial Therapy Choose one from Column A and one from Column B Column A Efavirenz Indinavir Nelfinavir Ritonavir + indinavir Ritonavir + lopinavir Ritonavir + saquinavir Column B Stavudine + lamivudine Stavudine + didanosine Zidovudine + lamivudine Zidoviduine + didanosine Didanosine + lamivudine 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 Efavirenz: Study 006 Undetectable VL< 50atcopies/ml 48 Weeks 48 Week Data: HIV RNA Patients (N=450) - CD4 > 50 cells/mm3 - HIV RNA > 10,000 copies/ml - Naive to PI, non-nucleoside, and 3TC 100 80 Patients % Regimens - AZT + 3TC + IDV - EFV + IDV - AZT + 3TC + EFV AZT + 3TC + EFV AZT/3TC/EFV AZT + 3TC + IDV AZT/3TC/IDV EFV + IDV EFV/IDV 90% 90 79% 75% 64 64% 60 43% 47% 40 20 0 On Treatment From: Staszewski S. N Engl J Med 1999;341:1865-73. ITT (NC=F) DHS/ARV Rx /PP 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. AIDS 2001 December 7;15(18):2385-2395 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) • Regimens – AZT + 3TC + Abacavir – AZT + 3TC + Indinavir Staszewski, S. JAMA 2001;285:1155-63. % of patients with VL < 50 – therapy-naïve adults – HIV VL > 10,000 – CD4 > 100 48 week data: HIV VL < 50 100 90 80 70 60 50 40 30 20 10 0 AZT/3TC/ABC 82 AZT/3TC/IDV 69 VL > 100,000 40 46 45 31 As Rx ITT ITT 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! From: Hetherington S, et al. 12th World AIDS Conference, Geneva, 1998: Abstract 12353 DHS/ARV Rx/PP 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? Antiretroviral Therapy: Optimal Response 1000000 HIV RNA 100000 Medications Started 10000 1000 100 50 50 10 0 1 2 3 4 5 6 7 Months DHS/ARV Rx/PP 8 Several trials indicate the need to achieve better viral suppression, i.e. < 50 cps/ml Proportion of subjects with sustained virologic success* (%) INCAS (AZT/ddI/NVP) AVANTI-2 (AZT/3TC/IDV) 100 80 60 40 20 0 0 8 16 24 32 40 AVANTI-3 (AZT/3TC/NFV) 100 48 0 Viral load Nadir 20 copies/ml 21–400 copies/ml >400 copies/ml 8 16 26 32 40 48 40 48 All trials combined 80 60 40 20 0 0 8 16 24 32 40 Weeks *HIV-1 RNA <1000 copies/ml Montaner J. 12th World AIDS Conference Geneva 1998 48 0 8 16 24 32 Weeks 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”) 100000 Medications Started HIV RNA 10000 1000 100 50 10 50 Case continued • At her next blood draw, her viral load is 100 copies/mL • what do you do? 100000 Medications Started HIV RNA 10000 1000 100 50 10 50 Antiretroviral Therapy: Intermittent Viremia (“blips”) 100000 Medications Started HIV RNA 10000 1000 100 50 10 50 Predictive Value of Intermittent Viremia • Methods • Follow-up at 6 months – 96 (40%) of 241 had “blips” – 145 (60%) had no “blips” * AZT + 3TC + Indinavir (ACTG 343) Virologic Failure 50 Virologic Failure (%) – 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 40 Viral Blip No Viral Blip 30 20 10 0 10 14 Antiretroviral Therapy: Low-level Viremia 100000 Medications Started HIV RNA 10000 1000 100 50 10 50 Predictive Value of Low-Level Viremia Virologic Failure – N=1858 adults on HAART – HIV VL <50 copies/mL x 2 at outset – low level rebound: VL = 51-500 – blip: rebound followed by VL < 50 – virologic failure: VL > 500 x 2 • Follow-up at 6 months – 604 (33%) with low-level rebound Virologic Failure (per 100 person-years) • Methods 50 45 40 35 30 25 20 15 10 5 0 Sustained low level rebound Single viral blip No viral blip Greubl G et al. 8th CROI, 2001: Abstract 522 22 8 5 Salvage Antiretroviral Therapy Guiding Principles, Strategies and the Role of Resistance Testing HIV: Case History A 26-year-old man with an HIV RNA level of 106,000 and a CD4 count of 121 cells/mm3 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? DHS/ HIV/PP 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 Antiretroviral Therapy: Viral Failure 100000 Medications Started HIV RNA 10000 1000 100 50 50 10 DHS/ARV Rx/PP Antiretroviral Therapy: Failure to Suppress 100000 Medications Started HIV RNA 10000 1000 100 50 50 10 DHS/ARV Rx/PP 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 HIV: Case History A 26-year-old man with an HIV RNA level of 106,000 and a CD4 count of 121 cells/mm3 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? DHS/ HIV/PP 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? HIV Case continued 100000 Medications Started HIV RNA 10000 1000 100 50 50 10 DHS/ARV Rx/PP 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 Pre-treatment: wild-type On Treatment: resistance Poor Adherence Wild-type HIV Resistant HIV 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 Study N Primary endpoint Study Arms VIRADAPT 108 24 weeks GART 153 4-8 weeks Havana 274 24 weeks Genotype + expert advice vs SOC (no expert advice) Genotype + expert advice vs SOC (no expert advice) Genotype +/- expert advice vs SOC (+/- expert advice) Expert advice +/- genotype vs SOC (no expert advice) +/genotype Genotype + expert advice vs SOC (no expert advice) Phenotype (no expert advice) vs SOC (no expert advice) Genotype (no expert advice) vs phenotype plus expert advice vs SOC (no expert advice) ARGENTA 174 6 months VIRA3001 274 16 weeks NARVAL 541 12 weeks Change in viral load (log10) % with undetectable VL -1.15 vs –0.67 (p=0.05) 32% vs 14% <200 copies/mL (p=0.67) N/A -1.19 vs –0.61 (p < 0.001) -1.1 vs –0.8 (p=0.02) -1.0 vs –0.9 (p=0.03) N/A -1.23 vs -0.87 (P = .004) N/A 58% vs 42% <400 copies/mL (p=0.01) 59.1% vs 41.1% <400 copies/mL (P = .003) 21% vs 17% <500 copies/mL (p=NS) 45% vs 34% <400 copies/mL (P = 0.099) 41% vs 33% vs 34% <200 copies/mL (P =0.249) Antiretroviral Resistance Testing: Guidelines for Implementation Clinical Setting/Recommendation Recommended Virologic failure during HAART Rationale Determine the role of resistance in drug failure and maximize number of active drugs in a new regimen if indicated Suboptimal suppression of viral load after Determine the role of resistance and maximize initiation of HAART number of active drugs in new regimen Consider Acute (Primary) HIV Infection Determine if drug resistant virus was transmitted and design initial regimen accordingly Not Generally Recommended Chronic HIV infection prior to initiation of HAART Current assays unlikely to detect minor drug resistant quasispecies After discontinuation of drugs Resistant quasispecies tend to become minor species in the absence of selective drug pressure, making detection by current assays unlikely Plasma viral load < 1000 copies/mL Current assays unreliable at low viral loads Antiretroviral Therapy: Viral Failure 100000 Medications Started HIV RNA 10000 1000 100 50 50 10 DHS/ARV Rx/PP Antiretroviral Therapy: Failure to Suppress 100000 Medications Started HIV RNA 10000 1000 100 50 50 10 DHS/ARV Rx/PP HIV Primary Infection Isolates N = 108 Patients Newly HIV-Infected 10 Phenotypic Data: 10-fold Resistance Resistant Isolates % 8 1996-1998 1999-2000 7 6 6 4 2 3 2 2 1 0 NRTI NNRTI From: Little SJ. JAMA 1999;282:1142-9. Little SJ. 8th Conf Retrovirus. Abstract 756 PI DHS/HIV/Resistance /PP Resistance Testing: Acute vs. Chronic HIV Infection Chronic HIV Acute HIV No Therapy Wild-type HIV Resistant HIV Resistance Testing: On (Failing) Therapy vs Off Therapy Off Therapy On Therapy ARV Rx stopped Wild-type HIV Resistant HIV 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 HIV Access Data RT Proteas e Virtual Phenotype Wild-type HIV Resistant HIV Genotype & Phenotype Data 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) 994-8773 pager, (206) 731-1058 VM • University of Washington MEDCON – (800) 326-5300 • National HIV Telephone Consultation Service (Warmline) – (800) 933-3413 • National Clinicians’ Post-Exposure Prophylaxis Hotline (PEPline) – (888) HIV-4911