Doerfler, R Eric, NP, CCH

Woodward, William C, DO

Yozviak, Joseph L, DO, FACP

English

Lehigh Valley Health Network: LVHN Scholarly Works

Lehigh Valley Health NetworkLVHN Scholarly WorksDepartment of MedicineIntermittent Antiretroviral Therapy (ART) CanInduce Reduction of Viral Rebounding DuringART-InterruptionJoseph L. Yozviak DO, FACPLehigh Valley Health Network, joseph.yozviak@lvhn.orgR Eric Doerfler NP, CCHBornemann Internal MedicineWilliam C. Woodward DOBornemann Internal MedicineFollow this and additional works at: http://scholarlyworks.lvhn.org/medicinePart of the Infectious Disease Commons, and the Medical Sciences CommonsThis Presentation is brought to you for free and open access by LVHN Scholarly Works. It has been accepted for inclusion in LVHN Scholarly Works byan authorized administrator. For more information, please contact LibraryServices@lvhn.org.Published In/Presented AtYozviak, J.L., Doerfler, R.E., & Woodward, W.C. (1999, October 23-27). Intermittent antiretroviral therapy (ART) can induce reduction ofviral rebounding during ART-interruption. Presented at: The 7th European Conference on Clinical Aspects and Treatment of HIV-Infection, Lisbon, Portugal.Intermittent Antiretrovral Therapy (ART) Can Induce Reduction of Viral Rebound During ART-Interruption. JL Yozviak1, RE Doerfler2 and WC Woodward2 1Philadelphia College of Osteopathic Medicine, Philadelphia, PA USA 2Bornemann Internal Medicine Reading, PA USA Response to ART Interruption  Patient 27 (JP) - 3 Interruptions <500<400 <4003849 259624541 108 189 267 350 57511010010001000010000010000000 100 200 300 400 500 600 700Time (days)HIV-1 RNA(copies per ml plasma)0100200300400500600700800900CD4 T-Lymphocytes(cells per ml blood)VLCD4        On ART          Off ARTBackground - Why? • Why is this of interest when current therapy has dramatically altered the course of HIV? – Long term complications of ART – Can ART be taken indefinitely • Strategies to deal with ART complications – simplification  – switch – ART interruption (STI, i-ART) • “Structured” implies understanding? Background - Initial Reports • Interruption: Viral load returns to baseline after long term suppression. – Rapid return to baseline (Jubault, AIDS 98 & Staszewski, AIDS 98) – Intermittent ART lead to increased time to rebound (n=3) (Lori, 6th CROI) – COMET: Rapid return to baseline but no deleterious effect after re-initiation (n=10)  (Neumann, AIDS 99) – Increase of ~0.2 log10 in total viral burden/day (n=6) (Harrigan, AIDS 99) Background - Recent Studies • Prospective study (n=8) all returned to baseline (doubling time = 2.01 days) and all re-suppressed. No viral drug resistance. (Garcia, AIDS 99) • Some patients remain suppressed or, after initial rebound, decline toward level of  quantification. – “Berlin patient” (Lisziewicz NEJM 99) – Long term suppression in PHI (n=4) doubling time ~ 1.6 days. 3/4 peaked at 4.32 log10 and declined to 3.53 log10 (Markowitz, ICAAC 99, LB16) – NoHRT study 12/18 received IL-2. 1/18 has VL 50 - 500. (Davey, ICAAC 99, I-689) Background - Immunology • Protective cellular immunity returns after ART – Discontinuation of PCP Prevention (Lopez, ICAAC 99 LB24) • HIV antibody response • CD8 cytotoxic response (CTL) • HIV-specific CD4 response strong in long term non-progressors – may be present in many patients but significantly decreases after PHI. Wanes with ART (Pitcher, Nat Med 99) – Is there sufficient antigen present in patients with viral load BLQ and restored immune system? Working Hypothesis Patients with long-term viral suppression and a significant increase in CD4 T-cells, should have an increase in naïve CD4 T-cells. Naïve CD4 cells should be able to “respond” to HIV antigen during initial interruption. Subsequent ART interruption may result in a reduction of rebound viral load (reduced set point) due to immunologic control of HIV. Idealized Patient Response to ART Interruption < 50720610550430370240210011010010001000010000010000000 100 200 300 400 500 600 700 800Time (days)HIV-1 RNA(copies per ml plasma)050100150200250300350400450500CD4 T-Lymphocytes(cells per ml blood)VLCD4        On ART          Off ART Methods • A retrospective analysis of 268 patient charts (N ~ 500) to identify patients who interrupted ART. • 123 (45.9%) interrupted ART at least once. 36 had baseline and follow-up data. – 23 had data for an initial interruption.  – 18 had data for a subsequent interruption. – 5 had data for initial and subsequent interruptions (overlap) Methods • Charts examined for: – Composition and duration of ART regimen. – Duration viral load was BLQ (< 50 mid-1997.) – Change in CD4 levels on ART. – Reason(s) for interruption. – Duration of interruption. – Change in viral load. ART Interruption - Why? • Common event in clinical practice • Why do patients interrupt ART? – Rule One, All or None! • Reasons for interruption: – Side Effects – Ran Out of Meds – Active Drug Use – No Insurance – Viral Resistance – Non-adherence – Prison – Depression/Anxiety – Difficulty Eating – Leaving U.S.A. – RTV Oral Solution – Patient Choice Return to Baseline After First Interruption VL* – n = 23‡ – Mean = +0.059 log10 – Median = +0.028 log10 – Standard Deviation = 0.35 log10  VL at longest duration of interruption used for each patient ‡ Patients #81 and #104 were not included in calculations due to unquantified results (> upper limit of test).   Effect of Duration of First Interruption on VL Slope = 1.64 x 10-4 Standard Error of Linear Regression = 0.480 log10 copies Before Subsequent ART Interruptions (14/18) Pt. # Interruption#ART Duration ofARTDuration BLD Reason forInterruption70 2 AZT/3TC/NFV 264 132 (<25) + 92(<400)Depression79 3 D4T/3TC/NVP 84 0 Viral Failure27 4 AZT/3TC/NFV/SQV 91 40 (<500) N/V12 2 D4T/3TC/NVP 486 266 (<400) +192(<50)Drug Use30* 4 NFV/SQV 5 0 Pt. Choice23 2 D4T/3TC/RTV/SQV 278 255 (<200) Not ToleratingRTV Solution67* 2 AZT/3TC/RTV/SQV 8 0 Ran Out69 3 D4T/3TC/RTV/SQV 23 0 AbdominalEnlargementInterruption resulting in largest VL is shown.Slide 1 of 2 Before Subsequent ART Interruptions (14/18) Pt. # Interruption#ART Duration ofARTDuration BLD Reason forInterruption77 2 D4T/3TC/NVP 43 >1 (<400) Fatigue15 3 DDI/3TC/NVP 231 126 (<50) Left USA14 3 D4T/3TC/NFV 273 89 (<400) Oral Cancer54 4 D4T/3TC/RTV/SQV 76 14 (<400) ?25 2 DDI/3TC/NVP 225 69 (<400) +73 (<50)Fatigue &Headaches24 2 AZT/3TC/NVP 348 99 (<400) +217 (<50)NoncomplianceSlide 2 of 2 Return to Baseline After Subsequent Interruptions: Responders (10/18) Pt # Inter # Duration CD4 VL108 3 39 +273 -1.3970 2 153 +245 -1.2179 3 25 +219 -1.1027 3 86 +333 -1.0912 2 109 +199 -1.0630 4 70 +92 -1.06107 6 21 +194 -1.0323 2 57 +314 -0.9367 2 21 +80 -0.86112 2 112 +151 -0.72Return to Baseline After Subsequent Interruptions: Non-Responders (8/18) Pt # Inter # Duration CD4 VL69 3 49 0 -0.61113 2 73 0 -0.5477 2 69 +136 -0.4615 3 92 +72 -0.3414 3 86 +46 -0.3354 4 106 +10 -0.2225 2 77 +5 0.0024 2 71 +27 +0.58• Slope = -3.26 x 10-3 • Standard Error of Linear Regression = 0.659 log10 copies Effect of CD4 on VL for Subsequent Interruptions Effect of CD4 on VL for Subsequent Interruptions Summary: Subsequent Interruptions (n=18) • Virologic Response (At longest duration of interruption.) – 10/18 (56%) “reset” set point > 0.70 log10 below baseline viral load for 21 - 153 days. 4/10 reset > 1.0 log10 for > 70 days. (6/10 on PI • CD4 Response (prior to interruption) – Responders (10/18): average CD4 cell increase = 210 (95% CI: 149, 271) – Non-Responders (8/18): average CD4 increase = 37 (95% CI: -2, 76) – absolute CD4 does not appear to correlate • 6/10 responders on PI, 3/8 non-responders on PI   Response to ART Interruption Patient 79 (DJ) - 4 Interruptions <50<400<50 <50 <50<5023 days off ART25 days off**99646043535131034 147 1531101001000100001000000 200 400 600 800 1000Time (days)HIV-1 RNA(copies per ml plasma)01002003004005006007008009001000CD4 T-Lymphocytes (cells per ml blood)VLCD4On ART          Off ARTNote: DJ <5000 @ 3 months during 4th interruption   Response to ART Interruption Patient 108 (LG) - 3 Interruptions 504005040053744116715314023 1101101001000100001000000 100 200 300 400 500 600Time (days)HIV-1 RNA(copies per ml plasma)020040060080010001200CD4 T-Lymphocytes (cells per ml blood)VLCD4On ART          Off ARTNote: LG <5000 @ 3 months during 4th interruption Reduction of Viral Set Point - Why?  • With the return of HIV-naïve T-cells, the first interruption may result in HIV “vaccination.”  • If ART restarted before these cells are lost, HIV-specific responses should be retained. • A second ART interruption may stimulate HIV-specific proliferative responses with reduction in  viral rebound (reduced set point). • By preventing depletion of HIV-specific CD4 T-cells during interruption, successive interruptions may result in further set point reduction. Alternative Explanations • Type I error - this is a small retrospective analysis with limited data points. • Original virus replaced with a less fit virus. • Original set point not accurately determined. • Laboratory variation and error • Further analysis of the entire cohort is planned Conclusions - Questions • Randomized, controlled trials are required to answer the following questions: – How is balance maintained between activated HIV-specific CD4 cells (target) and virus? – What is the optimal duration of ART interruption? – OR, What is the optimal VL rebound?  (BOTH?) – Is the response different between PI and NNRTI? – What are the predictive immunologic parameters? – Will this be an “insurance policy” for occasional non-adherence? Acknowledgments • Charles Farthing • Bornemann Internal Medicine – Juanita Goodwin – Eric Doerfler – Jody Yozviak – Christine Morrison – Judy Lash • Saint Joseph Medical Center (Reading, PA) – Chris Rumpf – Lee Meyers – Sr. Bridget McNamara • Joyce Woll (Agouron)  • Patients 

Intermittent Antiretroviral Therapy (ART) Can Induce Reduction of Viral Rebounding During ART-Interruption

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Intermittent Antiretroviral Therapy (ART) Can Induce Reduction of Viral Rebounding During ART-Interruption

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