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Structured Treatment Interruptions: Approaches to Training

Structured Treatment Interruptions: Approaches to Training. Chris Behrens, Amy Kindrick, And Trudy Larson Asilomar Faculty Development Conference April 11, 2001. For Copies of STI Presentation . Avk@itsa.ucsf.edu Behrens@u.washington.edu Tal@med.unr.edu.

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Structured Treatment Interruptions: Approaches to Training

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  1. Structured Treatment Interruptions: Approaches to Training Chris Behrens, Amy Kindrick, And Trudy Larson Asilomar Faculty Development Conference April 11, 2001

  2. For Copies of STI Presentation • Avk@itsa.ucsf.edu • Behrens@u.washington.edu • Tal@med.unr.edu

  3. Structured Treatment Interruptions: Key Points • Still experimental • Don’t try this at home! • Rapidly evolving field • Stay tuned for the next episode!

  4. A Sample Presentation…. Structured Treatment Interruptions: Theory & Controversy

  5. Estimated Incidence of AIDS and Deaths of Adults/Adolescents with AIDS*, 1985-1999, United States 25,000 1993 definition AIDS implementation Deaths 20,000 15,000 Number of Cases/Deaths 10,000 5,000 0 1987 1985 1986 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 Quarter-Year of Diagnosis/Death *Adjusted for reporting delays

  6. AIDS Cases by Exposure Category and Year of Report, 1985-1997, United States 80 70 Men who have sex with men (MSM) 60 50 40 Percent of Cases Injecting drug use (IDU) 30 Heterosexual contact 20 MSM & IDU 10 0 1985 1987 1989 1991 1993 1995 1997 Year of Report 11 Cases with other or unreported risk excluded pending medical record review and reclassification.

  7. AIDS Incidence* for Women and Percentage of AIDS Cases, January 1986 - June 1999, United States 8,000 30 25 6,000 20 Percent of Cases Number of Cases 4,000 15 10 2,000 5 0 0 1990 1993 1986 1987 1988 1989 1991 1992 1994 1995 1996 1997 1998 1999 Half-Year of Diagnosis* *Adjusted for reporting delay

  8. Dianna and her Sons, 1995

  9. Why Does HAART Fail?

  10. Alternatives To HAART • More HAART • More potency • Better tolerability • New targets • Immune-based strategies

  11. STI Rationale • Enhance HIV-specific immune response • In primary infection • In chronic infection • Reduce treatment-associated complications • Toxicity • Cost • Treatment fatigue

  12. Case 1: STI in Primary HIV Infection Richard is a 43 year old white gay male with a PhD in mathematics. He was diagnosed with primary HIV infection two years ago and immediately began treatment with Combivir and nelfinavir. He is extraordinarily compliant and has had an undetectable viral load since starting therapy. He reads “all the time” and has made an appointment with you to discuss interrupting his medications.

  13. You Decide To: • Tell him that since he is doing so well he shouldn’t stop therapy now; “the first treatment is the best treatment” • Discuss with him the fact that you don’t really know his “set point”; maybe he should stop so you can find out • Ask him why he wants to interrupt his medications; did he hear something about STIs or STDs or something?

  14. Structured Treatment Interruptions in Primary HIV Infection (PHI) • Prevention of early immune system damage with HAART, esp. the HIV-specific CD4 cells • Allow for periodic ‘priming’ of immune system by allowing HIV to replicate in a controlled manner • Goal is improved immunologic control over HIV, to reduce rate of clinical progression and/or obviate the need for HAART

  15. The Berlin Patient • Treated soon after acute HIV infection with HU, ddI, IDV • baseline VL 80,000 - 89,000 pre-treatment • treatment interrupted briefly twice in first four months of treatment: viral rebound during first interruption but not the second • VL remained undetectable after third time treatment stopped Lisziewicz J et al. NEJM 1999; 340: 1683-1684.

  16. The Berlin Patient Lisziewicz J et al. NEJM 1999; 340: 1683-1684.

  17. CD4 Cells, CD8 Cells, and CTLs: a Brief Review • CD4 cells: • “Command & control” the cell-mediated immune response by directing the action of various other immune cells, including Cytotoxic T Lymphocytes (CTLs) • CTLs: • Predominantly CD8 cells • Kill infected cells of various types, including infected CD4 cells

  18. HIV Immunity: HIV-specific CTL CD4 Cells Mature CD8 CTL Cell Picture DHS/HIV/Pathogenesis/PP

  19. HIV Immunity: HIV-specific CTL CD4 Cells Mature CD8 CTL Cell Picture DHS/HIV/Pathogenesis/PP

  20. HIV Immunity: HIV-specific CTL CD4 Cell HIV HIV-Infected CD4 Activated CD4 Cell Lymphokines Antigen-Presenting Cells Mature CD8 CTL Picture CD8 Cell Activated CD8 Pre CTL HIV Adapted from: Walker B. IDSA. 1998 DHS/HIV/Pathogenesis/PP

  21. Loss of HIV Specific CTL Activated CD4 Cell CD4 Cell APC HIV HIV Picture DHS/HIV/Pathogenesis/PP

  22. Loss of HIV-specific CTL CD4 Cell HIV HIV-Infected CD4 Activated CD4 Cell Lymphokines Antigen-Presenting Cells Picture Mature CD8 CTL CD8 Cell Activated CD8 Pre CTL HIV Adapted from: Walker B. IDSA. 1998 DHS/HIV/Pathogenesis/PP

  23. Evidence That This Is More Than a Just a Pretty Cartoon • Lack of HIV-specific CD4 cells in most patients with untreated HIV infection • Immune system is capable of controlling HIV in certain situations • Strong CTL response seen in long-term non-progressors • Higher CD8 counts associated w/ lower viral set point in animal models

  24. How to Preserve HIV-specific CTL? CD4 Cell HIV HIV-Infected CD4 Activated CD4 Cell Lymphokines Antigen-Presenting Cells Mature CD8 CTL Picture CD8 Cell Activated CD8 Pre CTL HIV Adapted from: Walker B. IDSA. 1998 DHS/HIV/Pathogenesis/PP

  25. Structured Treatment Interruptions

  26. But Does It Work?

  27. STIs During PHI: Evidence of Immunologic Recovery • 18 patients with recent HIV infection identified and treated with HAART • Strong HIV-specific CD4 responses seen in the 15 patients who achieved complete viral control • These responses maintained at levels similar to those seen in long-term non-progressors Rosenberg ES, et al. Nature 2000; 407:523-6.

  28. STIs During PHI: Evidence of Immunologic Recovery Rosenberg ES, et al. Nature 2000; 407:523-6.

  29. STIs During PHI: Corroborating Evidence From Animal Model • STIs with HAART (3 weeks on/3 weeks off) compared to HAART in macaques acutely infected with SIV and with chronic infection • In acutely infected macaques, viral rebound rate decreased significantly during subsequent treatment interruptions • Virologic control in these animals associated with vigorous SIV-specific CD8-mediated immunity Lori F et al. 40th ICAAC, September 2000, abstract L-17.

  30. STIs During PHI: Evidence of Improved Virologic Control • Ongoing trial at Massachusetts General Hospital • STIs administered to 14 patients to date • All patients initiated HAART during PHI, prior to seroconversion, and had full viral suppression for at least 8 months • All ARVs are discontinued simultaneously • Therapy re-instituted if VL persistently (> 3 weeks) over 5,000 or if VL at any time over 50,000 Walker B. State of the Art Lecture and Summary. 8th Conference on Retroviruses and Opportunistic Infections, Session #37.

  31. STIs During PHI: Evidence of Improved Virologic Control • 7/14 patients remain off therapy with VL less than 500 copies/mL • 4 patients gained virologic control after just one treatment cessation • 2 gained control after two STIs, 1 after 3 STIs • 6 patients still undergoing STIs • Only one failure by study’s criteria: VL 7,500 after four STIs • Increased HIV-specific CTLs seen in all patients Walker B. State of the Art Lecture and Summary. 8th Conference on Retroviruses and Opportunistic Infections, Session #37.

  32. Case 2: STI After Successful HAART Fred is a 36 year old casino worker with very long and variable hours of work. He was infected 6 years ago and has been on a stable, successful regimen BID for the last 18 months. He had problems with explosive diarrhea in the past which resulted in treatment failure and he has just had a recurrence. He comes in discouraged wanting to stop his medications right now. He reasons, “since I feel so good, maybe my virus is gone and I can be off medications”.

  33. You Decide To: • Plead with him to stay on his medications and treat his side effects because the regimen is effective and not his first one. • Be sympathetic and tell him to go ahead and stop; you’ll work with him. • Counsel him about the effects of an UTI

  34. Rationale For STIs In Chronic HIV Infection • When HAART is successful • Preserve (or regain) HIV-specific immune response • Minimize treatment complications • When HAART is not successful • Minimize treatment complications • Enhance response to subsequent salvage regimens

  35. STIs in Chronic Infection With Successful Viral Suppression • Swiss-Spanish Intermittant Treatment Trial (SSITT)* • 128 patients (31% women) • HIV RNA<50 for >6 months (median 22 mos.) • On first HAART regimen (median 26 mos.) • 77% 2 NRTIs + 1 PI • NNRTI naïve • Median baseline CD4 740 cells/μL • Median baseline HIV RNA 31,622 c/ml *Fagard, et al., 8th CROI, 2001, Abstract 357

  36. SSITT Study Design % VL<5,000 Stable HAART HAART HAART HAART HAART 2 10 12 20 22 30 32 40 52 Study Entry WEEKS

  37. SSITT Interim Results (N=99) • During 2 week STIs • 11% had no viral rebound > 100 c/ml • 4% had CD4 < 400 during 4th STI • During 8 week treatment periods • 5-8% (during each period) did not resuppress to < 50 c/ml • At 52 weeks • 21% were “responders” (HIV RNA < 5,000 c/ml) • But 24% of these had pre-Rx set point < 5k

  38. SSITT: Who Was Likely to Respond? • Low pre-treatment VL “set point” • 32/32 with VL > 60,000 were non-responders • No viral rebound during first STI • But 58% without rebound were non-responders and • 13% with rebound were responders • No viral rebound during all 4 STIs

  39. SSITT: Conclusions • 1 in 5 patients were responders • Pre-treatment VL > 60,000 precluded response • HIV-specific CTL function increased during 4 cycles of interruption and re-treatment • Correlation between CTL function and response remains to be determined

  40. Case 3 Joy is a 22 year old female infected when she was 16 and living on the streets. She has had a very difficult life and has been in and out HIV treatment settings. She has taken most treatment regimens and has just had viral breakthrough on a quadruple drug salvage regimen. She has had no hospitalizations and her CD4 count is 300.

  41. You Decide To: • A. Do resistance testing and try DOT • B. Stop therapy and wait for better and newer options to emerge while continuing follow up • C. Discuss clinical trials at a distant site • D. Give in to her requests and try STIs • E. Keep her on therapy and wait for better options to emerge and continue follow up

  42. STIs In Chronic Infection With Failed Viral Suppression • Frankfurt HIV Cohort* • 165 patients off HAART > 2 months • Median CD4 ~ 150 cells/mm3 • HIV RNA ~ 120,000 c/ml • PI history • 100% > 1 • 30% > 4 *Miller, et al. Antiviral Tx 1999

  43. Frankfurt STI Cohort • Virologic impact • 104/165 (63%) suppressed when HAART resumed • 90/104 (86%) of initially suppressed subsequently rebounded • Immunologic impact • 25% failed to regain lost CD4 cells 3 months after HAART resumed

  44. Frankfurt STI Cohort • Clinical impact • 15 patients had 17 AIDS-defining events • Esophageal candidiasis 3 • Pulmonary TB 3 • Encephalopathy 2 • Kaposi’s Sarcoma 2 • Wasting 2 • CMV disease 2 • Disseminated HSV 1 • Extra-pulmonary TB 1 • Cryptosporidiosis 1

  45. STIs and Viral Resistance • Subset of Frankfurt cohort with pre- and post-STI resistance testing • 33/55 (60%) suppressed after STI • 24/33 (73%) of responders rebounded (median 78 days) • 35/55 (64%) had shift to wild type in all ARV classes

  46. Shift To Wild Type • Virologic impact • No significant difference in rebound rate (75% in WT vs. 100% in resistant group) • Immunologic impact • No significant difference in CD4 recovery • Average time to CD4 recovery 251 days in both groups

  47. Viral “Fitness” • Better to stay on HAART even without complete suppression

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