Delaying HIV-1 Disease Progression in Pre-HAART Positives Treating Endemic Co-infections Judd L. Walson, MD, MPH Universit...
Today’s Talk <ul><li>Hypothesis testing in resource limited settings </li></ul><ul><li>Pre-HAART Positives - explaining th...
The office
Global Burden of Disease <ul><li>www.bvgh.org/GlobalHealthChallenge.asp </li></ul>
Copyright ©2002 BMJ Publishing Group Ltd. Isaakidis, P. et al. BMJ 2002;324:702 No of clinical trials in Sub-Saharan Africa
Copyright ©2002 BMJ Publishing Group Ltd. Isaakidis, P. et al. BMJ 2002;324:702 Burden of Disease and Number of Trials
 
Evidence Based Medicine for Resource Limited Settings
 
Pre-HAART Positives - explaining the focus <ul><li>Of the 22.5 million individuals infected with HIV-1 in Africa, only 31%...
Pre-HAART Package of Care <ul><li>PROVEN </li></ul><ul><ul><li>Septrin </li></ul></ul><ul><ul><li>TB prophylaxis </li></ul...
 
0.3 log 10  increase 0.5 log 10  increase 1.0 log 10  increase Increase in likelihood of heterosexual transmission 20% 40%...
Effect of modest VL reduction Gupta et al. JID 2007; 195 (Feb 15).
“ In most parts of the world there are two types of people, those that know they have worms,…and those that don’t”
Worms – Why NOT?
Epidemiology <ul><li>Over  2 billion  people are estimated to be infected with at least one species of helminths. </li></u...
 
 
 
Distribution of helminths and HIV-1 in Africa Clinical Microbiology Reviews, October 2004, p. 1012-1030, Vol. 17, No. 4
 
www.mcld.co.uk/hiv/ ?q=The%20human%20immune%20...   Immunology of response to infection
 
<ul><li>Helminth egg burden correlated with  HIV-1 viral load </li></ul>J Acquir Immune Defic Syndr, Volume 31(1).Septembe...
Changes in HIV plasma viral load after treatment of helminths.  Group A: persistently helminth-negative. Group B: successf...
Cochrane Review Walson JL , John-Stewart G. Treatment of helminth co-infection in HIV-1 infected individuals in resource-l...
    Year Study Design   Outcomes Comparator Group Kallestrup Zambia 2005 Randomized Controlled Trial (no blinding) 64 Earl...
Walson JL , John-Stewart G. Treatment of helminth co-infection in HIV-1 infected individuals in resource-limited settings....
Treatment of helminth co-infection: short term effects on HIV-1 progression markers and immune activation
Study Justification <ul><li>There were no randomized clinical trials evaluating the effect of eradicating soil-transmitted...
Objectives <ul><li>To determine the prevalence and correlates of helminth co-infection in HIV-1 infected individuals in Ke...
Outcomes <ul><li>The primary study outcomes were CD4 counts and log 10  plasma HIV-1 RNA levels in the two study arms. </l...
Inclusion Criteria <ul><li>Antiretroviral na ï ve </li></ul><ul><li>CD4 count >250 cells/mm 3 </li></ul><ul><li>At least 1...
Exclusion Criteria <ul><li>Received or receiving ART </li></ul><ul><li>Received treatment for helminth infection in the pa...
12 week follow up <ul><li>All patients with stool positive for helminth infection at week 12 treated with three 400 mg dos...
Obstacles <ul><li>Need to screen large numbers of patient samples for helminths </li></ul><ul><li>Unclear what the prevale...
 
The Mobile Study Team
 
 
 
 
 
 
Walson JL,  Otieno PA, Mbuchi M, Richardson BA, Lohman-Payne B, et al.  Albendazole treatment among adults with HIV-1 and ...
Effects on CD4 and Viral Load Walson JL,  Otieno PA, Mbuchi M, Richardson BA, Lohman-Payne B, et al.  Albendazole treatmen...
 
Change in Log10 HIV-1 RNA
Change in CD4 Count
Next? <ul><li>Screening is relatively expensive and not sensitive – who to deworm? </li></ul><ul><li>Are the findings tran...
Empiric therapy of helminth co-infection to reduce HIV-1 disease progression.
Study Plan 850 individuals enrolled in Targeted Evaluation Month 0 Month 3 Month 6 Month 12 Month 15 Month 18 Month 21 Ful...
Obstacles <ul><li>Need stable clinic sites to provide 2 years of follow up, including unscheduled visits </li></ul><ul><li...
PHE Helminth Study Sites KEMIR/UW HQ Kisumu Study Office -Kisumu District Hosp -Patient Support Centre (PSC) Kisii Study O...
Kisii Container Office <ul><li>No existing office/clinic </li></ul><ul><li>No extra containers in Kisii </li></ul><ul><li>...
 
Samples Delivered Daily <ul><li>Kilifi, Kisii, Kisumu </li></ul><ul><ul><li>Picked at approx 4:30pm </li></ul></ul><ul><ul...
Completing CRFs Programming DB Maintenance Recording Lab Results
Patient Enrolment Page
International Interns/Scholars <ul><ul><li>ID Fellows </li></ul></ul><ul><ul><li>RN </li></ul></ul><ul><ul><li>Bioinformat...
 
The HELMINTHS ANGELS
Questions that remain? <ul><li>Reduced sexual transmissibility or susceptibility </li></ul><ul><li>Improved response to AR...
Additional Studies <ul><li>Currently finalizing protocol for ITN/Filter study </li></ul><ul><ul><li>PRIMARY AIM </li></ul>...
Acknowledgements <ul><li>All the study participants </li></ul><ul><li>Grace John-Stewart, Phelgona Otieno, Ben Piper, Bens...
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DGH Lecture Series: Judd Walson

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Department of Global Health Lecture Series

Judd Walson
December 2, 2008
'Delaying HIV-1 Disease Progression in Pre-HAART Positives; The Role of Treating Endemic

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Transcript of "DGH Lecture Series: Judd Walson"

  1. 1. Delaying HIV-1 Disease Progression in Pre-HAART Positives Treating Endemic Co-infections Judd L. Walson, MD, MPH University of Washington Kenya Medical Research Institute Centre for Clinical Research
  2. 2. Today’s Talk <ul><li>Hypothesis testing in resource limited settings </li></ul><ul><li>Pre-HAART Positives - explaining the focus </li></ul><ul><li>Studies </li></ul><ul><li>Unanswered Questions/Future Research </li></ul>
  3. 3. The office
  4. 4. Global Burden of Disease <ul><li>www.bvgh.org/GlobalHealthChallenge.asp </li></ul>
  5. 5. Copyright ©2002 BMJ Publishing Group Ltd. Isaakidis, P. et al. BMJ 2002;324:702 No of clinical trials in Sub-Saharan Africa
  6. 6. Copyright ©2002 BMJ Publishing Group Ltd. Isaakidis, P. et al. BMJ 2002;324:702 Burden of Disease and Number of Trials
  7. 8. Evidence Based Medicine for Resource Limited Settings
  8. 10. Pre-HAART Positives - explaining the focus <ul><li>Of the 22.5 million individuals infected with HIV-1 in Africa, only 31% of those in need are currently on ART. </li></ul><ul><li>ART is expensive relative to other health care interventions (between $300 and $400 per individual per year). </li></ul><ul><li>Delaying immunosuppression will “buy time” until the development of AIDS, the need for ART and will allow critical infrastructure to be developed. </li></ul>UNAIDS, 2007
  9. 11. Pre-HAART Package of Care <ul><li>PROVEN </li></ul><ul><ul><li>Septrin </li></ul></ul><ul><ul><li>TB prophylaxis </li></ul></ul><ul><li>UNCLEAR BENEFIT </li></ul><ul><ul><li>Micronutrients </li></ul></ul><ul><ul><li>Macronutrients </li></ul></ul><ul><ul><li>Acyclovir </li></ul></ul><ul><ul><li>Deworming </li></ul></ul><ul><ul><li>Bednets </li></ul></ul><ul><ul><li>Water filters </li></ul></ul>
  10. 13. 0.3 log 10 increase 0.5 log 10 increase 1.0 log 10 increase Increase in likelihood of heterosexual transmission 20% 40% 100% Increase in risk of progression to AIDS or death 25% 44% 113%
  11. 14. Effect of modest VL reduction Gupta et al. JID 2007; 195 (Feb 15).
  12. 15. “ In most parts of the world there are two types of people, those that know they have worms,…and those that don’t”
  13. 16. Worms – Why NOT?
  14. 17. Epidemiology <ul><li>Over 2 billion people are estimated to be infected with at least one species of helminths. </li></ul><ul><li>In fact, about 25% of the worlds population is infested with one or more soil transmitted helminth. </li></ul><ul><li>Of the approximately 25 million people infected with HIV-1 in Africa, as many as 50-90% may also be infected with a soil transmitted helminth. </li></ul>
  15. 21. Distribution of helminths and HIV-1 in Africa Clinical Microbiology Reviews, October 2004, p. 1012-1030, Vol. 17, No. 4
  16. 23. www.mcld.co.uk/hiv/ ?q=The%20human%20immune%20... Immunology of response to infection
  17. 25. <ul><li>Helminth egg burden correlated with HIV-1 viral load </li></ul>J Acquir Immune Defic Syndr, Volume 31(1).September 1, 2002.56-62
  18. 26. Changes in HIV plasma viral load after treatment of helminths. Group A: persistently helminth-negative. Group B: successful treatment of helminths. Group C: persistently helminth-positive. No significant change in CD4 counts were observed. J Acquir Immune Defic Syndr, Volume 31(1).September 1, 2002.56-62 P value of B compared to C = 0.04, A + C = 0.02
  19. 27. Cochrane Review Walson JL , John-Stewart G. Treatment of helminth co-infection in HIV-1 infected individuals in resource-limited settings. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD006419. DOI: 10.1002/14651858.CD006419.pub2.
  20. 28.     Year Study Design   Outcomes Comparator Group Kallestrup Zambia 2005 Randomized Controlled Trial (no blinding) 64 Early Treatment 66 Delayed Treatment Plasma HIV-1 RNA and CD4 Count HIV and Helminth co-infected individuals - delayed therapy for helminths Modjarrad Zambia 2005 Observational Cohort Study 54 HIV and helminth co-infected individuals 57 HIV infected helminth uninfected Plasma HIV-1 RNA Helminth uninfected individuals Brown Uganda 2004 Observational Cohort Study 294 HIV and helminth co-infected individuals 253 HIV infected, helminth uninfected controls Plasma HIV-1 RNA and CD4 Count Helminth uninfected individuals Wolday Ethiopia 2002 Observational Cohort Study 56 HIV and helminth co-infected individuals Plasma HIV-1 RNA and CD4 Count Historical Self Controls Kassu Ethiopia 2003 Observational Cohort Study 21 HIV infected helminth negative participants, 9 HIV infected, helminth uninfected individuals CD4 Count Data on HIV infected individuals not presented Lawn Kenya 2000 Observational Cohort Study 30 individuals with HIV and schistosomiasis HIV-1 RNA levels Historical Self Controls Elliott Uganda 2003 Observational Cohort Study 39 HIV and helminth co-infected individuals 69 HIV infected, helminth uninfected controls CD4 Count Helminth uninfected individuals
  21. 29. Walson JL , John-Stewart G. Treatment of helminth co-infection in HIV-1 infected individuals in resource-limited settings. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD006419. DOI: 10.1002/14651858.CD006419.pub2.
  22. 30. Treatment of helminth co-infection: short term effects on HIV-1 progression markers and immune activation
  23. 31. Study Justification <ul><li>There were no randomized clinical trials evaluating the effect of eradicating soil-transmitted helminths on markers of HIV-1 disease progression. </li></ul><ul><li>Treatment of helminth co-infection may offer a useful strategy to delay HIV-1 progression among individuals in resource-poor settings? </li></ul>
  24. 32. Objectives <ul><li>To determine the prevalence and correlates of helminth co-infection in HIV-1 infected individuals in Kenya. </li></ul><ul><li>To randomize 234 HIV-1 seropositive adults with CD4 counts greater than 250 cells/mm 3 to immediate versus delayed (twelve weeks) anti-helminth therapy. </li></ul><ul><li>To determine the effect of deworming on markers of HIV-1 disease progression. </li></ul>
  25. 33. Outcomes <ul><li>The primary study outcomes were CD4 counts and log 10 plasma HIV-1 RNA levels in the two study arms. </li></ul><ul><li>Secondary outcomes included CD4 counts and log 10 plasma HIV-1 RNA levels in the two arms stratified by helminth species. </li></ul>
  26. 34. Inclusion Criteria <ul><li>Antiretroviral na ï ve </li></ul><ul><li>CD4 count >250 cells/mm 3 </li></ul><ul><li>At least 18 years of age </li></ul><ul><li>Able and willing to participate and give written informed consent. </li></ul><ul><li>Have at least one stool specimen positive for a soil transmitted helminth. </li></ul>
  27. 35. Exclusion Criteria <ul><li>Received or receiving ART </li></ul><ul><li>Received treatment for helminth infection in the past 6 months (by self report or chart review) </li></ul><ul><li>Pregnant by urine HCG testing </li></ul><ul><li>Other serious co-morbidities such as severe anemia, malaria or tuberculosis </li></ul>
  28. 36. 12 week follow up <ul><li>All patients with stool positive for helminth infection at week 12 treated with three 400 mg doses of Albendazole, regardless of initial randomization group. </li></ul><ul><li>All patients referred for further HIV care at the conclusion of the study period, regardless of disease stage. </li></ul>
  29. 37. Obstacles <ul><li>Need to screen large numbers of patient samples for helminths </li></ul><ul><li>Unclear what the prevalence of helminth infection is in adults at various geographic sites </li></ul><ul><li>Sites are diverse, organized and assisted by different partners, differing capacities </li></ul><ul><li>Budget - $50,000 (Initially) </li></ul>
  30. 39. The Mobile Study Team
  31. 46. Walson JL, Otieno PA, Mbuchi M, Richardson BA, Lohman-Payne B, et al. Albendazole treatment among adults with HIV-1 and helminth co-infection: A randomized, double blind, placebo-controlled trial. Submitted to AIDS , January 2008.
  32. 47. Effects on CD4 and Viral Load Walson JL, Otieno PA, Mbuchi M, Richardson BA, Lohman-Payne B, et al. Albendazole treatment among adults with HIV-1 and helminth co-infection: A randomized, double blind, placebo-controlled trial. Submitted to AIDS , January 2008.
  33. 49. Change in Log10 HIV-1 RNA
  34. 50. Change in CD4 Count
  35. 51. Next? <ul><li>Screening is relatively expensive and not sensitive – who to deworm? </li></ul><ul><li>Are the findings transient? Need longer follow up. </li></ul><ul><li>What is the outcome that matters – Focus on TIME TO QUALIFY FOR ART. </li></ul>
  36. 52. Empiric therapy of helminth co-infection to reduce HIV-1 disease progression.
  37. 53. Study Plan 850 individuals enrolled in Targeted Evaluation Month 0 Month 3 Month 6 Month 12 Month 15 Month 18 Month 21 Full Blood Count CD4 Count HIV-1 RNA Study Arm A Study Arm B Standard Care and Treatment Albendazole 400mg/day X 3 days Praziquantel 25mg/kg X 1 Albendazole 400mg/day for 3 days Albendazole 400mg/day for 3 days Albendazole 400mg/day for 3 days Albendazole 400mg/day for 3 days Full Blood Count CD4 Count HIV-1 RNA Full Blood Count CD4 Count Full Blood Count CD4 Count HIV-1 RNA Full Blood Count CD4 Count Month 9 Albendazole 400mg/day for 3 days Month 24 Albendazole 400mg/day for 3 days Albendazole 400mg/day X 3 days Praziquantel 25mg/kg X 1 Figure 1. Flow Chart of Planned Targeted Evaluation
  38. 54. Obstacles <ul><li>Need stable clinic sites to provide 2 years of follow up, including unscheduled visits </li></ul><ul><li>Need well controlled laboratory facilities with QA/QC </li></ul><ul><li>Again, working with different partners, different capacities </li></ul>
  39. 55. PHE Helminth Study Sites KEMIR/UW HQ Kisumu Study Office -Kisumu District Hosp -Patient Support Centre (PSC) Kisii Study Office -Kisii Provincial Hosp -Patient Support Centre (PSC ) Kilifi Study Office -Kilifi District Hosp -Comprehensive Care and Research Clinic (CCRC) -KEMRI/Wellcome Trust
  40. 56. Kisii Container Office <ul><li>No existing office/clinic </li></ul><ul><li>No extra containers in Kisii </li></ul><ul><li>Collaboration with Merlin </li></ul><ul><li>Highest rate of enrollment! </li></ul>
  41. 58. Samples Delivered Daily <ul><li>Kilifi, Kisii, Kisumu </li></ul><ul><ul><li>Picked at approx 4:30pm </li></ul></ul><ul><ul><li>Delivered to HQ NBO by 10am </li></ul></ul><ul><li>Have not lost one sample </li></ul>
  42. 59. Completing CRFs Programming DB Maintenance Recording Lab Results
  43. 60. Patient Enrolment Page
  44. 61. International Interns/Scholars <ul><ul><li>ID Fellows </li></ul></ul><ul><ul><li>RN </li></ul></ul><ul><ul><li>Bioinformatics/MD Student </li></ul></ul><ul><ul><li>MD Students </li></ul></ul><ul><ul><li>Lab Technologists </li></ul></ul>Local Intern Program <ul><li>3 – 4 month rotation </li></ul><ul><ul><li>Information Technology/DB </li></ul></ul><ul><ul><li>Statistics </li></ul></ul><ul><ul><li>Nursing </li></ul></ul><ul><ul><li>Accounting </li></ul></ul><ul><li>Small stipend </li></ul>
  45. 63. The HELMINTHS ANGELS
  46. 64. Questions that remain? <ul><li>Reduced sexual transmissibility or susceptibility </li></ul><ul><li>Improved response to ARV’s </li></ul><ul><li>Reduction in the immune reconstitution inflammatory syndrome (IRIS) </li></ul><ul><li>Children vs. Adults </li></ul><ul><li>PMTCT </li></ul><ul><li>Improved response to vaccine </li></ul><ul><li>Effects on TB, malaria, etc. </li></ul>
  47. 65. Additional Studies <ul><li>Currently finalizing protocol for ITN/Filter study </li></ul><ul><ul><li>PRIMARY AIM </li></ul></ul><ul><ul><li>To determine the effect of insecticide treated bednets and a simple water purification system on markers of HIV progression (time to HAART eligibility, changes in CD4 counts, WHO Clinical Staging and mortality). </li></ul></ul>
  48. 66. Acknowledgements <ul><li>All the study participants </li></ul><ul><li>Grace John-Stewart, Phelgona Otieno, Ben Piper, Benson Singa, King Holmes, Barbara Payne, Barbra Richardson, Margaret Barrett, Chris Kealy, Rekha Patel, Rowena de Saram </li></ul><ul><li>The fantastic study staff in Nairobi </li></ul><ul><li>The staff of all of the study sites </li></ul><ul><li>KEMRI CCR – Dr. Wasunna, Dr. Rashid </li></ul><ul><li>Wellcome Trust Kilifi – Kevin Marsh, James Berkley, Eduard Sanders </li></ul><ul><li>CDC – Marta Ackers, Jonathan Mermin, Becky Bunnell </li></ul>

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