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DGH Lecture Series: Judd Walson
 

DGH Lecture Series: Judd Walson

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Department of Global Health Lecture Series

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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    DGH Lecture Series: Judd Walson DGH Lecture Series: Judd Walson Presentation Transcript

    • 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
    • Today’s Talk
      • Hypothesis testing in resource limited settings
      • Pre-HAART Positives - explaining the focus
      • Studies
      • Unanswered Questions/Future Research
    • The office
    • Global Burden of Disease
      • www.bvgh.org/GlobalHealthChallenge.asp
    • 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
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    • Evidence Based Medicine for Resource Limited Settings
    •  
    • Pre-HAART Positives - explaining the focus
      • Of the 22.5 million individuals infected with HIV-1 in Africa, only 31% of those in need are currently on ART.
      • ART is expensive relative to other health care interventions (between $300 and $400 per individual per year).
      • Delaying immunosuppression will “buy time” until the development of AIDS, the need for ART and will allow critical infrastructure to be developed.
      UNAIDS, 2007
    • Pre-HAART Package of Care
      • PROVEN
        • Septrin
        • TB prophylaxis
      • UNCLEAR BENEFIT
        • Micronutrients
        • Macronutrients
        • Acyclovir
        • Deworming
        • Bednets
        • Water filters
    •  
    • 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%
    • 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
      • Over 2 billion people are estimated to be infected with at least one species of helminths.
      • In fact, about 25% of the worlds population is infested with one or more soil transmitted helminth.
      • 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.
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    • 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
    •  
      • Helminth egg burden correlated with HIV-1 viral load
      J Acquir Immune Defic Syndr, Volume 31(1).September 1, 2002.56-62
    • 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
    • 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.
    •     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
    • 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.
    • Treatment of helminth co-infection: short term effects on HIV-1 progression markers and immune activation
    • Study Justification
      • There were no randomized clinical trials evaluating the effect of eradicating soil-transmitted helminths on markers of HIV-1 disease progression.
      • Treatment of helminth co-infection may offer a useful strategy to delay HIV-1 progression among individuals in resource-poor settings?
    • Objectives
      • To determine the prevalence and correlates of helminth co-infection in HIV-1 infected individuals in Kenya.
      • 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.
      • To determine the effect of deworming on markers of HIV-1 disease progression.
    • Outcomes
      • The primary study outcomes were CD4 counts and log 10 plasma HIV-1 RNA levels in the two study arms.
      • Secondary outcomes included CD4 counts and log 10 plasma HIV-1 RNA levels in the two arms stratified by helminth species.
    • Inclusion Criteria
      • Antiretroviral na ï ve
      • CD4 count >250 cells/mm 3
      • At least 18 years of age
      • Able and willing to participate and give written informed consent.
      • Have at least one stool specimen positive for a soil transmitted helminth.
    • Exclusion Criteria
      • Received or receiving ART
      • Received treatment for helminth infection in the past 6 months (by self report or chart review)
      • Pregnant by urine HCG testing
      • Other serious co-morbidities such as severe anemia, malaria or tuberculosis
    • 12 week follow up
      • All patients with stool positive for helminth infection at week 12 treated with three 400 mg doses of Albendazole, regardless of initial randomization group.
      • All patients referred for further HIV care at the conclusion of the study period, regardless of disease stage.
    • Obstacles
      • Need to screen large numbers of patient samples for helminths
      • Unclear what the prevalence of helminth infection is in adults at various geographic sites
      • Sites are diverse, organized and assisted by different partners, differing capacities
      • Budget - $50,000 (Initially)
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    • The Mobile Study Team
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    • 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.
    • 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.
    •  
    • Change in Log10 HIV-1 RNA
    • Change in CD4 Count
    • Next?
      • Screening is relatively expensive and not sensitive – who to deworm?
      • Are the findings transient? Need longer follow up.
      • What is the outcome that matters – Focus on TIME TO QUALIFY FOR ART.
    • 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 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
    • Obstacles
      • Need stable clinic sites to provide 2 years of follow up, including unscheduled visits
      • Need well controlled laboratory facilities with QA/QC
      • Again, working with different partners, different capacities
    • 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
    • Kisii Container Office
      • No existing office/clinic
      • No extra containers in Kisii
      • Collaboration with Merlin
      • Highest rate of enrollment!
    •  
    • Samples Delivered Daily
      • Kilifi, Kisii, Kisumu
        • Picked at approx 4:30pm
        • Delivered to HQ NBO by 10am
      • Have not lost one sample
    • Completing CRFs Programming DB Maintenance Recording Lab Results
    • Patient Enrolment Page
    • International Interns/Scholars
        • ID Fellows
        • RN
        • Bioinformatics/MD Student
        • MD Students
        • Lab Technologists
      Local Intern Program
      • 3 – 4 month rotation
        • Information Technology/DB
        • Statistics
        • Nursing
        • Accounting
      • Small stipend
    •  
    • The HELMINTHS ANGELS
    • Questions that remain?
      • Reduced sexual transmissibility or susceptibility
      • Improved response to ARV’s
      • Reduction in the immune reconstitution inflammatory syndrome (IRIS)
      • Children vs. Adults
      • PMTCT
      • Improved response to vaccine
      • Effects on TB, malaria, etc.
    • Additional Studies
      • Currently finalizing protocol for ITN/Filter study
        • PRIMARY AIM
        • 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).
    • Acknowledgements
      • All the study participants
      • Grace John-Stewart, Phelgona Otieno, Ben Piper, Benson Singa, King Holmes, Barbara Payne, Barbra Richardson, Margaret Barrett, Chris Kealy, Rekha Patel, Rowena de Saram
      • The fantastic study staff in Nairobi
      • The staff of all of the study sites
      • KEMRI CCR – Dr. Wasunna, Dr. Rashid
      • Wellcome Trust Kilifi – Kevin Marsh, James Berkley, Eduard Sanders
      • CDC – Marta Ackers, Jonathan Mermin, Becky Bunnell