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  • In an untreated person several months after infection, a relatively steady state of between 1000 and 100,000 circulating virus particles (“copies of HIV RNA) per milliliter of plasma is reached. (determined partly b y host genetics, partly by the nastiness of the infecting virus) [Genetic polymorphisms in chemokine receptors and haplotypes of the human leukocyte antigen are the best-defined host determinants] [HIV virions = mature infectious virus particles] At lest 10 million to 100 million CD4 lymphocytes are productively infected by one billion contain HIV genetic material (HIV nucleic acid). Rates of virus clearance seem similar in all pts and all disease stages, so steady state levels of circ HIV are determined by the rate of virus production. The higher the RNA levels the faster the loss of CD4 cells and the shorter the duration of HIV infection before death. CD4 count determines the risk of disease and death and the level of HIV FRNA determines the rate of CD4 cell decline. Activated CD4 lymphocytes and macs are the predominant host cells for HIV replication. Latently infected CD4 lymphocytes represent a small fraction of infected cells during active infection and have a half-life of at least 6 months. So many such cells survive for years, archiving virus that can re-emerge and propagate after the withdrawal of chemotherapy. So Infec can’t be eradicated. Rx death of infected activated cd4 lymphs and prevention of new infections. Second phase clearance may be due to infected macs or virions bound to dendritic cells in lymph nodes, and also to chronically Infec cd4 lymphs w a longer half-life and lower rates of virus replication.
  • Remember that in the Netherlands transmission of resistant strains declined from > 10% to < 5% after treatment programmes improved. HIV drug resistance does not spread like wildfire.

Transcript

  • 1. Anti Retroviral Drug Resistance Dr Dimple Kasana Asstt. Director (R&D) National AIDS Control Organization Ministry Of Health and family welfare
  • 2. What is HIV DR
    • The ability of HIV to enter human cells and multiply in the presence of antiretroviral drugs
  • 3.  
  • 4. Daily production of HIV mutations in an untreated HIV-infected person
    • Up to 10 billion new viruses are produced daily 1.
    • 10 million viruses per day will have one new "error" (mutation) 1
    • 100 million new cells are infected/day
    • Under drug selection pressures, complete replacement of wild-type (WT) virus by drug-resistant virus can occur in 14-28 . days 4
    1Coffin. Science 1995;267:483. 2Mansky. J Virol 1995;69:5087. 3Perelson. Science 1996;271:1582. 4Wei. Nature 1995;373:117.
  • 5. Background
    • Some degree of HIV drug resistance (HIVDR) is inevitable
      • Lifelong treatment, no cure
      • high rate of mutation
    • “ Minimizing HIVDR” = reducing the rate of emergence and spread of HIVDR and limiting its public health consequences.
  • 6. Few facts about HIV DR
    • Drug resistance is the biggest reason HIV drugs stop working
    • 3 out of 4 people taking HIV drugs have drug resistance
    • 1 out of 4 people with HIV who have never taken HIV drugs already have drug resistance
    • Taking HIV drugs on time, every day can help fight drug resistance
    • A resistance test can help doctors pick better drugs for people living with HIV.
  • 7. Indian scenario
    • Free ART was started by Govt. of India in April 2004
    • Currently 60 ART centers are functioning.
    • 21000 patients are on free ART.
    • Approximately similar no. of patients are on ART in Pvt. Sectors.
    • 9000 patients are being treated by inter-sectoral partners
  • 8. Steps being taken to prevent emergence of Drug Resistance
    • Simple ART implementation guidelines.
    • Patient education & counseling on ensuring maximum levels of adherence.
    • Ensuring uninterrupted supply of ARV drugs.
    • NGOs linkages with all ART centers.
    • ART Centers to be Family counseling centres as well.
  • 9. Prevention of emergence of HIV Drug Resistance (HIV DR) is accorded a high priority and is a crucial component of the National ART Programme
  • 10. HIV DR Surveillance
    • When should large scale surveillance for transmitted resistance begin?
    •  Not until there is some indication that transmitted resistance is sufficiently widespread to be measured
    • WHO proposes use of HIVDR Threshold Surveys
    • to evaluate whether HIVDR remains <5% or above 15% in areas/site(s) where transmitted HIVDR is likely to be seen first
  • 11. Key Questions for designing HIV DR Strategy
    • Is HIV DR being transmitted at levels <5% or >15%?
    • Are patients eligible for ART already having evidence of HIV DR?
    • Are patients receiving ART under national programme developing drug resistance?
  • 12. Public Health Action for a > 15% result
    • Avoid panic – this does not mean &quot;HIVDR is > 15% in the country&quot;! More study is needed.
    • Ensure contamination in lab did not occur and that persons on ART were not included by mistake
    • Begin surveys in additional sites in the area and in surrounding geographic areas.
  • 13.
    • Repeat surveys in the area in year 2
      • If result is confirmed in more sites, considering larger representative sampling in the following year
    • Review treatment programme monitoring &quot;HIVDR early warning measures&quot; in the area.
    • Consult with clinicians and policy makers on further action if results are confirmed
  • 14. Steps taken By NACO-National Consultation at Chennai , following preliminary meeting at Pune
    • National strategy on HIV DR surveillance –” threshold survey ” for resistance in recently infected persons.
    • Need to initiate HIV DR monitoring in those eligible for ART and those already on ART for 12 months.
    • Identify the sites for study and finalize the study protocols.
  • 15. Criteria for pilot sites
    • Sites for threshold survey would be PPTCT & VCT centers in vicinity of testing laboratories.
    • Sites for HIV DR monitoring will be centers that have already rolled out ART as per the Government program for at least 1 year (to be linked to one of the reference labs).
    • Sites selected should have facilities for blood collection, storage and transportation as per protocol.
  • 16. Study design for threshold survey
    • As per WHO/HIV Resnet recommended protocol using 60 – 70 specimens from HIV positive recently infected population.
    • Anonymous unlinked testing of those fulfilling inclusion criteria.
  • 17. Steering Committee Technical Committee WG WG WG WG WG HIVResNet WHO Secretariat Epidemiology Data use Technology transfer Data Management Lab T he World Health Organization has brought together a global group of experts and organizations to develop and implement surveillance and monitoring methods to support the containment of HIV drug resistance (HIVDR) as antiretroviral treatment (ART) is rolled out worldwide. A formal laboratory network with QA/QC and certification will begin this year. Each working group (WG) is co-chaired by 1 developing country expert + 1 industrialized country expert
  • 18. Study design for DR monitoring
    • Dual cross-sectional survey with two groups:
      • Patients enrolled for commencing ART;
      • Patients already on ART under national programme for 12 months.
    • Inclusion criteria :
      • Consecutive patients enrolled into Government ART programme for first time;
      • Consecutive patients completing 12 months after enrolment in the national ART programme.
  • 19. Possible sites
    • Sites
      • GHTM, Chennai
      • JJ Hospital, Mumbai
    • Testing laboratories
      • TRC, Chennai.
      • NARI, Pune
    • Convenient logistics considerations should guide site selection
  • 20. Operational aspects
    • Laboratory :
      • Detailed SOP to be developed –to be circulated by NARI
      • Labs to agree on common lab protocol & exchange samples for quality control
      • International standards/quality assurance to be established to ensure international comparability
  • 21. MUTATION INTERPRETATION
    • WHO Offer – WHO should provide the international mutation list to define the major mutaions.
    • Create a national database (WHO support)
    • Criteria – meet international QC standards
    • Join HIVResNet
  • 22. Establishment of National HIV DR committee
    • Programme officer (1)
    • Epidemiologists (2)
    • Statistician (1)
    • Laboratory experts (virologist, molecular biology)-(2)
    • Clinician from ART centers (2)
    • WHO representatives (2)
    • NACO representatives (2)
    • (Member Secretary should be a WHO representative
    • Chairman –Project Director, NACO)
  • 23. TOR of the HIV DR committee
    • To develop a national strategy for prevention, surveillance and monitoring of HIV DR
    • To Plan and budget the HIV DR studies
    • To monitor the progress/implementation of studies
    • To review results and provide direction for next steps and future strategies
    • To review existing information from other sources and document it as part of the overall report
    • To disseminate reports on HIV DR.
  • 24. Co-ordination
    • Sites---laboratories—IRMS---HIVDR---NACO (DR Committee) – WHO – HIV
    • Overall co-ordination—Focal person at NACO
  • 25. Photo Album by abc Thank you …………………..