CD4 T cell Enumeration in the Diagnosis and Management of Pediatric HIV infection

Transcription

1 CD4 T cell Enumeration in the Diagnosis and Management of Pediatric HIV infection Maurice (Mo) R.G. O Gorman, Ph.D. Professor of Pathology and Pediatrics Keck School of Medicine, U. of Southern California Chief of Laboratory Medicine Department of Pathology and Laboratory Medicine Children s Hospital of Los Angeles, Los Angeles CA

2 Introduction General Review of Global Pediatrics HIV Infection Update 2013 on Global Plan Diagnosis of HIV Infection in Infants Why Measure CD4 T cells in Pediatric HIV Infection In the context of the new 2013 WHO Guidelines

3 Value of CD4 Testing : Pediatric HIV Infection in Resource Limited Settings Guidelines 2006 to guidelines/paediatric pdf

4 WHO Guideline June 2013 November 2012

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6 Estimated number of children newly infected with HIV in low- and middle-income countries, Global HIV/AIDS Response, Towards Universal Access, Progress Report 2011 WHO, UNAIDS, UNICEF

7 Estimated number of children (<15 years) newly infected with HIV by WHO Region Americas [ ] Europe [ ] Eastern Mediterranean [ ] Africa [ ] South-East Asia [ ] Western Pacific [ ] 2003-Total: 560, Total: 430, Total: Total: 330, Total: 210,000

8 PMTCT 2010 to 2011 Caribbean had largest increase of all WHO regions

9 Reality: Care and Treatment of HIV Exposed Children Today in million children are HIV infected Significant obstacles to scaling up pediatric HIV care remain including: Limited HIV screening Lack of affordable simple diagnostic testing technologies for children less than 18 months of age Lack of human resources to provide the care that is required Insufficient advocacy and understanding that ART is efficacious in children Limited experience with simplified, standardized treatment guidelines Lack of affordable, practicable pediatric ART formulations Health care systems remain unable to meet the demands of national pediatric ART coverage - therefore far too few children have been started on ART in resource limited settings The need to treat an ever increasing number of HIV-infected children highlights the primary importance of prevention of transmission from mother to child in the first place Antiretroviral Therapy for HIV infect infants. WHO 2011, 2013

10 Percentage of children living with HIV receiving antiretroviral therapy in low- and middle-income countries, 2005, 2009 and 2010 Global HIV/AIDS Response, Towards Universal Access, Progress Report 2011 WHO, UNAIDS, UNICEF

11 Reality: Children in Low-Resource Countries Who Receive ART are Starting Treatment When Older, Already Severely Immune Deficient, Wasted and with Advanced Disease Baseline Median Age Davies/S Africa 2010 N=6, McConnell/Thailand 2010 N=3, Janssen/S Africa 2010 N= Anaky/Cote d Ivoire 2010 N= Sauvageot/MSF (focus <5 yrs) 2010 N=3, Yotebieng/S Africa 2010 N=1, Rajasekaran/India 2009 N= Slide Courtesy of S. Crowley, WHO Baseline Median CD4 WHO Stage 3/4 3.9 yrs 12% 50% 7.3 yrs 5% 51% 6.2 yrs 17% 67% 5.3 yrs 11% 43% 2.6 yrs 82% severe 9.2 yrs 82% severe 68% 67% 7.6 yrs 14% 98%

12 Pediatric HIV Diagnostic Testing Virologic Testing (WHO 2010 recommendation) Most reliable methodology in children <18 months of age however It is expensive Requires a sophisticated laboratory Requires skilled personnel Availability is usually centrally located away from most of the population But the use of the Dried Blood Spots system should enable all health facilities in a country to access virologic testing services Urgent need for point of care virologic testing in resource limited settings

13 HIV Diagnosis in HIV Exposed Infants and Children-WHO Guidelines 2013

14 Why Measure CD4+ T cells in HIV Infected Children ? Standardize classification systems for HIVassociated Immunodeficiency Case Definitions/statistical monitor Assessing Prognosis - Risk of AIDS or Death When to Prophylax opportunistic pathogens When to Immunize When to start antiretroviral therapy Monitoring antiretroviral therapy When to change ART: CD4 levels provide the immunological definition of treatment failure

15 CD4+ T cells in Children: Age Associated Reference Ranges CD4 absolute T cell counts (per mm 3 ) change significantly with age in infants Percentages of CD4+ T cells (%CD4) change less with age Recommendations Use CD4% in children <5 years of age Use Absolute CD4 T cell counts in children >5 years of age

16 Percent CD4+ CD4 T cell Normal Range in Children: Birth through 5 years. O Gorman et. al Absolute Counts 70 Percentages <52.5 <124.5 <336.5 <691 <1115 < > th 50th 95th 5th 50th 95th Absolute CD4 count cell/mm 3 DAYS

17 CD4 & Prognosis Short term risk of Disease Progression Study estimated 12 month risk of death and risk of AIDS in 3,941 HIV-1+ children receiving no antiretroviral therapy or zidovudine monotherapy [only]: a meta analysis CD4% and Viral load were independent predictors but CD4% was the stronger individual predictor. Immunological STAGING: Classification of HIVassociated Immunodeficiency in Infants and Children HIV Paediatric Prognostic Markers Collaborative Study Group Dunn et. al. The Lancet 2003;362:

18 Immunological STAGING: Classification of HIVassociated Immunodeficiency in Infants and Children Classification of HIVassociated Immunodeficiency <11 months %CD4+ (cells/mm 3) Age Related CD4 Values months % (cells/mm 3) months % (cells/mm 3) > 5 years cells/mm 3 Not significant (1) >35 >30 >25 >500 Mild (2) Advanced (3) Severe*(4) <25% <1500) <20% (<750) <15% (<350) <15% (<200) Based on WHO global and regional consultations and Dunn et. al. Lancet 15:1625 (2003). *level at which patient has >10% chance of progressing to AIDS or >5% of death within 1 year WHO Clinical stage (1,2,3,4)

19 Clinical Staging: HIV-Associated Disease harmonized for adults and children WHO 2010 **Classification of HIV- Associated Clinical Disease WHO Clinical Stage Asymptomatic 1 Mild 2 Advance 3 Severe 4 ** Details on Staging and the criteria for recognizing them are published in Annex C of the 2010 WHO Recommendations Document

20 CD4+ T cells: When to Initiate Antiretroviral Therapy? Dramatic changes in WHO recommendations since 2006 Based on clinical trial data showing markedly improved outcomes with early initiation of ART in infants

21 When to Start? According to Clinical stage and availability of Immunological Markers (WHO-2006) WHO Clinical Stage 4* CD4 Availability of a CD4 measurement No CD4 3* CD4 Treat all No CD4 Age-Specific Treatment Recommendation <11 months >12 Months Treat All CD4-guided in those children with TB, LIP, OHL, thrombocytopenia Treat all 2 CD4 CD4-guided No CD4 TLC-Guided 1 CD4 CD4-Guided No CD4 Do Not Treat *Stabilize any OI before beginning ART Baseline CD4 is useful for monitoring ART (even if not required to start ART)

22 WHO Age-Related CD4 and TLC values for ART Decisions in Children Start ARV When CD4% or Count is + : <11 mo 1 yr - <3 yr 3 yr - <5 yr >5 yr CD4%* <25% <20% <15% <15% CD4 count* <1,500 <750 <350 <200 *CD4% preferred in children <5 years; CD4 count preferred in children >5 years. If CD4 Assay Not Available, Start ARV When TLC Is + : <11 mos 1yr - <3yr 3yr - <5 yr >5 yr TLC <4,000 <3,000 <2,500 <1,500 + ART should be started at these levels regardless clinical stage NOTE: All clinical stage 3 & 4 infants (<11 months) should start ART regardless of CD4 level

23 Revised Guidelines for ART in Pediatric HIV Infection

24 Revised WHO Guidelines 2009 : When to Start Antiretroviral Therapy in HIV-Infected Children < 12 months HIV Confirmed < 12 months Presumptive Severe HIV* 1-4 yrs > 5yrs All regardless of CD4/clinical All regardless of CD4/clinical Clinical or immune criteria Clinical or immune criteria <20% or mos: <750/uL mos: <350/uL <15% or <200/uL (as in adults) *If Viral test is not possible, use presumptive diagnosis of severe HIV in infants with +ve HIV antibody test and with clinical symptoms of severe HIV (thrush, severe pneumonia or sepsis) confirm infection status as soon as possible.

25 Failure Probability CHER STUDY : 76% Reduction in the Risk of Death with Immediate Compared to Deferred ART Deferred Immediate Time to Death (months) Patients at risk Most deaths occurred within first 6 months (i.e., before age 10 months) Month 0 Month 3 Month 6 Month 9 P = Month 12 deferred immediate 16% 4% Deferred Immediate Violari A,et al. N Engl J Med2008 Nov 20;359(21):

26 WHO recommendations for initiating ART in HIV-infants and Children Revised in 2010 Simpler, aligned with adult recommendations Age Infants and Children <24 months of age 24 months of age to 59 months of age Five years of age or older %CD4 All 25% NA Absolute CD4 All 750 cells/mm cells/mm 3 (As in Adults) All HIV-infected infants should receive ART due to rapid rate of disease progression Countries with reliable access to CD4 monitoring may choose to apply clinical and Immunological criteria for initiation of ART in children between months In children with absolute lymphopaenia, the CD4% may be falsely elevated.

27 Reconstitution in children, unlike adults is mainly via the naïve T cell compartment De novo production of T cells from the thymus falls with age Delaying ART in childhood will impair the expected CD4 T cell concentration in adulthood First indication of the importance of considering long terms outcomes when deciding on when to initiate ART in children and the need to consider the increased likelihood that children will survive into adulthood

28 United States : UNAIDS November 2012

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30 WHO 2013 When to Initiate ART in Infants and Children

31 Ramifications of New Guidelines How many more children become eligible for ART How many more pregnant women become eligible for ART CD4 testing in HIV exposed/infected Infants?

32 Ramifications of New 2013 Guidelines

33 Monitoring HIV infected infants and children - WHO recommendations 2010 CD4 Monitoring 1. Measure at the time of diagnosis and every 6 months thereafter. Monitor more frequently as CD4 count approaches threshold for starting ART 2. Measure if new clinical staging event develops, including growth faltering and neural developmental delay 3. If CD4 testing is limited, target CD4 monitoring to assess the significance of a clinical event The inability to perform CD4 testing should not prevent children from receiving ART Percent CD4 is preferred for children less than 5 y/o Routine monitoring of viral load is not essential however if possible should be used to confirm suspected clinical or immunological failure

34 What to expect in the first 6 months of ART CD4 In most children CD4 cell counts will rise with the initiation of ART, increase during first year, reach a plateau and then continue to rise over the second year Sutcliffe et al. Lancet Infec.Dis.2008, Lewis JID 2012 The lower the CD4 at the start of ART the slower the recovery In some children, severe immunosuppression may persist It is important to allow sufficient time on therapy Lancet Inf Dis before judging the effectiveness of a regimen and to consider the possibility of IRIS in children with worsening disease in the first few months of ART

35 When to change first line ART? Treatment Failure general considerations A switch to a second line regimen is recommended after at least 24 weeks on ART in an adherent child when they experience: Clinical failure is recognized (appearance or reappearance of WHO clinical stage 3 or 4 events) Immunological failure is recognized (based on CD4 levels) Virological failure is recognized (persistent VL >5,000 RNA copies per ml) Assessment of adherence is always required in assessing treatment failure Immunological and virological confirmation of clinical failure is advised whenever possible Delayed switching is likely to allow for greater resistance to first line ART and possibly diminished efficacy of second line ART

36 WHO: When to change therapy. Immunological Failure The younger the child, the greater the likelihood of disease progression and death for any CD4 threshold. Children less than 2 years of age with CD4 values below 10% represents severe immunosuppression and must be managed by a specialist Recognition of treatment failure on the basis of immunological values relies on comparison with previous immunological values

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39 2013 WHO

40 CD4 & Prophylaxis for Opportunistic Disease (globally): Co-trimoxazole Can cut mortality in half and reduce hospital admissions of children Inexpensive about US$10/child/year In 2008 ~ 1.4 women with HIV gave birth in low and middle income countries All babies born to these moms should receive Cotriomoxazole prophylaxis HOWEVER coverage was only about 8% in 2008

41 CD4 and Co-Trixomazole Prophylaxis 2006 WHO Recommendations for: HIV-exposed infants and children: all should be treated starting at 4 6 weeks after birth and maintained until at least 6 weeks after cessation of risk of HIV transmission and definitive exclusion of HIV infection HIV confirmed infection: Infants: indicated regardless of CD4 or clinical status 1 4 years old: WHO clinical stages 2, 3 or 4 regardless of CD4 percentage and CD4%<25 regardless of clinical stage >5 years old: follow WHO s adult guidelines

42 2013 WHO

43 CD4 and Immunizations in HIV infected Infants and Children As early in life as possible all HIV-exposed infants and children should receive all vaccines under the Expanded Programme for Immunization (EPI) with the modification notes below: Measles unless severely immunocompromised should receive standard dose at 6 months of age because of the risk of early and severe infection Pnemococcal delay if child is severely immunocompromised Haemophilus influenzae H.Flu type B conjugate should be delayed is severely immunocompromised BCG new findings indicate risk of disseminated BVG disease, therefore BCG vaccine should not be given to children known to be HIV infected however infants cannot always be identified as HIVinfected at birth so in areas of high TB and HIV, BCG vaccination should generally be given to all infants at birth.

44 CD4 and Vaccinations (cont d) WHO 2013

45 POC CD4 testing significantly improved patient retention and rates of initiation of anti-retroviral therapy Jani et al

46 After the introduction of Point of Care CD4 T cell enumeration Proportion of patients lost to follow up fell from 64% to 33% Proportion of enrolled patients initiating ART rose from 12% to 22% Median time from enrollment to initiation of ART decreased from 48 days to 20 days CD4 staging decreased from 32 days to 3 days Point of care CD4 testing enabled clinics to stage patients rapidly on-site after enrolment reducing opportunities for pre-treatment loss to follow up.

47 Summary General Pediatric HIV PMTCT programs are extremely effective for preventing HIV infections in infants (and for the health of pregnant women) Programs are being implemented and the rate of adoption and treatment of pregnant HIV+ women in the Caribbean is very encouraging For infants acquiring HIV at or around birth, disease progression occurs very rapidly in the first few months of life and often leads to death All HIV+ infants and children less than 5 years of age need to start ART immediately All HIV exposed and infected infants in areas of high HIV endemicity and high infant mortality due to infectious diseases require co-trimoxazole prophylaxis starting 4 6 weeks after birth

48 Summary HIV Diagnosis in Infants and Children All infants and children need to have their HIV exposure status established because saving children s lives depends on early identification of HIV-exposure and definitive diagnosis Early initiation of ART in infants and children prevents death and earlier treatment appears to improve potential for immune reconstitution Viral testing should be performed at 4 6 weeks for all HIV exposed children Children months of age should be offered an antibody test and if positive should be tested in an HIV viral assay Children aged 18 months and older can be diagnosed with an HIV antibody test

49 Summary: CD4+ T cells in HIVinfected Infants and Children Why measure CD4 in HIV infected children? Aids in the Prognosis of AIDS or Death Basis for the developments of a standardized classification system for level of immune deficiency Determine when to prophylax and when NOT to vaccinate When to start ART in older children and adolescents Best immunological marker for monitoring ART Used to determine immunological failure and when to change ART

50 Six challenges, and six interventions for better access to pediatric testing and treatment 1 Infants are hard to diagnose yet very vulnerable Expand access to Early Infant Diagnosis (EID) Too few pediatric specialists Fragmentation of the ARV market by many similar products Increasing number. of adolescents with particular needs Too many children are LTFU all along the care continuum Access to pediatric treatment lags partly due to low targets Task shift pediatric ART Rationalise pediatric ARV formularies Meet special needs of adolescents Increase pediatric retention Set higher targets for pediatric testing and treatment

51 Bid to Cure HIV Ramps up Mississippi Infant cured of HIV IMPAACT study - 71 sites worldwide Screen and treat hundreds of babies to find infants who have acquired HIV from untreated mothers or from those whose HIV was not well controlled during pregnancy Because diagnosing HIV takes up to 7 days, all screened babies will automatically receive a similar treatment to the Mississippi baby: a cocktail of three drugs within 48 hours of birth. Physicians will add a fourth drug if babies then test positive for HIV Around the age of three, the children will be tested to see whether their immune systems make antibodies to HIV or if it can be detected in their blood. Those testing negative on both counts would then be taken off the drugs to see whether they can remain HIV-free.

52 Thank you for your attention