Early diagnosis and treatment options for children living with HIV Dr Siobhan Crowley Paediatric & Family HIV Care World Heath Organization, E-mail: crowleys@who.int http://www.who.int/hiv/paediatric/en/index.html

Overview Progress Rationale for early diagnosis and treatment Ways forward Revised WHO recommendations

More children are receiving ART Increased from 75,000 in 2005 to almost 200,000 in 2007 19 of 20 countries with highest PMTCT burden are in sub-Saharan Africa 90% of burden is in 20 countries The number of children receiving ART increased form about 75,000 in 2005 to almost 200,000 in 2007, However, many children living with HIV are still not receiving treatment, and mortality among them remains high. The estimation of need for ART will need to be revised based on these recent revised criteria for eligibility for ART in infants , hence coverage is not provided Most children receiving ART are older and the mortality in the first few months of starting ART remains high, retention in care continues to decline beyond the first year , and most children are starting ART very late Average age of children starting ART in the KIDS-ART-LINC Cohort Collaboration (17 participating clinics) was 4.9 years ( with only 12% <12-month) 70% - had severe immunodeficiency, 60% - started on a NNRTI based regimen The 2-year risk of death on ART was 6.9% (95% confidence interval [CI]: 5.9-8.1), And was independently associated with: baseline severe anaemia (adjusted hazard ratio [aHR]: 4.10 [CI: 2.36-7.18]), immunodeficiency (aHR: 2.95 [CI: 1.49-5.83]) advanced clinical disease (aHR: 3.65 [CI: 1.95-6.83]); Risk of LTFU was 9.5% (CI: 8.3-10.9), higher in children with severe clinical status. And persists out through the second year. Only 8% of infants born to pregnant women with HIV in 2007 were tested for HIV within the first two months of birth. In addition, only 4% of infants born to women living with HIV initiated co-trimoxazole prophylaxis as indicated in WHO guidelines. Towards Universal Access: Scaling up priority HIV/AIDS interventions in the health sector, WHO/UNAIDS/UNICEF 2008

ART outcomes - more good news National programmes reporting good outcomes 1 year survival estimated as 93-95% 2 year survival 91%

Country Treatment Outcomes Malawi # 5% mortality overall @ 6 mo, 13% at 12 mo > Death & default in younger kids Zambia Overall 6.6 mortality, good CD4 responses, higher mortality in <18mo most early Haiti # 81% in care @ 12 mo, 9% mortality Kenya Decreased hospitalisation; 6-9 % mortality Cote d'Ivoire 3.5 - 12% mortality at 36 mo, RNA < 300 in 46-66% Thailand # Decreased hospitalisation; 5.7% mortality decreased to 0.6 after 24 wks Tanzania 0% mortality (instutionalised orphans) South Africa 8.6 % mortality most early; 80% RNA undetectable at 12 mo 15% mortality at 12 mo, 70% RNA < 400 MSF (Asia, Africa ) # 3% mortality/ 8% LFU at 12 mo; 7% still severe immunosuppression at 12mo China 2% mortality, 55% RNA < 400 at 12 mo; Cambodia # 92 % survival at 24 mo; 81% RNA undetectable # programme reporting Sutcliffe. Lancet Infect Dis 2008;8: 477–89

Children are Starting Treatment Late Baseline Median Age Baseline Median CD4 Janssens/Cambodia 2007 N=212 6.0 yrs 6% George/Haiti 2007 N=100 6.3 yrs 12% Wamawala/Kenya 2007 N=67 4.4 yrs Reddi/S Africa 2007 N=151 5.7 yrs 8% Puthanakit/Thailand 2007 N=107 7.7 yrs 5% Kamya/Uganda 2007 N=250 9.2 yrs 8.6% Rouet/Cote d’Ivoire 2006 N=78 6.5 yr Meta-analysis 1,195 children from 8 African clinical trials 53% >5 years of age, 70% severe immune deficiency, 12% aged < 12 months (KIDS-ART-LINC) Arrive 2008

Starting ART when severely immunodeficient increases mortality Months from ART start Probability of Death After Starting ART Immune Deficient at Start ART Not Immune Deficient at Start ART 6 months 7.8% 1.8% 12 months 8.2% 2.2% 6% excess mortality Arrive E et al. 14th CROI, Los Angeles, CA, 2007 Abs. 727 73% median age > 5 years of age, > 50% start with severe immune deficiency, most deaths within 6 months of starting ART. Risk factors for death: low CD4 < 18 months age WHO stage 3/4 Viral load greater than 6·0 log severe malnutrition Sutcliffe et al. Lancet Infect Dis 2008;8: 477–89

CHER STUDY : 76% Reduction in the Risk of Death with Immediate Compared to Deferred ART 0.00 0.20 0.40 0.60 0.80 1.00 3 6 9 12 P = 0.0002 Deferred Immediate Most deaths occurred within first 6 months (i.e., before age 10 months) Failure Probability 16% deferred CHER: Trial recruited and enrolled 377 infants with confirmed HIV infection without advanced immune suppression between 6 and 12 weeks of age who had CD4 cell percentages equal to or greater than 25 percent.  Eligible infants were randomly enrolled in one of three groups immediate antiretroviral therapy (Zidovudine (AZT) + Lamivudine (3TC) + Lopinavir/Ritonavir (LPV/r) for 40 weeks, immediate antiretroviral therapy for 96 weeks, control group: ART was only initiated after doctors observed signs of clinical or immunological progression (e.g. CD4 cell percentage decline) Deferring the start of ART until an infant has clinical or immunologic decline was the standard of care in South Africa; however, the specific immunologic and clinical criteria for starting therapy in this study were slightly different from South African or World Health Organization (WHO) guidelines, and were changed over time to reflect revised WHO recommendations.  In this study, ART is started or restarted when %CD4 dropped below 20 % for infants greater than one-year old or %25 for infants less than one-year old or if symptomatic and severe disease occurs as defined by (CDC) criteria. All participants followed a schedule of regular clinical visits for a minimum of 3.5 years, with the clinical team available 24 hours a day for consultation, referrals and advice. All children received Co-trimoxazole and Pneumococcal vaccine Inclusion: HIV DNA PCR confirmed HIV infection CD4 >25% ART naïve except for pMTCT Age <12 weeks ART Regimen: ART: ZDV + 3TC + LPV/r On June 20, 2007, the DSMB reviewed the interim data and found a significant increase in survival among infants who received immediate ARV therapy (96 percent) compared to infants who received therapy later (84 percent) based on declining immune function linked to a defined CD4+ T-cell count and/or clinical progression.  Based on this finding, the DSMB recommended that no additional infants be placed in the deferred-treatment arm of the study and infants in this arm be evaluated for potential initiation of ARV therapy. The DSMB also recommended that all infants enrolled in the study be followed for the planned duration of approximately 3.5 years. 20% breast fed Endpoints: Primary: Death OR failure of 1st line ART regimen Secondary, including: Cumulative rate of disease progression and hospitalisation Grade 3 & 4 adverse events Development of ART Resistance Death rate per 100 person-years (Arm 2&3 vs 1) 3 months 10 vs 41 3 to 6 months 4 vs 23 6 to 12 months 3 vs 9 Conclusions: Starting ART before 12 weeks of age in HIV infected infants without sign of severe or advance immunodeficiency reduces early mortality by 75% 4% immediate Time to Death (months) Patients at risk 52 99 145 213 252 Immediate 22 44 72 104 125 Deferred Month 12 Month 9 Month 6 Month 3 Month 0

Entry points for children - Malawi Kenya - IPD 69% Cote D' Ivoire 64% IPD 12% PMTCT 24% PLHA Index 18%

Southern Africa – HIV prevalence in population based surveys Botswana Swaziland South Africa Source: CSO, Measure DHS. Swaziland Demographic and Health Survey 2006-7. Preliminary report, 2007. NACA, CSO. Botswana AIDS Impact Survey II 2004. Central Statistics Office: Gaborone, Botswana, 2005. Shisana, O., et al., South African National HIV Prevalence, HIV Incidence, Behaviour and Communication Survey, 2005. HSRC Press: Cape Town, 2005. SLIDE courtesy of E Gouws UNAIDS

only 8% of HIV exposed infants tested in 1st 2 months of life only 4 % started on co-trimoxazole We can only diagnose HIV in the first months of life using virological tests (HIV DNA PCR, HIV RNA PCR or bDNa or NASBA or ultrasenstive p24 antigen) As it takes some time to develop HIV infection and for HIV to start replicating, testing immediately at birth will not detect all those infants who HAVE HIV. To date the HIV DNA PCR is the only testing method that can be performed using DBS specimens ( i.e. and is therefore most useful in context of PMTCT follow up. HIV RNA methods are reliable can be done on plasma and whole blood specimens and are well suited to inpatient or sick infants where specimens using DBS are not essential) For ALL methods robust QA is required. Estimation of proportion of truly infected infants detected by testing at certain ages if all infants are breastfed would produce numbers as below for South Africa , base don performance of HIV DNA testing E.G. South Africa Tot infected (BF) % missed diagnosis at time of testing of total if BF Birth 59527 70 1st week 60012 50 2nd week 60497 30 3rd week 60980 20 4th week 61463 11 6th week 61944 5 2nd month 62425 4 3rd month 64445 5 4th month 66450 5 5th month 68438 5 6th month 70410 5 The ongoing missed diagnosis reflects those who have recently acquired HIV through breastfeeding and are in the window period. Estimated numbers do not adjust for those who would have died. WHO therefore recommends to perform testing at or around 4-6 weeks for PMTCT follow up and whenever sick or HIV is suspected in infants known to be exposed. Towards Universal Access: Scaling up priority HIV/AIDS interventions in the health sector, WHO/UNAIDS/UNICEF 2008

Ways forward Each infection can and should be prevented Early diagnosis prior to disease progression Earlier initiation of ART Expand PITC and screening for HIV in health care facilities

WHO recommendations for provider initiated testing approaches infants & children Population Recommendation Strength of recommendation HIV exposure unknown Ask all about HIV exposure as early as possible Strong Unknown HIV exposure High HIV burden Ensure /maternal/ infant testing within first 6 weeks or at first contact with health system Conditional – (HIV prevalence) HIV exposed Virological testing at 4-6 weeks of age Any signs or symptoms suggestive of HIV Age appropriate testing urgently Sibling, parent or carer has HIV (family) Age appropriate testing

WHO -new recommendations for starting ART in infants All infants under 12 months of age with confirmed HIV infection should be started on antiretroviral therapy, irrespective of clinical or immunological stage. GRADE Evidence profile = Moderate Strength of Recommendation = STRONG http://www.who.int/hiv/pub/paediatric/WHO_Paediatric_ART_guideline_rev_mreport_2008.pdf

What ART to Start in infants – 2008 revision NVP triple ART No infant or maternal ARV exposure 18% 34% PI triple ART# Sd NVP or NNRTI containing ART MTCT ARV Exposure NVP triple ART Non NNRTI exposure Unknown infant maternal MTCT Exposure NVP triple ART # If no PI is available use NVP triple ART Simplified weight based dosing availabe at; http://www.who.int/hiv/paediatric/en/index.html

Immunological thresholds to start ART Age %CD4 CD4/mm3 # Infants < 1 yr All- irrespective of CD4 12-35 months <20 <750 36-59 months <350 5 years or over <15 As in adults # Absolute CD4 count is naturally less constant and more age-dependent than %CD4; it is not therefore appropriate to define a single threshold.

Thank you Please feel free to contact me if you need more information Dr Siobhan Crowley crowleys@who.int Acknowledgments: HIV Care and treatment: Technical Reference group Paediatric ARV dosing working group WHO colleagues Lynne Mofenson Eleanor Gouws F Dabis/V Leroy Robert Gass/Patricia Doughty