The CHER Trial: successful early treatment of HIV infected infants - What are the next steps?

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Valerie Phillips
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1 The CHER Trial: successful early treatment of HIV infected infants - What are the next steps? Avy Violari, FCPaed (SA) University of Witwatersrand, Chris Hani Baragwanath Hospital, Johannesburg, South Africa BHIVA Autumn Conference 9- October, London, UK Rationale for trial Higher risk of death and disease progression in infancy CD4 and viral load are poor predictors of disease progression in infants All these factors suggest earlier initiation Initiation of ARV s commits to lifelong therapy Adherence Resistance Availability of regimens Toxicity Resources 2

2 CHER Trial - Hypothesis Early limited ART until st or 2 nd may: birthday Feasible, safe Have long-term benefit by delaying disease progression Delay the time when long-term continuous ART needs to be started 3 CHER Trial n= 375 HIV infection diagnosed before 2 weeks and CD4% >25% Arm Deferred treatment N=25 Arm 2 Short course (to first birthday) N=25 Arm 3 Long course ( to second birthday) N=25 ART (start or re-start) when CD4% <2% or clinical event (<25% from August 26) FOLLOW UP For a minimum of 3.5 years 4 2

3 CHER Trial Design ART: ZDV + 3TC + LPV/r All children received Co-trimoxazole and Pneumococcal vaccine Endpoints: Primary: Death OR failure of st line ART regimen Secondary, including: Cumulative rate of disease progression and hospitalisation Grade 3 & 4 adverse events Development of ART Resistance 5 Screening & Enrolment Number of Participants prescreened: 5985 Number of Participants HIV+: 45 (6.8% of prescreened) Number of referred HIV+ participants: 55 Total Number of HIV+ Participants: 56 Number of Participants screened: 532 Participants enrolled to Part A: 377 Participants enrolled to Part B: 4 Participants with a CD4% < 25%: 64 Not enrolled for Other reasons: 5 6 3

4 Criteria for starting ART in Arm Immunological criteria CD4% <2% (WHO guidelines 23 and SA guidelines) Then from August 26: CD4% <25% or CD4 count <cells/mm 3 if age <2mo Clinical Criteria CDC Stage C Selected Stage B: Chronic lung disease including bronchiectsis and LIP Nephropathy Cardiomyopathy FTT in absence of remediable causes Recurrent bacterial pneumonia Severe or recurrent oral candidiasis 7 Review and Monitoring Reviewed by Independent International DSMB Africa Annual review for safety and efficacy concerns Additional 3 monthly death review Statistical criterion for proof beyond reasonable doubt was Haybittle-Peto rule (p<.) Second interim analysis DSMB recommended modification of the study release results of Arm versus Arms 2&3 combined infants in Arm not already on ART should be urgently recalled and assessed for ART trial follow-up to continue Interim data presented after median follow-up of 32 (*IQR: 2-48) weeks 8 4

5 Baseline characteristics 5985 babies were screened using DNA PCR to enrol 377 HIV pos infants Variable Arm 2 & 3 Arm Number of participants enrolled Sex: Female (%) 47 (58.3 %) 74 (59 %) Age (weeks, median (IQR) 7.4 ( ) 7. ( ) Mother receiving ART for PMTCT No Therapy 26 (.3 %) 5 (2 %) NVP (%) 62 (64.3 %) 72 (58 %) AZT (%) 8 (3.2 %) 5 (4 %) AZT + NVP (%) 5 (2.2 %) 26 (2 %) HAART (%) 2 (.8 %) 5 (4 %) Weight (Median IQR (kg) 4.4 ( ) 4.5 ( ) CDC Classification Class N & A (%) 237 (94. %) 2 (96.8 %) Class B (%) (4.4 %) 3 (2.4 %) CD4 % (median (IQR) CD4 Count (cells/mm 3 ) median (IQR) ( ) ( ) ( ) ( ) 9 Follow-up and use of ART Variable Arm 2 & 3 n = 252 Arm n = 25 Lost to follow-up (4. %) 4 (3.2 %) No. of participants initiating ART 25 6 Participants on ART at: Week 2 Week 24 Week 32 Week 4 % time spent on ART by week % 96.5 % 95.6 % 95. % 98.6 % 8. % 48.8 % 59. % 52.3 % 32. % 5

6 Mortality Rates Variable Arm 2 & 3 n = 252 Arm n = 25 Total n = 377 Died (%) (4%) 2 (6%) 3 (8%) Person Years of follow-up Rate per PY (95% CI) 6. (2.9; ) 25.3 (5.5; 39.) 2.2 (8.2; 7.4) Hazard Ratio.24 (.;.5) P - value.2 Time to Death Failure Probability P = Time to Death (months) Arm Arm 2 & 3 Patients at risk Month Month 3 Month 6 Month 9 Month 2 Arm Arm 2 & Arm

7 Risk of death Death rate per person-years (Arm 2&3 vs. ) 3 months vs. 4 3 to 6 months 4 vs to 2 months 3 vs. 9 3 Causes of Death Variable Arm 2 & 3 Arm Total Died at home/unknown Gastroenteritis Pneumonia/sepsis 4 4 PCP /CMV 3 3 SIDS Liver failure Total

8 Commonly reported infections Arm 2 & 3 Arm G3/4 Gastroenteritis G/2 Gastroenteritis G3/4 Pneumonia G/2 Pneumonia Meningitis Tuberculosis 29 (4.) 8 (87.5) 25 (2.2) 66 (32.) (.5) 7 (8.3) 36(38.2) 23(3.5) 25(26.5) 56(59.4) 6(6.4) 9(2.2) * (events per PY) 5 Disease progression in all patients Variable Arm 2 & 3 n = 252 Arm n = 25 Total Failure to thrive Developmental delay 8 9 PCP 4 4 Oesophageal candidiasis Extrapulmonary TB 2 Recurrent infections 2 2 CMV pneumonitis 2 2 CMV disseminated HIV waisting LIP Chronic lung disease Number patients

9 Summary & Conclusions The results of CHER demonstrated that early ART reduced mortality by 76% and HIV progression by 75% Findings from other trials concur with these findings Durban Trial European Infant collaboration 7 Change in recommendations Amended US, WHO, PENTA Guidelines On 28 February 28, Revised USA guidelines recommended that all HIV-infected children <2 months of age receive immediate ART ( On 3th June 28, the Technical Reference Group of the WHO made an identical recommendation ( September 28, PENTA - same recommendation 8 9

10 Are these guidelines immediately possible in poor countries? 9 Access to care after birth Early initiation of ART only possible in a setting of successful MTCT programs and early infant diagnosis PCR s and early diagnosis require considerable expense and logistics Only 8% of HIV exposed infants in low and middle income countries had access to early infant testing Only 4% of exposed 2-month-olds received Cotrimoxazole prophylaxis Source:WHO(28) Towards Universal Access: Scaling up Priority HIV?AIDS Interventions in the Health Sector 2

11 Will early treatment place the health system under strain? In CHER: 66% had started ART during median follow-up of 4 weeks Mphatswe et al: 85% of infants met WHO criteria for ART initiation (CD4% <2%) by 6 months of age 2 Kaplan Meier Plot of the Time to initiating Antiretroviral Therapy in the Deferred Treatment Arm Kaplan-Meier failure estimate Time from Randomisation to the initiation of Antiretroviral Therapy (weeks) Number of Patients at Risk of starting Antiretroviral Therapy

12 Delaying treatment? Deferred Therapy delays ART only by a few weeks requires intensive monitoring results in considerable mortality and morbidity No good monitoring markers to guide treatment decisions May be more complicated and resource draining Likely that treating all HIV-infected infants from time of diagnosis will be easier and more cost-effective 23 Is treatment for a limited time an option? CHER trial Trial in Kenya (continuous vs interruption at 2 years) 24 2

13 Starting HIV positive babies on ART: Mothers perspectives Positive attitudes ART was seen as able to fight HIV disease, thereby increasing the chances of the baby s survival. it would be painful knowing that your baby is ill and he is not taking treatment they [ARVs] give me hope that she will be fine feeling good confident optimistic. he will survive they [ARVs] will make changes in his life, just as they did for me I can see my baby is doing well on them [ARVs] 25 Starting HIV positive babies on ART: Mothers perspectives Doubts and concerns The life-long nature of ART was a concern I am worried about him that he going to take these drugs until he gets old and he won t be able to stop taking them he will have to take them for the rest of his life I didn t see any reason or sense in giving a small baby such strong drugs Fears about the toxicity of ARVs 26 3

14 What does it mean for PMTCT? If this approach not possible should we divert resources towards treating all pregnant mothers with HAART in pregnancy in order to drive transmission down to below %? 27 Reality Check: a question of scale Annual pregnancies in HIV positive women: United States < 7, Rwanda 8,6 Botswana 4, Europe 5, Kenya, South Africa 25, Soweto 9, 28 4

15 Reality Check CD4 counts need to be available for HIV positive pregnant women in order to decide on appropriate treatment options, and few PMTCT services have moved to include CD4 at all health service levels Provision of more complex ART requires more laboratory and toxicity monitoring, additional procurement infrastructure, and more intensive follow up Most PMTCT services (based on antenatal care) do not yet have the capacity to deliver ART 29 The need for effective PMTCT Regimens for Resource-Poor Countries WHO Paediatric HIV/AIDS in 25 Global Estimate Sub- Saharan Africa Resource- Rich Countries Children Living with HIV/AIDS 2.3 million 2. million 4, New Infant HIV Infections 7, 63, 7 Deaths in Children with HIV/AIDS 57, 48, 2 MTCT has been reduced to <2% in countries which bear.6% of the global paediatric HIV burden 3 5

16 Setting priorities for implementing early ART Access to PCR for HIV-exposed babies is the key to moving forward Overcome programmatic barriers of infant follow up Attitudes of staff Advocacy Moving towards early ART will be increasingly possible as treatment programmes mature 3 Acknowledgments: With thanks to: Diana Gibb James McIntyre Mark Cotton Abdel Babiker for use of their data and slides The CHER Trial was done in collaboration with researchers from CTU,MRC,UK Funded by the Division of AIDS,NIAID,NIH Pharmaceutical Support provided by GSK and South African Dept. of Health 32 6

Antiretroviral therapy for HIV infection in infants and children: Towards universal access

Antiretroviral therapy for HIV infection in infants and children: Towards universal access Executive summary of recommendations Preliminary version for program planning 2010 Executive summary Tremendous