HIV Testing at Birth: Brief Summary Potential Pros and Cons

Transcription

1 HIV Testing at Birth: Brief Summary Potential Pros and Cons Lynne M. Mofenson, M.D. Senior HIV Technical Advisory Elizabeth Glaser Pediatric AIDS Foundation

2 Why Consider HIV Testing at Birth? Goal of HIV testing is identification of an infected infant in order to initiate antiretroviral therapy (ART) early and therefore reduce morbidity and mortality. Testing without early initiation of ART will not be helpful. How early do you need to start ART to reduce mortality/morbidity? Is there an incremental gain in reducing morbidity and mortality with birth testing compared to current standard 6 week PCR? Lots of assumptions, but very little data!

3 Pros vs Cons of HIV Testing at Birth POTENTIAL PROS POTENTIAL CONS Mortality Morbidity Neurodevelopment Viral reservoir Clinical benefit Laboratory test performance Sensitivity Specificity Prevalence of HIV Programmatic issues Turn-around time Health resources Acceptability Retention Cost Let s examine some assumptions underlying these benefits/risks

4 Question: What proportion of infected children will be detected by adding an HIV test at birth? HIV Testing and Time of HIV Transmission in Current ART Era

5 Timing of Infection and HIV Testing Pregnancy Early Late Labor- Delivery Breastfeeding Early Late Without ART In utero 10-25% Intrapartum 35-40% Postpartum 35-40% <28 wks >28 wks 0-1 mo 1-6 mos 6-24 mos

6 Birth test detects only in utero infection Pregnancy Timing of Infection and HIV Testing Early Late Nduati R. Kenya BF Study JAMA 2000;283: wk test detects in utero + intrapartum/ early PP infection Labor- Delivery Breastfeeding Early 9 and 18 mo test includes postnatal infection Late OVERALL Without 37% ART 7% absolute In utero 10-25% (19% proportion) 13% absolute Intrapartum (35% 35-40% proportion) 17% absolute Postpartum 35-40% (46% proportion) <28 wks >28 wks 0-1 mo 1-6 mos 6-24 mos Without ARV, IU infection accounts for only small proportion of infections, although absolute rate relatively high. In presence of ARVs, will there be change in proportion of infections in utero vs intrapartum vs postnatal? May see in proportion of infection occurring in utero depending on when maternal ART is started OR postnatal depending on duration breastfeeding and ARV adherence.

7 Timing of Transmission in Maternal ART Studies Very Few Studies Provide Data on HIV Status at Birth Overall 6 mo Birth 1d-6 wk 6 wk-6 mo Historical 10-25% 35-40% 35-40% Kesho Bora (N=394) 4.9% 1.8% 1.5% 1.6% proportion of overall tx 37% 31% 33% KiBS (N=487) 5.0% 2.5% (7 d) 1.7% 0.8% proportion of overall tx 50% 34% 16% Mma Bana (N=709) 1.1% 0.8% 0% 0.3% proportion of overall tx 72% 0% 27% Zambia B+ (N=219) 4.1% 18 mo 0.9% 0.5% 2.7% (all >6 mos) proportion of overall tx 22% 12% 66% There does appear to be a shift toward proportion in utero infection with maternal ART but the extent varies btn studies and duration BF Absolute rate of IU infection (<1-3%) relatively low with maternal ART Kesho Bora Lancet 2011; Thomas PLosMed 2011; Shapiro NEJM 2010: Ngoma JIAS 2015

8 Question: Does it make a clinical difference if detect the infected child at birth compared to 6 weeks? Time of HIV Transmission and Mortality Risk

9 Time of Transmission and Mortality Pregnancy Early Late Labor- Delivery Breastfeeding Early Late Without ART In utero 10-25% Intrapartum 35-40% Postpartum 35-40% <28 wks >28 wks 0-1 mo 1-6 mos 6-24 mos Overall mortality in HIV-infected infants in first year of life is very high (35-50% 1, 3 ). However, mortality significantly varies by timing of transmission. 1 Newell ML et al. Lancet 2004;364: Zijenah LS et al. AIDS 2004;18: Mirinda E et al. PIDJ 2007;26: Marston M et al. Int J Epi 2011;40: Becquet R et al. PLosOne 2012;7:e28510

10 Does Time of Infection Make a Difference? Higher Early Death with Perinatal (IU+IP) vs Postnatal HIV Becquet R et al. PLosOne 2012;7:e28510 Cumulative probability of death Meta-analysis of 12 studies including 12,112 infants of HIV+ mothers (8,964 uninfected and 2,509 infected) 1,363 perinatal (med PCR 19 d) 565 unknown time 581 postnatal (HIV- >4 weeks, + later) 12 mo death Perinatal HIV+ 52% Unknown time HIV+ 38% Postnatal HIV+ 26% Uninfected 4%

11 Limited Data But Not a Clear Difference - Between In Utero and Intrapartum Infection for Very Early Mortality Newell ML et al. Lancet 2004;364: In this meta-analysis of 9 trials including 3,468 children, not much difference IU vs IP infection in early mortality Zijenah LS et al. AIDS 2004;18:273-80? In utero Intrapartum/ early PP Survival from 56 days to 6 months IU vs IP Included 89 IU, 104 IP/ePP infants. Analysis restricted to those alive at 8 weeks. IU vs IP/early PP: HR 1.91 ( ), with differences not emerging until >90 days

12 Is Very Early Mortality an Issue? Emerging Peak in Early Infant Mortality, South Africa Bourne DE et al. AIDS 2009;23: Evaluated overall mortality birth-5 years , S Africa Saw emerging peak in mortality at 2-3 mos by 2002

13 Is Very Early Mortality an Issue? Emerging Peak in Early Infant Mortality, South Africa Bourne DE et al. AIDS 2009;23: Evaluated reported cause death as likely HIV related or not 2-3 mo peak was due to likely HIV-related mortality, whereas non-hiv mortality did not change over time HIV/AIDS-related mortality Presumed HIV infection only, and no data on time of transmission

14 Early Infant Mortality in HIV-Infected Infants - Zimbabwe Marinda E et al. PIDJ 2007;26: ZVITAMBO trial ( ), N=13,792: HIV-unexposed (9,510) 2 Year Mortality 2.9% HIV-exposed uninfected (3,135) 9.2% Postnatal infection (258) Intrapartum infection (508) In utero infection (381) 33.2% 65.0% 67.5% Similar to Bourne study, see rapid mortality with IU/IP infection starting ~60 days (2 months) to days (3-6 months) Similar to Zijenah Study, see potential difference IU-IP after ~ days Not clear differences HIV+ & HIV- in the neonatal 0-2 month period

15 Early Infant Mortality in HIV-Infected Infants - Zimbabwe Marinda E et al. PIDJ 2007;26: ZVITAMBO trial ( ), N=13,792: HIV-unexposed (9,510) If there is not significant HIV-exposed uninfected (3,135) 2 Year Mortality 2.9% 9.2% effect of HIV on mortality Postnatal infection (258) before age 2 mos, will Intrapartum infection (508) birth testing In add utero infection any (381) 33.2% 65.0% 67.5% benefit in terms of mortality? Similar to Bourne study, see rapid mortality with IU/IP infection starting ~60 days (2 months) to days (3-6 months); and similar to Zijenah Study, see potential initial difference IU-IP after ~ days Not clear differences HIV and HIV- in the neonatal 0-2 month period

16 But What About Early Morbidity? Violari A et al. NEJM 2008;359: : CHER: randomized at 6-12 wks to early vs deferred ART. Screening <6-12 weeks children who did NOT enter CD4 <25%: 110/560 (19.6%) Symptoms: 16/560 (2.9%) Died: 7/560 (1.3%) Innes S et al. JIAS 2014;17:18914 Record review 403 kids starting early ART S Africa; started median age 8.4 wks ( ) (no data on time infection) Prior to starting ART (so age <8 wks): 51% had CD4 <25% 29% WHO stage 3 or 4 62% had advanced disease before starting ART Each month increase in age at ART associated with 1.69 increased odds of developing advanced disease

17 But What About Early Morbidity? Violari A et al. NEJM 2008;359: : CHER: randomized at 6-12 wks to early vs deferred ART. Screening Does<6-12 appear weeks children to be who did early NOT enter CD4 <25%: 110/560 (19.6%) effect Symptoms: of 16/560 HIV (2.9%) on CD4 and Died: 7/560 (1.3%) symptoms before age 8 Innes S et al. JIAS 2014;17:18914 Record wks; review could 403 kids starting birth early testing ART S Africa; started median age 8.4 wks ( ) (no data on time infection) Prior and to starting early ART (so ART age <8 wks): make a 51% had CD4 <25% 29% WHO stage difference? 3 or 4 62% had advanced disease before starting ART Each month increase in age at ART associated with 1.69 increased odds of developing advanced disease

18 HIV Test Performance

19 HIV Test Performance Important Factors Affecting Assay Accuracy Time of acquisition of infection birth test only detects IU infection. Critical need for 2 nd test at 6-10 weeks for those testing negative to diagnose IP/early PP infection. HIV prevalence in infants (depends on PMTCT). Low prevalence number false positive tests must have CONFIRMATORY test for those testing +. Possibly maternal/neonatal ARV use (potential delay in detection but not enough data to determine now). Should 6 week test be delayed until weeks (after infant prophylaxis completed)?

20 At Low HIV Prevalence (e.g., PMTCT), Rate of False Positive Single Test Increases Performance of HIV assay with sensitivity of >95% and specificity of 98% at various HIV prevalence levels

21 At Low HIV Prevalence (e.g., PMTCT), Rate of False Positive Single Test Increases False + results are common if only a single test is performed when transmission rates are low (regardless of time transmission). If resources allow for only 2 viral tests, would a single test at birth and 6 weeks with no confirmation of + result be better than 1 st test at 6 weeks with confirmation of + result? Strategy # False +/ 100 ART initiations 6 wk only, with confirmatory test if Birth + 6 wk test, no confirmatory test 34.5 Modeling analyses by Andrea Ciranello for WHO

22 Programmatic Issues EID Total TAT time: 61.7 days (CI = 55.3, 68.7) Michelle Gill, EGPAF-2013 IAS Abs. MOAD0202

23 Programmatic Issues How early can ART be started? Turn-around time from test to ART start Availability of treatment for neonates Formulation, dosing, safety Assay sensitivity/specificity need for confirmatory test what if start ART & confirmatory test negative? How will birth testing affect return/retention? Will mothers return for 6 week test? Health resources who tests, extra visit for results, lab burden? Incremental cost vs benefit

24 Even if Tested in Timely Fashion, There are Significant Delays from Testing to ART Start - S Africa Example Lillan RR et al. PIDJ 2013;32: PCR test 6.6 wks PCR result visit 10.6 wks 1 st visit for care 12.6 wks ART started16.0 wks Viral suppression 36.5 wks

25 High Early Infant Mortality in Infants Infected In Utero/Intrapartum Marinda E et al. PIDJ 2007;26: HIV-unexposed PCR 6.6 wk Start ART 16 wk Suppress VL 37 wk HIV-exposed uninfected Postnatal infection Intrapartum infection In utero infection Rapid increase in mortality in infants with in utero/intrapartum infection beginning <60 days (2 months) through days (3-6 months)

26 With Birth PCR, How Quickly Need to Start ART to Achieve Suppression Before Rapid Increase Mortality? PCR birth Start ART 2-4 wk Suppress VL 12 wk HIV-unexposed HIV-exposed uninfected Postnatal infection Intrapartum infection In utero infection Without POC test, will it be possible to do test, give results and start ART by age 2 weeks? (Maybe - Abs 4: med time to start in kids <12 mo/o was 8 d)

27 EID coverage in 2014 Source: Global AIDS Response Progress Reporting (WHO/UNICEF/UNAIDS); Proportion of HIV-exposed infants receiving virological testing by their second month of age. Zimbabwe Zambia United Republic of Tanzania Uganda Swaziland South Africa Nigeria Namibia Mozambique Malawi Lesotho Kenya Ghana Ethiopia Democratic Republic of the Congo Côte d'ivoire What about optimizing Chad Cameroon current recommendations? Burundi Botswana Angola 50% HIV-exposed Infants received a virological test in 21 African Global Plan countries 0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1

28 Pros vs Cons of HIV Testing at Birth POTENTIAL PROS POTENTIAL CONS Mortality Morbidity Neurodevelopment Viral reservoir Clinical benefit Laboratory test performance Sensitivity Specificity Prevalence of HIV Programmatic issues Turn-around time Health resources Acceptability Retention Cost ROUNDTABLE PANEL MEMBER THOUGHTS - DISCUSSION