Early infant HIV-1 diagnosis programs in resource-limited settings: opportunities for improved outcomes and more cost-effective interventions

Early infant diagnosis (EID) of HIV-1 infection confers substantial benefits to HIV-infected and HIV-uninfected infants, to their families, and to programs providing prevention of mother-to-child transmission (PMTCT) services, but has been challenging to implement in resource-limited settings. In order to correctly inform parents/caregivers of infant infection status and link HIV-infected infants to care and treatment, a 'cascade' of events must successfully occur. A frequently cited barrier to expansion of EID programs is the cost of the required laboratory assays. However, substantial implementation barriers, as well as personnel and infrastructure requirements, exist at each step in the cascade. In this update, we review challenges to uptake at each step in the EID cascade, highlighting that even with the highest reported levels of uptake, nearly half of HIV-infected infants may not complete the cascade successfully. We next synthesize the available literature about the costs and cost effectiveness of EID programs; identify areas for future research; and place these findings within the context of the benefits and challenges to EID implementation in resource-limited settings.

[1]  W. Borkowsky,et al.  Ritonavir-Based Highly Active Antiretroviral Therapy in Human Immunodeficiency Virus Type 1-Infected Infants Younger Than 24 Months of Age , 2005, The Pediatric infectious disease journal.

[2]  R. Sell,et al.  Cost‐Effectiveness of Elective Cesarean Delivery in Human Immunodeficiency Virus–Infected Women , 2001, Obstetrics and gynecology.

[3]  N. Shaffer,et al.  Early Diagnosis of HIV‐1‐Infected Infants in Thailand Using RNA and DNA PCR Assays Sensitive to Non‐B Subtypes , 2000, Journal of acquired immune deficiency syndromes.

[4]  W. Grobman,et al.  The cost-effectiveness of voluntary intrapartum rapid human immunodeficiency virus testing for women without adequate prenatal care. , 1999, American journal of obstetrics and gynecology.

[5]  F. Dabis,et al.  Early mixed feeding and breastfeeding beyond 6 months increase the risk of postnatal HIV transmission: ANRS 1201/1202 Ditrame Plus, Abidjan, Côte d'Ivoire. , 2008, Preventive medicine.

[6]  P. Kazembe,et al.  Effect of provider-initiated testing and counselling and integration of ART services on access to HIV diagnosis and treatment for children in Lilongwe, Malawi: a pre- post comparison , 2009, BMC pediatrics.

[7]  W. Prasitsuebsai,et al.  Boosted p24 antigen assay for early diagnosis of perinatal HIV infection. , 2010, Journal of the Medical Association of Thailand = Chotmaihet thangphaet.

[8]  S. Omer,et al.  Slower clearance of nevirapine resistant virus in infants failing extended nevirapine prophylaxis for prevention of mother-to-child HIV transmission. , 2011, AIDS research and human retroviruses.

[9]  M. Mcgrath.  Cost Effectiveness in Health and Medicine. , 1998 .

[10]  J. Stringer,et al.  Rapid testing and zidovudine treatment to prevent vertical transmission of human immunodeficiency virus in unregistered parturients: a cost-effectiveness analysis. , 1999, Obstetrics and gynecology.

[11]  James Bethel,et al.  Performance Characteristics of HIV-1 Culture and HIV-1 DNA and RNA Amplification Assays for Early Diagnosis of Perinatal HIV-1 Infection , 2003, Journal of acquired immune deficiency syndromes.

[12]  S. Bertozzi,et al.  Cost-effectiveness of strategies to reduce mother-to-child HIV transmission in Mexico, a low-prevalence setting. , 2003, Health policy and planning.

[13]  J. Stockman.  Early Antiretroviral Therapy and Mortality among HIV-Infected Infants , 2010 .

[14]  D. Ridley,et al.  Cape Town, South Africa , 1986, Journal of clinical ultrasound : JCU.

[15]  Ovidio Paredes.  San Francisco 2010 , 2010 .

[16]  M. Tanner,et al.  Adaptation of the Ultrasensitive HIV-1 p24 Antigen Assay to Dried Blood Spot Testing , 2007, Journal of acquired immune deficiency syndromes.

[17]  J. Berkley,et al.  Dynamics and Constraints of Early Infant Diagnosis of HIV Infection in Rural Kenya , 2011, AIDS and Behavior.

[18]  D. Mcintyre,et al.  The cost-effectiveness of Antiretroviral Treatment in Khayelitsha, South Africa – a primary data analysis , 2006, Cost effectiveness and resource allocation : C/E.

[19]  J. Wiener,et al.  Ultrasensitive p24 Antigen Assay for Diagnosis of Perinatal Human Immunodeficiency Virus Type 1 Infection , 2007, Journal of Clinical Microbiology.

[20]  R. Walensky,et al.  Effectiveness of pediatric antiretroviral therapy in resource-limited settings: a systematic review and meta-analysis. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[21]  Julia E. Aledort,et al.  Reducing stunting among children: the potential contribution of diagnostics , 2006 .

[22]  D K Owens,et al.  A meta-analytic evaluation of the polymerase chain reaction for the diagnosis of HIV infection in infants. , 1996, JAMA.

[23]  L. Moulton,et al.  Making a working clinical diagnosis of HIV infection in infants in Zimbabwe , 2008, Tropical medicine & international health : TM & IH.

[24]  Matilu Mwau,et al.  Rapid identification of infants for antiretroviral therapy in a resource poor setting: the Kenya experience. , 2008, Journal of tropical pediatrics.

[25]  G. Kvåle,et al.  Achieving progress in maternal and neonatal health through integrated and comprehensive healthcare services – experiences from a programme in northern Tanzania , 2009, International journal for equity in health.

[26]  髙折 晃史,et al.  19th Conference on Retroviruses and Opportunistic Infections , 2012 .

[27]  J. Tappero,et al.  Cost-Effectiveness of Routine Rapid Human Immunodeficiency Virus Antibody Testing Before DNA-PCR Testing for Early Diagnosis of Infants in Resource-Limited Settings , 2009, The Pediatric infectious disease journal.

[28]  Stephanie A. Jones,et al.  Is early HIV testing of infants in poorly resourced prevention of mother to child transmission programmes unaffordable? , 2005, Tropical medicine & international health : TM & IH.

[29]  F. Dabis,et al.  Cohort profile: the paediatric antiretroviral treatment programmes in lower-income countries (KIDS-ART-LINC) collaboration. , 2008, International journal of epidemiology.

[30]  S. Kellerman,et al.  HIV Testing for Children in Resource-Limited Settings: What Are We Waiting For? , 2010, PLoS medicine.

[31]  R. Bollinger,et al.  Nevirapine Resistance and Breast-Milk HIV Transmission: Effects of Single and Extended-Dose Nevirapine Prophylaxis in Subtype C HIV-Infected Infants , 2009, PloS one.

[32]  Stephanie A. Jones,et al.  Oral Fluid Human Immunodeficiency Virus Tests: Improved Access to Diagnosis for Infants in Poorly Resourced Prevention of Mother to Child Transmission Programs , 2005, The Pediatric infectious disease journal.

[33]  B. Walker,et al.  High frequency of rapid immunological progression in African infants infected in the era of perinatal HIV prophylaxis , 2007, AIDS.

[34]  N. Rollins,et al.  Paediatric HIV management at primary care level: an evaluation of the integrated management of childhood illness (IMCI) guidelines for HIV , 2009, BMC pediatrics.

[35]  S. Pelton,et al.  Seroreversion in human immunodeficiency virus‐exposed but uninfected infants , 1995, The Pediatric infectious disease journal.

[36]  N. Shaffer,et al.  Factors Associated with Low Early Uptake of a National Program to Prevent Mother to Child Transmission of HIV (PMTCT): Results of a Survey of Mothers and Providers, Botswana, 2003 , 2009, AIDS and Behavior.

[37]  E. Denamur,et al.  The sensitivity of HIV‐1 DNA polymerase chain reaction in the neonatal period and the relative contributions of intra‐uterine and intra‐partum transmission , 1995, AIDS.

[38]  A. Sohn,et al.  Failure of Human Immunodeficiency Virus Enzyme Immunoassay to Rule Out Infection Among Polymerase Chain Reaction-Negative Vietnamese Infants at 12 Months of Age , 2009, The Pediatric infectious disease journal.

[39]  R. Chou,et al.  Screening for Human Immunodeficiency Virus: Focused Update of a 2005 Systematic Evidence Review for the U.S. Preventive Services Task Force , 2007 .

[40]  James A McIntyre,et al.  Early antiretroviral therapy and mortality among HIV-infected infants. , 2008, The New England journal of medicine.

[41]  A. Tanuri,et al.  Early Diagnosis of Human Immunodeficiency Virus in Infants Using Polymerase Chain Reaction on Dried Blood Spots in Botswana's National Program for Prevention of Mother-to-Child Transmission , 2008, The Pediatric infectious disease journal.

[42]  F. Dabis,et al.  Field efficacy of zidovudine, lamivudine and single-dose nevirapine to prevent peripartum HIV transmission , 2005, AIDS.

[43]  C. Beck-Sague,et al.  Diagnosis of Human Immunodeficiency Virus Type 1 Infection in Infants by Use of Dried Blood Spots and an Ultrasensitive p24 Antigen Assay , 2008, Journal of Clinical Microbiology.

[44]  E. Denamur,et al.  The sensitivity of HIV-1 DNA polymerase chain reaction in the neonatal period and the relative contributions of intra-uterine and intra-partum transmission , 1995 .

[45]  H. van Rooyen,et al.  Universal HIV testing of infants at immunization clinics: an acceptable and feasible approach for early infant diagnosis in high HIV prevalence settings , 2009, AIDS.

[46]  J. Stringer,et al.  Potential Cost-Effectiveness of Maternal and Infant Antiretroviral Interventions to Prevent Mother-to-Child Transmission During Breast-feeding , 2005, Journal of acquired immune deficiency syndromes.

[47]  Y. Bryson,et al.  Diagnosis of HIV infection in children. , 2000, Pediatric clinics of North America.

[48]  R. Elghanian,et al.  p24 Antigen Rapid Test for Diagnosis of Acute Pediatric HIV Infection , 2010, Journal of acquired immune deficiency syndromes.

[49]  Adeeba Kamarulzaman,et al.  AIDS Res Hum Retroviruses , 2006 .

[50]  C. Giaquinto,et al.  Virologic, immunologic, and clinical benefits from early combined antiretroviral therapy in infants with perinatal HIV-1 infection. , 2006, AIDS.

[51]  J. Crump,et al.  Evaluation of a dried blood spot HIV-1 RNA program for early infant diagnosis and viral load monitoring at rural and remote healthcare facilities , 2009, AIDS.

[52]  J. Levison,et al.  Rapid HIV versus enzyme-linked immunosorbent assay screening in a low-risk Mexican American population presenting in labor: a cost-effectiveness analysis. , 2005, American journal of obstetrics and gynecology.

[53]  Maria H. Kim,et al.  Inadequate Coordination of Maternal and Infant HIV Services Detrimentally Affects Early Infant Diagnosis Outcomes in Lilongwe, Malawi , 2011, Journal of acquired immune deficiency syndromes.

[54]  J. Moye,et al.  The relationship between serum human immunodeficiency virus type 1 (HIV-1) RNA level, CD4 lymphocyte percent, and long-term mortality risk in HIV-1-infected children. National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial Study Group. , 1997, The Journal of infectious diseases.

[55]  G. Schutze,et al.  False-negative post-18-month confirmatory HIV tests in HIV DNA PCR-positive children: a retrospective analysis , 2012, AIDS.

[56]  Gerald P. Douglas,et al.  Using Touchscreen Electronic Medical Record Systems to Support and Monitor National Scale-Up of Antiretroviral Therapy in Malawi , 2010, PLoS medicine.

[57]  A. Ades,et al.  Risk of human immunodeficiency virus type 1 transmission through breastfeeding , 1992, The Lancet.

[58]  C. Rouzioux,et al.  Early versus deferred antiretroviral multidrug therapy in infants infected with HIV type 1. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[59]  R. Wanyenze,et al.  Provider‐initiated HIV testing for paediatric inpatients and their caretakers is feasible and acceptable , 2009, Tropical medicine & international health : TM & IH.

[60]  W. Mphatswe,et al.  Antiretroviral Drugs in the Cupboard are Not Enough: The Impact of Health Systems' Performance on Mother-to-Child Transmission of HIV , 2011, Journal of acquired immune deficiency syndromes.

[61]  A. Foulkes,et al.  Low-Cost HIV-1 Diagnosis and Quantification in Dried Blood Spots by Real Time PCR , 2009, PloS one.

[62]  M. Eckman,et al.  The Impact of Expected HIV Transmission Rates on the Effectiveness and Cost of Ruling Out HIV Infection in Infants , 2002, Medical decision making : an international journal of the Society for Medical Decision Making.

[63]  N. Rollins,et al.  Surveillance of mother-to-child transmission prevention programmes at immunization clinics: the case for universal screening , 2007, AIDS.

[64]  J. Read.  Diagnosis of HIV-1 Infection in Children Younger Than 18 Months in the United States , 2007, Pediatrics.

[65]  Peter B Gilbert,et al.  Breastfeeding plus infant zidovudine prophylaxis for 6 months vs formula feeding plus infant zidovudine for 1 month to reduce mother-to-child HIV transmission in Botswana: a randomized trial: the Mashi Study. , 2006, JAMA.

[66]  Julian Gold,et al.  Antiretroviral therapy for HIV infection in infants and children: towards universal access. Recommendations for a public health approach. , 2007 .

[67]  R. Kumar,et al.  The effect of interrupted 5-day training on Integrated Management of Neonatal and Childhood Illness on the knowledge and skills of primary health care workers. , 2009, Health policy and planning.

[68]  R. Subbaye,et al.  Prevention of mother to child transmission of HIV (PMTCT) programme in KwaZulu‐Natal, South Africa: an evaluation of PMTCT implementation and integration into routine maternal, child and women’s health services , 2010, Tropical medicine & international health : TM & IH.

[69]  L. Mofenson,et al.  The Relationship between Serum Human Immunodeficiency Virus Type 1 (HIV-1) RNA Level, CD4 Lymphocyte Percent, and Long-Term Mortality Risk in HIV-1—Infected Children , 1997 .

[70]  Julia E. Aledort,et al.  Reducing the burden of HIV/AIDS in infants: the contribution of improved diagnostics. , 2006, Nature.

[71]  W. Tsai,et al.  Effects of early, abrupt weaning on HIV-free survival of children in Zambia. , 2008, The New England journal of medicine.

[72]  B. Walker,et al.  Early virological suppression with three-class antiretroviral therapy in HIV-infected African infants , 2008, AIDS.

[73]  F. Dabis,et al.  Estimating the rate of mother‐to‐child transmission of HIV. Report of a workshop on methodological issues Ghent (Belgium), 17–20 February 1992 , 1993, AIDS.

[74]  Victoria Nankabirwa,et al.  Introducing a multi-site program for early diagnosis of HIV infection among HIV-exposed infants in Tanzania , 2010, BMC pediatrics.

[75]  L. Kalish,et al.  Viral load and disease progression in infants infected with human immunodeficiency virus type 1. Women and Infants Transmission Study Group. , 1997, The New England journal of medicine.

[76]  G. Sherman,et al.  Psychosocial consequences of early diagnosis of HIV status in vertically exposed infants in Johannesburg, South Africa. , 2005, Health care for women international.

[77]  A. Coovadia,et al.  Evaluation of the Ultrasensitive Human Immunodeficiency Virus Type 1 (HIV-1) p24 Antigen Assay Performed on Dried Blood Spots for Diagnosis of HIV-1 Infection in Infants , 2007, Clinical and Vaccine Immunology.

[78]  M. Fowler,et al.  Infant human immunodeficiency virus diagnosis in resource-limited settings: issues, technologies, and country experiences. , 2007, American journal of obstetrics and gynecology.

[79]  Kenneth A. Freedberg,et al.  The “ART” of Linkage: Pre-Treatment Loss to Care after HIV Diagnosis at Two PEPFAR Sites in Durban, South Africa , 2010, PloS one.