Continuing Education Activity

Over 95% of HIV-infected pediatric cases are a result of vertical transmission. Neonatal HIV is the concern for HIV in an infant born to a mother with known or suspected HIV disease. It is important to identify those patients early so that appropriate treatment and monitoring can be implemented. This activity outlines the evaluation and management of neonatal HIV and reviews the interprofessional team's role in managing these patients.

Objectives:

• Identify the etiology and epidemiology of neonatal HIV.
• Assess the common presentation, history, and diagnosis of neonatal HIV.
• Determine the appropriate treatment and management options available for neonatal HIV.
• Determine interprofessional team strategies for improving care coordination and communication to advance the identification of those at risk for neonatal HIV and improve outcomes.

Introduction

Over 95% of HIV-infected pediatric cases are a result of vertical transmission. The pathophysiology of the HIV disease state in the pediatric population is similar to adults. However, differences occur in the clinical presentation, mode of infection, and therapeutic options. The pediatric and neonatal populations have a weaker immune system than adults; therefore, if infected with HIV, they are at a greater risk of opportunistic infections. As such, the delay of treatment may result in a rapid progression of the disease.

One of the greatest advancements in medicine has been the prevention of mother-to-child transmission (MTCT) of HIV type 1 (HIV-1). The rate of transmission of HIV to neonates has been reduced to less than 1% with the implementation of appropriate strategies and careful planning. The increase in comprehensive serologic screening and the treatment of HIV-infected pregnant females has resulted in the reduction of vertical transmission. There are evidence-based prevention modalities that can be utilized at different stages of pregnancy and postpartum to improve outcomes. Antiretroviral therapies (ART) can be prescribed during gestation, antepartum during vaginal or elective cesarean delivery, postnatally to the neonate, or when breastfeeding.[1][2]

Etiology

HIV is a ribonucleic acid (RNA) viral pathogen with 2 subtypes: HIV-1 and HIV-2. HIV-1 is the most common type worldwide and is more transmissible and progresses faster than HIV-2. Presumably, this Retroviridae family originated from wild chimpanzees in Central Africa.[3] The virus is transmitted across mucous membranes via penetrative unprotected sexual intercourse or intravenous drug use, blood transfusions in developing countries, vertical transmission, or through breastfeeding.[4][5] The risk of transmission via lactation is about 12-14%, with the risk increasing in high viral load states.[6][7] Overall, the probability of vertical transmission is about 25% without the utilization of appropriate ART therapy during pregnancy. Several risk factors that increase the chance of this transmission were observed in clinical trials. The risk factors include elevated maternal plasma viral RNA concentrations, maternal breast milk viral load, acute maternal seroconversion, advanced maternal disease, and decreased CD4+ T-cell count of the mother.[8][9][10][11][12]

Epidemiology

The burden of MTCT is a worldwide epidemic, with an estimated 160,000 infants infected annually with HIV as of 2018. The majority of mothers and neonates infected with HIV are located in sub-Saharan Africa.[13] Overall, the rate of perinatal transmission of HIV has decreased substantially over the past 20 years to less than 1% in the United States and Europe.[14][15] In the United States, approximately more than 5,000 pregnant females are HIV positive.[16] In the year 2013, nationwide in the United States, there were only 69 infants born with HIV infection, leading to an estimated incidence of 1.8 out of 100,000 live births for perinatally-acquired HIV infection.[14] The Centers for Disease Control and Prevention (CDC) in the United States (US) has set goals to eliminate perinatal HIV spread, which has caused a significant decline in MTCT transmission. The goal is to reduce the incidence of perinatal HIV to less than 1 in 100,000 births.[14] During the peak of HIV transmission in 1991, the reported incidence of neonates born with HIV was 42.8 per 100,000 births, with a substantial decline to 1.3 per 100,000 live-born infants in 2015.[17] Due to racial disparities in healthcare, the incidence of perinatal HIV is 5 times greater in Black versus White infants.[18]

Pathophysiology

The main target for HIV entry into the cells is through infection of cells expressing the CD4 receptor and chemokine receptors CCR5 and CXCR4.[19] Additionally, the HIV virus infects dendritic cells, activated CD4 T-lymphocytes, monocytes, and macrophages.[20] The result is increased host susceptibility to diseases due to decreased immune-protective functions. 

Infants with HIV-1 infections have higher viral loads and a faster progression to AIDS than adults with HIV.[21][22] The most common mode of transmission in a neonate with HIV is mother-to-child transmission (MTCT). The virus may be transmitted during different stages of pregnancy and postpartum, with the perinatal period as the most common transmission time.[23]

In-utero Transmission

The mechanism of in-utero transmission is predicted to be by transcytosis across placental cells. The placenta may also host the virus to replicate before moving to the fetus.[24] The HIV-1 virus may also traverse the trophoblastic placental barrier via endocytosis, specifically crossing cytotrophoblasts or syncytiotrophoblasts within the uterine wall. HIV-1 may also spread to the fetus via villous capillaries. The risk of in-utero transmission increases with inflammation and infection of the placenta and amniotic membranes.[24][25][26][27][28]

Intrapartum Transmission

Intrapartum transmission is predicted to be the greatest risk of vertical infections. The risk increases with longer exposure to maternal cervicovaginal secretions and blood. Research also demonstrates that the chance of infection is greater with membrane rupture of more than 4 hours.[29] Moreover, data also demonstrates that neonates with low birth weights and those born prematurely have an increased rate of transmission due to their reduced immunologic defenses and weaker skin barrier.[30]

Postnatal MTCT 

Postnatal MTCT occurs during breastfeeding. The mechanism of transmission through breast milk is not fully understood. However, multiple large prospective cohort trials have demonstrated a greater risk of spread of the HIV virus with breast-feeding. In addition to breast milk, studies have also confirmed that HIV RNA can also be found in colostrum.[31][32] Potential entry of the HIV virus from breast milk to the infant is through their intestines or tonsillar tissues.[33][34][35][36]

Histopathology

Due to the nature of the disease state, early identification of HIV may be difficult due to subtle clinical symptoms. As such, the use of histopathology of tissue samples may help identify HIV in patients. The capsid size of the HIV-1 virus varies between 110 and 146 nm.[37] It can be visualized with structured illumination microscopy (SIM). It is almost impossible to visualize individual virions using confocal microscopy. Assessing the histopathology of the placenta may identify the presence of intrauterine HIV infection. Multiple studies have demonstrated that full-term placenta from HIV-1–positive females contained infection in syncytiotrophoblasts, cytotrophoblasts, and villous-endothelial cells.[38] In vitro, studies of trophoblast barriers have demonstrated that the direct interaction between the trophoblast barrier and HIV-1 infected cells resulted in viral transcytosis.[24]

History and Physical

Neonates may not display any symptoms for the initial few months of life, as such complicating the diagnosis of HIV. Studies have suggested that children may remain asymptomatic until 3-5 years of age. In untreated children, the most commonly exhibited manifestations of HIV infection include but are not limited to recurrent bacteremia, increased opportunistic infections, frequent diarrhea, cardiomyopathy, hepatitis, generalized lymphadenopathy, splenomegaly, hepatomegaly, oral candidiasis, cancers, and central nervous system manifestations, such as growth delay, delayed cognition, low IQ, and frequently global developmental delay.

The CDC strongly recommends testing all pregnant females for HIV as part of the standard prenatal care. This testing proves to have a better prognosis for the neonate. However, due to a lack of adequate healthcare access in certain geographical areas of the world, the unknown HIV status of pregnant females leads to inadequate treatment and poor outcomes for the neonate.[39][40] Females who have an unknown HIV status should be offered a rapid diagnostic test at the time of delivery. A definitive HIV diagnosis can be made in infants by the age of 4 to 6 months using virologic testing.

Evaluation

Neonatal HIV diagnostics differs from that of adults and older children. It is not appropriate to test for HIV antibodies. The utilization of novel combination antigen/antibody immunoassays to confirm the diagnosis of HIV in neonates is not recommended as positive results confer passive transfer of maternal antibodies. Maternal HIV antibodies persist until 18 months.[5][40] Using viral load assays or nucleic acid tests (NATS), which include qualitative RNA assays, quantitative HIV RNA assay, or DNA polymerase chain reaction (PCR) assays, is more appropriate to confirm the diagnosis of HIV in neonates. The only FDA-approved qualitative RNA test is the APTIMA HIV-1 RNA Qualitative Assay.[41] These assays are able to detect the virus in at least 30% to 50% of cases at birth and an almost 100% confirmation by the age of 4 to 6 months. HIV quantitative RNA assay has been found to be just as comparable to HIV DNA PCR, with 100% specificity at birth, 1 month, 3 months, and 6 months.[42] Two negative virologic tests completed at 1 month and before 6 months of age are required to definitely exclude the diagnosis of HIV. Additionally, the infant must have negative clinical evidence and other laboratory markers of HIV, including normal to high CD4 T-lymphocyte count.[5][43]

Infants are categorized as high or low risk for HIV infection. Neonates born to mothers who received adequate prenatal care and were adherent to their ART, and who had undetectable viral loads are considered low risk. On the contrary, neonates are considered high risk if they were born to mothers who lacked prenatal care, had elevated HIV viral loads, and had a new diagnosis of HIV infection while pregnant.[5]

The table below indicates (X) the proposed recommended testing schedule for HIV perinatal exposure.[43][40]

Table

Birth                        14-21 Days                   

After a confirmed diagnosis of HIV, additional labs should be ordered, including CD4+ T-cell count, CD8+ T-cell count, plasma viral load of RNA, growth or development factors, and HIV-associated conditions, such as anemia, leukopenia, thrombocytopenia, hepatic transaminitis, etc. Before initiating ART, obtain genetic testing, a baseline CD4 count, plasma viral load, complete blood count (CBC), hepatic function, renal function, comprehensive metabolic panel, urinalysis, serum lipids, and blood glucose.

Treatment / Management

The Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV strongly recommends the initiation of ART in all pediatrics with HIV.[44] There has been a significant 80% to 90% decrease in morbidity and mortality since the introduction of ART initiation in neonates.[45][46] As confirmed by the CHER trial and other studies, there is a decrease in viral reservoirs, opportunistic infections, and disease progression to AIDS with early initiation of effective and early ART.[47][48][49][50][51][52] Infants with any level of risk of exposure to HIV should be started on the appropriate ART within 6 hours of birth. The goals of treatment for HIV-exposed neonates include a reduction in morbidity and mortality, suppression of viral replication, facilitation of HIV remission, viral control, prevention of disease progression, maintenance of immunologic function, reduction of opportunistic infections, and prevention of drug resistance.[53][54] 

There aren’t many randomized control trials that compare different regimens in pediatrics and neonates, and the available literature is variable. Most of the data is extracted from non-randomized studies, pharmacokinetic trials, and phase 1 or 2 of drug trials. In general, the initiation of an antiretroviral regimen in pediatrics should include 2 nucleoside reverse transcriptase inhibitors (NRTIs) with an additional drug from another class, including an integrase strand transfer inhibitor (INSTI), a protease inhibitor (PI) with a booster, or a non-nucleoside reverse transcriptase inhibitor (NNRTI). Before initiating a regimen, Factors to consider include the patient’s age, weight, family preference, drug resistance, genetic testing, mutation testing, and sexual maturity rating (SMR). In children with other confections, such as hepatitis B virus (HBV), the choice of agent should include coverage for HIV and the co-contagion. 

There are 3 studies that compared the addition of a PI-boosted versus NNRTI to the 2 NRTI backbones. In the P1060 trial, a total of 288 children from 6 African countries and India with ages from 2 to 36 months were enrolled in a randomized trial. The children received zidovudine (ZDV) plus lamivudine as the NRTI backbone and were randomized to either the PI with booster group (ritonavir booster [LPV/r]) or NNRTI group (nevirapine [NVP]). The data demonstrated that LPV/r is superior to NVP in NVP-naive children; however, there were limitations.[55] Whereas the PROMOTE trial did not find any differences between the 2 groups.[56] Of note, LPV/r should be avoided in neonates before 42 weeks of age and those who are younger than 14 days.

Data for utilizing an INSTI-based regimen are extracted from safety trials and adult comparative trials. Four INSTIs are approved for the treatment of ART-naïve children with HIV, which include: bictegravir (BID), dolutegrevir (DTG), Elvitegravir/cobicistat (EVG/c), and raltegravir (RAL).[57] INSTI regimens are attractive due to their lack of drug interactions, low toxicity, and virologic efficacy. RAL is FDA-approved for neonates and infants weighing 2 kg or more. DTG is FDA-approved for children 30 kg or more, and BIC is approved for children weighing 25 kg or more.[58][59]

Zidovudine (ZDV) plus lamivudine (3TC) or emtricitabine (FTC) are the preferred dual NRTI backbone in neonates and infants under 3 months. ZDV is FDA-approved for prophylaxis and for HIV treatment initiation in infants ≥ 4 weeks of age.[60][61][62][63] The preferred regimen for infants 3 months and older is abacavir (ABC) plus 3TC or FTC.[64][65][66][67] Alternatively, ZDV plus ABC can be used in infants 3 months and older; however, European studies have demonstrated lower rates of viral suppression and increased toxicity with this combination.[65][68] In addition to the 2 NRTI backbones, the following combination regimens are preferred in each age group:

• NVP: Age under 14 days 
• RAL: Age under 14 days and a weight of 2 kg or more
• LPV/r or RAL (alternative: NVP): Age 14 days or older to 3 years 

Differential Diagnosis

There are other diseases that need exclusion when diagnosing HIV. These include malnutrition, lymphadenopathy, pediatric chronic anemia, malabsorption syndrome, constitutional growth delay, autoimmune and chronic benign neutropenia, and other immunodeficiencies. Furthermore, the clinician should also look for other congenital co-infections, including syphilis, TORCH infections (Toxoplasmosis, Rubella, Cytomegalovirus, herpes simplex virus), hepatitis B, hepatitis C, or tuberculosis infection.

Toxicity and Adverse Effect Management

Any ART is associated with a variety of side effects. Many ARTs result in increased levels of hepatic transaminases as a result of hepatitis. Baseline labs are recommended before initiation of any regimen.

• Zidovudine: Can induce leukopenia, anemia, and macrocytosis
• Protease inhibitors: May lead to hyperglycemia
• Atazanavir: Can cause hyperbilirubinemia.

Prognosis

If untreated, HIV can increase the rate of morbidity and mortality. However, due to the advancement of ART, increased monitoring, and data from clinical trials, pediatric and adult patients have better prognoses and outcomes. The average survival rate is about 10 years of age, with approximately 15% of children having a rapid progression of the disease. The clinician should collaborate with the patient to optimize their nutrition, control viral replication, initiate aggressive treatment for opportunistic infections, and decrease social stressors. The risk of complications is greater with co-infections and hematological disturbances, such as anemia, thrombocytopenia, and neutropenia.

Complications

Complications of HIV infection in neonates and pediatric populations occur as a result of their immunocompromised status. They are at greater risk for opportunistic infections, candida esophagitis, Pneumocystis jirovecii pneumonia, and cancers. Furthermore, complications are more likely to occur with antiretroviral drug resistance. However, with careful monitoring and drug-resistance testing, the ability to select more optimized and effective regimens is possible.

Consultations

Consultation with a perinatologist and a pediatric infectious disease consultant is strongly encouraged to help provide a more comprehensive workup, diagnosis, and ongoing monitoring and management.

Deterrence and Patient Education

Before initiating or altering ART, the clinician should identify potential barriers and compliance issues. Developing novel drugs and enhanced formulations has led to better medication tolerability, less toxicity, and increased adherence.

HIV-positive mothers should be discouraged from breastfeeding neonates who do not have a confirmed HIV-positive status. If a female continues to breastfeed, the infant should be monitored and tested every 3 months throughout breastfeeding and postdiscontinuation of breastfeeding at the interval of 4 to 6 weeks, 3 months, and at 6 months.[69][70] Mothers should also be warned about the risks of feeding premasticated food to the infant.[71][72][73]

Pearls and Other Issues

Key facts to keep in mind about neonatal HIV are as follows:

• When making a selection for appropriate ART to initiate in a pregnant female, it is important to consider tolerability, neonatal risk of exposure, pharmacokinetic differences, and overall risk-benefit of each regimen.
• The monitoring of infants with HIV is challenging as there is variability with viral loads and CD4 counts depending on the age.
• Studies have demonstrated that administering zidovudine (ZDV) monotherapy to both the mother and neonate reduces MTCT from 25% to 8%. The MTCT rate is reduced to less than 1% when combined with other ART.[7] ZDV exhibits its actions by metabolizing into its active form in the placenta, thus inhibiting the replication of HIV within the placental cells.
• Repeated negative HIV test results are needed postpartum due to the increased risk of transmission of HIV during labor and delivery.[5]

Enhancing Healthcare Team Outcomes

The treatment of perinatal HIV exposure involves a team approach involving an infectious disease specialist, perinatalist, pediatrician, neonatologist, obstetrician, HIV pharmacist, and nursing staff. Prompt and early communication between all team members assures comprehensive and optimized care for the neonate. Infectious disease specialists and neonatologists are usually involved in acute management during the neonatal period. Infectious disease specialists are responsible for monitoring disease progression and drug regimens.

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References

1.

Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. World Health Organization; Geneva: Jun, 2013. [PubMed: 24716260]

2.

Hurst SA, Appelgren KE, Kourtis AP. Prevention of mother-to-child transmission of HIV type 1: the role of neonatal and infant prophylaxis. Expert Rev Anti Infect Ther. 2015 Feb;13(2):169-81. [PMC free article: PMC4470389] [PubMed: 25578882]

3.

Worobey M, Gemmel M, Teuwen DE, Haselkorn T, Kunstman K, Bunce M, Muyembe JJ, Kabongo JM, Kalengayi RM, Van Marck E, Gilbert MT, Wolinsky SM. Direct evidence of extensive diversity of HIV-1 in Kinshasa by 1960. Nature. 2008 Oct 02;455(7213):661-4. [PMC free article: PMC3682493] [PubMed: 18833279]

4.

Mofenson LM. Mother-child HIV-1 transmission: Timing and determinants. Obstet Gynecol Clin North Am. 1997 Dec;24(4):759-84. [PubMed: 9430166]

5.

Siberry GK. Preventing and managing HIV infection in infants, children, and adolescents in the United States. Pediatr Rev. 2014 Jul;35(7):268-86. [PMC free article: PMC4071508] [PubMed: 24986927]

6.

Bispo S, Chikhungu L, Rollins N, Siegfried N, Newell ML. Postnatal HIV transmission in breastfed infants of HIV-infected women on ART: a systematic review and meta-analysis. J Int AIDS Soc. 2017 Feb 22;20(1):21251. [PMC free article: PMC5467610] [PubMed: 28362072]

7.

Bansaccal N, Van der Linden D, Marot JC, Belkhir L. HIV-Infected Mothers Who Decide to Breastfeed Their Infants Under Close Supervision in Belgium: About Two Cases. Front Pediatr. 2020;8:248. [PMC free article: PMC7266974] [PubMed: 32537442]

8.

Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O'Sullivan MJ, VanDyke R, Bey M, Shearer W, Jacobson RL. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994 Nov 03;331(18):1173-80. [PubMed: 7935654]

9.

Shaffer N, Chuachoowong R, Mock PA, Bhadrakom C, Siriwasin W, Young NL, Chotpitayasunondh T, Chearskul S, Roongpisuthipong A, Chinayon P, Karon J, Mastro TD, Simonds RJ. Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: a randomised controlled trial. Bangkok Collaborative Perinatal HIV Transmission Study Group. Lancet. 1999 Mar 06;353(9155):773-80. [PubMed: 10459957]

10.

Jamieson DJ, Sibailly TS, Sadek R, Roels TH, Ekpini ER, Boni-Ouattara E, Karon JM, Nkengasong J, Greenberg AE, Wiktor SZ. HIV-1 viral load and other risk factors for mother-to-child transmission of HIV-1 in a breast-feeding population in Cote d'Ivoire. J Acquir Immune Defic Syndr. 2003 Dec 01;34(4):430-6. [PubMed: 14615662]

11.

Jackson JB, Musoke P, Fleming T, Guay LA, Bagenda D, Allen M, Nakabiito C, Sherman J, Bakaki P, Owor M, Ducar C, Deseyve M, Mwatha A, Emel L, Duefield C, Mirochnick M, Fowler MG, Mofenson L, Miotti P, Gigliotti M, Bray D, Mmiro F. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial. Lancet. 2003 Sep 13;362(9387):859-68. [PubMed: 13678973]

12.

John GC, Nduati RW, Mbori-Ngacha DA, Richardson BA, Panteleeff D, Mwatha A, Overbaugh J, Bwayo J, Ndinya-Achola JO, Kreiss JK. Correlates of mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission: association with maternal plasma HIV-1 RNA load, genital HIV-1 DNA shedding, and breast infections. J Infect Dis. 2001 Jan 15;183(2):206-212. [PubMed: 11120927]

13.

Kempton J, Hill A, Levi JA, Heath K, Pozniak A. Most new HIV infections, vertical transmissions and AIDS-related deaths occur in lower-prevalence countries. J Virus Erad. 2019 Apr 01;5(2):92-101. [PMC free article: PMC6543482] [PubMed: 31191912]

14.

Nesheim SR, Wiener J, Fitz Harris LF, Lampe MA, Weidle PJ. Brief Report: Estimated Incidence of Perinatally Acquired HIV Infection in the United States, 1978-2013. J Acquir Immune Defic Syndr. 2017 Dec 15;76(5):461-464. [PMC free article: PMC6267853] [PubMed: 28991886]

15.

Peters H, Francis K, Sconza R, Horn A, S Peckham C, Tookey PA, Thorne C. UK Mother-to-Child HIV Transmission Rates Continue to Decline: 2012-2014. Clin Infect Dis. 2017 Feb 15;64(4):527-528. [PubMed: 28174911]

16.

Nesheim SR, FitzHarris LF, Lampe MA, Gray KM. Reconsidering the Number of Women With HIV Infection Who Give Birth Annually in the United States. Public Health Rep. 2018 Nov;133(6):637-643. [PMC free article: PMC6225876] [PubMed: 30265616]

17.

Peters H, Thorne C, Tookey PA, Byrne L. National audit of perinatal HIV infections in the UK, 2006-2013: what lessons can be learnt? HIV Med. 2018 Apr;19(4):280-289. [PMC free article: PMC5901012] [PubMed: 29336508]

18.

Nesheim SR, FitzHarris LF, Mahle Gray K, Lampe MA. Epidemiology of Perinatal HIV Transmission in the United States in the Era of Its Elimination. Pediatr Infect Dis J. 2019 Jun;38(6):611-616. [PubMed: 30724833]

19.

Maartens G, Celum C, Lewin SR. HIV infection: epidemiology, pathogenesis, treatment, and prevention. Lancet. 2014 Jul 19;384(9939):258-71. [PubMed: 24907868]

20.

Lucas S, Nelson AM. HIV and the spectrum of human disease. J Pathol. 2015 Jan;235(2):229-41. [PubMed: 25251832]

21.

Ahmad N. Molecular mechanisms of HIV-1 mother-to-child transmission and infection in neonatal target cells. Life Sci. 2011 May 23;88(21-22):980-6. [PMC free article: PMC3049197] [PubMed: 20888841]

22.

Little K, Thorne C, Luo C, Bunders M, Ngongo N, McDermott P, Newell ML. Disease progression in children with vertically-acquired HIV infection in sub-Saharan Africa: reviewing the need for HIV treatment. Curr HIV Res. 2007 Mar;5(2):139-53. [PubMed: 17346131]

23.

Saharan S, Lodha R, Agarwal R, Deorari AK, Paul VK. Perinatal HIV. Indian J Pediatr. 2008 Apr;75(4):359-62. [PubMed: 18536891]

24.

Al-Husaini AM. Role of placenta in the vertical transmission of human immunodeficiency virus. J Perinatol. 2009 May;29(5):331-6. [PubMed: 19020526]

25.

Ehrnst A, Lindgren S, Dictor M, Johansson B, Sönnerborg A, Czajkowski J, Sundin G, Bohlin AB. HIV in pregnant women and their offspring: evidence for late transmission. Lancet. 1991 Jul 27;338(8761):203-7. [PubMed: 1676777]

26.

Rouzioux C, Costagliola D, Burgard M, Blanche S, Mayaux MJ, Griscelli C, Valleron AJ. Estimated timing of mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission by use of a Markov model. The HIV Infection in Newborns French Collaborative Study Group. Am J Epidemiol. 1995 Dec 15;142(12):1330-7. [PubMed: 7503054]

27.

Bornstein MH. Qualities of color vision in infancy. J Exp Child Psychol. 1975 Jun;19(3):401-19. [PubMed: 1176886]

28.

King CC, Ellington SR, Kourtis AP. The role of co-infections in mother-to-child transmission of HIV. Curr HIV Res. 2013 Jan;11(1):10-23. [PMC free article: PMC4411038] [PubMed: 23305198]

29.

Landesman SH, Kalish LA, Burns DN, Minkoff H, Fox HE, Zorrilla C, Garcia P, Fowler MG, Mofenson L, Tuomala R. Obstetrical factors and the transmission of human immunodeficiency virus type 1 from mother to child. The Women and Infants Transmission Study. N Engl J Med. 1996 Jun 20;334(25):1617-23. [PubMed: 8628356]

30.

Kourtis AP, Bulterys M, Nesheim SR, Lee FK. Understanding the timing of HIV transmission from mother to infant. JAMA. 2001 Feb 14;285(6):709-12. [PubMed: 11176886]

31.

Van de Perre P, Simonon A, Msellati P, Hitimana DG, Vaira D, Bazubagira A, Van Goethem C, Stevens AM, Karita E, Sondag-Thull D. Postnatal transmission of human immunodeficiency virus type 1 from mother to infant. A prospective cohort study in Kigali, Rwanda. N Engl J Med. 1991 Aug 29;325(9):593-8. [PubMed: 1812850]

32.

Van de Perre P, Lepage P, Homsy J, Dabis F. Mother-to-infant transmission of human immunodeficiency virus by breast milk: presumed innocent or presumed guilty? Clin Infect Dis. 1992 Sep;15(3):502-7. [PubMed: 1445596]

33.

Lehman DA, Farquhar C. Biological mechanisms of vertical human immunodeficiency virus (HIV-1) transmission. Rev Med Virol. 2007 Nov-Dec;17(6):381-403. [PubMed: 17542053]

34.

Shen R, Smythies LE, Clements RH, Novak L, Smith PD. Dendritic cells transmit HIV-1 through human small intestinal mucosa. J Leukoc Biol. 2010 Apr;87(4):663-70. [PMC free article: PMC2858307] [PubMed: 20007245]

35.

Veazey R, Lackner A. The mucosal immune system and HIV-1 infection. AIDS Rev. 2003 Oct-Dec;5(4):245-52. [PubMed: 15012003]

36.

Lapenta C, Boirivant M, Marini M, Santini SM, Logozzi M, Viora M, Belardelli F, Fais S. Human intestinal lamina propria lymphocytes are naturally permissive to HIV-1 infection. Eur J Immunol. 1999 Apr;29(4):1202-8. [PubMed: 10229087]

37.

Marno K, Al'Zoubi L, Pearson M, Posch M, McKnight Á, Wheeler AP. The evolution of structured illumination microscopy in studies of HIV. Methods. 2015 Oct 15;88:20-7. [PubMed: 26071977]

38.

Moonim MT, Alarcon L, Freeman J, Mahadeva U, van der Walt JD, Lucas SB. Identifying HIV infection in diagnostic histopathology tissue samples--the role of HIV-1 p24 immunohistochemistry in identifying clinically unsuspected HIV infection: a 3-year analysis. Histopathology. 2010 Mar;56(4):530-41. [PubMed: 20459560]

39.

Gilleece DY, Tariq DS, Bamford DA, Bhagani DS, Byrne DL, Clarke DE, Clayden MP, Lyall DH, Metcalfe DR, Palfreeman DA, Rubinstein DL, Sonecha MS, Thorley DL, Tookey DP, Tosswill MJ, Utting MD, Welch DS, Wright MA. British HIV Association guidelines for the management of HIV in pregnancy and postpartum 2018. HIV Med. 2019 Mar;20 Suppl 3:s2-s85. [PubMed: 30869192]

40.

Abdollahi A, Saffar H. The Diagnosis of HIV Infection in Infants and Children. Iran J Pathol. 2016 Spring;11(2):89-96. [PMC free article: PMC4939637] [PubMed: 27499768]

41.

Lilian RR, Kalk E, Bhowan K, Berrie L, Carmona S, Technau K, Sherman GG. Early diagnosis of in utero and intrapartum HIV infection in infants prior to 6 weeks of age. J Clin Microbiol. 2012 Jul;50(7):2373-7. [PMC free article: PMC3405609] [PubMed: 22518871]

42.

Burgard M, Blanche S, Jasseron C, Descamps P, Allemon MC, Ciraru-Vigneron N, Floch C, Heller-Roussin B, Lachassinne E, Mazy F, Warszawski J, Rouzioux C., Agence Nationale de Recherche sur le SIDA et les Hepatites virales French Perinatal Cohort. Performance of HIV-1 DNA or HIV-1 RNA tests for early diagnosis of perinatal HIV-1 infection during anti-retroviral prophylaxis. J Pediatr. 2012 Jan;160(1):60-6.e1. [PubMed: 21868029]

43.

Havens PL, Mofenson LM., American Academy of Pediatrics Committee on Pediatric AIDS. Evaluation and management of the infant exposed to HIV-1 in the United States. Pediatrics. 2009 Jan;123(1):175-87. [PubMed: 19117880]

44.

Foster C, Bamford A, Turkova A, Welch S, Klein N., PENTA Guidelines Writing Group and PENTA steering committee. Paediatric European Network for Treatment of AIDS Treatment Guideline 2016 update: antiretroviral therapy recommended for all children living with HIV. HIV Med. 2017 Feb;18(2):133-134. [PMC free article: PMC5248631] [PubMed: 27385585]

45.

Kapogiannis BG, Soe MM, Nesheim SR, Abrams EJ, Carter RJ, Farley J, Palumbo P, Koenig LJ, Bulterys M. Mortality trends in the US Perinatal AIDS Collaborative Transmission Study (1986-2004). Clin Infect Dis. 2011 Nov;53(10):1024-34. [PMC free article: PMC3202314] [PubMed: 22002982]

46.

Mirani G, Williams PL, Chernoff M, Abzug MJ, Levin MJ, Seage GR, Oleske JM, Purswani MU, Hazra R, Traite S, Zimmer B, Van Dyke RB., IMPAACT P1074 Study Team. Changing Trends in Complications and Mortality Rates Among US Youth and Young Adults With HIV Infection in the Era of Combination Antiretroviral Therapy. Clin Infect Dis. 2015 Dec 15;61(12):1850-61. [PMC free article: PMC4657532] [PubMed: 26270680]

47.

Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA, Jean-Philippe P, McIntyre JA., CHER Study Team. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med. 2008 Nov 20;359(21):2233-44. [PMC free article: PMC2950021] [PubMed: 19020325]

48.

Kuhn L, Paximadis M, Da Costa Dias B, Loubser S, Strehlau R, Patel F, Shiau S, Coovadia A, Abrams EJ, Tiemessen CT. Age at antiretroviral therapy initiation and cell-associated HIV-1 DNA levels in HIV-1-infected children. PLoS One. 2018;13(4):e0195514. [PMC free article: PMC5896970] [PubMed: 29649264]

49.

Tagarro A, Chan M, Zangari P, Ferns B, Foster C, De Rossi A, Nastouli E, Muñoz-Fernández MA, Gibb D, Rossi P, Giaquinto C, Babiker A, Fortuny C, Freguja R, Cotugno N, Judd A, Noguera-Julian A, Navarro ML, Mellado MJ, Klein N, Palma P, Rojo P. Early and Highly Suppressive Antiretroviral Therapy Are Main Factors Associated With Low Viral Reservoir in European Perinatally HIV-Infected Children. J Acquir Immune Defic Syndr. 2018 Oct 01;79(2):269-276. [PMC free article: PMC6173292] [PubMed: 30211778]

50.

Nesheim S, Taylor A, Lampe MA, Kilmarx PH, Fitz Harris L, Whitmore S, Griffith J, Thomas-Proctor M, Fenton K, Mermin J. A framework for elimination of perinatal transmission of HIV in the United States. Pediatrics. 2012 Oct;130(4):738-44. [PubMed: 22945404]

51.

Centers for Disease Control and Prevention (CDC). Revised surveillance case definition for HIV infection--United States, 2014. MMWR Recomm Rep. 2014 Apr 11;63(RR-03):1-10. [PubMed: 24717910]

52.

Flynn PM, Abrams EJ. Growing up with perinatal HIV. AIDS. 2019 Mar 15;33(4):597-603. [PubMed: 30531318]

53.

Kuhn L, Shiau S. The pharmacological treatment of acute HIV infections in neonates. Expert Rev Clin Pharmacol. 2017 Dec;10(12):1353-1361. [PMC free article: PMC6078387] [PubMed: 29098898]

54.

Mofenson LM, Brady MT, Danner SP, Dominguez KL, Hazra R, Handelsman E, Havens P, Nesheim S, Read JS, Serchuck L, Van Dyke R., Centers for Disease Control and Prevention. National Institutes of Health. HIV Medicine Association of the Infectious Diseases Society of America. Pediatric Infectious Diseases Society. American Academy of Pediatrics. Guidelines for the Prevention and Treatment of Opportunistic Infections among HIV-exposed and HIV-infected children: recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. MMWR Recomm Rep. 2009 Sep 04;58(RR-11):1-166. [PMC free article: PMC2821196] [PubMed: 19730409]

55.

Violari A, Lindsey JC, Hughes MD, Mujuru HA, Barlow-Mosha L, Kamthunzi P, Chi BH, Cotton MF, Moultrie H, Khadse S, Schimana W, Bobat R, Purdue L, Eshleman SH, Abrams EJ, Millar L, Petzold E, Mofenson LM, Jean-Philippe P, Palumbo P. Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children. N Engl J Med. 2012 Jun 21;366(25):2380-9. [PMC free article: PMC3443859] [PubMed: 22716976]

56.

Ruel TD, Kakuru A, Ikilezi G, Mwangwa F, Dorsey G, Rosenthal PJ, Charlebois E, Havlir D, Kamya M, Achan J. Virologic and immunologic outcomes of HIV-infected Ugandan children randomized to lopinavir/ritonavir or nonnucleoside reverse transcriptase inhibitor therapy. J Acquir Immune Defic Syndr. 2014 Apr 15;65(5):535-41. [PMC free article: PMC3999287] [PubMed: 24326597]

57.

Tsiang M, Jones GS, Goldsmith J, Mulato A, Hansen D, Kan E, Tsai L, Bam RA, Stepan G, Stray KM, Niedziela-Majka A, Yant SR, Yu H, Kukolj G, Cihlar T, Lazerwith SE, White KL, Jin H. Antiviral Activity of Bictegravir (GS-9883), a Novel Potent HIV-1 Integrase Strand Transfer Inhibitor with an Improved Resistance Profile. Antimicrob Agents Chemother. 2016 Dec;60(12):7086-7097. [PMC free article: PMC5118987] [PubMed: 27645238]

58.

Oliveira M, Ibanescu RI, Anstett K, Mésplède T, Routy JP, Robbins MA, Brenner BG., Montreal Primary HIV (PHI) Cohort Study Group. Selective resistance profiles emerging in patient-derived clinical isolates with cabotegravir, bictegravir, dolutegravir, and elvitegravir. Retrovirology. 2018 Aug 17;15(1):56. [PMC free article: PMC6098636] [PubMed: 30119633]

59.

Neogi U, Singh K, Aralaguppe SG, Rogers LC, Njenda DT, Sarafianos SG, Hejdeman B, Sönnerborg A. Ex-vivo antiretroviral potency of newer integrase strand transfer inhibitors cabotegravir and bictegravir in HIV type 1 non-B subtypes. AIDS. 2018 Feb 20;32(4):469-476. [PMC free article: PMC5790636] [PubMed: 29239896]

60.

Mulenga V, Musiime V, Kekitiinwa A, Cook AD, Abongomera G, Kenny J, Chabala C, Mirembe G, Asiimwe A, Owen-Powell E, Burger D, McIlleron H, Klein N, Chintu C, Thomason MJ, Kityo C, Walker AS, Gibb DM., CHAPAS-3 trial team. Abacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial. Lancet Infect Dis. 2016 Feb;16(2):169-79. [PMC free article: PMC4726762] [PubMed: 26481928]

61.

Van Dyke RB, Wang L, Williams PL., Pediatric AIDS Clinical Trials Group 219C Team. Toxicities associated with dual nucleoside reverse-transcriptase inhibitor regimens in HIV-infected children. J Infect Dis. 2008 Dec 01;198(11):1599-608. [PMC free article: PMC2737265] [PubMed: 19000014]

62.

Moyle GJ, Sabin CA, Cartledge J, Johnson M, Wilkins E, Churchill D, Hay P, Fakoya A, Murphy M, Scullard G, Leen C, Reilly G., RAVE (Randomized Abacavir versus Viread Evaluation) Group UK. A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. AIDS. 2006 Oct 24;20(16):2043-50. [PubMed: 17053350]

63.

Carr A, Workman C, Smith DE, Hoy J, Hudson J, Doong N, Martin A, Amin J, Freund J, Law M, Cooper DA., Mitochondrial Toxicity (MITOX) Study Group. Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: a randomized trial. JAMA. 2002 Jul 10;288(2):207-15. [PubMed: 12095385]

64.

DeJesus E, Rockstroh JK, Lennox JL, Saag MS, Lazzarin A, Zhao J, Wan H, Rodgers AJ, Walker ML, Miller M, DiNubile MJ, Nguyen BY, Teppler H, Leavitt R, Sklar P., STARTMRK Investigators. Efficacy of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naïve HIV-1-infected patients: week-192 overall and subgroup analyses from STARTMRK. HIV Clin Trials. 2012 Jul-Aug;13(4):228-32. [PubMed: 22849964]

65.

Green H, Gibb DM, Walker AS, Pillay D, Butler K, Candeias F, Castelli-Gattinara G, Compagnucci A, Della Negra M, de Rossi A, Feiterna-Sperling C, Giaquinto C, Harper L, Levy J, Saidi Y, Wintergerst U., Paediatric European Network for the Treatment of AIDS (PENTA). Lamivudine/abacavir maintains virological superiority over zidovudine/lamivudine and zidovudine/abacavir beyond 5 years in children. AIDS. 2007 May 11;21(8):947-55. [PubMed: 17457088]

66.

Sax PE, Tierney C, Collier AC, Fischl MA, Mollan K, Peeples L, Godfrey C, Jahed NC, Myers L, Katzenstein D, Farajallah A, Rooney JF, Ha B, Woodward WC, Koletar SL, Johnson VA, Geiseler PJ, Daar ES., AIDS Clinical Trials Group Study A5202 Team. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med. 2009 Dec 03;361(23):2230-40. [PMC free article: PMC2800041] [PubMed: 19952143]

67.

Smith KY, Patel P, Fine D, Bellos N, Sloan L, Lackey P, Kumar PN, Sutherland-Phillips DH, Vavro C, Yau L, Wannamaker P, Shaefer MS., HEAT Study Team. Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with lopinavir/ritonavir for initial HIV treatment. AIDS. 2009 Jul 31;23(12):1547-56. [PubMed: 19542866]

68.

Paediatric European Network for Treatment of AIDS (PENTA). Comparison of dual nucleoside-analogue reverse-transcriptase inhibitor regimens with and without nelfinavir in children with HIV-1 who have not previously been treated: the PENTA 5 randomised trial. Lancet. 2002 Mar 02;359(9308):733-40. [PubMed: 11888583]

69.

Committee on Pediatric Aids. Infant feeding and transmission of human immunodeficiency virus in the United States. Pediatrics. 2013 Feb;131(2):391-6. [PubMed: 23359577]

70.

King CC, Kourtis AP, Persaud D, Nelson JA, Ziemniak C, Hudgens MG, Tegha G, Chasela CS, Jamieson DJ, van der Horst CM. Delayed HIV detection among infants exposed to postnatal antiretroviral prophylaxis during breastfeeding. AIDS. 2015 Sep 24;29(15):1953-61. [PMC free article: PMC4665628] [PubMed: 26153671]

71.

Gaur AH, Freimanis-Hance L, Dominguez K, Mitchell C, Menezes J, Mussi-Pinhata MM, Peixoto MF, Alarcon J, Coelho DF, Read JS. Knowledge and practice of prechewing/prewarming food by HIV-infected women. Pediatrics. 2011 May;127(5):e1206-11. [PMC free article: PMC3081188] [PubMed: 21482608]

72.

Centers for Disease Control and Prevention (CDC). Premastication of food by caregivers of HIV-exposed children--nine U.S. sites, 2009-2010. MMWR Morb Mortal Wkly Rep. 2011 Mar 11;60(9):273-5. [PubMed: 21389930]

73.

Hafeez S, Salami O, Alvarado M, Maldonado M, Purswani M, Hagmann S. Infant feeding practice of premastication: an anonymous survey among human immunodeficiency virus-infected mothers. Arch Pediatr Adolesc Med. 2011 Jan;165(1):92-3. [PubMed: 21199989]

Disclosure: Malak Abbas declares no relevant financial relationships with ineligible companies.

Disclosure: Arsala Bakhtyar declares no relevant financial relationships with ineligible companies.

Disclosure: Rima Bazzi declares no relevant financial relationships with ineligible companies.