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Neonatal HIV
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
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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]
|
Birth |
14-21 Days |
1-2 Months |
2-3 Months |
4-6 Months |
|
|
Low risk of perinatal HIV transmission |
X |
X |
X |
||
|
High risk of perinatal HIV transmission |
X |
X |
X |
X |
X |
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] (A1)
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.(A1)
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:(A1)
- 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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