Clinical manifestations

Presentation and course

The consequences of CNS infection by HIV-1 are highly variable among infected children and can be delayed for several years (07). Neurologic symptoms, however, should not be viewed in isolation from, but associated with, other clinical symptoms and with immunological and virological results: the course of clinical symptoms and biological signs distinguishes a severe infantile mode of evolution from a slowly progressive disease.

At birth, the majority of congenitally HIV-1-infected neonates are clinically well and are indistinguishable from uninfected newborns. Some HIV-1-infected neonates, however, may be ill due to comorbid conditions such as those associated with prematurity, in utero exposure to drugs and alcohol, or congenital infections, mostly cytomegalovirus (09).

Twenty percent of infected children suffer from a severe infantile disease characterized by a progressive encephalopathy and opportunistic infections, with an onset during the first 3 years of life (14; 07; 54). In a large prospective study the cumulative incidence of encephalopathy was 9.9% at 12 months and 13.1% at 24 months, whereas new cases steadily accumulated to reach a cumulative incidence of 16.3% at 84 months. These measurements are associated with other AIDS-defining symptoms (which can also occur in isolation) as well as with an early decrease in the number of circulating CD4 lymphocytes and a high number of viral particles in blood (usually designated as a high "viral load"). These viral particles are present from the first weeks of life (54). Prevalence of HIV encephalopathy has decreased from 40.7% to 18.2% in patients born after 1996, thought to be related to the response of intravenous zidovudine monotherapy. In another prospective study reported in the year 2000, rates were as a low as 1.6% in children on highly active antiretroviral therapy (HAART) therapy, but also relatively higher at 10% regarding rates of arrested HIV encephalopathy. There has been no link between progressive HIV encephalopathy and ADHD or isolated developmental delay (32; 18; 52; 58).

Common initial presentations include cases of Pneumocystis jirovecii pneumonia (PCP), mucosal candidiasis infections, recurrent bacterial infections, failure to thrive or wasting, pulmonary tuberculosis infection, or disseminated herpes zoster infection. Pneumocystis jirovecii pneumonia peaks from 3 to 6 months and is rare within the first month of life. Episodes of oral candidiasis can occur in infants with intact immune systems, but if the infant has severe, recurrent, or persistent infections, then HIV or other immunodeficiency needs to be considered. Recurrent bacterial infections can present as pneumonia, sinusitis, and/or otitis. HIV infected individuals are more likely to develop tuberculosis due to immunologic impairment. Therefore, if a child is diagnosed with tuberculosis, investigation for an underlying HIV infection should be completed. In less severe forms without serious infections, the child may present with a constellation of lymphadenopathy, chronic interstitial lung disease, and persistent parotid gland swelling (50).

Neurologic manifestations of HIV are heterogeneous and may evolve with time. The first abnormal neurologic signs are usually observed between the ages of 3 and 12 months. Motor symptoms are initially noted with both abnormal rigidity of limbs and abnormal postural tone, not unlike those symptoms observed in cerebral palsy. Over time, these symptoms result in spastic paraparesis or quadriparesis, sometimes associated with dystonic posturing and a loss of motor milestones. Thirty percent to 50% of children develop buccolingual dyspraxia: the mouth remains open with abnormal and permanent drooling as well as difficulties with chewing small pieces of food (at appropriate age). Stagnation of cognitively, behaviorally, and socially adaptive skills usually occurs a few months later; patients initially appear comparatively less affected. The pattern of regression is quite variable from 1 child to another, although most decline in a stepwise manner with long plateau periods over 2 to 4 years. After 3 years, affected children are significantly delayed, with small head circumference and severe spastic tetraparesis. Interestingly, the group of infants with subsequent early HIV encephalopathy had a significantly lower head circumference than other HIV-1 infected children (54). It is not unusual for the children to make some cognitive or even motor acquisitions during the plateau periods. Death usually occurs before the age of 5 years.

Eighty percent of infected children have a slowly progressive disease during which, for several years, they remain either asymptomatic or have reversible symptoms. Similarly, there is no severe immune deficiency, and viral load in the blood is low. At school age, the children usually have normal school results and cognitive levels, except for visuospatial and temporal orientation tests, which are more frequently abnormal than in the general population (29; 55; 08). In 1 case series, when compared to healthy controls, HIV-infected pediatric patients did not show worsening of memory or executive function over several years, although history of AIDS defining illness and higher viral load were associated with worse cognitive functioning overall (34).

Prognosis and complications

The risk of development of early and severe form of the disease is highly linked to the viral load in the mother’s peripheral blood at time of birth as well as that of the baby during first weeks of life (13; 27). Viral load influences the time of transmission from mother to fetus as well (most likely) as the time of penetration of the virus into the central nervous system. Severe symptoms (including encephalopathy) occur more frequently in infants, with a heavy virus load in the blood at birth that is tightly linked to maternal status at delivery (Blanche et al 1996; 53; 49). An early treatment with combinations of highly active antiretroviral drugs associated with preventive treatment of opportunistic infections does improve the quality of life of infected children and shows a positive impact of neurodevelopmental trajectory with cognitive and motor impairments. More long-term studies are needed to assess the role of antiretroviral therapy and neurodevelopmental function (30).

There are indeed large inequalities between children in undeveloped countries. The survival rate of infected children was close to 60% at 7 years of age (55) but has been further improved by HAART and efficient preventive treatment of opportunistic infections. A multicenter, prospective birth cohort study from 1985 until 2004 showed statistically significant 10-year survival rates of 94% in children who received HAART therapy compared to 45% in children who did not receive HAART therapy (24).

During the course of HIV-1 infection, several secondary lesions of the CNS can be clinically observed (Table 1). In most cases, all of them occurred after the onset of a severe immune deficiency (at least on a biological background, ie, when CD4 lymphocyte counts were less than 200). Although their description is beyond the scope of this short annotation, 4 clinical situations can be distinguished: (1) acute retinitis and encephalitis, the most frequent etiologic agent being cytomegalovirus; (2) tumor-like lesions (toxoplasmosis, lymphoma, and sarcoma); (3) acute focal lesions sometimes associated with multiple brain infarcts due to aneurysmal lesions of large vessels and multiple areas of vascular obstruction of small cortical vessels; and (4) progressive encephalopathy with abnormal appearance of white matter on MRI. This might be due to a secondary infection with a papovavirus, leading to a progressive multifocal leukoencephalitis, subsequently resulting in a progressive HIV-1-related encephalopathy, but also to infections with mycobacteria, mycoplasma, and viruses such as cytomegalovirus and varicella zoster virus. A firm diagnosis is always difficult to establish, but new techniques involving amplification of genetic material by polymerase chain reaction are of major support.

Development of vascular lesions has been associated with HIV-1 infection, and is thought to result from endothelial dysfunction secondary to chronic inflammation and cytokine imbalances from the infection. This has sometimes been referred to as HIV-associated vasculopathy. Moyamoya syndrome has been described in association with pediatric HIV-1 infection, with evidence of worse outcomes associated with poor HIV control (63).

Cardiovascular problems associated with HIV infection including left ventricular dysfunction and increased left ventricular mass are common and clinically important indicators of survival for children infected with HIV (25).

Table 1. Secondary CNS Complications

Clinical vignette

A 17-month-old female patient accompanied by her mother presented to a medical mission clinic in Port au Prince, Haiti with a 2-month duration of muscle rigidity and general failure to thrive. Although the child had these symptoms for months, the mother brought her in due to altered mental status, or more specifically described by her mother as “my daughter just isn’t herself today”. On exam the child had a small head circumference and generalized muscle rigidity. Upon further questioning, the mother had an unknown HIV status but had 2 previous children who died of a “cerebral palsy”-like illness and multiple infections.

Biological basis

Etiology and pathogenesis

Human immunodeficiency virus type-1, the etiologic agent of AIDS, is an RNA retrovirus that belongs to the lentivirus subfamily of nononcogenic cytopathic retroviruses.

Principal targets of HIV-1 are the human peripheral blood CD4+ T lymphocytes and monocytes. The loss of CD4 lymphocytes occurs due to direct cytopathic effects of the virus and due to indirect effects on uninfected cells causing cell death. Similarly, HIV causes a cytopathic infection in monocytes; the infection is of a lesser degree, as compared to that not seen in CD4 cells, but it causes monocytes to collapse with one another forming multinucleated giant cells most prominent in the brain parenchyma. It also leads to prominent macrophage activation in various tissues including brain, peripheral nerve, kidney, heart, and other tissues. It is postulated that this massive macrophage activation leads to release of various cytokines that are injurious to neurons in the brain and other cell types in various tissues. The pathogenesis of HIV infection has been best studied in CNS tissues, where it is clear that HIV infects astrocytes other than cells of monocytic lineage. These infected cells also release viral proteins that have toxic properties and hence have been termed “virotoxins.” A number of subcellular mechanisms have been proposed with regards to end organ damage caused by these virotoxins. The virotoxins also lead to the release of chemo-attractant molecules called chemokines, which hone in mononuclear cells into the endorgan, thus setting up a positive feedback loop. HIV-1 is found mostly within cells of the basal ganglia, subthalamic nucleus, substantia nigra, dentate nucleus, and white matter (08).

In children, 1 of the first immunologic abnormalities is impairment of B-cell function, manifested by polyclonal hypergammaglobulinemia, spontaneous B-cell proliferation, and increased in vitro spontaneous production of immunoglobulin. Although the quantity of immunoglobulins is elevated, there are diminished in vivo vaccine responses to both T-cell dependent and independent antigens as well as decreased responses to B-cell mitogens (11; 26). It has been shown that a 25-gene signature in resting memory B cells was able to distinguish H1N1 vaccine responders from nonresponders in HIV patients, as well as a separate 28-gene signature in resting memory B cells distinguishing HIV patients on antiretroviral therapy from healthy controls (19). In vitro studies demonstrate diminished lymphocyte proliferation to B-cell mitogens. The decreased antibody responses predispose these infants and children to serious bacterial infections, which at times may be overwhelming. The B-cell activation may also result in polyclonal polymorphic B-cell lymphoproliferative disorders, such as lymphoid interstitial pneumonitis, parotitis, and unusual B-cell related complications such as B-cell lymphomas.

Increased production of autoantibodies may also result from B-cell dysfunction. Circulating immune complexes, antinuclear antibodies, antibody to double-stranded DNA, red cell antibodies, and antiplatelet antibodies have been reported (26). Hypogammaglobulinemia, another manifestation of B-cell dysfunction, has also been noted in some infants with severe advanced disease.

It is likely that the developmental maturational stage of the nervous and immune system is an important variable when exposed to the direct or indirect effects of the virus. Thymic abnormalities in some fetuses of HIV-1-infected women suggest that an interaction between the virus and the developing fetal immune system may account for the early and severe immune deficiency observed in 15% to 25% of congenitally infected HIV-1 infants. The pathophysiologic mechanism is as yet unclear; both an induction of an immune deficiency in utero and a state of immune tolerance have been proposed (14; 39).

Resting T cells and astrocytes are chronically infected with HIV-1, persisting as stationary cell intermediates from which HIV may be induced. It is unknown whether overall virus burden in peripheral blood reflects the level of compartmentalization of HIV-1 in tissues, and whether differences in relative tissue distribution of the retrovirus may contribute to differences in the clinical outcome. It is possible that the subsequent disease course may be determined in part by tissue distribution as well as the maturity of CD4 cells and bone marrow-derived myelomonocytic cells in the immature host (47). Additional factors, including differential timing of infection, strain of virus, increased sequence diversity, and the high mutation rate of specific HIV-1 genes, may allow the virus to evade immune surveillance and persist within the host. Emergence of genotypic variants with altered biologic activity, such as increased replication rate and cytopathicity, may also increase the pathogenicity of the virus (Conner and Ho 1994; 47).

The pathogenesis and pathophysiology of HIV-1 infection is complex and may lead to a heterogeneous neuropathologic correlation. Table 2 summarizes potential neuropathologic findings in HIV-1 infected patients.

Table 2. Brain Neuropathologic Findings

Epidemiology

The worldwide increase in the number of AIDS cases in women of childbearing age is paralleled by an increasing number of children with congenital HIV-1 infection. The true number of HIV-1-infected children is unknown because surveillance systems still rely in most countries on identification of children with clinical manifestations of AIDS. HIV-1 infection in children represents 1% to 3% of reported AIDS cases in industrialized countries but 20% in sub-Saharan Africa (53; 36). In the United States, the number of HIV-1 infections related to mother-to-child transition is less than 2% due to treatment with antiretrovirals in HIV-1 infected pregnant women (Read and Committee on Pediatric AIDS 2007). Maternal coinfection with other sexually transmitted infections increases transmission rate, and this seems to be most significant with multiple sexually transmitted infections or CMV coinfection alone (01; 02).

The most important recent change in pediatric AIDS has been the dramatic reduction of the transmission rate of the virus from mother to offspring. During the natural history of the disease, the transmission rate in large prospective studies ranged from 25% to 30% in the absence of antiretroviral treatment and non-breastfeeding mothers, but can be as high as 50% with prolonged breastfeeding of the infant. It depended on the viral load in peripheral blood of the mother, genetic factors, and, probably, other factors such as sanitary conditions (53; 36; 50). Antiretroviral treatment during the end of pregnancy, at time of delivery, and during the first weeks of the baby’s life has dramatically reduced the transmission rate to less than 2% in most recent studies in industrialized countries. Simplified and less expensive treatments have also been tested with a good efficiency (61).

Prevention

Clearly, the most effective strategy for prevention of congenital HIV-1 transmission is to prevent HIV-1 infection in the mother before pregnancy and indeed in all women of childbearing age. Congenital infection may occur during gestation in the perinatal period, and rarely, via transmission by breast milk postnatally. It remains unclear, however, when most maternal-to-infant transmission occurs (ie, early in pregnancy or around delivery). HIV testing is recommended as early as possible for all pregnant women. Women with high risk factors for HIV infection who were seronegative on initial testing should consider retesting during late pregnancy. Women are at higher risk if they have a history of an HIV infected partner, history of drug abuse, history of sexually transmitted disease, signs or symptoms of acute HIV infection, live in areas with increased incidence of HIV infections in women of childbearing age (≥17 HIV cases per 100,000 person-year), or receive care in facilities with at least 1 diagnosed HIV case per 1000 person-years. If testing was not completed during pregnancy or a woman presents during labor without prenatal care, a rapid HIV antibody test should be completed. A confirmatory HIV test should be drawn as soon as possible if HIV antibody testing is positive (50).

Transmission of HIV-1 from mother to infant can be interrupted with antiretroviral agents or by elective cesarean sections. Use of triple therapy started in pregnancy has increased significantly from less than 1% (1/153) in 1997 to 44% (47/107) in 1999. Exposure to antiretroviral therapy was not associated with prevalence or pattern of congenital abnormalities (P = 0.88) but was associated with reversible anemia in the infant (P < 0.002). The elective cesarean section rate has increased from 10% in 1992 to 71% in 1999/2000. The vertical transmission rate declined from 15.5% by 1994 to 2.6% after 1998. In multivariate analysis, adjusting for maternal CD4 cell count, risk of vertical transmission was reduced by 66% (95% confidence interval, 37% to 82%) with the full 076 regimen and by 60% (95% confidence interval, 33% to 73%) with elective cesarean section delivery. Current recommendations from the American College of Obstetricians and Gynecologists and the Department of Health and Human Services are as follows: (1) HIV infected women with plasma viral loads greater than 1000 copies/mL should be informed of the benefits of elective cesarean sections; (2) elective cesarean delivery should be at the completion of 38 weeks gestation; (3) HIV infected women should receive antiretroviral therapy during pregnancy, which should not be discontinued prior to cesarean delivery; and (4) mothers should receive intravenous zidovudine 3 hours prior to elective cesarean delivery (28). Because HIV can be transmitted via breast milk, HIV infected women are advised against breastfeeding regardless of whether the mother and/or infant are on antiretroviral therapy in the United States. Outside of the United States where replacement feeds are not possible, additional antiretroviral therapies are given during the breastfeeding period to help reduce the risk of transmission while allowing the infant to maintain nutrition (50).

The rate of mother-to-child transmission of HIV-1 ranges from 5% to 10% during pregnancy, 20% to 30% during delivery, and 10% to 20% through breastfeeding in the absence of treatment, whereas it is reduced to less than 2% with antiretroviral therapy during gestation (04).

Differential diagnosis

The infant or child with congenital HIV-1 infection may present with several clinical manifestations. Differential diagnosis, therefore, is dependent on the presenting signs and symptoms as well as the age of the child. In infancy, lymphadenopathy, hepatosplenomegaly, thrombocytopenia, anemia, or leukopenia may occur with other congenital or perinatal infections (toxoplasmosis, rubella, cytomegalovirus, herpes, syphilis, Epstein-Barr virus). Moreover, these infections are often associated with immunologic abnormalities. However, each of these infections is usually associated with an increased concentration of specific immunoglobulin. Additionally, cytomegalovirus may be cultured in urine or blood, and syphilis can be determined by dark field exam, antibody titer, and immunoglobulin-fluorescent treponemal antibody (26).

Later in infancy and in childhood, if the presenting symptoms are chronic, recurrent, or opportunistic infections, the most important and likely diagnosis is an immunodeficiency disorder. Primary, congenital, and secondary immunodeficiency disorders are included in the differential diagnosis. Inherited forms of cellular congenital immunodeficiency diseases that may be considered include severe combined immunodeficiency or variants such as Nezelof syndrome, adenosine deaminase or nucleoside phosphorylase deficiency, Omenn syndrome, Bare lymphocyte syndrome, severe combined immune deficiency with graft-versus-host disease, and DiGeorge syndrome. Other congenital immunodeficiencies include Wiskott-Aldrich syndrome, ataxia-telangiectasia, X-linked lymphoproliferative syndrome, mucocutaneous candidiasis, agammaglobulinemia, and dysgammaglobulinemia. An appropriate history, examination, and immunologic analysis, including HIV-1 serologic testing, can usually rule out these conditions. Hematological disorders that should be considered in the differential diagnosis include neutrophil disorders, reticuloendotheliosis, lymphoma, and idiopathic thrombocytopenic purpura. Secondary immunodeficiencies include malignancy, malnutrition, nephrotic syndrome, protein-losing enteropathy, and severe diarrhea (26).

The differential diagnosis in the infant or child who presents with progressive neurologic dysfunction includes other neurodegenerative diseases (particularly the progressive genetic metabolic diseases, especially if the child has hepatosplenomegaly) and other CNS infections. A thorough history (including family history), physical and neurologic examination, and laboratory studies, including neuroimaging and anti-HIV-1-antibody (for a child greater than 18 months of age), help to make the diagnosis.

Diagnostic workup

The goal of the diagnostic workup is to establish the presence or absence of HIV-1 infection and, if present, to determine the stage of the disease, extent of immune dysfunction, and presence or absence of neurologic involvement. Table 3 demonstrates the recent guidelines for diagnosis of HIV-1 infection in infants and children.

Infants. Newborns and young infants (up to 18 months of age) present special diagnostic challenges. Although the detection of anti HIV-1-specific IgG antibody in peripheral blood in older children and adults is taken as proof of HIV-1 infection, a positive antibody test in a well infant or young child is uninterpretable, as maternal IgG crosses the placenta and may persist for up to 18 months. Thus, a positive IgG antibody test only confirms the seropositivity of the mother. However, a rising titer in the infant may be indicative of HIV-1 infection, as may anti-HIV-1-IgA (IgA is produced by the infant). Direct evidence for HIV-1 infection may be sought by HIV-1 culture, polymerase chain reaction, and assays of circulating p24 in the peripheral blood. Viral load determination is the most sensitive indicator for HIV infection in infants and can be used for diagnosis as early as 5 days postinfection. RNA-PCR-based assays are much more sensitive than the DNA-PCR assays, although both tests are considered the gold standard for diagnosis. Infants with known exposure to HIV-1, either by positive maternal testing or positive rapid antibody test of the infant after birth, are recommended to have HIV-1 DNA-PCR or RNA-PCR assays within the first 14 days of life, between age 1 to 2 months, and between age 3 to 6 months. Two positive HIV-1 DNA-PCR or RNA-PCR assays are required to make the diagnosis. Therefore, if testing reveals a positive result, a repeat test to confirm the diagnosis is recommended (45; Read and Committee on Pediatric AIDS 2007).

Current guidelines no longer recommend ELISA antibody testing at 18 months to confirm absence of HIV infection. However, the authors of a study recommend that serological testing at 18 months should be done to look for the presence or absence of HIV infection in an attempt to increase the diagnosis of HIV in infants born to HIV infected mothers. In their report, and another one by Frange and colleagues, a total of 6 children were found to have delayed diagnosis at 18 months of age (22; 43).

Children. The initial laboratory evaluations of a child over age 18 months who is suspected of having HIV-1 infection should include HIV-1 serologic testing (screening enzyme-linked immunosorbent assay and confirmatory Western blot); a complete blood count; IgA, IgM, IgG levels; and lymphocyte subsets (CD3, CD4, CD8) enumeration. Other routine diagnostic tests, such a chest x-ray, urine analysis, appropriate cultures for pathogens, and a chemistry panel may also be warranted. Most children will have a normal blood count, a positive antibody test, elevated immunoglobulin levels, and variable T-cell abnormalities, dependent on the age of the patient and the stage of disease (03).

Currently, clinical prognostic and therapeutic decisions are based on virologic markers of HIV-1 infection (preferably viral load) and the degree of CD4 lymphopenia relative to normal values for age.

Evaluations of the competence of the immune system, such as lymphocyte proliferative responses to mitogens (phytohemagglutinin, poke weed mitogen) and antigens (tetanus toxoid, Candida, etc), delayed hypersensitivity skin tests, antibody titers to vaccine antigens (eg, tetanus, diphtheria, rubella, Hemophilus), and surrogate markers of immune activation, such a B2 microglobulin assays, may be used to determine immunologic response to therapeutic protocols. Surprisingly enough, the viral load in CSF is usually low in patients with early severe neurologic symptoms, but remains the best predictor of HIV encephalopathy (54; 18).

The evaluation of the HIV-1-infected child for neurologic involvement requires the clinical skills and major diagnostic tools of the neurologist. The approach to the diagnosis of HIV-1-associated CNS disease, including differential diagnosis (secondary complications, confounding comorbid complications), involves a careful medical and developmental history, HIV-1 systemic disease history, current immunologic status, neurologic examination, psychological assessment, and neuroimaging studies (06; 07; 03).

Neuroimaging. CT and MRI findings in infants and children with HIV-1 infection are dependent on the severity of CNS involvement. This can be further complicated by the presence of other opportunistic infections, such as cytomegalovirus and toxoplasmosis, which can also demonstrate intracranial calcifications, microcephaly, hydrocephalus, and atrophy. Table 4 summarizes imaging findings based on neuroanatomical localization. CT and MRI abnormalities are frequent in these patients and can consist of enlargement of the subarachnoid space and ventricles, calcifications of basal ganglia and subcortical areas, and white matter abnormalities (07). In addition to these findings, some children may also develop cerebral aneurysms resulting in subarachnoid hemorrhage or cerebral infarcts. The aneurysms are usually fusiform, involving the major blood vessels that can be seen on vascular imaging studies (40).

Table 3. CDC Surveillance Case Definition for HIV Infection

(17)

Table 4. Neuroimaging Findings

Management

Antiretroviral therapy. Drugs that treat HIV-1 infection attempt to interfere with the replication of HIV. Targeted points in the growth cycle of the virus include blockage of viral entry (soluble CD4+ preparations), prevention of transcription of RNA to DNA (reverse transcriptase inhibitors), interference with translation (drugs acting on regulatory genes or their proteins), inhibition of assembly (protease inhibitors), release of virus (interferon), and integrase inhibitors.

In clinical trials, children treated with zidovudine had improvement in weight gain and growth, stabilization of CD4 counts, reduction in serum and CSF p24 antigen levels, decrease in immunoglobulin levels, and improvement or stabilization of cognitive function (42; 15; 12). In 2011, a review of 25 trials (22 trials of randomized mothers with follow-ups of their infants and 3 randomized infant trials) assessed the effectiveness of antiretrovirals for reducing the risk of mother-to-child transmission of HIV infection and concluded that triple antiretroviral therapy is the most effective at preventing transmission of HIV from mother to child (51).

Any infant with HIV exposure should receive zidovudine prophylaxis as soon as possible after birth; the goal is within 6 to 12 hours after delivery. Children 25 weeks or older should receive 4 mg/kg orally twice daily for 6 weeks. Zidovudine can be given intravenously if oral medications are not tolerated. In high-risk infants with mothers who did not receive antiretrovirals during pregnancy, 3 doses of nevirapine should be given within the first 48 hours after birth in addition to the zidovudine. The antiretrovirals are generally well tolerated, and the most common side effects are anemia and neutropenia related to the zidovudine (50).

A national observational study in Italy from 2001 to 2011 examined the effects of antiretroviral exposure on birth defects. The study supported that first trimester exposure to antiretroviral therapy did not increase risk of congenital abnormalities in infants (21). An analysis of the Quebec Pregnancy Cohort indicated that major congenital malformations were more common in HIV-positive mothers without antiretroviral exposure compared to the general population, but this was not true for HIV-positive mothers with exposure to antiretroviral therapy (10).

A population analysis study with surveillance data from the UK and Ireland found that pregnant women who received lopinavir/ritonavir (LPV/r) containing ART regimens had a good safety profile, and they were effective for viral suppression during pregnancy. This regimen also had a low associated rate of mother-to-child transmission, which is always the goal (56).

A long-term follow-up of the IMPACCT P1060 randomized trial in 2016 found that in comparison to the nevirapine-based ART, LPV/r-based ART was associated with fewer virologic failures or deaths over time in an extended 5-year follow-up (05). Short-term superiority of the nevirapine arm in CD4 percentage recovery did not persist beyond 1 year. This evidence provides support for the continued use of LPV/r-based regimens as part of first-line treatment of pediatric HIV.

Outcomes

The PHACS SMARTT study evaluated the safety of in utero exposure to antiretroviral (ARV) medications and found that overall the data is generally reassuring, with minimal evidence for serious adverse events. However, they did find increased rate of premature delivery and selected birth defects with certain antiretroviral exposure. Specifically, atazanavir exposure was associated with lower language achievement at 1 year, a 2-fold risk of congenital anomalies, and was known to increase unconjugated bilirubin levels in the blood. Tenofovir exposure was associated with decreased newborn bone mineral content and reduced growth at 1 year. Some subclinical cardiac abnormalities were also noted, but it is unclear if these will predict a future premature heart disease (57).

A French perinatal multicenter cohort of 13,124 live births from HIV infected mothers with HAART found a significant association between first trimester zidovudine exposure and congenital heart defects, specifically a prevalence of 2.3% (58% VSD, 18% ASD cases). In a U.S. prospective cohort (SMARTT study) of 2580 HIV exposed but uninfected children, Williams and colleagues looked at first trimester exposure to antiretrovirals and found that the prevalence of congenital anomalies was 6.8% (62; 59).

The Pediatric AIDS-Defining Cancer Project Working Group found that in a study of 24,991 children in Africa, Europe, and Asia, HIV infected children from sub-Saharan Africa but not those from other geographical regions were at high risk for developing Kaposi sarcoma after cART initiation. Therefore, they suggest that early cART initiation in these children may help reduce Kaposi sarcoma risk (41).

Hrapcak and colleagues found that there is an overall 24% prevalence of hearing loss (which is 82% conductive hearing loss) in children aged 4 to 14 years with congenital HIV in Lilongwe, Malawi (23). Although this amount is lower than previous reports, it is still significant. The authors state that there is urgent need for improved screening tools, identification, and treatment of hearing to prevent adverse effects on school functioning and quality of life. Suggestions include more frequent ear assessments and hearing evaluations than for children without congenital HIV infection. Another study found similar rates of hearing loss when tested by objective measures between HIV-positive children and healthy controls (37), despite significantly higher numbers of self-reported hearing loss in HIV-positive patients.

Future directions of therapeutics include antilatency drugs, which work by activating viral production from latently infected cells to purge and clear HIV-1 reservoirs. Martinez-Bonet and colleagues discuss the possibility of the role of antilatency drugs in chronically HIV infected pediatric patients (35).

In a review article discussing the challenges of eliminating pediatric HIV infection, Luzuriaga and Mofenson also commented that additional research needs to be done to improve methods of early diagnosis in resource-limited settings and methods to define the size and distribution of the latent HIV-1 reservoir in children more actively (33).

Special considerations

Pregnancy

It is not clear what proportion of in utero transmission occurs in early, mid, or late gestation. Both the risk factors of perinatal transmission and its timing are still under active investigation. Several factors appear to contribute to the differential transmission rates of HIV-1 from mother to infant, including HIV-related influences such as persistent viremia of the mother, stage of maternal HIV-1 disease, presence of maternal neutralizing antibody, and intrinsic host factors (60). Studies indicate that the risk of transmission to the fetus is highest during the viremic phases of the illness (stage of maternal infection) (46; 20; 13). The rate of HIV transmission to the fetus can be decreased to less than 5% by use of antiretrovirals during pregnancy (31). A multitude of studies have shown these drugs to be safe for the mother, fetus, and newborn.