A majority of infants are usually asymptomatic until approximately 3 years of age, which is considered to be the median age for the appearance of symptoms [15]. Clinical criteria for children < 13 years of age with HIV infection somewhat differs from adult criteria and divides children into categories [6] [15]:

Category N: Asymptomatic
Children without any signs or symptoms considered to be the result of HIV infection or those who have only one of the conditions listed in category A.

Category A (mildly symptomatic) - Infants or children that present wth 2 or more of the following: dermatitis, hepatomegaly, splenomegaly, lymphadenopathy ( > 2 sites involved or bilateral involvement of one site), parotitis, recurrent or persistent upper respiratory tract infection, sinusitis, or otitis media.

Category B (moderately symptomatic) - The list of conditions included as defining criteria, in addition to category A symptoms, include:

• Oral candidiasis that persists for more than two months in a child of more than six months of age.
• Single episode of bacterial meningitis, pneumonia or sepsis.
• Recurrent or chronic diarrhea.
• Herpes simplex virus (HSV) infection (recurrent stomatitis, bronchitis, pneumonitis or esophagitis), toxoplasmosis or cytomegalovirus (CMV) infection before 1 month of age.
• Disseminated varicella infection.
• Hepatitis
• Nephropathy
• Persistent fever lasting more than one month
• Neutropenia (< 1,000/µL), thrombocytopenia (< 100,000/µL) or anemia (< 8 g/dL).
• Cardiomyopathy
• Leiomyosarcoma
• Lymphoid interstitial pneumonitis

Category C (severely symptomatic) - considered as the most severe stage of HIV infection and the prelude to AIDS, various life-threatening conditions fall under this category:

• Wasting syndrome - persistent weight loss of > 10%, downward crossing of two or more percentile lines on the weight-for-age chart in a child older than 1 year, accompanied by either chronic diarrhea or fever for 30 or more days.
• Recurrent septicemia, pneumonia, meningitis, osteomyelitis, arthritis, or other internal organ infections.
• Disseminated or extrapulmonary mycobacterium infection, either tuberculosis or non-tuberculous mycobacteria (NTM).
• Fungal infections - Pneumocystis jirovecii pneumonia (PCP), candidiasis (esophageal or pulmonary), cryptococcosis, histoplasmosis (extrapulmonary), cerebral toxoplasmosis and disseminated coccidiomycosis.
• Malignant diseases - Various forms of lymphoma (Burkitt's, immunoblastic, large-cell) and Kaposi's sarcoma.
• Severe CMV or HSV infection.
• Encephalopathic findings such as failure to thrive and impaired brain growth, as well as the presence of motor deficits (paresis, ataxia, gait disturbance or abnormal reflexes).
• Progressive multifocal leukoencephalopathy (PML).

If there is clinical suspicion of HIV in infants and children, based on signs and symptoms, then rapid confirmation of HIV as an underlying cause should be made. Detection of HIV antibodies through an enzyme-linked immunoassay (EIA) is the initial diagnostic test of choice, followed by detection of specific amino acid sequences through Western blot (WB) if the result comes back positive [4]. In most cases, only HIV-1 antibodies are tested because HIV-2 infection is rare in the developed world. But if clinical signs and symptoms are highly suggestive of HIV, and HIV-1 results are negative,then HIV-2 WB must be performed, especially in children whose mothers are from endemic regions [5]. Recently, a new generation of tests that include detection of the p24 antigen (which codes for the viral core) and IgG/IgM antibodies to p24 have been shown to be more sensitive than traditional testing. However, their use in general practice is yet to be solidified [4]. Once a confirmation of HIV infection is made, it is necessary to perform a quantitative detection of HIV genetic material (known as the viral load), a procedure performed by using PCR assays [4]. In general, detection of RNA in blood is performed, but in children, levels of HIV DNA are preferably measured (when possible) [4]. In addition to determining viral load, it is necessary to determine the CD4+ and total lymphocyte count, in order to categorize children according to immunologic findings [6]:

• In infants (< 1 year of age), no evidence of immune suppression is seen if ≥ 1500 lymphocytes/µL are present, with at least 34% being CD4+ T lymphocytes, while moderate suppression is diagnosed if between 750-1499 lymphocytes/µL, of which 26-33% are CD4+ T lymphocytes. Severe suppression is seen in in infants with < 750 lymphocytes/µL, with < 15% of CD4+ T cells.
• For children between years 1 and 5, ≥ 1000 lymphocytes/µL and ≥ 25 % of CD4+ T cells indicate no evidence of suppression, between 500-999 lymphocytes/µL and 15-24% of CD4+ T cells show evidence of moderate suppression, while severe suppression is diagnosed if < 500 lymphocytes/µL are detected with < 15% of CD4+ T cells.
• For children over 5 years, ≥ 500 lymphocytes/µL and 26% of CD4+ T cells, 200–499 lymphocytes/µL and 14–25% of CD4+ T cells and < 200 lymphocytes/µL with < 14% of CD4+ T cells determine little, moderate or severe suppression, respectively.

Although numerous challenges may be faced when initiating and maintaining treatment in young HIV-infected patients, including limitation of available drugs, toxicity of therapy, adherence to therapy and the development of resistance, it should be pointed out that therapy should be started as early as possible, with studies showing a 75% decreased mortality when treatment is started in early infancy [7]. The WHO has recently changed its guidelines and now recommend immediate initiation of therapy in children under 2 years of age regardless of the clinical stage or CD4+ cell count [16]. More importantly, disease progression is substantially reduced with early therapy, while a reduction in opportunistic infections, improved neurocognitive abilities and growth and a better quality of life,in general, have been observed [7]. This further strengthens the principle of immediate therapy to prevent MTCT. Of the many antiretroviral drugs, six are currently recommended for use in neonates - Lamivudine, emtricitabine and stavudine (RT inhibitors) nevirapine (NNRT inhibitors) and lopinavir-ritonavir, a protease inhibitor [8]. Most common side-effects of therapy are fat wasting, dyslipidemia, insulin resistance and suboptimal bone growth [16]. Management of non-AIDS-defining infections and diseases that lead to multiorgan failure must be considered, as studies have shown that they are a major cause of mortality in HIV infected children, rather than opportunistic infections and other AIDS-related conditions [17].

The progression of HIV disease in infants and children occurs at a much higher rate [7], but it is important to distinguish between the three modes of MTCT, as major differences in clinical progression and the pathogenesis of HIV infection exist [2]. The primary reason for a poorer prognosis of untreated neonates and infants compared to adults is the level of maturity of the immune system, which may be able to provide some form of protection when the infection is contracted during breastfeeding and adulthood, but intrapartum and in utero transmission carry a much worse prognosis, as the immune system is still not fully activated [2] [14].

Congenital AIDS is caused by HIV-1 and HIV-2 in a small subset of cases [5]. These are single-stranded enveloped RNA retroviruses that possess genes for three main enzymes that enable their life-long survival in CD4+ T-cells: reverse transcriptase (forms DNA from viral RNA), integrase (integrates viral genetic material into host DNA) and protease (cleaves necessary proteins and prepares the newly formed virion for release into the extracellular environment) [9]. Through a multi-step process that involves invasion of CD4+ T-cells and replication using the host machinery, the virus is able to persist. During pregnancy or delivery, MTCT may occur and result in congenital HIV infection which can progress to AIDS, if left untreated.

Current epidemiology studies estimate that 34 million people are living with HIV and that 10% comprise individuals younger than 15 years [10]. Of those 3.4 million children, 95% acquired the infection via MTCT, but a clear distinction between perinatal (or vertical) and behavioral (or horizontal) transmission is yet to be made [4] [11]. In the United States, approximately 4500 children < 15 years suffer from a perinatal HIV infection [4] [6]. Modes of vertical transmission include intrauterine, postnatally through breastfeeding or intrapartum, with estimated transmission rates of 5-10%, 5-15% and 10-20%, respectively [2]. In African countries, transmission rates are as high as 25%-45% in the absence of any forms of prevention [3], while other studies indicate that prolonged breastfeeding by HIV+ women who do not take therapy increases the transmission rate to 50% [4].

HIV viruses belong to a group of single-stranded RNA viruses that insert into the host DNA through a complex pathophysiologic mechanism. After transmission of the virus from an HIV+ individual, usually through sexual intercourse, the virus targets CD4+ T-helper cells, specifically the co-receptors CCR5 or CXCR4, initiating the first step in infection: fusion of the viral particle with the host cell [4]. This mechanism enables the virus to gain access to the intracellular environment where it can freely proceed to the next steps in its replication. Firstly, reverse transcriptase (RT) synthesizes DNA from viral RNA, which is then integrated into the cellular DNA through the activity of integrase. Finally, the host machinery transcribes viral DNA and produces viral RNA, as well as all the necessary viral particles (with the aid of a third viral enzyme, protease), eventually leading to release of virions into the extracellular environment [9]. In this way, HIV is integrated into the host DNA and is able to persist throughout life either in active or latent form [12], which is why life-long treatment is necessary [4]. MTCT of HIV infection may occur at three separate points [2]:

• In utero transmission - Despite the fact that the fetus is exposed to the maternal infection throughout the entire pregnancy, one of the possible reasons why only 5-10% of children are infected during this phase is because HIV replicates only in active CD4+ T-cells and they are practically non-existent in the fetus [2]. However, recent studies have shown that CD4+ T-cells harboring CCR5 coreceptors are found in the intestinal system of the fetus, which may be the primary mode of in utero MTCT [13]. Recent HIV-1 acquisition, high viral load and presence of Neisseria gonorrhoeae infection have shown to increase the risk of transmission during this period [2].
• Intrapartum transmission - Current theories hypothesize that transplacental transfer of the virus during delivery or exposure of the neonate to maternal secretions may be the cause of intrapartum infection, but viral shedding through the mucosal surfaces in this period are most likely the cause [8]. Scalp trauma of the neonate during delivery, vaginal candidiasis, prolonged rupture of membranes, chorioamnionitis,and a high maternal viral load predispose infants to a much higher risk for infection [2].
• Breastfeeding - Although the levels of HIV RNA are 100 times lower in breast milk than in the circulation, MTCT is possible through this mechanism, especially in the setting of mastitis and other inflammatory changes in the breast [2].

The single most important preventive strategy for congenital AIDS and mother-to-child transmission of HIV is early recognition and initiation of therapy [18] [19]. Zidovudine, an inhibitor of reverse transcriptase (RT), is recommended for administration in infants who were exposed to HIV within 6-12 hours of delivery, in doses of 4 mg/kg PO q12h for 6 weeks [4]. Nevirapine is given in addition to zidovudine when women did not use ART during their pregnancy and it is administered in three oral doses of 8-12 mg, depending on body weight at birth [4]. Other strategies include replacement feeding instead of breast milk for HIV+ positive mothers and elective cesarean section that will reduce the chance of contracting HIV during delivery [4]. Additionally, the recent identification of broadly neutralizing antibodies (bNAbs) as potential vaccine candidates is a major step toward HIV eradication, but further research is necessary [20].

Congenital acquired immune deficiency syndrome (AIDS) is a clinical entity characterized by mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV), which causes life-long infection of CD4+T-helper cells [1]. It is estimated that approximately 3.4 million children are infected by HIV+ . In 95% of the cases, MTCT (also known as vertical transmission) is the cause, but the rate of transmission depends on the period when HIV is transferred to the child - intrauterine, intrapartum or through breastfeeding [2]. One of the factors that substantially increases the risk for congenital AIDS is non-adherence of women to antiretroviral therapy (ART), increasing the risk to 45-50% [3] [4]. Most cases occur due to HIV-1 infection, but in a small number of children, HIV-2 is responsible for congenital HIV+ infection, most commonly in West African countries - Nigeria, Sierra Leone, Gambia, Senegal and Guinea-Bissau [5]. HIV-2 is far less potent and infective, however, which is why reports show that perinatal transmission of HIV-2 is almost 6-fold lower compared to HIV-1 [5]. The pathogenesis model of congenital AIDS is complex and involves initial infection of the mother (through sexual intercourse, intravenous drug use or contaminated blood derivatives), viral replication and subsequent transfer of virions to the fetus [4]. Several theories exist why not all infants become infected with HIV, the most common theories being a relatively silent and immature immune system that renders HIV unable to replicate under such circumstances, but numerous conditions have been implied as possible determinants, including infections (gonorrhea, vaginal candidiasis and mastitis) prolonged rupture of membranes and other obstetric complications [4]. The clinical presentation of infants and children encompasses a broad classification of diseases and signs that may appear and classifies patients into categories: Category N: asymptomatic patients or with only one condition listed under Category A; Category A (examples include hepatosplenomegaly, parotitis, dermatitis and chronic respiratory infection); Category B (moderate signs including hepatitis, nephropathy, herpes simplex virus infections, neutropenia, etc.) and Category C, in which AIDS-defining illnesses such as Kaposi sarcoma, progressive multifocal leukoencephalopathy (PML), non-Hodgkin lymphoma and severe fungal and bacterial infections develop [6]. To make the diagnosis of congenital AIDS, it is imperative to perform a thorough physical examination and obtain a detailed patient history that includes the mother and associated risks for HIV. To confirm HIV infection, however, determination of HIV-antibodies in serum, followed by identification of specific amino-acid sequences through Western blot testing and determination of CD4+ T-cell count is necessary [1] [4] [6]. Initiation of treatment as soon as possible has recently been recommended (regardless of the CD4+ T-cell count and general condition of the child) and drugs such as zidovudine, nevirapine, lopinavir/ritonavir and stavudine have been shown to be safe for use in the neonatal population [7] [8]. MTCT of HIV and congenital AIDS may be prevented or even completely eliminated through wide-scale testing and early initiation of treatment in HIV-positive women, while avoidance of breast-feeding and introduction of cesarean sections during delivery are additional strategies to reduce the possibility of HIV transmission [4].

Congenital acquired immune deficiency syndrome (AIDS) is a condition that occurs after transmission of human immunodeficiency virus (HIV) from the mother to her child, which may occur during fetal life, labor or through breast feeding. HIV is a virus that infects CD4+ T-cells, one of the most important cells in the immune system and is able to replicate inside them using cellular organelles and its own specific enzymes. HIV is one of the most difficult viruses to treat because it is able to integrate its genetic material into our own, making viral eradication from the body practically impossible. Not all children are infected if their mothers are HIV-positive. Varying percentages have been observed depending on the mode of transmission, but the risk is highest if pregnant women are not on antiretroviral therapy (ART), leading to a 50% chance of transferring the infection to their child, primarily because much higher concentrations of the virus are present in untreated women. It is estimated that 34 million people are living with HIV and approximately 10% of total cases are children who developed an infection from their mother (also known as vertical transmission). Once HIV, which was previously contracted by the mother through sexual intercourse, intravenous drug use, or contact through contaminated blood or blood products (transfusions), reaches the fetus or neonate during birth, it is able to cause a more severe form of infection compared to adults, as the immune system of the child is still immature and has very few mechanisms of defense. For this reason, early initiation of treatment has been shown to be essential. Firstly, clinical signs and symptoms of HIV infection are well defined and should be recognized, followed by various tests such as detection of antibodies against HIV, detection of specific proteins that this virus carries (known as Western blot) and quantitative determination of viral genetic material in the blood (known as viral load). If there is suspicion of HIV infection in the newborn, treatment can be initiated within 6-12 hours after delivery for preventive purposes and drugs that target the enzymes necessary for viral reproduction can be used. Once HIV+ status in infants and children is confirmed, treatment is life-long. This may be challenging from several aspects - adherence to therapy, development of drug resistance and the appearance of adverse effects. For this reason, one of the most important goals in the medical world is the prevention of HIV transmission through early recognition and treatment of HIV-positive individuals.

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