Although a real opportunity exists to decrease the number of children infected with HIV, the number of infected adults of childbearing age continues to increase, resulting in a rapidly escalating number of children orphaned by the epidemic. With 15 million HIV orphans worldwide and many more children whose parents are incapacitated by illness, orphaned children are often looked after by family members, frequently by aging grandparents, or adolescent siblings, in institutional settings, or by other street children (2). However, as the infection rate in a community increases, there are fewer working adults; the result is a decrease in the resources available to care for orphaned children.

Few studies exist that describe the actual psychosocial symptoms of orphans in low resource countries, though it is increasingly recognized that many who have been orphaned by HIV/AIDS do not thrive. A study of orphans in Uganda found that those whose parents died of AIDS had higher depression scores than other orphans (25). The children showed signs of unresolved grief, and the study called for professional counseling interventions for orphans. Another study found that orphans were more likely to experience internalizing symptoms such as anxiety, a sense of failure, and suicidal thoughts when compared with non–orphan matched controls (26). Not addressing these issues results in children growing into adults who are not able to be as functional as others in their society and who are more likely to engage in high risk behavior, including sexual activity and criminality (27,28,29).

At least half of new HIV infections worldwide occur in adolescents and young adults, with higher rates among females and those of ethnic minority backgrounds (2,30). Although mother-to-child transmission has become infrequent in the
United States, youth who were infected when rates of mother-to-child transmission were higher represent approximately one-fifth of HIV-infected persons (7,31). The advent of ART, decreases in HIV prevention funding, and numbing to the fear of the disease are all reasons for a resurgence of unsafe sexual practices among youths and adults (32). Rates of infection with other sexually transmitted diseases (STDs) continue to be very high among youth and serve as indicators of their elevated risk of HIV infection. Of the 12 million cases of STDs that occur each year in the United States, one-fourth occur among teenagers, and two-thirds are acquired by 25 years of age (33). Drug use among adolescents can also increase the risk of HIV infection, not only through direct infection from injecting drug use but also through increased risk for unsafe sexual practices. Persons under the influence of alcohol or other drugs experience both decreased inhibitions and physical sensitivity, resulting in sexual practices that are more likely to result in damaged membranes and therefore transmission of HIV.

Neurological, neuropsychological, and developmental manifestations of HIV disease can be the earliest and most devastating markers of infection in children. In fact, neurodevelopmental dysfunction was one symptom of HIV infection that brought children to the attention of a medical community that still saw AIDS as an adult disease in the early 1980s (38). The virus was shown to cross the blood brain barrier readily and create both direct and indirect injury in the central nervous system (CNS). Early studies of CNS manifestations of HIV disease suggested that between 40% and 90% of infected children had some degree of neurologic involvement (39,40). These studies, however, were generally conducted in cohorts of children with more advanced disease. Later prospective studies documented rates of serious neurodevelopmental signs in 8% to 13% in HIV-infected children and in 19% to 31% in children who met diagnostic criteria for AIDS (13,41,42,43). Although early, aggressive, and well monitored treatment has dramatically reduced progressive HIV encephalopathy for children, there remain aspects of CNS effects that warrant attention by infectious disease specialists and also by mental health professionals monitoring the child’s wellbeing.

Prior to the widespread use of HAART in the United States and other industrialized countries, three-fourths of children with HIV encephalopathy were diagnosed before the age of 36 months (42). HIV encephalopathy is a general term for HIV-associated CNS pathology resulting in structural damage (e.g., atrophy) and/or impaired function. This is predominately a clinical diagnosis, at times supported by neuroimaging and laboratory findings; and, in children, it usually refers to a progressive process. The definition of HIV encephalopathy adopted by the Pediatric AIDS Clinical Trials Group identifies three criteria: 1) impaired brain growth, 2) loss of or failure to achieve developmental milestones, and 3) clinically apparent neurological dysfunction. Impaired brain growth refers to acquired microcephaly and/or cerebral atrophy, or other findings from imaging studies. Decline in or failure to achieve developmental and cognitive milestones is evaluated by clinical observation, parental report, and serial neuropsychological testing. Clinical neurological difficulties often present as progressive motor dysfunction, most often symmetrical deterioration of previously attained functional motor skills, diffuse and symmetric loss of power or strength, diffuse and symmetric abnormalities of tone, and diffuse, symmetric, and pathologically increased deep tendon reflexes. HIV encephalopathy in the newborn and infant can also be manifested by significant changes in neurobehavioral status, including changes in range and regulation of arousal and attention, and decrements in alertness, responsivity, and attention. Improved neurodevelopmental status in these domains was one important marker of the effects of early, single drug ART for symptomatic children; and neurodevelopmental decline was seen as an indicator of the ineffectiveness of specific drug therapy (36).

Children with HIV/AIDS can also exhibit static neurodevelopmental deficits. They do not lose milestones; but as they grow older, deficits in neuromotor or cognitive development become more evident, and new skills are acquired at a
slower rate than normal. It is often not clear whether these developmental difficulties are a direct or indirect effect of HIV infection, are unrelated to the disease, or are the result of a complex interaction of direct effects on the CNS, indirect toxicities of disease or drug treatment on the brain, or the various economic and psychosocial adversities faced by many children with HIV/AIDS.

Important for the medical or mental health practitioner, however, the devastating, early, and progressive manifestations of HIV activity in the brain are all but eliminated for children diagnosed early and treated successfully with HAART, that is, for whom viral activity in the brain is suppressed. The neurodevelopmental and behavioral risks for children with HIV disease in wealthier countries have changed dramatically but certainly have not been eliminated. To date there are few studies of the neurodevelopmental and psychological consequences of HIV and its treatments for the new cohort of children living with HIV/AIDS as a chronic disease. It is likely that the effects represent not only neurological injury to the CNS when viral suppression is not adequate but also the toxicities of drugs used to treat HIV/AIDS over a long period of time. In addition, the development and mental health of children living with HIV/AIDS will be affected by the economic and other psychosocial difficulties in their lives, e.g., the death of parents, changes in caregivers, the stigma of the disease.

An extensive history focusing on developmental milestones and a detailed neurologic examination are important in alerting the clinician to the possibility of the neurodevelopmental and learning effects of HIV/AIDS. A full neurodevelopmental assessment is warranted when there is any suggestion of developmental abnormalities or sign of neurologic disease. Neuropsychological testing can be useful in establishing an initial baseline, monitoring subsequent alterations in cognitive processing secondary to CNS involvement, and devising appropriate developmental or educational interventions.

In general, results of cerebrospinal fluid studies are normal in HIV encephalopathy, although there may be slightly elevated protein and a mild, predominantly lymphocytic pleocytosis. Abnormalities in imaging studies associated with HIV encephalopathy are nonspecific and include enlargement of the ventricles, cortical atrophy, attenuation of periventricular white matter, and cerebral calcifications (44). The calcifications, when they occur, are usually symmetrical and are located in the basal ganglia and periventricular frontal white matter, or occasionally in the cerebellar regions. Computed tomography scanning is most helpful in demonstrating cerebral calcifications, whereas magnetic resonance imaging is better at detecting the abnormalities in white matter. Abnormalities can be seen on neuroimaging studies, even in the absence of other signs of encephalopathy; however, repeated assessments are usually helpful in assessing progression of disease and failure of treatment in an individual patient.

Formerly, the approach to treating HIV/AIDS in children was to reserve the use of antiretroviral medications for patients who already had fairly advanced disease, as evidenced by a decline in CD4+ T lymphocyte cells or the development of symptoms of their disease. However, once it was understood that the period that preceded clinical signs of disease was not a period of latency, but, in fact, a period characterized by continuous replication of the virus and destruction of the immune system, newer recommendations for treatment were developed (45,46). In addition, the current treatment of HIV infection in adults and children has progressed from the use of a single antiretroviral drug designed to thwart the entry of the virus into the blood stream, to multiple drugs that, taken at the same time, attack the virus and its replication at different points in its pathophysiological process. The advent of a new class of drugs in the 1990s, the protease inhibitors, resulted in dramatic improvements in HIV-associated mortality and morbidity by preventing viral replication. It is now recommended that treatment decisions, such as when to start and when to change a treatment regime, be made from measures of the extent of viral replication and CD4+ T lymphocyte count. The extent of viral replication, commonly referred to as the viral load, is quantified by measuring the HIV ribonucleic acid (RNA) by polymerase chain reaction amplification.

The present treatment approach, referred to as highly active antiretroviral treatment (HAART), includes starting treatment early and achieving maximal suppression of viral replication using a combination of at least three different antiretroviral medications, including nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors. Fortunately, these combination drug protocols have successfully reduced viral load to undetectable levels and preserved immune functioning in as many as one-half of the children who adhered to the protocol (47,48). Of course, these successes have been documented in wealthy countries in which these expensive treatments are feasible, but not in low resource countries where HIV/AIDS in children is most prevalent.

Unfortunately, there is a potential for the virus to develop resistance to antiretroviral medications, particularly if someone has already been treated with a single medication before starting triple therapy and if adherence is inconsistent. In such cases, once there is a rebound in the viral load, the virus is likely to be resistant to all three medications, and all three will need to be changed. In addition, within the different classes of medications is a tendency for cross-resistance to develop: If the virus is resistant to one medication in a class, it may also be resistant to others within the same class. Thus, even in this era of multiple medications from which to choose, the choices become limited once viral resistance has developed, and chronic medication nonadherence should be considered in selection of pharmacotherapy strategies. Despite this limitation, some evidence indicates that although patients may have a rebound in viral load measurements on triple therapy, they continue to do better and have a slower progression of disease than would otherwise be expected (49). As with other manifestations of HIV disease in children, advances in management are almost certainly having an effect on decreasing the prevalence and severity of CNS disease among children. Such a decrease in CNS manifestations of HIV disease has been well documented in adults, has been observed in children, but awaits further study in children and adolescents (50).

All of the antiretroviral medications have adverse effects, some of which may be mitigated by the use of other medications, including psychotropic medications. The finding that antiretroviral medications, particularly the protease inhibitors, can cause significant derangements in metabolic processes resulting in abnormal lipid profiles and glucose levels, and alterations in body composition, are among the most important adverse effects (51). This latter, referred to as the lipodystrophy syndrome, may be very distressing to patients because of the changes in physical appearance. There is wasting and disappearance of fat from the face and limbs but an increase in fat in the abdominal region and over the lower part of posterior neck.

A major challenge posed by the advances in therapy of HIV disease has been the need to ensure that patients consistently are able to take all of their medicines. Inconsistent adherence
can provide the window for resistant viral strains to replicate and dominate, increasing viral load, this time with a virus that is not affected by the current treatment. One study reported a linear association between self-reported adherence and level of HIV viral suppression. Patients taking fewer than 80% of their prescribed doses of antiretroviral medications had a significant increase in viral load measurements compared with those who took more of their medications. As noted above, successes of HAART have been documented for those children with good adherence (6). Despite this serious risk, adherence is not simple or easy for children and families. Treatment regimens often call for a large number of medications, taken at regular intervals each day. Some of the medications are available only as large capsules that are difficult to swallow; others have a particularly bad taste. Important interventions for the care of children with HIV/AIDS include support and strategies for children and families in taking medications on time and more easily.