Bulletin of Experimental Treatments for AIDS, No. 29; June, 1996
Leslie Hanna, Associate Editor of BETA.

The first U.S. case of pediatric AIDS was reported in 1982. Early reports attributed HIV/AIDS in children to perinatal (vertical) transmission, transfusion and the use of contaminated blood products. Since the implementation of screening protocols for blood products and donor self-deferral, the proportion of children infected postnatally through transfusions and use of blood products has decreased substantially. Today, nearly 90% of cumulative pediatric AIDS cases and nearly 100% of new HIV infections in children result from perinatal transmission. Each year, an estimated 1,750 children in the U.S. are infected with HIV. AIDS is now the fifth leading cause of death for all children under 15 years old, and the leading cause of death for children 1-4 years of age, according to the NCHS.

Increasingly, perinatal infections are traced to women who report acquisition of the virus through heterosexual contact with a partner whose HIV status and risk factors were unknown. Heterosexual contact is the mode of HIV transmission increasingly responsible for new infections in women. In the U.S. Northeast and South, women of color are predominantly affected by rising rates of infection; thus, children of color likely will be disproportionately affected in years to come. In 1994, the annual rate of adult female AIDS cases per 100,000 population was:

Caucasian, 3.8; African American, 62.7; Latina, 26.0; all women, 12.8.

The rate among African American women was 15 times that for Caucasian women, and 3 times higher than among Latinas. The median age at AIDS diagnosis for women was 35. Urban areas with high seroprevalence rates among women may in turn be predicted to have high seroprevalence rates among children. In New York City and in Oakland, CA, in 1990-1991, seroprevalence of HIV among women of childbearing age was 40/1,000.

Defining children as persons less than 13 years of age is important for medical research and practice. The official CDC definition of pediatric AIDS for the purposes of case diagnosis and reporting pertains to children under 13. Clinical trial data specifies age group or developmental stage, and drug approvals and package insert labeling agrees with data gathered in rigorously conducted studies. Adults are persons 18 years of age and over, and adolescents are those from 13-17. (Some adult studies include adolescents 13-17.)

Statistics gathered on Americans under age 20 indicate that the rate of HIV infection in this group is increasing. In addition to children with perinatally transmitted HIV infection, this group includes adolescents at risk. A related topic that will not be a focus of this article is often termed "youth and HIV/AIDS," which tends to refer to HIV/AIDS in older children or adolescents.

According to the March 1996 "Youth & HIV/AIDS: A Report to the President," increased access to HIV counseling and testing for adolescents will be key elements in improving prevention and treatment efforts for this group. In this article, pediatric infection refers to HIV in children less than 13 years of age.

Identification of HIV Positive or At-Risk Children

Since mother-to-child infection is by far the most common route of transmission for children, intense research is underway to develop methods for reducing the risk of perinatal transmission. AZT (Retrovir) is now approved for use during pregnancy as a risk reduction strategy, according to the regimen used in AIDS Clinical Trials Group (ACTG) 076. (See BETA, June 1995, for a review of ACTG 076, the study that showed that use of AZT by mother and child could substantially reduce the risk of mother-to-child transmission.) An ACTG study currently underway is evaluating the utility of HIV immune globulin (HIVIG) and pooled intravenous immune globulin (IVIG) regimens for reducing transmission rates. Other antiretroviral agents, such as nevirapine (Viramune), are candidates for this use as well. A study of nevirapine has begun in which mothers and infants receive a single dose; another perinatal transmission reduction study evaluting ddI for this purpose is now beginning to enroll. Much has been written and publicized elsewhere about public health and policy issues associated with maternal HIV treatment.

Perinatal exposure to HIV is the backdrop, but infected children and their treatment are the focus of this article. In order to initiate prompt, optimal healthcare for perinatally exposed children, the CDC adjures healthcare providers to promptly identify infants born to HIV positive women in order to begin monitoring, diagnostic procedures and Pneumocystis carinii pneumonia (PCP) prophylaxis (recommendations appear later in this article). Approximately 1 in 4 children born in the U.S. to HIV positive mothers who use no perinatal transmission reduction strategy (AZT) will have confirmed HIV infection; since children routinely carry their mothers's antibodies for up to 18 months, various strategies have been implemented for HIV testing and care before that time.

The best way to identify at-risk children is to diagnose women with HIV before pregnancy, which is also critical for initiating care for the women themselves. To this end, the CDC has recommended that HIV counseling and voluntary testing be routinely offered to all pregnant women. If the mother's HIV status is not determined before delivery, pediatric healthcare providers should attempt to identify infants born to HIV positive women as soon as possible after birth. Symptoms of illness in all infants should be taken very seriously, since they may be signs of serious, life-threatening conditions (e.g., PCP) and HIV infection.

Diagnosis of Pediatric Infection

All infants born to HIV positive women should be monitored for HIV status as close to birth as possible. If test results at birth are negative by polymerase chain reaction (PCR), HIV culture and p24 antigen, testing should be repeated either at 1, 3 and 6 months of age (Dorenbaum), or before 1 month and again before 4 months (CDC). PCR and HIV culture are the preferred methods for HIV detection. If results are negative for HIV on at least 2 occasions, ELISA testing (HIV antibody test) should be performed at 12, 15 and 18 months of age. HIV ELISA and Western blot antibody tests are used as screening tools; confirmatory tests include HIV culture, PCR, immune-complex dissociated (ICD) p24 antigen and IgA assay. A positive HIV test result in an infant should be confirmed by repeat testing.

For at-risk infants who are being monitored for HIV status and for infants who have tested positive, CD4 cell counts should be obtained as an adjunct diagnostic tool. Although PCP prophylaxis is not initiated on the basis of CD4 count, the count is still clinically useful. For example, the CD4 count may help determine prognosis or risk for disease progression and guide decisions about whether or not to continue PCP prophylaxis after 1 year of age. The CDC recommends obtaining CD4 counts and percentages for HIV-exposed infants at 1 and 3 months of age, and for infants and children who are HIV indeterminate or HIV positive at ages 6, 9 and 12 months.

Recently, a University of South Florida study showed that a commercial PCR test was quicker and less expensive than HIV culture for detecting HIV in newborns. PCR results are available in 3-10 days compared with 3-4 weeks for HIV culture results; PCR costs about $175, compared to $300-600 for HIV cultures. This study is considered one of the first to establish the accuracy of PCR as a tool for diagnosing pediatric HIV infection. The investigators suggest that PCR be regarded as a standard, rather than investigational, clinical test for pediatric infection. In this study, PCR was performed in a commercial laboratory on blood samples from 286 newborns older than 1 week and children at risk for HIV infection. Samples were collected and mailed for testing. Among infants between the ages of 1 week and 1 month, PCR accurately detected HIV infection 95% of the time and correctly ruled it out 100% of the time. Standard HIV IgG antibody tests can diagnose HIV in children older than 18 months.

Pediatric HIV Classification

The CDC case definition for pediatric AIDS pertains to children through 12 years of age. Initially created in 1983, the definition was last revised in 1987 (unlike the adult AIDS case definition, which was revised most recently in 1993). The pediatric HIV/AIDS definition is similar to the adult definition in terms of HIV disease staging, but also contains conditions specific to children such as lymphoid interstitial pneumonitis (LIP) and recurrent serious bacterial infections. In the U.S. and Europe, an AIDS diagnosis requires a positive diagnostic test result for HIV infection.

In developing nations or places where diagnostic tests for HIV are not readily available, pediatric AIDS diagnoses are based on clinical criteria published by the World Health Organization. The CDC has established an HIV classification system to define the spectrum of pediatric HIV disease. HIV-infected children are first grouped into 3 immunologic categories: no evidence of immunosuppression, moderate immunosuppression or severe immunosuppression. There are also 4 clinical categories: N, A, B and C. Children in category N have no signs or symptoms. Those in clinical category A may have lymphadenopathy, splenomegaly (enlarged spleen), hepatomegaly (enlarged liver), parotitis (inflamed salivary glands), dermatitis (skin condition), recurrent upper airway infections, bilateral otitis media (BOM, an ear infection) or sinusitis (sinus infection).

Those in category B may have recurrent herpes simplex virus (HSV), herpes zoster/varicella (VZV, chickenpox, shingles), bacterial infections, chronic fever, cardiomyopathy (heart muscle disease), cytomegalovirus (CMV), chronic diarrhea, hepatitis (liver infection), anemia (low red cell count), leiomyosarcoma (muscle tumor), neuropathy or LIP. Finally, those in category C may have classic AIDS-related opportunistic infections (OI) such as PCP, Mycobacterium avium complex (MAC), cryptosporidial diarrhea, severe failure to thrive, toxoplasmosis, lymphoma, encephalopathy (brain disease), severe recurrent bacterial infections or cryptococcal meningitis.

Pathogenesis of Pediatric HIV Infection

Because HIV-related immunosuppression is imposed upon still-developing immune, nervous and other systems, HIV disease tends to be more aggressive in children than in adults, and leads to a range of unique problems.

Among children as a group, 2 patterns of HIV disease progression have been observed. The first is characterized by rapid progression, with 10-25% developing AIDS by 2 years of age. Mortality in rapid progressors approaches 100% by 4 years of age.

The second pattern is characterized by slower progression. Earlier studies that evaluated the mode of HIV acquisition found that children who were perinatally HIV-infected progressed more rapidly than children who were infected after birth, e.g., by transfusion. As perinatal transmission increasingly becomes the predominant route of pediatric infection, children in the latter group will account for progressively fewer infections.

In the case of the perinatally infected child, the timing of transmission also impacts the child's health. Perinatal transmission may occur in utero (during pregnancy), intrapartum (during delivery) or postpartum (after birth), primarly through breast-feeding. Studies suggest better clinical prognoses for children infected relatively late, e.g., during childbirth or through breast-feeding. Children infected during pregnancy, particularly earlier during pregnancy, tend to progress much more rapidly. Infants infected in utero who are positive by HIV culture or by PCR at birth often develop symptoms by 4-8 months; PCP is frequent in these babies and LIP is rare.

They often develop AIDS by 1 year of age and their prognosis is poor. Infants infected during delivery usually are negative by PCR or HIV culture at birth; in these babies, LIP is frequent and PCP less common. They are more likely than those infected in utero to have lymphoid hyperplasia (increased amounts of lymphoid cells and tissue) and to survive longer.

Neurological Concerns

Neurodevelopmental delays and neurological complications often occur in children with HIV, especially after an AIDS diagnosis. HIV infection itself may cause developmental delays in the areas of speech and fine and gross motor skills. Progressive cognitive impairment may be due to central nervous system (CNS) effects of HIV. Children may even lose pediatric milestones already passed. They may experience short-term memory loss or have attention deficit disorder. Acquired microcephaly (abnormally small brain) is another neurological condition found in children with HIV/AIDS. Computerized tomography (CT) scans reveal cerebral atrophy (brain tissue wasting), calcifications (calcium deposits) in basal ganglia (nerve structures deep inside the brain) and white matter changes.

Psychosocial Considerations for Children

In addition to their medical problems, children also are likely to have enormous social and emotional problems. Many have parents who are ill or dead; many are in foster care and thus are involved in the social service or juvenile justice systems. Many HIV-infected children are economically disadvantaged and likely to have poor access to health care.

HIV-related neurodevelopmental impairment may impact daily functioning. Children may have extra difficulty expressing themselves; they may perform poorly on intelligence tests taken, e.g., at school. All of these factors are likely to affect an HIV positive child's overall socialization and growth.

Older HIV-infected children are also at risk for depression, which may manifest as apathy, withdrawal and loss of appetite. Moreover, children often lack the coping skills or defense mechanisms more mature people have developed. HIV-related dementia may also occur in children or adolescents, with symptoms similar to those in adults with AIDS-related dementia or encephalopathy. Although the psychology of children with HIV/AIDS has not been well studied, psychotherapy and psychopharmacology (use of drugs) may be helpful.

Complications of HIV Disease in Children

While the clinical categories that define stages of pediatric and adult HIV infection are similar, the clinical manifestations of HIV disease in children can differ greatly from those in adults. Children develop OI at much higher CD4 counts than do adults. They also have a somewhat different pattern of clinical manifestations, e.g., children have a much higher rate of recurrent and serious bacterial infections. Certain developmental problems are also uniquely pediatric; e.g., failure to grow and to thrive at an early age is common in HIV-infected children, albeit somewhat parallel to the adult problem of HIV-related wasting. However, while wasting occurs late in HIV disease for adults, failure to grow and thrive may occur early for children.

Children are more likely than adults to have enlarged livers, spleens and lymph nodes. LIP, common in children, is uncommon in adults. Malignancies are uncommon in children but more common in adults. CNS abnormalities may occur early in the course of HIV disease in children, whereas AIDS dementia complex (ADC), a specific HIV-related CNS condition, occurs late in HIV disease for adults. Parotitis is another primarily pediatric concern. At one time, HIV-infected children were considered at risk for a disability called HIV-related dysmorphic syndrome. Researchers have since attributed this condition to alcohol use by the mother, and now generally relate the condition to fetal alcohol syndrome rather than to HIV.

Pediatric infections common among all children are exacerbated in children with HIV, including chronic ear infections and respiratory tract infections. Chronic infection of both middle ears, known as bilateral otitis media (BOM), is common in HIV-infected children without AIDS, as is thrush (oral candidiasis). In children with an AIDS diagnosis, thrush has been estimated to occur in more than 80%. Thrush is frequently the initial clinical sign of HIV disease. It is rarely disseminated but frequently involves the esophagus.

The top 4 AIDS-defining conditions in children are, in order of decreasing frequency: PCP, other OI, LIP and recurrent bacterial infections. PCP is often diagnosed in the first few months of life, and actually may occur at CD4 cell counts considered normal for the child's age. Often, PCP occurs before a child's HIV infection has been identified.

Gastrointestinal pathogens commonly found in children with AIDS include protozoa (Cryptosporidium, Isospora, Giardia), viruses (CMV, HSV, Epstein-Barr virus [EBV], adenovirus, hepatitis viruses), bacteria (Salmonella, Shigella, Mycobacterium tuberculosis, Mycobacterium avium, Clostridium difficile) and fungi (Candida albicans, Histoplasma gondii, Coccidioides immitis, Cryptococcus neoformans).

HIV Disease Management Guidelines for Children

Optimal management of HIV disease in children often requires a team approach which involves physicians, nutritionists, social workers and psychotherapists.

Diligent primary care is essential. According to Ho and Wei (1995), several features of pediatric HIV disease make a compelling case for aggressive HIV treatment. Newly infected infants usually have a very homogenous population or type of HIV-1 virus, which means that the virus is very sensitive and thus relatively more responsive to antiretroviral treatment. Today, scientists know that HIV replication in the body is a continuous, dynamic and rapid process. Tests now available to measure viral RNA (viral load) in plasma can be used after primary infection, when the viral RNA concentration reaches a plateau, to try to predict longer-term clinical progress or outcomes. Finally, there are powerful anti-HIV inhibitors now available, such as the protease inhibitors and combinations of other antiretroviral agents, that have been shown in studies of adults to reduce the concentration of virus in blood serum by as much as 2-3 logs, or 100- to 1,000-fold. Although protease inhibitor data in children are sparse, it is hoped that these powerful compounds will be as important for pediatric as for adult treatment.

The goals for antiretroviral treatment are to slow or eradicate viral replication, which is likely to mean life-long therapy for children. Prophylaxis and treatment, when necessary, for OI are also essential. Acute medical care may be necessary at times. Pain management as well as nutritional and psychosocial support are extremely important aspects of HIV disease management in children.

Antiretroviral Treatment

Antiretroviral therapy is warranted in children who have developed an AIDS-defining condition such as PCP, failure to thrive, HIV-related progressive encephalopathy, recurrent serious bacterial infections, thrombocytopenia (low platelet count), hypogammaglobulinemia (low antibody levels) or low CD4 cell count, even without symptoms. Antiretroviral drug choices for children are nearly the same as for adults, with a few important qualifications and exceptions. In some cases antiretroviral drugs involve different side effect profiles for children, or there are insufficient pediatric data to substantiate their use.

An important pediatric antiretroviral treatment update came on February 28, 1996, with the official release of final data from ACTG 152. The large nationwide trial enrolled nearly 900 children with AIDS, aged 3 months to 18 years, who had little or no prior antiretroviral treatment. The study's goal was to compare the efficacy of 3 different antiretroviral treatment regimens for delaying disease progression when used as initial or first-line antiretroviral strategies. Originally, participants were randomized to receive one of 3 treatments: AZT monotherapy, ddI monotherapy or combination AZT/ddI. However, an interim analysis about a year ago indicated that children receiving AZT monotherapy were faring much worse than children in either of the other 2 arms. Children receiving AZT alone had "more rapid rates of disease progression as measured by growth failure, new opportunistic infections, neurologic and neurodevelopmental deterioration or death." A Public Health Service press release dated February 13, 1995, states that interim results show that "zidovudine (AZT) alone was the least effective as an initial therapy to prevent HIV disease progression." In February 1995, the AZT monotherapy arm was discontinued, and the study continued with the 2 remaining arms.

Therefore, final results compare ddI monotherapy to combination ddI/AZT treatment. At this time, the data suggest that there are no significant differences in disease progression or survival between the 2 treatment strategies. Even though AZT is believed to penetrate the CNS better than ddI, children taking ddI alone did not fare worse than those taking combination ddI/AZT in terms of neuropsychological dysfunction or deterioration (experienced by about 19% of all participants).

Although some physicians feel that clinically stable children may fare well on AZT monotherapy, others feel that the results of ACTG 152 argue strongly against the use of AZT monotherapy in any HIV-infected child. Thus, the emerging trend for antiretroviral treatment in children is similar to that for adults, with providers and advocates on the "cutting edge" proposing that first-line treatment for children, like adults, should consist of combination antiretroviral therapy. AZT, the first antiretroviral approved for children, is available in tablet, intravenous (IV) and raspberry-flavored syrup formulations. The dose recommendations are 2-3 mg/kg (180 mg/m2) every 6 hours for children older than 3 months. Children absorb oral AZT well (about 65% absorption). AZT, which penetrates the blood-brain barrier to the CNS, is found in cerebrospinal fluid at amounts equal to about 25% of serum concentration. Another advantage of AZT is its ability to readily cross the placenta. HIV resistance to AZT develops as a function of length of time used, not dose; in children, resistance correlates with disease progression.

ddI is also approved for pediatric use. At 40%, its oral bioavailability is lower than that of AZT or ddC (87%). ddI must be taken on an empty stomach, during fasting, which may be difficult for children. It is available in chewable tablet, powder and pediatric oral solution forms. The dose is 200 mg/m2 twice daily. ddI fails to penetrate the CNS well. Pancreatitis, peripheral neuropathy, retinal damage and diarrhea may result from its use.

ddC is 10 times as potent against HIV as AZT in vitro. It is available on the market in tablet form, and in clinical trials only in syrup form. The suggested dose is 0.005-0.01 mg/kg orally, every 8 hours. ddC has poor CNS penetration. Side effects include neuropathy, stomatitis (mouth sores), esophageal ulcers and rash.

d4T is considered to have good bioavailability and CNS penetration. There are limited Phase I data in children; a Phase II/III trial is in progress.

Other drugs being studied in children include the new class of protease inhibitor drugs. Nevirapine and delavirdine, also under study, belong to a class of drugs that seems to be powerful in vitro and minimally toxic, although HIV mutates extremely quickly to become highly resistant to them.

Other agents used in pediatric antiretroviral therapy include those that diminish HIV stimulation, those that decrease antigen stimulation and those that block mediators that stimulate HIV infection. Agents used to stimulate the immune system include certain hormones and growth factors, certain cytokines, immunizations, bone marrow transplants and gene therapy.

Prophylaxis and Treatment of OI and Childhood Conditions

Since PCP is the most common serious OI in children with AIDS, prevention is of paramount concern. While recommendations for beginning prophylaxis in adults are based on a CD4 cell count of fewer than 200 CD4 cells/mm3, the CD4 count is an inadequate marker for infants and children. CD4 counts vary more from child to child than among adults, and thus are not particularly helpful indicators of when to begin PCP prophylaxis. Because PCP kills many infants younger than 1 year, recommendations are to begin prophylaxis at 4-6 weeks of age in all infants, regardless of CD4 count, born to HIV positive mothers. (Prophylaxis is delayed until 4 weeks of age because it takes about that long for an infant to develop the necessary ability to metabolize bilirubin.) Infants who are identified as HIV positive after 6 weeks of age should immediately begin PCP prophylaxis.

Currently, the National Pediatric and Family HIV Resource Center and the CDC recommend PCP prophylaxis for all "at-risk" infants 1-4 months of age, until HIV status can be firmly determined, and for all HIV-infected infants 4-12 months of age. After 12 months of age, recommendations for PCP prophylaxis for infected children are based on CD4 cell counts and history of PCP.

Because CD4 percentages vary less than CD4 counts, some physicians prefer to use them as a marker. Generally, PCP prophylaxis is recommended for children 1-2 years of age with fewer than 750 CD4 cells/mm3 or 15%; children 2-5 years of age with fewer than 500 CD4 cells/mm3 or 15%; and children 6-12 years of age with fewer than 200 CD4 cells/mm3 or 15%. The first-line choice for PCP prophylaxis is trimethoprim/sulfamethoxazole (TMP/SMX, Bactrim or Septra) at an oral combined dose of 150 mg/m2 TMP and 750 mg/m2 SMX 3 times a week.

For children who cannot tolerate TMP/SMX, alternative regimens are oral dapsone, 1-2 mg/kg once daily; aerosolized pentamidine, 300 mg monthly (only for children over 5 years of age); and parenteral (by injection, bypassing the gastrointestinal tract) pentamidine, 4 mg/kg every 2-4 weeks. Breakthrough PCP has been documented in infants on dapsone and pentamidine. Also, the CDC currently recommends that infants who received AZT for the prevention of vertical transmission not begin prophylaxis with TMP/SMX until AZT has been discontinued at 6 weeks, per the ACTG 076 regimen, because of potential liver toxicity. (Some physicians feel that the high risk of PCP before 1 year of age warrants beginning PCP prophylaxis with TMP/SMX at 4 weeks, even while infants finish the AZT regimen.)

Prophylactic use of TMP/SMX also protects against bacterial infections. IVIG has also been used to prevent bacterial infections and related hospitalizations. IVIG has been used at a dose of 400mg/kg every 28 days in HIV-infected children, especially those with hypogammaglobulinemia, thrombocytopenia or recurrent infections not ameliorated by routine use of antimicrobial agents. Prophylaxis for other OI depends on the child's age, degree of immunosuppression and other individual factors, such as physician and parent preferences. In general, different dose levels of the same drugs that are used to prevent OI in HIV-infected adults are used for children.

In the February 1996 issue of Pediatrics, the American Academy of Pediatrics (AAP) published an updated policy on tuberculosis (TB) skin testing for children. The AAP now recommends that children's risk level for TB be assessed, and that testing schedules complement risk level determination. For example, children who have recently come into contact with a TB-infected person should be tested immediately. Children with HIV should be tested annually. HIV-infected children are at elevated risk for more severe versions of common childhood illnesses like measles and chickenpox, which may be fatal. Common, minor symptoms like cough and fever must be taken very seriously in HIV-infected children, for they may herald potentially life-threatening infections.

Certain immunizations routinely given to HIV negative children are also recommended for HIV positive children; others are not (see chart). The main caveat about routine vaccinations is the possibility that consequent immune system stimulation may activate CD4 cell activity and, in turn, enhance HIV replication. For example, the wisdom of vaccinating HIV-infected adults and children against influenza has been widely debated. Some researchers have argued that HIV positive children tend to be at even greater risk for the flu than adults, e.g., through contact with large numbers of other children in daycare or at school. In a recent study at the University of Texas Medical Center in Dallas, Octavio Ramilo and others used viral load tests to investigate the effects of flu vaccines on HIV activity in infected children. Investigators found that 5 of 16 children experienced significant post-vaccination viral load increases. However, viral load changes were transient, with levels returning within 2 months to baseline in 4 of the 5 children. Investigators concluded that children, relative to adults, were less likely to experience increases in HIV burden (but demurred, recommending further studies in children with different disease stages taking different treatment regimens). The debate is likely to continue.

RECOMMENDATIONS FOR IMMUNIZATIONS IN THE CHILD WITH HIV/AIDS FROM THE AMERICAN ACADEMY OF PEDIATRICS

-Vaccine: DPT (diptheria, tetanus, pertussis) Known Asymptomatic: Yes Known Symptomatic: Yes**

-Vaccine: OPV (Sabin, oral polio vaccine) Known Asymptomatic: No Known Symptomatic: No

-Vaccine: IPV (Salk, inactivated polio vaccine) Known Asymptomatic: Yes Known Symptomatic: Yes**

-Vaccine: BCG (Bacille Calmette-Guerin, for tuberculosis) Known Asymptomatic: No Known Symptomatic: No

Vaccine: MMR (measles, mumps, rubella -- live-attenuated) Known Asymptomatic: Yes Known Symptomatic: Yes

-Vaccine: Hibc (Haemophilus influenza type b/c) Known Asymptomatic: Yes Known Symptomatic: Yes**

-Vaccine: Pneumococcal* Known Asymptomatic: Yes Known Symptomatic: Yes**

-Vaccine: Influenza* Known Asymptomatic: Yes Known Symptomatic: Yes**

NOTES:

* Pneumococcal vaccines should begin when a child reaches 2 years of age. Flu vaccines should be given annually starting at 6 months of age.

** Inactivated vaccines are recommended, although patient responses may not be optimal. Definitely, HIV positive children and even HIV negative children residing in the same household should receive the killed polio Salk vaccine and not the live attenuated Sabin product.

Nutritional Considerations and Therapy

Competing theories on the role of nutrition in HIV disease abound. Important research continues to delineate the roles played by nutrients and micronutrients, and will permit the formulation of recommendations for diet and nutritional supplementation. Associations between nutritional deficiencies and disease stage in adults have been fairly well established; as disease advances, so does the extent of nutritional depletion. While malnutrition enhances disease-related immunosuppression in persons of all ages, the nutritional requirements of any child differ significantly from those of any adult. So far, little data exist to establish the impact of HIV infection on nutritional status in children. The known catabolic and metabolic problems experienced by HIV positive children, as well as endocrine problems and failure to grow and thrive, underscore the importance of optimal nutrition. Adequate dietary intake of nutrients is the most important, first-line approach to nutritional management; children must receive adequate calories and protein. However, supplementation should be considered for children who fail to grow despite adequate oral intake.

In France, a recent study evaluated nutritional abnormalities in 21 generally healthy children with HIV. The prospective study involved a group of HIV positive children and a matched control group of HIV negative children. Investigators assessed health history (e.g., fever, diarrhea), height, weight, dietary intake and nutritional status, including total calories, protein, fiber, fat, cholesterol, vitamins, calcium, iron, zinc, copper and fatty acids. All children were relatively well-nourished. Measures of nutritional status appeared unaffected by origin of maternal infection (injection drug use versus heterosexual contact), ethnic background, or socioeconomic or educational status. Within the HIV positive group of children, about half were symptomatic but "non-AIDS." The remainder had AIDS diagnoses, and a lower average CD4 cell count that was associated with lower vitamin A levels. There was no correlation between CD4 cell count and vitamin E, beta carotene, zinc, copper or selenium. CD8 levels were significantly correlated with zinc levels.

HIV positive children did not differ from HIV negative children in dietary intake, nor was their ability to absorb nutrients impaired. Generally, study data suggest that, as HIV disease progresses, so does the extent of vitamin level depletion (with the exception of beta carotene, levels of which did not appear to change after receiving an AIDS diagnosis). This finding was particularly true for the micronutrients known to influence immune status--vitamins A and E and the carotenoids, zinc, copper and selenium--and mirrors the same phenomenon known to occur in HIV-infected adults.

Although more significant as HIV progressed, micronutrient deficiencies were noted even in children with early-stage HIV disease. However, remedial supplementation is not automatically recommended; for example, iron supplementation to address the low iron levels often seen in people with infections often exacerbates infectious complications by providing fuel for the pathogens. Essential findings indicated that, despite adequate diets, notable micronutrient alterations were common in these children, even though none of them manifested signs of malnutrition. Research into the utility of nutritional interventions early in the course of pediatric HIV disease remains to be done.

Various studies have demonstrated that vitamin A supplementation benefits immune status in HIV-infected children. In a study from South Africa, researchers studied the effects of vitamin A supplementation on morbidity (sickness) in 118 children born to HIV positive mothers. Vitamin A plays various roles in optimizing immune function and maintaining the health and integrity of epithelial tissues, which include the mucosal tissues of the gastrointestinal tract and the eye. These characteristics led to dubbing vitamin A the "anti-infective" vitamin. (Durban, the study locale, is not considered a vitamin A deficient area.) The study was randomized, double-blind and placebo-controlled. At 1 and 3 months of age, children received 50,000 International Units (IU); at 6 and 9 months, 100,000 IU; and at 12 and 15 months, 200,000 IU of vitamin A. HIV status was determined at 15 months, and data on health status were collected up to 18 months of age.

HIV negative children had roughly the same number of illnesses and hospitalizations, whether or not they received supplemental vitamin A. However, HIV positive children who received supplemental vitamin A had less diarrhea, fewer hospitalizations for diarrhea and less severe illnesses overall (e.g., respiratory infections, rashes) than those who received placebo. The researchers hope that vitamin A supplementation in HIV positive children, especially economically disadvantaged children, may be an effective and inexpensive means for reducing illness. (See the report "Mother-to-Child HIV Transmission," by Leslie Hanna, on vitamin A levels and vertical HIV transmission in the September 1994 BETA.)

A Clinical Research Agenda for Children

According to pediatrician Paula Botstein, MD, Deputy Director of FDA's Office of Drug Evaluation, FDA is encouraging clinical trials in children. She explains that the majority of approved drugs have been studied in and labeled for adults, and that package inserts commonly rely on disclaimers that explain that safety and efficacy have not been established for children.

Historical reasons for lack of pediatric research include little financial incentive on the part of pharmaceutical companies and the difficulties inherent in pediatric research. Parents and guardians as well as children must understand what involvement in a trial means and must provide informed consent. The collection of data on a drug's safety and efficacy is important because children may metabolize drugs differently than adults; adult doses cannot simply be reduced for use in children.

Botstein says FDA is trying actively to encourage drug companies to test drugs in children during the drug development process, and that FDA reviews of new drug applications (NDA) include consideration and evaluation of pediatric data. FDA is also creating ways to evaluate a drug's post-marketing use in children.

Recently, however, the Office of AIDS Research called for dramatic cuts to the pediatric research budget through the nation's largest research mechanism, the ACTG. There are 2 rumored reasons for the proposed cuts: 1) the pediatric ACTG has in the past been too generously supported, relative to adult studies, and 2) now that AZT has been officially approved for use in pregnant women, fewer children will be HIV-infected so less research will need to be done.

Conclusion

Early identification of children at risk for HIV infection and especially HIV positive children is essential for optimal treatment, defined as early, aggressive treatment. Quality counseling about HIV disease and testing should be routinely offered to all pregnant women. Counseling ensures that women have adequate information to make informed choices.

Infants of women considered "at risk" should be monitored so that infants and children who develop lymphadenopathy (lymph node swelling) or frequent bacterial infections, or who have low platelet counts or other unusual clinical findings may be promptly attended. Mothers of such children must be integrally involved in their children's medical care, one reason being that HIV testing of such children guarantees revelation of the mother's serostatus.

The epidemic in children less than 13 years of age reflects the epidemic in women. According to the CDC, the proportion of cases among women has increased steadily over the past decade. The official hope of government and medical researchers is that Public Health Service recommendations for routine counseling and voluntary prenatal HIV testing for women, and the use of AZT and forthcoming antiretroviral strategies (e.g., protease inhibitors) for interrupting perinatal transmission will minimize the pediatric epidemic. Nevertheless, new pediatric infections are likely at least in the near future. It is important for research to go foward to better understand HIV disease in children and to learn how best to treat it.

Sources

Genetic test improves ability to diagnose HIV in newborns. AIDS Weekly Plus: 23-24. February 26, 1996. Dorenbaum A. HIV and AIDS in children. The Fourth Annual Women and HIV Conference. San Francisco, CA. October 20, 1995.

Grossman M. Pediatric AIDS. Chapter 27 of The Medical Management of AIDS, 3rd edition. Sande and Volberding, editors. W.B. Saunders Company. Philadelphia. 1992.

Interim results lead to discontinuation of AZT-only study arm. Public Health Service/National Institutes of Health press release. February 13, 1995.

Martorell R and Ramakrishnan U. Vitamin A supplementation in children born to HIV-infected women. The American Journal of Public Health 85(8): 1,049-1,051. August 1995.

1995 revised guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with or perinatally exposed to human immunodeficiency virus. Morbidity and Mortality Weekly Report 44(RR-4). April 28, 1995.

Peckham C and Gibb D. Mother-to-child transmission of the human immunodeficiency virus. The New England Journal of Medicine 333(5): 298-302. August 3, 1995.

Periquet BA and others. Micronutrient levels in HIV-1-infected children. AIDS 9(8): 887-893. August 1995. Ramilo O and others. Pediatric Infectious Disease Journal 15: 197-203. 1996.

Stephenson KS. Pediatric HIV infection. Chapter 15 of HIV Manual for Health Care Professionals. Appleton and Lange. 1994.

Vitamin A supplementation in children born to HIV-infected women. Medical Alert: 4. November/December 1995. U.S. Public Health Service Recommendations for Human Immunodeficiency Virus Counseling and Voluntary Testing for Pregnant Women. Morbidity and Mortality Weekly Report 44(RR-7). July 7, 1995.

Why FDA is encouraging drug testing in children. FDA Consumer Special Report: From Test Tube to Patient, 2nd edition. January 1995.

Protease Inhibitor News for Children

Important recent news in antiretroviral treatment for persons with HIV concerns protease inhibitors and combination antiretroviral therapy, often including a protease inhibitor. Most new drug approvals have been granted for adult HIV infection; unfortunately, there is relatively little news about protease inhibitors for children.

Abbott Laboratories' protease drug, ritonavir (Norvir), FDA-approved on March 1, 1996, was widely hailed because data showed a survival benefit in people with advanced HIV disease. The clinical studies that led to ritonavir's approval have also been denounced for failing to gather safety and efficacy data in children. In late February, when FDA advisory committee meetings which led to FDA approval were held, no pediatric data were reported. Part of the approval agreement between FDA and Abbott was a plan that requires Abbott to conduct trials to provide additional data, including a pediatric trial of ritonavir to provide safety and efficacy data for children. A small pediatric study is currently underway at the National Cancer Institute (NCI), and other protocols are being developed.

Hoffmann-La Roche's (Roche) protease inhibitor saquinavir (Invirase), which received FDA marketing approval in December 1995, is indicated for use in adults and children over 16. Currently, Roche will only say that it is committed to developing a sprinkle formulation for use by children, and that the process is underway.

Merck's protease inhibitor indinavir (Crixivan) was FDA-approved on March 14, 1996, on the basis of studies in over 2,000 volunteers with AIDS. Study participants showed improvements in markers of HIV disease such as CD4 count increases and viral load decreases, especially when indinavir was used in combination with AZT.

The indicated use is for adults older than 18 years of age only. There are no current indications for pediatric use; the adult dose cannot be adjusted or altered. "With Crixivan, it is very, very important, in order to keep viral load down and to erect and maintain a wall against resistance, to start with and maintain the optimal, approved dose: 800 mg 3 times daily. You cannot titrate up or down, you cannot try drug holidays. Timing and conditions around taking doses are important, too; Crixivan must be taken every 8 hours, in a fasting state or with a very light meal, in order for maximum absorption," says Kyra Lindemann of Merck Corporate Public Affairs. Therefore, until studies establish the optimal dose(s) for children, there will be no indication for pediatric use. A pediatric dose-ranging study using a capsule form of indinavir is currently underway at NCI, where safety and efficacy data for the different doses are being gathered. Meanwhile, Merck is working to develop an oral suspension formulation for pediatric use.

960601
BE962905

Copyright © 1996 - San Francisco AIDS Foundation. Reproduced by permission. Reproduction of this article (other than one copy for personal reference) must be cleared through BETA: PO Box 426182, San Francisco, CA 94142-6182. Tel: 415 487 8060 Fax: 415 487 8069 URL: http://www.sfaf.org/beta E-mail: beta@sfaf.org

ÆGiS is made possible through unrestricted grants from Boehringer Ingelheim, iMetrikus, Inc., John M. Lloyd Foundation, the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 1996. This material is designed to support, not replace, the relationship that exists between you and your doctor.

ÆGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.