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Pediatric HIV Infection

Tibisay I. Villalobos, M.D.
Tibisay Villalobos, M.D. is a former fellow in the Division of Pediatric Infectious Disease
/ Immunology at the University of Florida Health Science Center / Jacksonville.
She is currently at the Children's Hospital in Austin, Texas.

Introduction

Significant changes have occurred in the management of human immunodeficiency virus infection (HIV) in children since the first cases were reported in 1983. Still HIV infection continues to be one of the leading causes of death in children. The advent of new antiretroviral drugs has reduced the disease progression and mortality in many of these children and some of them are already approaching adulthood. The first of our HIV-infected children enrolled in college last year.

The ability to prevent transmission of HIV from mothers to their newborns has had the greatest impact on the epidemiology of pediatric HIV infection in the United States and the developed world. This article reviews the current status of HIV infection in children.

Epidemiology

By the end of 1997, a total of 30.6 million people were estimated to be living with HIV/AIDS worldwide, and 2.7 million children under the age of 15 years have died of AIDS.¹ In the United States during 1998, 48,269 persons were reported with AIDS, more than half from the states of New York, Florida, New Jersey, California, and Texas. Of them, 382 cases of AIDS were reported among children less than 13 years of age, a decrease from 473 in 1987. New York and Florida reported the greatest number of cases. As of December 31, 1998, 3509 children were reported to be living with AIDS in the United States, Puerto Rico, and the Virgin Islands. An additional 1,728 children were known to be infected in the 33 areas that conduct HIV infection surveillance (some states and the U.S. territories do not report HIV infection). Reasons for the decrease in pediatric HIV infection and AIDS include the prevention of perinatal transmission and changes in the clinical management of women and children.^2,3

In 1998, Florida reported 49 children with AIDS and 84 children with HIV infection (HIV infection reporting in Florida was initiated in July 1997). Locally, the Jacksonville metropolitan area reported a total of 266 persons with AIDS in 1998, down from 342 reported in 1997, for a cumulative 3,920 of whom 67 are children less than 13 years old.³ Children of minority populations have been disproportionately affected by the HIV epidemic. Although only 14% of children in the United States are black, 62% of children reported with AIDS in 1998 are black. Similarly, 22% of children reported with AIDS are Hispanic when only 17% of U.S. children are Hispanic.² The rate of AIDS among black children in 1998 (3.2 per 100,000 children), was 16 times higher than among white children (0.2 per 100,000) and 3.5 times higher than among Hispanic children (9 per 100,000).³ Because the majority of pediatric cases are attributed to perinatal HIV transmission, these rates also reflect the disproportionate racial / ethnic distribution of HIV/AIDS among black and Hispanic women in the United States.⁴

Among adolescents, HIV infection is becoming an increasing problem. In 1998, 297 adolescents were reported with AIDS nationwide and 728 adolescents were reported with HIV infection from the areas that have HIV reporting. Because of the possible lengthy incubation period from infection to the development of AIDS, most persons infected with HIV as adolescents may develop AIDS as adults. For this reason, HIV surveillance data is especially useful in documenting the impact of HIV on adolescents. Sites in the South and the eastern seaboard have the highest number of adolescents with HIV infection and AIDS.^3-4

Pathogenesis Of Pediatric Human Immunodeficiency Virus Type I Infection

Multiple factors can influence maternal_infant transmission of HIV and progression of the disease in the infant. Acquisition of infection can occur in utero or by exposure to the maternal blood or virus in the mucosa of the birth canal during labor and delivery.

Important maternal risk factors include high viral load and lower CD4+ cell count, which is also a reflection of advanced maternal disease. These factors enhance the possibility of transmission of HIV to the infant.⁵ Other risk factors for vertical transmission include chorioamnionitis and sexually transmitted diseases. These are associated with an increased viral load in the genital tract. Mode of delivery and possibly duration of labor and delivery and other intervention that may expose the infant to the mother's blood may also be important factors.

Definitions regarding the timing of infection have been proposed for infants who are not breastfed. Intrauterine HIV infection is defined as infants in whom the virus is detected in the peripheral blood by culture or PCR within 48 hours of life. Infants are regarded as infected during delivery (intrapartum) if HIV-1 culture and PCR are negative during the first week of life, but become positive thereafter.^5,6 Several investigators are trying to establish the time of infection and clinical outcome.⁶ The progression of HIV disease in perinatally infected infants is different than  in adults. Most HIV-infected infants reported to the CDC during 1981-1992 had AIDS diagnosed in the first year of life.³ In contrast, the median incubation period in adults in approximately 10 years, and very few adults develop AIDS in the first three years after infection.

Two patterns of disease progression in vertically acquired infection have been described. About 10-25% of infected children develop severe immunodeficiency often in association with failure to thrive and encephalopathy within the first two years of life. The rest of vertically infected children experience a slower progression of HIV-related disease, with some remaining asymptomatic or only mildly symptomatic through adolescence.

Some reports estimate the median survival of perinatally infected children to be 8.6 years and others estimate this to be greater than 13 years.⁷ In New York City, approximately 25% of HIV-infected children and adolescents, ages 9 to 16 years remained asymptomatic with relatively intact immune systems, but the rest had significant disease progression.⁸ It is projected that a substantial portion of infected children will survive to adolescence. Therefore, it is important that their education, medical, and other needs be addressed and appropriate services be made available.

Diagnosis Of HIV Infection

An early diagnosis of HIV infection in infants born to HIV-infected mothers can be made after the detection of virus in culture, the HIV genome by PCR, the presence of viral antibody beyond the age of 18 months. The sensitivity of viral culture and PCR is lower at birth, but rises sharply after one week in infants.⁵ The sensitivity of PCR increases to 95% and the accuracy >90% in the first month of life. After five weeks of age the accuracy to the test approaches 100%.⁹ To confirm the diagnosis, positive results on two separate blood samples are required. The diagnosis is supported by persistency of HIV antibody after 18 months of age.

To confirm that a child is not infected with HIV, follow up should continue until maternal antibody has disappeared. If two viral tests are negative both done after one month of age and at least one after four months of age, and there are no indications of HIV disease, infection is unlikely in a non-breastfed child. A child cannot be declared uninfected unless HIV antibody tests are non-reactive.

Prevention Of Perinatal Transmission

In April 1994, the United States Public Health Service released guidelines for zidovudine (ZDV) use to reduce perinatal HIV transmission; in 1995, recommendations for HIV counseling and voluntary testing for pregnant women were published. Since then, the so-called ACTG 076 preventive protocol has been implemented in most parts of the United States and use of ZDV in HIV-infected pregnant women and their exposed newborns has increased mark
edly. This increase in ZDV use, including perinatal, intrapartum, and neonatal, has been accompanied by a decrease in the number of perinatally HIV-infected children and is responsible for the dramatic decline in perinatally acquired AIDS.¹⁰ The results of ACTG 076 protocol showed a decrease in the risk of perinatal transmission.¹¹ Many parts of the U.S., including Jacksonville, have shown better prevention rates than the ACTG 076 research protocol.

Other Perinatal Interventions

There are some data suggesting that delivery by Caesarian section may help prevent viral transmission. At the present time, elective C-section for HIV-infection is not routinely recommended. A recent meta-analysis did not conclusively show that C-section can prevent perinatal transmission.^5-12 However, C-section may be appropriate in certain situations and women should be counseled regarding C-section as a possible mode of delivery.

Passive immunotherapy with HIV-1 hyperimmune gammaglobulin (ACTG 185) did not show significant advantage over the ACTG 076 protocol. Other anti-retroviral agents, alone or in combination, are being evaluated in research trials (many being done right here in Jacksonville) in the United States to provide additional options for HIV-infected pregnant women.¹² Preliminary studies using various HIV vaccines are in progress in the United States. Trials of abbreviated version of ACTG 076 and use of Nevirapine have also shown successful interruption of perinatal HIV infection in developing countries. However, these are not recommended for use in the U.S. at this time. It is also prudent to avoid unnecessary use of invasive procedures, placement of fetal-scalp electrodes and fetal blood sampling, and to ensure that sexually transmitted diseases are treated (Table 1).

Antiretroviral Therapy In Pediatric HIV Infection

Antiviral therapy is recommended of HIV-infected children with clinical symptoms of HIV infection or evidence of immune suppression, regardless of the age of the child and viral load. Ideally, antiretroviral therapy should be initiated in all HIV-infected infants younger than 12 months, as soon as confirmed diagnosis is established, regardless of clinical status, viral load or immunological status.¹³ HIV-infected infants younger than 12 months of age are considered at high risk for disease progression, and the predictive value of immunologic and virology parameters to identify those who will have rapid progression is less than for older children.

Two general approaches have been outlined by the working group on antiretroviral therapy and medical management of HIV-infected children.¹³ The first approach would be to initiate therapy in all HIV-infected children regardless of age. The aim of this approach is:

1. treatment of infected children as early as possible in the course of the disease; and
2. intervention before immunologic deterioration.

An alternative approach would be to defer treatment in asymptomatic children older than one year of age with normal immune status or in situations where the risk for clinical disease progression is low (e.g. low viral load) and when other factors (e.g. concerns with adherence, safety and persistence of antiretroviral response) favor postponement. In such cases, the healthcare provider should regularly monitor virologic, immunologic, and clinical status.¹³

The level of HIV RNA considered indicative of increased risk for disease progression is not well defined for young children. Regardless of age, any child with HIV RNA levels greater than 100,000 copies/ml is at high risk and antiretroviral therapy should be initiated regardless of clinical or immune status.

Issues associated with adherence to treatment are especially important in considering whether and when to initiate therapy. Antiretroviral therapy is most effective in the naïve patients and, therefore, those who are less likely to have anti retroviral-resistant viral strains.

Combination therapy is recommended for all infants, children, and adolescents (Table 2¹⁴). When compared with monotherapy, combination therapy has shown to:

1. slow disease progression and improve survival;
2. result in greater and more sustained virologic response; and
3. delay the development of resistant viral strains.

Assessment And Intervention: The Role Of Case
Management In Pediatric HIV Infection

HIV infection and related chronic or acute infectious processes with the potential multi-organ involvement requires constant evaluation with a multi-disciplinary team approach. Nurses and other health care providers who render services or case management are in a position to consistently assess a child's status, review adherence to recommended regimens, and consult other team members, additional resources and medical consultants.¹⁵ Most successful HIV programs and HIV care delivery models include a strong case management component. The goals of this important function range from accessing cost-effective care to utilizing all needed resources in the community. In a recent study, children with AIDS average 1-4 hospitalizations, 16 inpatient days, 2 emergency department visits, 18 ambulatory care visits and one dental visit per year, generating an estimated $37,928 in annual charges. The HIV-infected children used fewer services, with $9,382 in annual charges.¹⁶ The role of the case management and case coordination addresses these issues and works with the children and their families and the providers to anticipate discharge needs if children are hospitalized, and observes children through all stages of HIV, including ongoing home or hospice care. Good case management can avert serious problems by anticipating and pre-empting problems.

Summary

Continuous developments in the prevention and treatment of HIV infection in children are promising. As the number of cases of HIV infection and AIDS in children declines, better ways to monitor the epidemic and new approaches to target the population at most risk are needed. Success in preventing HIV transmission requires a concerted, coordinated effort by public policymakers, health care providers, basic science researchers, and community.

REFERENCES

1. Schwart Kander B, Sittitnal W. Global surveillance and forecasting of AIDS. WHO Bull; 1998; 76: 737-743.
2. Centers for Disease Control and Prevention. HIV/AIDS Surveillance Report. 1998; 10 (No. 2)(5)-26.
3. Centers for Disease Control and Prevention. AIDS among children, United States. MMWR. 1996; 45(46):1005-1110.
4. American Academy of Pediatrics. Committee of Pediatric AIDS. Surveillance of pediatric HIV infection. Pediatrics. 1998; 101:315-319.
5. Peckman C, Gibb D. Mother-to-child transmission of human immunodeficiency virus. N Engl J Med. 1995; 333:298-302.
6. Wilfert CM, Wilson C, Luzuriaga K, Epstein L. Pathogenesis of pediatric human immunodeficiency virus. J of Infect Dis. 1994; 170: 286-292.
7. Kuhn L, Thomas PA, Singh T, Tsai WY. Long-term survival of children with human immunodeficiency virus infection in New York City. Estimates from population-based surveillance data. Am J Epidemiol. 1998; 147:846-854.
8. Grubman S. Gross EE, Lemer-Weiss N, et al. Older children and adolescents living with perinatally acquired human immunodeficiency virus infection. Pediatrics. 1995; 95:657-663.
9. Nelson RP, Price LJ, Halsey AB, et al. Diagnosis of pediatric human immunodeficiency virus infection by means of two commercially available polymerase chain reaction gene amplification. Arch Pediatr Adoles Med. 1996; 150:49.
10. Wilfert CM. Prevention of perinatal transmission of human immunodeficiency virus: a progress report after completion of AIDS clinical trial group 076. Clin Infect Dis. 1996; 23: 438-441.
11. Connor EM, Sperling RS, Gelbert R, et al. Reduction of maternal infant transmission of human immunodeficiency virus types with zidovudine treatment: Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994; 331:1173-1180.
12. Wiznia AA, Lambert G. Paviakis S. Pediatric HIV Infection. Med Clin North Am. 1996; 80:1309-1336.
13. Working group on antiretroviral therapy and medical management of HIV-infected children. Antiretroviral therapy and medical management of pediatric HIV-infection. Pediatrics. 1998; 102:1005-1062.
14. Centers for Disease Control and Prevention. Guidelines for the use of antiretroviral agents in pediatric HIV infection. MMWR. 1998; 47 (RR-4): 1-43.
15. Walsek C, Valentine M. Nursing and midlevel provider roles in the care of children with HIV infection. In Pediatric AIDS: The Challenge of HIV Infection in Infants, Children, and Adolescents. Piuo P and Wilfter C, Editors; 3^rd edition. 1998; 677-701.
16. Hsia DC, Fleishman JA, East JA, Helinger FJ. Pediatric human immunodeficiency virus infection. Recent evidence on the utilization and costs of health services. Arch Pediatr Adolesc Med. 1995; 149:489-496.

Jacksonville Medicine / December, 1999