Pediatric HIV Infection

Significant changes have occurred in the management of human immunodeficiency virus infection (HIV) in children since the first cases were reported in June 5, 1981. 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 decrease in perinatal transmission of HIV from mothers to their newborns and the increase in spread of HIV infection among adolescents has had the greatest impact on the epidemiology of pediatric HIV infection in the United States and globally. This article reviews the current status of HIV infection in children.

Epidemiology

Based on WHO's report for the year 2000, a total of 37 million people were estimated to be living with HIV/AIDS worldwide, 10 new infections occurred every minute, 14,000 infection/day. Half of the new infections were in people ages 15-24 years.¹ In the United States there were 884,260 HIV/AIDS cases and 450,000 AIDS death by June 30, 2000 (based on the 2000 CDC estimates). In Florida the cumulative report of HIV/AIDS cases reported as of April 40/2001 include 82,343 with 45,276 deaths (based on the AIDS Surveillance Report June 19/2001)³. Florida ranks 3^rd in reported U.S AIDS cases, 2^nd in pediatric AIDS, and 1^st in HIV cases since July/1997. Six Florida cities rank higher than half of the U.S states for reported AIDS cases. These cities include Miami, Fort Lauderdale, Tampa, West Palm Beach, Orlando, and Jacksonville. It is estimated that 1 in 156 Floridians are currently living with HIV infection. 1 in 286 whites, 1 in 50 blacks, and 1 in 127 Hispanics are infected with HIV. As of December 31^st, 2000, 3695 children/Adolescents (<19 year) were reported to be living with AIDS in the United States. An additional 7,174 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). The number of perinatally acquired AIDS cases peaked in 1992 (901 cases), followed by a sharp decline through December 1999 (144 cases). 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 April 2001, Florida reported 1,940 children (less than 19 years of age) living with HIV/AIDS (HIV infection reporting in Florida was initiated in July 1997). Locally, the Jacksonville metropolitan area reported a total of 4,156 persons with HIV/AIDS in April 2001. Of these cases 63 are children less than 13 years old and 40 are between the ages of 13-19 years.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 2000 are black. Similarly, 22% of children reported with AIDS are Hispanic when only 17% of U.S. children are Hispanic.² 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. As of June, 2001 the number of adolescents reported with HIV/AIDS nationwide increased to 3,865, in Florida 541 adolescents were reported to be living with HIV/AIDS. It is believed that these numbers are only the tip of the iceberg. These numbers are expected to increase as more and more adolescents get tested for HIV. Also because of the possible prolonged incubation period from infection to the development of symptoms, most persons infected with HIV as adolescents may be diagnosed as adults. For this reason, HIV surveillance data is especially useful in documenting the impact of HIV on adolescents. Sites in the South and along the eastern seaboard have the highest number of adolescents with HIV infection and AIDS.^3-4

Pathogenesis of Pediatric HIV Type-1 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 DNA-PCR (polymerase chain reaction) within 48 hours of life. Infants are regarded as infected during delivery (intrapartum) if HIV-1 culture or DNA-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 weight, growth and cognitive failure 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 have estimated the median survival of perinatally infected children to be 8.6 years and others estimate this to 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 adulthood. 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, or p24 antigen. The presence of viral antibody is only diagnostic 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 the 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 (around 15 months of age); however, if two viral tests are negative both done after one month of age and at least one after three months of age, and there are no indications of HIV disease, infection is unlikely in a non-breastfed child. However, 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 is HIV-infected pregnant women and their exposed newborns has increased markedly. 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. have shown better prevention rates than the one observed in the ACTG 076 research protocol. In Jacksonville, the patients followed at the Rainbow Center have had only 2 perinatal infections since 1997. To potentially eradicate perinatal HIV-1 transmission or at least decrease the rate of transmission down to 1%, many of the developed countries and the United States are increasingly using highly active antiretroviral therapy (which may or may not include ZDV) in the treatment of HIV-1 infected pregnant women. The aim is to suppress viral replication below the levels of detection of the current assays (<400 copies/ml) and prevent vertical transmission of the HIV-1 virus.¹²

Other Perinatal Interventions

There is data suggesting that delivery by Caesarian section may help prevent viral transmission. Elective C-section for HIV-infected pregnant women is recommended if the viral load is high. However, "the potential incremental benefit of elective cesarean delivery in reducing transmission in a population of women at low risk of transmission, such as those receiving antiretroviral therapy who have HIV-1 RNA levels <1000 copies /ml must be weighed against the potential risk of operative delivery to the mother".¹²

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.¹³ 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 and opportunistic infections are treated/prevented (Table 1).

Table 1. Interventions to Reduce Perinatal Transmission of HIV

Maternal Factors

Early Diagnosis and Treatment of HIV-1 infected pregnant women
Controlled plasma Viremia levels during pregnancy and at time of Delivery (RNA <1000 copies/ml and preferably < 400 copies/ml).
Using highly active Antiretroviral therapy to suppress viral replication below levels of detection is strongly recommended:

Zidovudine + Epivir + Protease Inhibitor or

May use different combination of antiretroviral therapy depending on mother's past experience with the drugs and resistance patterns.

Stable Maternal Health including good nutritional & immunologic status; and treatment of STDs plus prevention of opportunistic infections.
Counseling regarding maternal drug use
Counseling regarding importance of Adherence to the antiretroviral regimen

Obstetrical Factors

Avoidance of intrapartum invasive procedures
Elective Cesarean Section
Treatment of sexually transmitted diseases
Vaginal disinfection

Post-partum/infant Factors

Avoidance of breastfeeding
Treating the newborn with Zidovudine for 6 weeks

Antiretroviral Therapy In Pediatric HIV Infection

Antiviral therapy is recommended for 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 diagnosis is confirmed. Infants should usually be treated regardless of their 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 1year of age or older.¹³ The first approach would be to initiate therapy in all HIV-infected children regardless of age. The aim of this approach would ensure 1) treatment of infected children as early as possible in the course of the disease, and 2) intervention before immunologic deterioration.

An alternative approach could 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 postponing treatment.

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. Factors to be considered in deciding to initiate therapy include: a) high or increasing RNA-PCR, b) rapidly declining CD4 T-lymphocyte count or percentage values, c) development of clinical symptoms. Regardless of age, any child with HIV RNA levels of greater than 100,000 copies/ml is at high risk for mortality 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 antiretroviral-resistant viral strains.

Combination therapy is recommended for all infants, children, and adolescents (Table 2¹⁵). 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.

Table 2. Antiretroviral Regimens For Initial Therapy For HIV Infection In Children

Recommended Regimen:

One highly active protease inhibitor plus two nucleosides reverse transcriptase inhibitors

Protease Inhibitors
- Nelfinavir or Ritonavir
- Indinavir (for children that can swallow capsules)
Recommended dual nucleoside reverse transcriptase inhibitors
- Zidovudine (ZDV) + dideoxynosine (ddI)
- Zidovudine (ZDV) + Lamivudin (3 tC)
- Stavudine (d4T) + ddI *
- Stavudine (d4T) + 3tC *

(* More limited data available in children).

Alternative for children who can swallow capsules

Efavirenz (Sustiva) plus 2 Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Efavirenz (Sustiva) plus Nelfinavir and 1 NRTI

Alternative Regimens

Nevirapine + two NRTI's
Abacavir + ZDV + 3TC

Offer only in Special Circumstances

2 NRTIs
Amprenavir in combination with 2 NRTIs or Abacavir

Antiretroviral Therapy for the HIV- Infected Adolescent

HIV-infected adolescents who were infected sexually or through injecting-drug use follow a clinical course that is more similar to that of adults than to that of children. Most adolescents who are infected during their teenage years are in an early state of infection, making them ideal candidates for early intervention. A limited but increasing number of HIV-infected adolescents are now long-term survivors of perinatally acquired HIV infection. Such adolescents have a unique clinical course that differs from that of adolescents infected later in life¹⁵. For one, they are experienced with antiretrovirals. Dosage of antiretroviral medications should be prescribes according to Tanner staging of puberty not on basis of age. Tanner stage I and II should receive pediatric dosages, whereas Tanner stage V should follow adult dosing schedules.

The Role Of Multidisciplinary approach In Pediatric HIV Infection

HIV infection and related chronic or acute infectious processes with the potential multi-organ and emotional involvement requires constant evaluation with a multi-disciplinary team approach. Nurse case managers, social service case managers, psychologists, nutritionists, health educators research nurses, pharmacists, practitioners, and other health care providers who render various services or case management are in a position to consistently assess the child's physical and cognitive health status as well as his family's social/mental health status, review adherence to recommended regimens, and consult/provide various needed services/resources.¹⁵Most successful HIV programs and HIV care delivery models include a strong case management and education component. The goals of this important function range from accessing cost-effective care to utilizing all needed resources in the community.

Collaborative effort between health care personnel and the affected community is very important in the fight against HIV. In an effort to reduce the risk of transmission of HIV, the Rainbow Center for Women, Adolescents, Children and Families has implemented the new strategic plan designed by the CDC: 1) intensity efforts to help all infected persons learn their HIV status; 2) establish new prevention programs to help HIV-infected persons establish and maintain safer behaviors. Combined with improved linkages to treatment and care; 3) expand highly targeted prevention programs to reach all HIV-negative persons at greatest risk.¹⁸

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 the community.