In 1987, while practicing in a walk-in pediatric clinic, I encountered an infant who was born to a newly diagnosed HIV-infected mother. At that time medical understanding of HIV infection was rudimentary at best, and our knowledge of pediatric HIV was even more primitive. I credit myself with recognizing that this infant required immunization with the inactivated (killed) polio vaccine as opposed to the live vaccine, which at that time was the standard vaccine administered to all children. Armed with this knowledge, I decided that these infants merited special attention and thus began my career as a pediatric HIV specialist. In the past 14 years, progress in the prevention and treatment of pediatric HIV infection has been extraordinary. I have had the privilege of seeing infants and children originally given grim prognoses, grow to be healthy, active teens and young adults.
One of the most practical advances in the field of pediatric HIV disease was the development of the Polymerase Chain Reaction (PCR) or viral load test, which allows us to make the diagnosis of HIV infection in an infant within the first few months of life. Prior to this technology, we had to wait 18 months to determine definitively whether an infant was infected or not. HIV infection in adults and children older than 18 months of age is diagnosed if the individual has a blood test that is positive for HIV. The problem with these tests is that they test for antibody to the HIV virus, not for the virus itself. Antibodies are the proteins that the body makes when it is exposed to an infectious organism. The antibodies help in fighting off the infection. When a woman is pregnant, she passes her antibodies (for example, antibodies to chicken pox, measles, or HIV) to her infant. It takes 18 months for the antibodies from the mother to disappear from the infant's blood. Thus, despite the fact that most infants born to HIV-infected mothers are not infected, they all have positive HIV antibody tests. The PCR detects HIV viral genetic material, not antibodies. It is a direct test for virus. An infant with a positive HIV PCR is infected. More importantly, an infant who has 2 negative HIV PCR tests obtained at greater than one month and greater than 4 months of age is not infected with HIV.
The most critical accomplishment in the field of pediatric HIV was the discovery that transmission of the HIV virus from mother to child can be prevented. The landmark ACTG 076 clinical trial demonstrated that when mothers took AZT (Retrovir) during pregnancy, the transmission rate was reduced from 25% to 8%. It is rapidly becoming apparent that with the use of highly active antiretroviral therapy (HAART) and perhaps elective Cesarean section, the transmission rate can be reduced even further to 2% or less. (See Dr. Eriksen's article.) Institution of these measures in pregnancy has had a dramatic impact on the incidence of perinatally acquired HIV in the developed world. In my own practice, I see 60 to 80 infants born to HIV-infected women each year. Without maternal treatment, I would predict 15 to 20 of these infants would become infected each year. However, because of successful treatment, I saw only one infected infant in 1999, no infected infants in 2000, and 2 infected infants in 2001.
Obviously, mothers must be identified during pregnancy for this strategy to be effective. Most women identified in pregnancy accept treatment. There is only a 5% refusal rate. More problematic is the fact that 15% of mothers are identified at the time of delivery of the infant. Most of these women have had no, or very late, prenatal care. Under these circumstances, transmission of the virus can be prevented by rapid treatment of the infant. Treatment of the infant with AZT within 24 to 72 hours can reduce transmission from 25% to 12%. It is fairly common practice for pediatric HIV specialists faced with this situation to give the infant one dose of nevirapine (Viramune) in addition to the standard regimen of 6 weeks of AZT. This strategy is based on findings of HIV NET 012, a clinical trial conducted in Uganda (published in the journal Lancet, 354, p. 1795, 1999). Pregnant women were given one dose of nevirapine during labor and the infant was given one dose of the drug at 48 to 72 hours after birth. This treatment resulted in a 50% reduction in transmission. At present there is no information on the outcomes of infants treated in this manner.
Anemia and neutropenia are the most common side effects observed in treated infants. The majority of infants do not require any treatment for these blood abnormalities other than withdrawal of medication. Rarely, an infant may need a blood transfusion. While the prevention of perinatal transmission appears to be an unqualified success, we must remain vigilant in our care and follow-up of these infants to detect any undesirable side effects, some of which may not be apparent for years.
Guidelines for treatment of pediatric AIDS developed by the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children is available at the Web site www.hivatis.org. These recommendations were developed by pediatric HIV specialists. The clinical and immunologic classification of children differs from that of adults. Children normally have higher T-cell counts than adults and manifest somewhat different clinical symptoms. For instance, a normal T-cell count in a newborn infant is on the order of 3,000 to 4,000, much higher than in adults. Children are classified immunologically by T-cell count and percentage. Children in class 1 are regarded has having normal immunologic response, whereas children in class 3 are severely immunosuppressed. Children who have mild clinical symptoms are in class A and those with severe clinical symptoms, usually opportunistic infections, are in class C. Almost all children are on antiretroviral therapy as recommended by the Working Group. Although American children rarely get Kaposi's sarcoma, cerebral toxoplasmosis, or cryptococcal meningitis, they do have significant problems with bacterial infections such as pneumonia.
Treatment with highly active antiretroviral therapy (HAART) has dramatically improved the health and well-being of HIV-infected children, but many challenges remain. The practical reality of pediatric HIV treatment is that we have problems with adherence to drug regimens, as well as resistance of the virus to drugs. Many drugs don't come in liquid formulations or taste so bad that children refuse to take them. Given the fact that most of these children will live into adulthood, we are concerned with the long-term side effects of treatment such as lipodystrophy, hypercholesterolemia, and osteopenia.
Adherence is a major issue. Only 33% of my pediatric patients have undetectable viral loads. Most adult HIV practices report 40% to 60% of patients with undetectable viral loads. Seventy percent of my patients have had serious problems with adherence at some point in their treatment. Treatment of newly infected infants illustrates some of the difficulty. Since it is not possible to distinguish between infants who will have a rapid and downhill course from those who will progress much more slowly, initiation of HAART is recommended for all infants less than 12 months of age. Unfortunately these infants are often born to mothers with substance abuse problems or mental health diagnoses. Many mothers are teenagers. Some are undocumented resident aliens with poor access to health care and are non-English monolingual. Many women have no social support such as family or friends to whom they can disclose their HIV status. They are almost all poor. Despite intense interaction with physicians, nurses, social workers, and case managers, it may take 1 to 2 years to establish an effective treatment plan. Even once an effective plan is in place, it is always in jeopardy. Many of the families exist in such marginal social situations that they often experience destabilizing circumstances such as eviction, break-ups of couples, or incarceration. Also, parents can become sick and die. When these situations occur, it is not uncommon for the children's viral loads to rise, necessitating medication changes because of resistance development. We really do not have enough drug options to cover these scenarios and many of my patients are on fourth and fifth regimens.
Adherence is a special issue in pediatrics not only because of social situations, but because many of the drugs are not child friendly. While AZT, 3TC (Epivir), d4T (Zerit), and abacavir (Ziagen) come in tolerable liquid formulations, ddI (Videx) has to be given on an empty stomach, twice a day, and is mixed in an unpalatable Maalox suspension. If didanosine is part of a child's regimen, then the child gets medicine at least 4 times a day. Adherence is clearly a problem in this situation. The introduction of Videx EC (ddI in a capsule given once daily) should make this drug more accessible to the pediatric population.
The protease inhibitors nelfinavir (Viracept), ritonavir (Norvir), lopinavir/ritonavir (Kaletra), and amprenavir (Agenerase) come in pediatric formulations. None are particularly palatable. Amprenavir cannot be given to children less than 4 years of age because of the high concentrations of vitamin E and propylene glycol. The taste of ritonavir liquid is particularly problematic. Consistent use of protease inhibitors requires patience, persistence, and creativity on the part of the mother or caregiver. The medical team must be supportive and available because these are difficult drugs to give. Nevirapine (Viramune) and efavirenz (Sustiva) are easy to give and are well tolerated, but lapses in adherence can allow the virus to develop resistance almost immediately.
Drug resistance is a problem in pediatrics because so many of the children have been sequentially treated with antiretroviral drugs. The average age of HIV-infected children in my practice is 11 years. None of the children born before 1996 were treated with HAART initially because it was simply not available when they were first diagnosed. Thus, they received less potent regimens and developed drug resistance, particularly to the nucleoside drugs like AZT, ddI, 3TC, and d4T.
Despite the problems associated with the management of HIV-infected children, the advances in treatment have prolonged their lives and made them healthier. Most attend school and fully participate in the activities of childhood. I have not had a child die in 4 years and it is rare for a child to be hospitalized for any long period of time. I expect these children to live well into adulthood and hope that they will continue to benefit from advances in treatment and ultimately be cured.
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