Pediatric Annals

Current Management of HIV Infection in Children

Therese A Cvetkovich, MD; Lisa M Frenkel, MD

Abstract

Since the human immunodeficiency virus (HIV) was identified as the cause of acquired immunodeficiency syndrome (AIDS), agents capable of blocking HIV replication have been developed to control the underlying infection. The time has passed for pediatric HlV infection to be considered an untreatable disease, as studies of these agents demonstrate their efficacy in prolonging health and life expectancy.

The rapid evolution of modalities for the diagnosis and treatment of HIV-infected children makes consultation with specialists in the care of HIV-infected children helpful, even though the primary care provider will assume more of the day-to-day care of these children as their numbers increase. Primary care pediatricians will continue to play a pivotal role in identifying children at risk for HIV infection, in providing and coordinating their medical care, and in attending to the complex psychosocial problems associated with HIV infection. The standard of care for HIV-infected children currently includes both antiretroviral therapy for those with symptomatic or immunologic abnormalities, and prophylaxis and treatment of opportunistic infections. The point at which antiretroviral treatment is begun, the agents used, and prophylactic regimens will change rapidly during the next few years as the results of ongoing studies become available.

INITIATION OF ANTIRETROVIRAL THERAPY

Children who are HIV infected and who have manifestations of progressive disease, regardless of immune status, are candidates for antiretroviral therapy. Table 1 lists indications for initiation of antiretroviral therapy based on clinical findings. Other conditions, listed in Table 2, constitute signs and symptoms of HIV infection that are not generally associated with rapidly progressive disease. The impact of antiretroviral therapy on progression of HIV disease in children with these findings has not been critically evaluated. Most experts would, however, treat children with these symptoms based on studies in adults.1,2 Asymptomatic HIV-infected children with abnormally low age-adjusted CD4 lymphocyte values have significant perturbation in immune response. These values are shown in Table 3. Again, although studies have not focused directly on this population, experts generally agree that children with this degree of immunologic compromise warrant treatment with antiretroviral therapy.

Table

Pneumonia caused by Pneumocystis carinii most often occurs in the first year of life in those children with perinatally acquired HIV infection. The median age at presentation is 3 to 6 months.16-18 Pneumocystis carimi pneumonia (PCP) is the most common AIDSdefining opportunistic infection in infancy and was the presenting illness in 9% of HIV-infected infants.17 The initial episode is frequently fatal. These facts underscore the importance of PCP prevention in HIV-infected infants and children.

Prophylaxis against PCP is recommended for all HIV-infected adults who have a history of PCP and those with a CD4 count of less than 200 cells^L or a CD4 percentage of less than 20. 19 Pneumocystis carinii pneumonia occurs in children who have significant dysregulation of their immune response; they may develop PCP with much higher CD4 counts than adults. Recent identification of age-adjusted normals for CD4 counts and percentages have allowed identification of those children at risk for PCP.20,21 Recommendations for the initiation of primary PCP prophylaxis for children based on CD4 count or percentage are provided in Table 7.22

Because HIV infection may not conclusively be diagnosed during the first year of life in infants, current recommendations include prophylaxis of HIVexposed infants at risk for PCP according to the CD4 guidelines (Table 7). Pneumocystis carinii pneumonia very rarely occurs in infants less than 1 month of age, therefore prophylaxis is not recommended in this age group. All children who have survived an episode of PCP should receive prophylaxis, regardless of their CD4 lymphocyte counts. Children age 13 and older should receive prophylaxis based on the…

Since the human immunodeficiency virus (HIV) was identified as the cause of acquired immunodeficiency syndrome (AIDS), agents capable of blocking HIV replication have been developed to control the underlying infection. The time has passed for pediatric HlV infection to be considered an untreatable disease, as studies of these agents demonstrate their efficacy in prolonging health and life expectancy.

The rapid evolution of modalities for the diagnosis and treatment of HIV-infected children makes consultation with specialists in the care of HIV-infected children helpful, even though the primary care provider will assume more of the day-to-day care of these children as their numbers increase. Primary care pediatricians will continue to play a pivotal role in identifying children at risk for HIV infection, in providing and coordinating their medical care, and in attending to the complex psychosocial problems associated with HIV infection. The standard of care for HIV-infected children currently includes both antiretroviral therapy for those with symptomatic or immunologic abnormalities, and prophylaxis and treatment of opportunistic infections. The point at which antiretroviral treatment is begun, the agents used, and prophylactic regimens will change rapidly during the next few years as the results of ongoing studies become available.

INITIATION OF ANTIRETROVIRAL THERAPY

Children who are HIV infected and who have manifestations of progressive disease, regardless of immune status, are candidates for antiretroviral therapy. Table 1 lists indications for initiation of antiretroviral therapy based on clinical findings. Other conditions, listed in Table 2, constitute signs and symptoms of HIV infection that are not generally associated with rapidly progressive disease. The impact of antiretroviral therapy on progression of HIV disease in children with these findings has not been critically evaluated. Most experts would, however, treat children with these symptoms based on studies in adults.1,2 Asymptomatic HIV-infected children with abnormally low age-adjusted CD4 lymphocyte values have significant perturbation in immune response. These values are shown in Table 3. Again, although studies have not focused directly on this population, experts generally agree that children with this degree of immunologic compromise warrant treatment with antiretroviral therapy.

Table

TABLE 1Conditions That Warrant Initiation of Antiretroviral Therapy

TABLE 1

Conditions That Warrant Initiation of Antiretroviral Therapy

Table

TABLE 2Conditions That May Indicate Need for Antiretroviral Therapy

TABLE 2

Conditions That May Indicate Need for Antiretroviral Therapy

Table

TABLE 3Indications for Antiretroviral Therapy for HIV-infected Children According to CD4 Lymphocyte Count

TABLE 3

Indications for Antiretroviral Therapy for HIV-infected Children According to CD4 Lymphocyte Count

Whether antiretroviral therapy will benefit asymptomatic HIV-infected children with normal immune function is being studied. Currently, antiretroviral therapy is not recommended for these children. Children in this category are candidates for clinical trials studying the effects of early treatment.

The recent advent of the HIV epidemic and the complex pathophysiology of the infection challenge clinical medicine in the development of effective treatments. Considerable efforts to define such treatments for children are underway at many centers. Centers participating in these studies as part of the AIDS Clinical Trials Group (ACTG) are sponsored by the National Institute of Health. Participation in this effort is recommended, and information regarding these trials and their sites is available by calling (800) TRIALS-A (800-874-2572).

INITIAL TREATMENT OF SYMPTOMATIC HIV-INFECTED CHILDREN

Zidovudine (ZDV, formerly AZT) and didanosine (DDl) are currently the only two antiretroviral agents approved by the Food and Drug Administration for use in children. Both drugs are dideoxynucleosides. They act by interfering with the HIV reverse transcriptase enzyme to prevent production of DNA from viral RNA. Data supports the use of ZDV as initial therapy for symptomatic HIV-infected infants and children.3'5 Didanosine is approved as second line therapy for children who are ZDV intolerant or have progression of HIV disease while taking ZDV. Studies in adults have shown the clinical superiority of ZDV over DDI for initial treatment6; however, switching from ZDV to DDI after 8 to 16 weeks of therapy was found to offer a clinical benefit.7

Clinical, immunologic, and virologie benefits of ZDV therapy in symptomatic children have been found to be similar to those found in adults.3'5 In the largest study,4 88 children with advanced HIV disease were treated with ZDV 180 mg/m2 every 6 hours for a median of 186 days. Neurodevelopmental improvement and weight gain at 6 months and decreases in serum and cerebrospinal fluid (CSF) p24 antigen levels and serum immunoglobulin were seen. An initial increase in CD4 lymphocyte counts was seen followed by a return to near baseline. Zidovudine was well tolerated overall by pediatric patients. Only three patients required permanent discontinuation of the drug due to hematologic toxicity. One third of the children required dose reduction due to neutropenia or anemia.

Table

TABLE 4Zidovudine Dosing by Age*

TABLE 4

Zidovudine Dosing by Age*

Children who are symptomatic or who have low CD4 counts are at the highest risk for progression of their disease. Treatment should be offered to these children at the earliest opportunity. Zidovudine is currently recommended at a dose of 180 mg/m2/dose every 6 hours. It is available as a 10 mg/mL raspberry' flavored syrup. Anemia and neutropenia are the most common adverse reactions to ZDV and may improve with dose reduction to 120 mg/m2/dose. Further reduction, dose interruption or the use of cytokine therapy (granulocyte -colony stimulating factor [GCSF], erythropoietin) are needed occasionally to prevent dangerously low hematologic values. Studies in adults found lower ZDV doses (500 to 600 mg/day) to be better tolerated and more effective in delaying adverse clinical events than the higher dose (1000 to 1200 mg/day).2 However, a study of low-dose ZDV (100 mg/m2 every 6 hours) in children suggested that there was less improvement in neurologic symptoms, p24 antigen and CD4 counts compared to previous high-dose studies.8 Results of a larger comparative study (ACTG 128) of standard-dose ZDV (180 mg/m2/dose) versus low-dose ZDV (90 mg/m2/dose) in children should be available within a year. This should ascertain whether a higher dose ZDV is more effective, especially in relation to neurologic disease.

Based on pharmacokinetic studies in newborns showing delayed ZDV elimination, neonates should receive lower doses.9 Oral doses of 2 mg/kg/dose every 6 hours for infants 0 to 2 weeks of age, and 3 mg/kg/dose every 6 hours for those 2 to 4 weeks of age are recommended. Children greater than one month of age may be given standard-dose ZDV.

Data on treatment of adolescents are lacking. Many experts recommend the adult dose of ZDV, 500 mg/day in divided doses, recognizing that higher doses may provide more effective therapy of HIV-related central nervous system disease. A summary of ZDV dosage recommendations is provided in Table 4.

MONITORING OF CHILDREN ON ZDV

Children receiving rherany wirb 7DV should he closely monitored for evidence of HIV disease progression and ZDV-related toxicity. Regular follow-up with a referral center experienced in the care of HIV-infected children is recommended whenever possible to identify unusual problems associated with either HIV disease or therapy.

Toxicity related to ZDV therapy in children is similar to that found in adults, mainly anemia and neutropenia. These effects are more frequent with advanced HIV disease and with higher doses of ZDV, and may improve with dose reduction.

Prior to initiation of ZDV therapy, baseline hematologic and hepatic function should be documented. An increase in liver transaminase levels not related to hepatitis A, B, C, or D is common in HIV-infected children and should not preclude therapy with ZDV. Alanine transaminase levels may decrease with therapy, and even when they do not, persistent hepatitis generally does not progress to liver failure. Evaluation of the complete blood count and differential should be performed biweekly for a month after therapy has been started and then monthly. Children who do not demonstrate hematologic or hepatic laboratory abnormalities during the first 6 months of therapy usually can be monitored adequately with less frequent laboratory testing. Hematologic toxicity can be observed as early as 2 weeks after initiation of therapy or at any time during therapy. Severity of the toxicity will determine management. In general, severe anemia (<7.5 gm/dL) will require changing to an alternate therapy. For less severe anemia, dose reduction by 30% may be tried. If transfusion is required in a patient on a reduced dose to maintain the hemoglobin >8.0 gm/dL, erythropoietin may be used. For patients who remain anemic on a reduced dosage of ZDV and erythropoietin, transfusions or changing to another antiretroviral agent are indicated. Zidovudine therapy often may be associated with an increase in red cell mean corpuscular volume (MCV). This value may be used to assess compliance with ZDV therapy.

Neutropenia is managed in a similar fashion. An absolute neutrophil count of <500 mm/mm3 warrants changing to another drug. Neutropenia (absolute neutrophil count between 500 and 1000 mm/mm2) may be managed with 30% dose reduction. If bone marrow recovery does not occur with reduction of the dose, G-CSF may be added. For patients who remain neutropenic on a reduced dose of ZDV with G-CSF, changing to another antiretroviral agent is recommended.

Nausea and vomiting occur in less than 5% of pediatric patients taking ZDV. Treatment with antiemetics may be attempted followed by dose reduction. Persistence of nausea and vomiting in spite of antiemetic therapy and dose reduction may best be dealt with by changing to another agent.

During therapy with any antiretroviral agent, the evaluation of the child's underlying disease currently includes growth, the occurrence of HIV-associated conditions (such as AIDS-defining opportunistic infections or malignancies), neurologic and psychological development, CD4 lymphocyte number, and percent and estimates of viral burden such as p24 antigen, plasma viremia, and proviral burden (percent of peripheral blood mononuclear cells infected wiuh HIV). Recommendations for serial evaluation of these parameters is provided in Table 5.

WHEN TO CHANGE ANTIRETROVIRAL THERAPY

Second-Line Agents

Careful monitoring of children receiving antiretroviral therapy will allow the clinician to identify those children who have evidence of toxicity and those who have progression of their disease. Either case warrants a change in antiretroviral therapy.

Progression of HIV disease has been defined by experts in HIV infection to include growth failure, neuropsychologic deterioration, organ dysfunction, occurrence of malignancy or opportunistic infections, or a significant drop in CD4 lymphocyte count or percentage. Most individuals demonstrate improvement in clinical and laboratory parameters after several weeks of ZDV treatment. Then they will be clinically stable for a variable period of time, after which symptoms worsen and CD4 number and percentage dwindle downward. The period of clinical stability is generally longer when the child is early in the course of disease with only mild HIV-related symptoms and may be relatively short (several months) when HIV disease is advanced at initiation of therapy. Data suggest that disease progression is associated with the development of HlV resistance to antiretroviral agents.10 As more pregnant women receive treatment with antiretrovirals, transmission of resistant HIV may occur and may preclude even a short- term benefit with certain agents.11

Before ascribing progression of HIV disease to ZDV failure, it is important to ascertain compliance and that the drug is being adequately absorbed from the gastrointestinal tract. This is commonly assessed by observing a persistent rise in the child's MCV. Zidovudine levels and assays for resistance are available at research centers, although currently not routinely used in directing patient management.

Table

TABLE 5Serial Evaluation of Children Receiving Zidovudine

TABLE 5

Serial Evaluation of Children Receiving Zidovudine

Growth failure is defined as a drop in greater than two percentile lines in height or weight or both. For those children who are below the fifth percentile line, a continued deviation from parallel growth defines growth failure. Many HIV-infected children demonstrate growth failure, and not all children will exhibit improvement in growth even when treated with antiretroviral agents to which their HIV is sensitive.4,5 Other treatable causes of growth failure including poor intake, diarrhea, or endocrine abnormalities should be identified and corrected when possible. If growth failure persists after these causes have been conected, then the failure may be considered to be caused by the HIV infection.

Deterioration in neurodevelopmental function may manifest as impairment in brain growth, decline in cognitive function, or progressive neurologic dysfunction. Brain growth may be documented by serial head circumference measurements or computed tomography scan. Serial standardized developmental and neurologic tests are sensitive indicators of deterioration warranting a change in therapy.5

Other clinical developments indicative of disease progression include HIV-related organ dysfunction such as cardiomyopathy requiring therapy, nephropathy, elevation of hepatic enzymes, development of an AIDS-defining opportunistic infection, or increased severity of incidence of infections. These and major changes in laboratory indices such as CD4 lymphocyte count (eg, a drop of greater than 50% when the initial CD4 count is greater than 200 µ/l) or percentage should be considered as reasons for changing therapy. Changes in antiretroviral therapy are usually not made after minor deleterious clinical or laboratory events because of the limited number of therapeutic agents available.

Table

TABLE 6Didanosine Dosage Recommendations

TABLE 6

Didanosine Dosage Recommendations

Didanosine is the only other antiretroviral agent available to those children who cannot tolerate ZDV or who have progressive disease while taking ZDV Didanosine has been shown to have antiretroviral activity in children,12 although it has been studied less than ZDV. Toxicities associated with DDI include pancreatitis and peripheral neuropathy. About 7% will develop pancreatitis,13 and less than 1% will develop peripheral neuropathy, although at doses higher than those currently recommended. Retinal depigmentation has been noted to occur in rare individuals but has not been associated with a decrease in visual acuity, however, the peripheral vision may be affected.14 In contrast to ZDV, there is no myelosuppression associated with DDI.

Didanosine has a prolonged intracellular half-life, allowing for dosing every 12 hours. Didanosine is not stable under acid conditions. Current formulations include buffering agents to increase stability in the gastric environment. Available preparations include mint-flavored chewable tablets, powder packets (sachets) for solution, and powder for suspension. Drugs that require an acidic environment for absorption such as dapsone or ketoconazole must be taken separately from DDI, usually by 2 hours. Bioavailability is greater from the chewable tablets or suspension compared to the sachets and is reflected in the dosage recommendations for each form (prescribing information, BristolMyers Squibb Company, Princeton, New Jersey). Dosing recommendations for DDI are detailed in Table 6. An ongoing study (ACTG 144) is comparing two doses of DDI (50 mg/mp 2/dose every 12 hours versus 150 mg/mp 2/ dose every 12 hours) in children with HIV disease progression or intolerance to ZDV.

Children receiving DDI therapy should be monitored for pancreatitis and peripheral neuropathy. Serum amylase and lipase levels should be checked monthly to identify pancreatic toxicity. Fractionation of amylase to define pancreatic versus salivary origin is often necessary as many children with parotitis will have abnormally high serum amylase levels. Parents or caretakers should be advised to report any tingling or pain in the child's feet or hands. Neuropathy regresses when diagnosed early and DDI is withdrawn. Some patients will tolerate reintroduction of DDI at a lower dose. Ophthalmologic evaluation should be performed prior to therapy, every 6 monrhs. and when clinically indicated.

Dideoxycytidine (DDC) is one of the most potent nucleoside analogues. It is available for second- line therapy in combination with ZDV in adults. Studies in children show evidence of antiretroviral activity.15 A large study comparing two doses of DDC is ongoing in children who have failed ZDV (ACTG 138). Painful peripheral neuropathy has been the limiting toxicity in adults, but appears very rarely in this large study in children (Spector S. November 1992. Personal communication).

Because alternatives at this time are limited for the treatment of HIV infected children, most toxicities are considered relative. Treatment to limit or reverse toxicity, such as transfusions for anemia or G-CSF for neutropenia used in the child on ZDV may allow for the continued use of the drug. Consultation with specialists in HIV infection may be helpful prior to decisions to switch or discontinue therapy.

The preceding guidelines for antiretroviral therapy using available agents are provided as a guide for the clinician caring for HIV infected children who are not enrolled in a clinical trial. Studies are currently underway comparing ZDV to DDI alone, and ZDV combined with DDI, as initial therapy for HIV-infected children. Results of these and other studies will modify our treatment of HIV infection in children in the near future.

Because our knowledge of HIV infection is in its infancy and a satisfactory regimen has not yet been found, it is hoped that consideration of entering the child into available clinical trials will be included in the management of all children with HIV infection.

SUPPORTIVE OR PROPHYLACTIC THERAPY

Early diagnosis, treatment, and prophylaxis of the HIV-infected child has changed the natural history of perinatally acquired HIV infection. Early identification of HIV infection followed by careful monitoring of the child's growth, health, and immune status provides the basis for the institution of antiretroviral therapy as well as for the prophylaxis of lifethreatening opportunistic infections and other supportive care.

Table

TABLE 7Pneumocystis carinii Pneumonia Prophylaxis Indications

TABLE 7

Pneumocystis carinii Pneumonia Prophylaxis Indications

Table

TABLE 8Prophylaxis Regimens for HIV-infected Children

TABLE 8

Prophylaxis Regimens for HIV-infected Children

Pneumonia caused by Pneumocystis carinii most often occurs in the first year of life in those children with perinatally acquired HIV infection. The median age at presentation is 3 to 6 months.16-18 Pneumocystis carimi pneumonia (PCP) is the most common AIDSdefining opportunistic infection in infancy and was the presenting illness in 9% of HIV-infected infants.17 The initial episode is frequently fatal. These facts underscore the importance of PCP prevention in HIV-infected infants and children.

Prophylaxis against PCP is recommended for all HIV-infected adults who have a history of PCP and those with a CD4 count of less than 200 cells^L or a CD4 percentage of less than 20. 19 Pneumocystis carinii pneumonia occurs in children who have significant dysregulation of their immune response; they may develop PCP with much higher CD4 counts than adults. Recent identification of age-adjusted normals for CD4 counts and percentages have allowed identification of those children at risk for PCP.20,21 Recommendations for the initiation of primary PCP prophylaxis for children based on CD4 count or percentage are provided in Table 7.22

Because HIV infection may not conclusively be diagnosed during the first year of life in infants, current recommendations include prophylaxis of HIVexposed infants at risk for PCP according to the CD4 guidelines (Table 7). Pneumocystis carinii pneumonia very rarely occurs in infants less than 1 month of age, therefore prophylaxis is not recommended in this age group. All children who have survived an episode of PCP should receive prophylaxis, regardless of their CD4 lymphocyte counts. Children age 13 and older should receive prophylaxis based on the adult recommendations listed above.

Trimethoprim-sulfamethoxazole (TMP-SMX) is the preferred agent used for prophylaxis of PCP. The recommended regimen is 75 mg/m2 of the TMP component twice a day on three consecutive days weekly.22 This regimen was tested in immunocompromised children without AIDS and was found to be as effective as daily therapy.23 Common side effects include rash, granulocytopenia, and nausea and vomiting and are more common in adults; this regimen generally is well-tolerated in children.

Aerosolized pentamidine may be offered to those who are intolerant of TMP-SMX, but in adults is less effective as is dapsone.23 Other PCP prophylaxis regimens include daily or weekly dapsone, dapsoneTMP, or weekly pyrimethamine-sulfadoxine. However, results of studies of these regimens in children are not yet available.

Other opportunistic infections for which prophylaxis is available include mycobacterial infections, recurrent herpes simplex infections, varicella-zoster infections, and recurrent mucocutaneous candidiasis. Recommendations for prophylaxis of these infections are in evolution and are not specific to children.24 Guidelines are provided in Table 8.

Intravenous immunoglobulin (IVIG) for prevention of serious bacterial infections has been studied in symptomatic HIV-infected children.25,26 It was found that for those children whose CD4 lymphocyte counts at entry were >200/µL, the use of immunoglobulin significantly prolonged the time free from serious bacterial infections. A more recent study examined the effects of IVlG on prevention of serious bacterial infections in children taking ZDV.27 Preliminary results from this study did not reveal a significant advantage for those given monthly IVIG if they were receiving TMP/SMX for PCP prophylaxis. Further analysis of this data to determine if other benefits for IVIG exist, such as fewer minor bacterial infections, decreased viral infections, or decrease in time to disease progression, is in progress. Current recommendations for the use of IVIG include HIV-related thrombocytopenia. Recommendations for the use of IVIG to prevent serious bacterial and opportunistic infections will be available later this year. In the interim, use of IVIG in children with recurrent serious bacterial infections and in class P2 of HIV-infected children not taking TMP-SMX with CD4 counts >200 appears reasonable.

The basic precepts of well child care must be included in the medical management of HIV-exposed or HIV-infected infants and children. Recommendations for routine immunization of HIV-infected children are available in the 1 991 Red Book.28 In addition, hepatitis B vaccination should be provided to infants in accordance with recent recommendations.29 Live viral and bacterial vaccines are not recommended for these patients who are immunosuppressed. Inactivated polio vaccine is used rather than oral polio vaccine; this recommendation includes family members of the immunosuppressed individual. The use of measlesmumps-rubella vaccine is the exception to this rule. Measles-mumps-rubella has been given to HIV-infected children without development of any unusual problems and is recommended for this group.30 Pneumococcal vaccine should be given to HIVinfected children at age 2. Yearly influenza vaccination also is recommended for those 6 months of age and older.

Because HIV-infected children may not have good immunologic responses to vaccines, they should be considered susceptible to exposures to vaccine preventable diseases even when vaccinated. Passive immunization should be provided after exposures to varicella and measles. Tetanus immune globulin should be administered to the child who has a wound considered tetanus-prone. Hepatitis B immunoglobulin should be administered to the infant at risk for perinatal transmission of this agent.

The diet and environment of the HIV-infected child requires evaluation. These children are at risk for nutritional deficiencies due to multiple causes. Assessment of dietary intake and appropriate recommendations should take place routinely. Specific therapy for treatable causes of diarrhea or esophagitis may improve intake and growth. Teaching regarding possibly harmful dietary practices should be provided to the child's caretakers. These include avoidance of foods that carry a high risk of contamination with infectious agents such as raw eggs or shellfish, undercooked meats, and unpasteurized milk.

Children also may be at risk for diseases acquired from their environment. Varicella, measles, cytomegalovirus, tuberculosis, and herpes simplex virus may be acquired in the day care, school, or home setting; the risk of these various exposures must be balanced against the social benefits on an individual basis. Exposures from pets may be another potentially preventable source of infection. Two examples would include the transmission of toxoplasmosis from cat feces or undercooked meat and salmonella from turtle or lizard feces.

DEVELOPMENT OF NEW TREATMENTS FOR HIV IN PEDIATRICS

Human immunodeficiency virus infection can no longer be considered untreatable. Therapy can improve and prolong life for infected children. The evolution of therapy is continuing at a rapid pace. Goals for future antiretroviral therapy include the development of less toxic agents that have convenient dosage schedules and that are palatable, well absorbed, and penetrate the blood brain barrier. These include other nucleoside analogues as well as agents that will interrupt the viral life cycle at other vulnerable stages. Additional classes of antiretrovirale will include non-nucleoside reverse transcript inhibitors, interferons, protease inhibitors, transactivated transcription gene product inhibitors, and more.

Critical to the development of optimum therapy is the enrollment of all eligible children into appropriate clinical trials. Many problems uniquely related to this pediatric population exist that stand in the way of conducting clinical trials. These include delay in diagnosis, differences in disease manifestations, parental illness or absence, and problems with access to health care. Adult studies may provide useful information, but cannot substitute for well carried out studies in children. A close working relationship between primary care providers and their regional tertiary care centers will ensure that all children eligible may participate in clinical trials.

REFERENCES

1. Fischi MA, Rkhman DD, Hansen N, et al. The safety and efficacy of zidovudine (AZT) in the Treatment of subjects with mildly symptomatic human immunodeficiency virus type 1 (HlV) infection. Ann intern Med. 1990;112:727-737.

2. Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic human immunodeficiency vims infection: a controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. N Engl) Med. 1990322:941-949.

3. McKinney RE. Pino PA, Scott GB, et al. Safety and tolerance of intermittent intravenous and oral zidovudine therapy in human immunodeficiency virus infected pediatric patients; a phase I study. J Pediatr. 1990;1 16:641-647.

4. McKinney RE. Maha MA, Connor EM, et al. A multicenter trial of oral zidovudine in children with advanced human immunodeficiency virus disease. N Engi J Med. 1991;324:1018-1025.

5. Brouwers P, Moss H, Wolters P, et al. Effect of continuous-infusion zidovudine on neuropsychologic functioning in children with symptomatic human immunodeficiency virus infection. J Pediarr. 1990;117:980-985.

6. Dolin R. ACTG I I6A data. Presented at the AIDS Clinical Trials Group Meeting; February 22, 1993; Washington, DC.

7. Kahn JO, Lagakos SW, Richman DD, et al. A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. N Engl J Med. 1992;327:581-587.

8. Blanche S, Duliege A-M, Navarette MS, et al. Low-dose zidovudine in children with an human immunodeficiency virus type I infection acquired in the perinatal period. Pediatrics. 1991;88:364-370.

9. Boucher FD, Modlin JF, Weiler S, et al. Phase I evaluation of zidovudine administered to infants exposed at birth to the human immunodeficiency virus. J Pediatr. 1993;122:137-144.

10. Tudor-Williams G. St. Clair MH, McKinney RE, et al. HIV-I sensitivity to zidovudine and clinical outcome in children. Lancet. 1992:339:15-19.

11. Frenkel LM, Demeter LM. Wagner L, er al. Perinaral transmission of an AZT resistance mutation from a mother to her infant. J Cell Bmthem. 1993;l7E(suppl):QZ102. Abstract.

12. Butler KM, Husson RN, Bales FM, et al. Dideoxyinosine in children with symptomatic human immunodeficiency virus infection. N Engt) Med. 1991;324:137-144.

13. Butler KM, Vernon D. Henry N, et al. Pancreatitis in human immunodeficiency virus-infected children receiving dideoxyinosine- Pediatrics. 1993;91:747-751.

14. Whitcup SM. Butler KM. Caruso R, et al. Retinal toxicity in human immunodeficiency virus-infected children treated with 2\3'-dideoxyinosine. Am J Ophthalmol. 1992;113:1-7.

15. Pino PA, Butler K, Balis F. et al. Dideoxycytidine alone and in an alternating schedule with zidovudine in children with symptomatic human immunodeficiency virus infection. J Pediatr. 1990-.1 17:799-808.

16. Scott GB. Hutto C, Makuch RW, et al. Survival in children with perinatally acquired human immunodeficiency virus type 1 infection. N Engl J Med. 1989:321:1791-1796.

17. Bernstein LJ, Bye MR, Rubenstein A. Prognostic factors and life expectancy in children with acquired immunodeficiency syndrome and Pneumocystis carinii pneumonia. Am J Dis CMi. 1989;143:775-778.

18. Leibovitz E. Rigaud M. Pollack H, et al. Pneumocystis corma pneumonia in infants infected with the human immunodeficiency virus with more than 450 CD4 T lymphocytes per cubic millimeter. N Engl J Med. 1990;323:531-533.

19. Recommendations for prophylaxis against Pneumocystis corma pneumonia for adults and adolescents infected with human immunodeficiency virus. MMWR. 1992:41:1-12.

20. Conner E, Bagarozzi M, McSheny G, et al. Clinical and laboratory correlates of Pneumocystis carinii pneumonia in children infected with HIVJAMA. 1991:265:1693-1697.

21. Kovacs A, Frederick T, Church J, Eller A, Oxtoby M. Mascola L. CD4 T-lymphocyte counts and Pneumocystis carmii pneumonia in pediatric HIV infection. JAMA. 1991:265:1698-1703.

22. Guidelines for prophylaxis against Pneumocystis carmii pneumonia for children infected with human immunodeficiency virus. MMUCR. 1991;40:1-13.

23. Hughes WT, Rivera GK, Schell MJ. Thornton D, Lott L. Successful intermittent chemoprophylaxis for Pneumocystis corina pneumonitis. N Engl J Med. 1987;3 16:1627-1632.

24. Jewett JF, Hecht FM. Preventive health care for adults with HIV infection. JAMA. 1993;269:1144-1153.

25. The National Institute of Child Health and Human Development Intravenous Immunoglobulin Study Group. Intravenous immune globulin for the prevention of bacterial infections in children with symptomatic human immunodeficiency virus infection. N Engl J Med. 1991;325:73-80.

26. Mofenson LM, Moye J Jr. Bethel J, Hirschom R, Jordan C. Nugent R (for the National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial Study Group). Prophylactic intravenous immunoglobulin in HIV-infected children with CD4 counts of 0.2OxIO9ZL or more: effect on viral, opportunistic, and bacterial infections. JAMA. 1992;268:483-488.

27. Spector SA. Sacks H. MPara D et al. Results of ACTG 051: a double-blind, placebo-controlled trial to evaluate intravenous gamma globulin in children with symptomatic HIV infection receiving zidovudine. Presented at the Infectious Diseases Society of America (IDSA) 30th Annual Meeting. 1992.

28. Report of the Committee on Infectious Diseases. Elk Grove Village, 111: American Academy of Pediatrics; 1991.

29. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: recommendations of the Immunization Practices Advisory Committee (AClP). MMwTR. 1991;40:1-25.

30. McLaughlin M, Thomas P, Onorato I, et al. Live virus vaccines in human immunodeficiency virus- infected children; a retrospective survey. Pediatrics. 1988:82:229-233.

TABLE 1

Conditions That Warrant Initiation of Antiretroviral Therapy

TABLE 2

Conditions That May Indicate Need for Antiretroviral Therapy

TABLE 3

Indications for Antiretroviral Therapy for HIV-infected Children According to CD4 Lymphocyte Count

TABLE 4

Zidovudine Dosing by Age*

TABLE 5

Serial Evaluation of Children Receiving Zidovudine

TABLE 6

Didanosine Dosage Recommendations

TABLE 7

Pneumocystis carinii Pneumonia Prophylaxis Indications

TABLE 8

Prophylaxis Regimens for HIV-infected Children

10.3928/0090-4481-19930701-09

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