GMHC Treatment Issues, Vol. 10, No. 3 - March 1996
Samuel Grubman, M.D.

ACTG 152 is a randomized, double blind trial comparing AZT monotherapy and ddI monotherapy with AZT plus ddI in HIV- infected children ages three months up to eighteen years. After an interim analysis in February, 1995, the Data Safety and Monitoring Board (DSMB) recommended closing the AZT monotherapy arm of the study. This recommendation was based on data showing that patients on the AZT monotherapy arm had a significantly increased risk of reaching a primary study endpoint compared with the ddI monotherapy or combination therapy arms. Primary endpoints for the study include survival and HIV disease progression based on growth failure, deterioration in neuropsychological status or the development of more than two new or recurrent opportunistic infections. The interim analysis also revealed an increase in toxicity (low red and white blood cell counts and abnormal blood chemistry) in patients in the AZT monotherapy arm.

Physicians caring for patients enrolled in the AZT monotherapy arm were advised to offer these patients what seemed the "best available" therapy. Children in the other two arms of the trial were followed through the completion of the study in August 1995.

A full analysis of the completed trial with an unblinding of the other two arms was released at the February 28 FDA advisory committee hearing that reviewed use of AZT, ddI and ddC alone and in combination. The new analysis, completed just days before the presentation, revealed that treatments with either ddI alone or a combination of ddI plus AZT were equally efficacious.

ACTG 152 opened in August 1991 and over a period of two years enrolled 839 children with a mean age of three years nine months at entry. The trial was meant to assess the comparative efficacy of the three antiretroviral regimens as first line therapy for HIV, so children who had been on antiretroviral therapy for more than six weeks were excluded. Just eight percent of patients had received any antiretroviral therapy prior to enrollment.

The trial was otherwise unusually broad in its inclusion criteria. Only asymptomatic children with relatively normal immunological laboratory test values were excluded. The median CD4 counts at study entry for trial participants younger than 30 months and older than 30 months were 1,191 cells/mm3 and 569 cells/mm3 respectively. (Note that children's CD4 counts normally start out higher than adults. The ACTG 152 medians are in the low-to-moderate immune suppression range.)

Interim efficacy analysis of the time to first opportunistic infection or death revealed that the AZT monotherapy arm performed significantly worse than the "best" treatment arm at the time (not further identified to keep the trial blinded). But when survival was evaluated separately, no statistically significant difference was noted.

With the AZT monotherapy arm eliminated, this February's final analysis of the study assessed whether there was a difference between the ddI monotherapy arm and the ddI plus AZT combination therapy arm. This analysis revealed that there was no distinction between the two arms with regard to disease progression (including neuropsychological deterioration) or survival.

Primary disease progression endpoints occurred in 24 percent of children receiving ddI alone and 25 percent of children receiving combination therapy. Of the primary endpoints, 52 percent were growth failure, nineteen percent were neuropsychological deterioration and twelve percent were deaths. (AZT has the reputation of penetrating the central nervous system better than ddI, but even though the incidence of neuropsychological dysfunction was lower in the children receiving ddI/AZT than those on ddI monotherapy, this gap did not reach statistical significance.) The primary endpoint figures are dominated by the children under 30 months old. Far fewer instances of disease progression and death occurred in the older children, and the trial could not distinguish between the performance of the two treatments in the older group of children.

Children receiving ddI monotherapy had significantly fewer hematologic toxicities compared to the other two arms. The increased toxicity with AZT occurred in both those receiving the lower dose (120 mg/m2 of body surface area/dose) on the combination arm and those on the higher dose monotherapy arm (l80 mg/m2). Results of ACTG 128, which directly compared 180 mg/m2 and 90 mg/m2 of AZT revealed that higher and lower AZT doses had similar toxicity. From a clinical standpoint, the two dosages were also equivalent in ACTG 128, with the exception that those children with neurological disease fared better on the higher dose.

After the interim analysis one year ago, many pediatric AIDS specialists continued immunologically and clinically stable children on AZT monotherapy. The recommendations from the National Institute of Allergy and Infectious Diseases (sponsor of ACTG 152) were extremely vague and gave the options of switching or continuing AZT monotherapy. Over time, and with the release of supporting data from ACTG 175 and the European Delta Study (which indicated an advantage to combination therapy and/or ddI monotherapy over AZT monotherapy in adults), physicians started leaning toward using combination antiretrovirals as first line therapy for HIV-infected children.

The final results of ACTG 152 clearly support the results of ACTG 175 (see Treatment Issues, October, pages 2-4) and indicate unequivocally that AZT monotherapy is not the most effective first line therapy. The finding that ddI monotherapy is superior to AZT monotherapy has surprised most clinicians caring for HIV-infected children.

PCP Prophylaxis Guidelines

Pneumocystis carinii pneumonia (PCP) is the most common serious opportunistic infection occurring among children with HIV. Most cases occur early in the first year of life with a peak incidence at two to six months of age. Guidelines on PCP prophylaxis for infants and children with HIV were published in the CDC's Morbidity and Mortality Weekly Report (MMWR) in 1991 and followed recommendations developed by an expert panel convened by the National Pediatric and Family HIV Resource Center. Those guidelines were based on the premise that HIV-infected infants and children are at risk for PCP, and therefore should receive prophylaxis, when their CD4 cell count falls below certain age-related thresholds: below 1,500 cells/mm3 for children one to eleven months of age, below 750 cells/mm3 for children twelve to 24 months, less than 500 cells/mm3 for children two to five years, and less than 200 cells/mm3 for children over six years old.

During the past three to four years, it has become evident that in the first six to twelve months of life, CD4 cell count is not as accurate a measure of the risk for PCP as it is in other age groups. Although an infant with a CD4 cell count below 1,500 cells/mm3 in the first year of life is clearly at risk for PCP, there is also a risk for HIV- infected infants with higher CD4 counts. A recent CDC survey of PCP in HIV-infected infants revealed that 22 of 86 HIV- infected infants less than six months of age with PCP had had CD4 counts greater that 1,500 cells/mm3 within two months of the diagnosis.

Subsequent to the publication of the 1991 guidelines, on- going surveillance of AIDS cases by the CDC demonstrated no significant decline in PCP among HIV-infected children. In addition, a CDC survey found that 59 percent of children with PCP who had not received prophylaxis had not been identified as being HIV-exposed soon enough to begin such prophylaxis.

In March, 1994, the National Pediatric and Family HIV Resource Center in collaboration with the CDC convened an expert panel to evaluate the 1991 PCP prophylaxis guidelines in light of this and other information. The consensus of the expert panel was that changes to the 1991 guidelines were appropriate. Revised guidelines were published in the MMWR on April 28, 1995 and are summarized in the table.

The most significant change involves the use of prophylaxis in the first year of life. The new guidelines recommend that all HIV-infected infants start prophylaxis at one month of age regardless of CD4 cell count. Since it is difficult to determine with certainty by one month of age which infants born to HIV-infected women are themselves infected, the new guidelines recommend initiating prophylaxis in all one-month old infants born to HIV-infected mothers and continuing the prophylaxis until HIV infection can be reasonably excluded. Attempts should be made to exclude HIV infection as soon as possible so that uninfected infants can be taken off medication expeditiously to thereby avoid potential side effects.

The guidelines call for the use of HIV culture and PCR in order to diagnose and reasonably exclude HIV infection. It was the consensus of the expert panel that HIV infection can be reasonably excluded with two negative HIV cultures or PCR viral load tests, one obtained at or after one month of age and the other at or after four months. Clinicians in research settings may feel comfortable excluding HIV infection prior to four months of age through serial HIV culture and/or PCR assays.

There are difficulties, though. HIV culture is not universally available outside of major medical centers with virology laboratories, and even then the test is not reimbursable by third party payers including Medicaid. PCR, although available commercially, is not uniformly reimbursable, either, and therefore difficult to use in a practical sense.

Without the use of HIV culture or PCR, it is impossible to rule out HIV infection until at least seven or eight months of age. Although HIV infection can be excluded on the basis of two negative HIV serologies, (the standard HIV antibody blood test) obtained after six months of age, many infants still have significant maternal antibodies present after six months. It is important at this time for third party payers, including the United States government, to reevaluate their reluctance to cover these important diagnostic assays. The New York State Department of Health, in response to the new guidelines, now offers free PCR testing for diagnostic purposes.

Maternal HIV Status

Although the substantive changes in the guidelines will be effective, one hopes, in preventing PCP in a larger percentage of infants and children, infants will continue to get PCP if they are not identified as being at risk for HIV infection. It has become increasingly obvious that knowledge of maternal HIV infection has an impact on the newborn infant. There are ample reasons why pregnant women should be counseled with regard to voluntary HIV testing. HIV-infected women need to be aware of the results of ACTG 076 and the possibility of reducing the rate of perinatal transmission with antiretroviral therapy.

HIV-infected women need to know, too, that HIV can be transmitted through breast milk (there is a 14 percent increased risk of transmission) and that breast feeding is contraindicated for HIV-infected women in the United States. Breast feeding is almost universally advocated in this country, and it is difficult to understand how an obstetrician or pediatrician can advise a mother to breast feed her infant without knowing whether or not the woman is infected with HIV.

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