Optimal dose appears to be 90 mg/m2 or less
Several years ago, a landmark study established that 600 mg/day of ZDV -- which was then regarded as half the standard dose -- was just as effective as 1200 mg/day in preventing disease progression in adults. As a result, the severe bone marrow suppression that was common among patients taking 1200 mg/day is now a distant memory. A similar finding is now reported by the AIDS Clinical Trials Group , this time for children. More than 400 children, ranging from 3 months of age to 12 years, were randomized in a double-blinded fashion to high-dose ZDV (180 mg/m2) or low-dose ZDV (90 mg/m2) in ACTG 128. Patients, who were symptomatic but without a diagnosis of AIDS, were followed for a mean of 35 months. Investigators were particularly interested in tolerance and neurodevelopmental changes, but they also tracked survival, clinical parameters, and surrogate markers of disease progression.
Overall, the two cohorts were remarkably similar by all assessments throughout the study period. Neuropsychological deterioration was found to be much more frequent in children under six years of age, but these changes occurred irrespective of dosage. Neither dose showed an advantage in preventing progression to an AIDS-defining condition or overall clinical deterioration. CD4 measurements and viral load assays did not differ significantly between the study arms. Furthermore, there was no difference in survival, which was 89% in each group at four years.
The only distinction regarding adverse events was a slightly lower incidence of neutropenia in low-dose recipients. Given the striking similarity between the two groups, the investigators speculate that the optimal dose of ZDV for pediatric AIDS patients might even be lower than 90 mg/m2. However, they caution that these findings should not be extrapolated to pediatric patients with important CNS disturbances.
Brady MT, McGrath N, Brouwers P, Gelber R, Fowler MG, Yogev R et al. Randomized study of tolerance and efficacy of high- versus low-dose zidovudine in human immunodeficiency virus-infected children with mild to moderate symptoms (AIDS Clinical Trials Group 128) J Infect Dis 1996; 173: 1097-1106.
A small study shows ZDV plus 3TC to be effective in patients who fail monotherapy
There is precious little information on the use of combination antiretroviral regimens in children to be found in the literature. One very small study makes a contribution to clinical management of these patients and is particularly valuable since in compares two commonly used antiretroviral combinations. Researchers at three German institutions recruited 10 children and adolescents (ages 3 months to 18 years) who were failing or not tolerating their antiretroviral monotherapy. Half were assigned to receive ZDV plus ddI ("Group A") and the others were treated with ZDV plus 3TC ("Group B"). One patient who began the trial in Group A was switched to Group B at week 32 because of progressive CD4 cell loss.
Overall, the patients in Group A had more advanced disease. For approximately nine months, trial participants were examined every four to eight weeks. Levels of CD4, p24 antigen, and HIV RNA were obtained, and clinical condition was assessed.
Surrogate markers responded more favorably to the combination of ZDV and 3TC. At four months of follow up, CD4 counts were up an average of 72% above baseline and viral load had decreased an average of 22%. At eight months, patients in Group B maintained CD4 increases of 50% above baseline while viral load continued to decrease -- to a value that was 74% lower than mean entry values. In contrast, patients treated with the ZDV/ddI combination saw their CD4 counts increase by only 20% above baseline at four months and return to original values by eight months. Viral load in these patients actually increased -- an average of 21% and 71%, respectively -- at four and eight months.
Patients in both groups exhibited clinical improvement during the study as reflected in appetite level, weight gain, and overall sense of well being. More participants treated with ZDV/3TC showed these improvements (5/6) than those who received ZDV/ddI (2/4.)
Solder B, Wintergerst U, Notheis G, Eberle J, Gurtler L, Belohradsky BH. Effect of antiretroviral combination therapy (zidovudine/didanosine or zidovudine/lamivudine) on quantitative plasma human immunodeficiency virus-ribonucleic acid in children and adolescents infected with human immunodeficiency virus. J Pediatrics 1997; 130 (2): 293-99.
Dr. Catherine M. Wilfert, author of the editorial in this issue, "Preventing Vertical Transmission: A Wise Investment," and a member of the editorial advisory board of HIV Newsline, comments:
We do not know, from the information provided, whether these patients were on ZDV monotherapy before they were switched to combination therapy with either ZDV/3TC or ZDV-ddI, so this switch may have involved adding another drug, in which case the effect seen when 3TC was added to the children's regimen may be the same as the effect seen in adults -- namely, the rapid emergence of resistance to 3TC, followed by a reversal of resistance to ZDV.
This small study was published just prior to the release of the executive summary of the results of ACTG 300, a three-arm clinical trial comparing ZDV/3TC to ZDV/ddI and to ddI monotherapy. Almost 600 children were enrolled in this trial, and those receiving combination therapy had better survival, better growth, and better changes in CD4 count than the children on monotherapy. These findings are conclusive proof that combination therapy is superior to monotherapy in symptomatic, antiretroviral-naïve children.
Compelling evidence of the efficacy of early, aggressive therapy in neonates
AIDS Clinical Trials Group investigators have concluded a fascinating study of maternally-infected infants. Eight infants ranging in age from 2 to 26 months were treated with an open-label antiretroviral combination of ZDV, ddI, and the non-nucleoside reverse transcriptase inhibitor nevirapine. The study lasted six months, but data from the follow-up period are reported as well. No adverse side effects of therapy were identified throughout the course of the study.
The efficacy of this triple-drug combination on HIV activity was impressive. Baseline plasma HIV RNA levels ranged from 41,000 to 1.5 million particles/mL. Over the first month of the study, seven of the eight participants experienced a greater than 95% reduction in viral load from entry levels. However, six of the eight infants did have greater than 103 HIV RNA remaining despite the induction of therapy. Plasma HIV cultures, originally positive in five infants, were negative in all by day 28; by the end of the study, only one culture was positive, and subsequent samples from the same patient were negative. However, proviral HIV DNA remained detectable in all infants. CD4 counts remained stable or increased in all patients throughout the study.
Viral strains with reduced sensitivity to nevirapine were isolated from five of the patients during the study, which is expected when measurably viral replication is continuing. All of these patients had demonstrated a partial rebound in their HIV RNA levels, and the authors speculate that there is an association between the two events.
The authors assert that their findings strongly support the very early and aggressive treatment of HIV infection in children. Such treatment should begin as early as the first two or three months of life, and perhaps earlier to achieve optimal effects.
Luzuriaga K, Bryson Y, Krogstad P, Robinson J, Stechenberg B, Lamson M, et al. Combination treatment with zidovudine didanosine, and nevirapine in infants with human immunodeficiency virus type 1 infection. New Engl J Med 1997; 336 (19): 1343-9.
Dr. Catherine M. Wilfert, the guest editor of this special issue of HIV Newsline devoted to antiretroviral therapy in women and children, comments:
One tantalizing finding of this study was that researchers were unable to detect HIV RNA in the plasma of two of their patients after the initiation of the triple-drug combination. These patients are fraternal twins who began therapy at 2.5 months of age. One patient did again become transiently positive for HIV RNA. He was switched to a regimen of ZDV, 3TC, and ritonavir, and his viral load became undetectable once again.
After starting treatment, the second twin had no detectable HIV RNA over the entire 18 months of follow-up. One of these twins demonstrated no active production of IgG and IgA antibodies against HIV despite detectable HIV DNA. This study provides reason for optimism that HIV can be suppressed in infected infants (see "Apparent clearance of HIV in a perinatally infected child," Vol. 1, No. 2, pages 29-30). However, it also illustrates how difficult it is to suppress viral replications in infants, most of whom have very high viral burdens. One might conclude that therapy must begin before viral burden reaches the million-plus level.
Data suggest that therapeutic strategies should emphasize reduction of viral load
The Women and Infants Transmission Study (WITS) evaluated 475 HIV-infected women, all of whom gave birth between 1989 and 1993, to yield some provocative findings pertaining to vertical transmission. The multicenter study included sites in New York, Boston, Worcester, Chicago, and San Juan. This was a cohort with relatively intact cellular immunity, the median CD4 count being 475 cells/mm3. Most of the participants (77%) were not treated with ZDV, and those who were tended to have more advanced disease.
Infants were diagnosed as HIV-positive if they had two separate positive blood cultures; one at less than one month of age, the other at less than six months. Overall, the transmission rate was 17.5%. The authors determined that significant associations existed between transmission and the following parameters: viral culture status and both CD4 and CD8 counts of the mother.
Participating mothers were placed in subcategorizes based on viral culture status over time. The highest transmission rate, 24%, occurred among women with persistently positive cultures. Women with cultures that were not consistently positive transmitted HIV 19% of the time. This transmission rate dropped to 7% among women who never had positive cultures. The numbers of women in each category were, respectively, 271, 109, and 86. The remaining women had indeterminate viral culture status. Quantitative measurements of viral load also pointed to increased risk in women with higher levels.
Immunologic analyses favored women with a combination of the highest CD4 and lowest CD8 cell percentages. The transmission rate in this quartile was 0% to 4%. Other variables -- including duration of ruptured membranes, maternal drug use, treatment with ZDV, gestational age, and birthweight -- did not alter these findings.
The strong association between viral load, persistent positivity, and HIV transmission argues in favor of treatment strategies that decrease indices of viral reproduction. Although the authors found no benefit to treatment with oral ZDV, they acknowledge that the number of women who were so treated was too small for an assessment of the value of therapy. Moreover, these women tended to have advanced disease, which probably exerted and independent influence on their transmission rate. These findings should encourage further studies of antiretroviral treatment in pregnant HIV-infected women.
Pitt J, Brambilla D, Reichelderfer P, Landay A, McIntosh K, Burns D, et al. Maternal immunologic and virologic risk factors for infant human immunodeficiency virus type 1 infection: findings from the women and infants transmission study. J Infect Dis 1997; 175: 567-75.
Both achieve dramatic reductions in perinatal transmission rates
Further evidence of the role ZDV can play in diminishing perinatal transmission has emerged from a retrospective study done at Yale-New Haven Hospital. However, a major distinction can be drawn between this study and ACTG 076, the landmark study that demonstrated reduced transmission with ZDV use: the women in the Yale study received only oral AZT. By contrast, the ACTG 076 protocol combined antepartum oral AZT with intravenous AZT intrapartum to achieve its favorable results -- a reduction in transmission rates from 25.5% in untreated mothers to 8.3% in ZDV recipients. In addition, most of the infants in that earlier study received ZDV postpartum.
The retrospective period covered 1985 to 1993. The authors divided these years into two major segments. From December 1985 to April 1990, the HIV-infected women who gave birth did not receive ZDV; in the second period, from May 1990 to December 1993, ZDV treatment was offered to all pregnant mothers (but not everyone took it). A total of 259 children were included in the analysis. The transmission rate during the first period was 20.6% (28/136 births); during the second, it declined to 9.8% (12/123 births). An overall comparison of AZT use vs. non-use showed dramatic differences in transmission rates. Among untreated women, the transmission rate was 18.6% (36/194). Among women who took oral ZDV, on the other hand, transmission occurred only 5.5% of the time (3/55).
Interestingly, the protective effects of ZDV were preserved across a broad range of CD4 levels. Mothers who received AZT were divided into three strata for the purposes of comparison. (The authors point out that study participants had their CD4 cells measured once, which they acknowledge is a weakness of their study design.) In the group with CD4 counts above 500 cells/mm3, no transmissions occurred. There was a 6.7% transmission rate among those with CD4 counts between 200 and 499 cells/mm3, and the comparable rate was 4.2% in women with counts below 200 cells/mm3.
Simpson BJ, Shapiro, ED, Andiman WA, et al. Reduction in the risk of vertical transmission of HIV-1 associated with treatment of pregnant women with orally administered zidovudine alone. JAIDS 1997; 14: 145-52.
Dr. Catherine M. Wilfert, guest editor of this issue and author of its editorial, comments:
Despite the fact that this study did not employ a prospective design, the data are compelling in view of the degree of correlation with ACTG 076. There was a clear advantage to antepartum treatment with ZDV, even among women with advanced immunodeficiency. Simpson et al. hold out hope that the protective effects of ZDV on the fetus need not require costly intravenous intrapartum treatment. It is further evidence that ZDV decreases transmission in the real world, at rates equivalent to those seen in ACTG 076. The authors observe that their study underscores the importance of offering HIV education, counseling, and testing to all women of child-bearing age.
Back to the August 1997 HIV Newsline contents page.
This article was provided by San Francisco General Hospital. It is a part of the publication HIV Newsline.