Of the 2233 children who were perinatally infected with HIV and were ≤13 years of age when they started receiving ART, those who received regimens containing ZDV had lower rates of both clinical and laboratory toxicities than did those receiving regimens containing d4T, thereby supporting the inclusion of ZDV in recommended first-line regimens. Regimens containing d4T/3TC, d4T/ddI, and ddI/3TC had similar rates of toxicities and are appropriate for second-line therapy in children.
ZDV/ddI, when compared with ZDV/3TC, was associated with a similar risk of clinical diagnoses but a significantly lower risk of laboratory test abnormalities. Overall, of the 5 NRTI pairs, ZDV/ddI was associated with the lowest rate of toxicities. However, it should be noted that its use was more common in earlier calendar years, and, thus, it was less often used as a part of HAART than were other combinations. In addition, it was used in younger children. However, even after adjustment for calendar year and subject age at initiation of therapy, pairwise comparisons still generally favored the use of ZDV/ddI. Thus, either ZDV/ddI or ZDV/3TC is appropriate for inclusion in first-line therapy, with the choice being informed by their differing toxicity profiles and formulations and the need to administer ddI without food. These pairs had similar toxicity profiles, except that neutropenia was more commonly associated with the use of ZDV/3TC, whereas pancreatitis and acidosis were slightly more commonly associated with the use of ZDV/ddI. Previous pediatric trials comparing ddI and ZDV demonstrated a significantly higher rate of anemia or neutropenia in association with ZDV and a higher rate of elevated liver enzyme levels in association with ddI [22
D4T/ddI, compared with the first-line backbone regimen ZDV/3TC, was associated with a significantly higher rate of clinical diagnoses but not of laboratory test abnormalities. The clinical diagnoses that were more commonly associated with d4T/ddI included pancreatitis and lipoatrophy/lipodystrophy, whereas hepatitis was more commonly associated with ZDV/3TC. No significant differences in clinical or laboratory toxicity rates were observed when d4T/ddI was compared with d4T/3TC, ZDV/ddI, or ddI/3TC.
D4T/3TC, compared with ZDV/ddI, was associated with a significantly higher rate of clinical diagnoses, as well as a higher rate of laboratory test abnormalities, which approached significance. As noted above, d4T/ddI was associated with a significantly higher rate of clinical diagnoses than was ZDV/3TC. Both of these pairwise comparisons involve a comparison between d4T and ZDV, with the addition of a second NRTI (either 3TC or ddI). These results, together with the supporting analysis comparing all NRTI pairs containing ZDV with those containing d4T, illustrate a significantly lower toxicity rate associated with regimens containing ZDV than with those containing d4T. Of pairs containing d4T, d4T/ddI and d4T/3TC had similar rates of toxicities, suggesting that each is appropriate for second-line therapy.
The combination of ddI/3TC was associated with a significantly higher risk of clinical diagnoses than was that of ZDV/3TC, with a higher risk of lipodystrophy/lipoatrophy but a lower risk of hepatitis; the rate of laboratory test abnormalities was similar. DDI/3TC was associated with rates of clinical abnormalities and laboratory test abnormalities similar to those associated with the remaining NRTI pairs. This finding suggests that ddI/3TC should be reserved for second-line therapy, although it might be considered as initial therapy for a child with preexisting liver disease.
Many of the adverse events associated with NRTI therapy are believed to result from mitochondrial toxicity, because these agents inhibit mitochondrial DNA (mtDNA) polymerase γ, resulting in inhibition of mtDNA synthesis [24
]. Toxicities related to mitochondrial toxicity include peripheral neuropathy, lactic acidosis, hepatitis, hepatic steatosis, myopathy, cardiomyopathy, and, possibly, lipoatrophy/lipodystrophy. The NRTIs most active in inhibiting DNA polymerase γ are zalcitabine, d4T, and ddI [26
]. Studies in adults have demonstrated lower concentrations of PBMC mtDNA in subjects receiving d4T/ddI than in those receiving other NRTI combinations [28
]. Mitochondrial haplogroup T has been associated with a significantly increased risk of developing peripheral neuropathy among white adult subjects, particularly among those who receive d4T/ddI [30
]. Because most HIV-infected children in the United States are African American or Hispanic, it is possible that mtDNA polymorphisms that predispose to d4T/ddI-induced mitochondrial toxicity are uncommon in these populations. Thus, both younger age and race may account for the modest rates of toxicity that we observed among children receiving d4T/ddI.
Because this was a retrospective study, we were able to examine only those laboratory evaluations dictated by the protocol. For instance, although pancreatic serum amylase is a much more specific marker of pancreatitis than is total amylase, its collection was not specified in the protocol, so results were available for very few subjects. The most common abnormality detected in the laboratory was an elevated anion gap, which occurred in 8%–13% of subjects. This abnormality was included as a marker for metabolic acidosis, which might suggest lactic acidosis. We recognize that the anion gap is neither a specific nor a sensitive indicator of metabolic acidosis. It would have been preferable to measure lactic acid directly, and future prospective studies may benefit from the availability of rapid point-of-care devices to measure blood concentrations of lactic acid.
A limitation of the present analysis is the use of observational data rather than a randomized design, raising the possibility of selection bias. Subjects who experience failure of a particular regimen are likely to be at an increased risk for treatment-related toxicities with subsequent regimens. We attempted to control for such potential confounding by adjusting for the number of previous ART regimens that each subject received and for whether subjects were concurrently receiving a PI, an NNRTI, or an additional NRTI, in which case the toxicities are unlikely to be solely attributed to the NRTIs. Although our ability to control for HIV disease status was limited by the lack of viral load information (a large proportion of regimens were initiated before the availability of viral load quantification), we conducted a sensitivity analysis controlling for the CD4+ percentage at the time of initiation, which generally gave similar if not stronger results.
The conclusions of our analysis must be viewed as somewhat exploratory in nature, given the fact that 10 comparisons were conducted for each of the 2 endpoints, and no adjustment was made for multiple comparisons. However, before conducting our analysis, we developed a detailed analysis plan for the stated protocol objectives, which clearly specified the comparisons of interest. In addition, all comparisons are presented rather than selecting post hoc comparisons on the basis of the observed results. Given the multiple comparisons conducted, we emphasize consistency across analyses and endpoints in drawing conclusions.
Finally, the small number of children in the PACTG 219C study who were receiving FTC, ABC, and tenofovir prevented their inclusion in the analysis. Currently, FTC and ABC are among the preferred first-line agent for children, and all 3 agents are preferred for adults. There is no pediatric formulation of tenofovir, and it is not approved for use in children <18 years of age. [5
] Additional studies are needed to fully define the safety profile of these agents in children.
In summary, regimens containing ZDV are preferred for initial therapy in children, because of their low rates of toxicity. However, regimens containing d4T and ddI/3TC have similar rates of toxicity, which are only modestly higher than those of regimens containing ZDV, and are appropriate for second-line therapy.