AZT regimens less toxic than d4T regimens in HIV-positive children

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A study directly comparing the toxicity of different NRTI backbones in HIV-positive children has provided reassurance to paediatric clinicians. Results from the PACTG 219C cohort, published in the December 1st issue of the Journal of Infectious Diseases, validate the safety of combinations with AZT (zidovudine, Retrovir) confirming it as a preferred drug in treatment guidelines, but also indicate that regimens with d4T (stavudine, Zerit) have a toxicity that is only modestly higher.

The US Public Health Service publishes guidelines for the treatment of paediatric HIV infection. The guidelines, last updated in mid-2008, indicate AZT or abacavir (Ziagen) plus 3TC (lamivudine, Epivir ) or FTC (emtracitabine, Emtriva), or FTC/ddI (didanosine, Videx / Videx EC), as preferred nucleoside reverse transcriptase inhibitor (NRTI) backbones for initial antiretroviral therapy regimens in children. Other combinations are given as alternative pairs. The WHO also publishes paediatric treatment guidelines for resource-limited settings. These guidelines recommend AZT/3TC, d4T/3TC or abacavir/3TC as preferred first regimens.

In addition to recommending certain treatments, guidelines also highlight therapies to be avoided. In the US guidelines, the combination of d4T/ddI is listed as “not recommended” due to evidence that it has been linked to increased serious side-effects.





Of or relating to children.


Inflammation of the pancreas.


A disruption to the way the body produces, uses and distributes fat. Different forms of lipodystrophy include lipoatrophy (loss of subcutaneous fat from an area) and lipohypertrophy (accumulation of fat in an area), which may occur in the same person.

clinical event

The occurrence of a physical sign or symptom, rather than an abnormality that can only be detected by laboratory tests.

Paediatric treatment guidelines often lag behind their adult counterparts due to a lack of clinical trials specifically targeting children. Toxicity profiles for each NRTI drug or drug combination in children are constantly evolving, but few clinical trials have compared the toxicity of different combinations. This information would help to differentiate regimens and guide recommendations.

To study the relative toxicity of common NRTI backbones, investigators with the Pediatric AIDS Clinical Trials Group 219C cohort turned to their extensive database. The PACTG 219C study is the largest database of information about HIV-infected children in the United States and includes prospective data from over 2500 HIV-positive children and adolescents. Investigators culled the data for HIV-positive children who started, before the age of 13 years, an antiretroviral regimen containing at least two NRTIs. The 2233 eligible records were then analysed for indications of toxicity, including both clinical diagnoses and abnormalities in laboratory test results.

The most popular NRTI backbone combinations in the database were: AZT/3TC, which is recommended in the both paediatric guidelines, d4T/3TC, ddI/d4T and ddI/3TC. There was insufficient data on abacavir and FTC within the database to include in the analysis, and the investigators acknowledge that these drugs need further study.

Looking at clinical diagnoses, investigators noted that hepatitis was the most common condition associated with AZT/3TC, AZT/ddI and d4T/3TC, affecting 1.6% of children with each combination. The most common condition associated with d4T/ddI was pancreatitis (1.7%) and, with ddI/3TC, lipodystrophy (1.6%).

Looking at laboratory abnormalities, elevated anion gap was the most frequently cited condition for all combinations, affecting from 8% to 21% of children. Anion gap is a measure of metabolic acidosis, which is linked with lactic acidosis and mitochondrial toxicity. Other abnormalities included increased levels of amylase and lipase (signs of pancreatitis) and changes in blood counts.

Combining clinical and laboratory results, d4T/3TC was associated with the highest incidence of any toxicity (4.1%). The investigators note that this combination was also associated with the longest median exposure time and the largest total time of exposure. AZT/ddI was associated with the lowest incidence, 1.9%. The investigators remark that this combination was used more often earlier in the study, and thus would less often be part of antiretroviral combinations with other drugs, perhaps explaining the lower rate of events.

Investigators then completed several pair-wise comparisons of the drugs, to better evaluate their relative toxicity. AZT/3TC, the most commonly prescribed combination, had a 66% lower risk of a clinical toxicity than ddI/3TC (hazard ratio [HR] 0.34, p = 0.05), but a 44% higher risk of laboratory toxicity compared with AZT/ddI (HR 1.44, p = 0.05).

No significant differences were seen between d4T/ddI, the combination not recommended, and d4T/3TC, ddI/3TC and AZT/ddI. However, d4T/ddI did have a higher rate of clinical events compared with AZT/3TC (HR 2.56, p = 0.01), including pancreatitis and lipodystrophy.

The emerging picture that AZT regimens generally had a lower rate of toxic events than d4T regimens was tested when investigators compared the time to first clinical event, or laboratory abnormality, between the two regimen types. For both types of events, AZT regimens had a significantly lower risk than d4T regimens. When investigators adjusted for all potential confounding factors, the risk of a clinical event with an AZT regimen was half that with a d4T regimen (HR 0.49, p = 0.02). In comparing 3TC regimens and ddI regimens, there was no difference in the risk of clinical events, but ddI regimens were less likely to produce laboratory abnormalities (HR 0.78, p = 0.4).

Overall, the investigators state that the study supports the preference for AZT and suggests that combinations with d4T still have an important role to paediatric HIV treatment. “In summary,” the investigators write, “regimens containing [AZT] 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 [AZT], and are appropriate for second-line therapy.”


Van Dyke RB et al. Toxicities associated with dual-nucleoside reverse-transcriptase inhibitor regimens in HIV-infected children. J Infect Dis 198: 1599 – 1608, 2008.