CROI: Simplified treatment regimens show promise in HIV-infected children

Two studies presented this morning at the Thirteenth Conference on Retroviruses and Opportunistic Infections in Denver have shown that simplified HIV drug regimens are safe and effective in HIV-infected children and adolescents.

Strategies to simplify HIV treatment, both for patients starting HIV therapy for the first time and for treatment-experienced patients, have been the subject of intense research activity over the past few years. Treatments with fewer pills every day and with once-daily dosing are often preferred by patients as they are easier to take and they may help increase adherence and reduce side-effects.

While the benefits of simpler HIV treatments have been demonstrated in numerous trials of adult patients, there have been fewer studies in HIV-positive children and adolescents. The two studies presented at the Denver conference show that simpler regimens may also be useful in younger patients.

Treatment simplification in experienced patients

The second study presented in Denver analysed the effects of switching children from a protease inhibitor-based anti-HIV regimen to one that only contained nucleoside reverse transcriptase inhibitors (NRTIs). Although small, the study showed that simplifying to a single-class drug combination can maintain CD4 cell counts in children, while reversing some of the blood fat changes that can occur with protease inhibitor treatment.

The investigators, from Bambino Gesù Children’s Hospital in Rome, recruited 20 children for their study. All of the children had had viral loads below 50 copies/ml for at least two years while taking an HIV regimen consisting of a protease inhibitor and two NRTIs. They had been treated for a median of four years and four months, with seven of the patients treated since birth.

The investigators replaced each child’s protease inhibitor with an NRTI, so that all of the children were now taking three drugs from the NRTI class. After switching, all of the children were taking 3TC (lamivudine, Epivir) and abacavir (Ziagen), along with either AZT (zidovudine, Retrovir) or d4T (stavudine, Zerit).

After a median of 108 weeks’ follow-up, the investigators did not detect any disease progression in the children, whose median age was 8.1 years. However, one of the patients experienced virological failure, after developing the M184V mutation. This was later found to be caused by the patient stopping therapy for personal reasons.

At the start of the study, the children had a mean CD4 percentage of 35%. This CD4 level was maintained throughout the study.

The investigators also found that replacement of the protease inhibitor was associated with improved blood fat levels. Total cholesterol levels decreased from a mean of 187 to 147mg/dl, while low-density lipoprotein (LDL or ‘bad’) cholesterol dropped from 113 to 81mg/dl. Triglycerides also fell from 92 to 74mg/dl.

Interestingly, the investigators found that the anti-HIV activity of the children’s immune systems became stronger after the treatment switch. Guido Castelli-Gattinara, presenting, suggested that this may indicate an inhibitory effect of protease inhibitors on the anti-HIV activity of the young immune system. However, more research is needed to investigate this hypothesis.

Once-a-day first-line treatment

The first study, presented by Ross McKinney of Duke University, examined the efficacy of a once-daily treatment regime, finding that a once-a-day treatment regimen was safe, effective and well tolerated by children and adolescents.

The investigators enrolled 37 HIV-positive children and adolescents from sixteen sites throughout the United States, aged between three and 21 years of age.

They treated the patients with a once-daily regimen of three anti-HIV drugs comprising ddI (didanosine, Videx / Videx EC), FTC (emtricitabine, Emtriva) and efavirenz (Sustiva) for at least 96 weeks. None of the children had received antiretroviral therapy previously, although some received short courses of anti-HIV drugs shortly after birth.

Using intent-to-treat analysis, 26 (72%) of the participants reached a viral load below 50 copies/ml by week 96.

Of the eleven patients who failed to achieve undetectable viral loads, five left the study due to factors unrelated to HIV, including being jailed, moving out of the United States and refusing to continue in the trial. However, two patients left the study early after developing a rash during the first two weeks of therapy, while three participants left due to viral failure on treatment. These may have been due to poor adherence.

The median CD4 cell count rose across the study, from 310 cells/mm³ at baseline to 673 cells/mm³ after 96 weeks. The median CD4 percentage also increased from 17 to 32%.

With the exception of the rash, the study drugs were generally well tolerated. Side-effects that were considered to be ‘possibly’ related to the drugs included one serious (grade 4) case of low blood glucose and three grade 3 events. There were no deaths.

Although blood levels of ddI and FTC were within the expected ranges, the investigators found that efavirenz levels in children receiving the oral solution were lower than anticipated. This required a dose escalation after the initial planned assessment point after two weeks of treatment.

In response to questions from the audience, Dr McKinney said that there did not seem to be any differences in response between the children and the adolescents in the study. Unfortunately, however, the investigators have not measured the effects of the treatment regimen on blood fats or body fat changes in the children.