Early Tx For Infants With HIV Beats Waiting

Posted on: Thu 22-08-2013

For neonates with HIV, early treatment followed by a drug holiday yielded better results than deferring treatment until it was medically necessary, researchers reported.

In a randomized, open-label study, children in the programmed therapy interruption arms were significantly less likely to die or to have treatment failure than those on deferred therapy, according to Mark Cotton, MD, PhD, of Stellenbosch University in Tygerberg, South Africa.

They were also significantly less likely to have HIV disease progression, Cotton and colleagues reported online in The Lancet.

The so-called CHER (children with HIV early antiretroviral) trial enrolled infants with HIV but without symptoms and randomly assigned them to deferred treatment or to therapy for either 40 or 96 weeks, after which it would be stopped until starting again became medically necessary.

Interim results showed that early therapy was life-saving and the final results indicate "we may be able to temporarily stop treatment and spare infants from some of the toxic effects of continuous (antiretroviral therapy) for a while, if we can monitor them carefully," Cotton said in a statement.

Some details of the study were reported in 2012 at the annual Conference on Retroviruses and Opportunistic Infections. The earlier interim results had led the World Health Organization to recommend antiretroviral treatment for all infants.

. Study Adds to Growing Evidence

The study "adds to a growing body of scientific evidence suggesting that most, if not all, young HIV-infected infants will benefit from early initiation of antiretroviral therapy," commented Mark Kline, MD, of Baylor College of Medicine in Houston.

Previously, he told MedPage Today in an email, physicians were inclined to treat only infants at high risk of HIV progression. "Thanks to evidence from CHER and a handful of other studies, that approach now is being abandoned," Kline said.

Treating young infants is "inherently challenging," he added, "but the benefits in most cases outweigh the risks."

The challenges are especially great in resource-poor settings, such as sub-Saharan Africa, where the largest numbers of HIV-infected women and children live, Kline said.

Among other issues, he noted, treating children requires liquid forms of HIV medications, some of which need refrigeration, which may not be readily available.

. Implementation Challenges Remain

But other challenges arise in implementing the CHER results, argued Robert Colebunders, MD, PhD, of the Institute of Tropical Medicine in Antwerp and Victor Musiime, MD, of the Joint Clinical Research Centre in Kampala.

Treatment interruptions, they argued in an accompanying comment article, require closely clinical and immunological monitoring -- an approach that "might not be feasible in most resource-poor settings in sub-Saharan Africa, which is where more than 90% of all children with HIV live."

There are also issues with the availability of drugs, they added.

Nonetheless, Colebunders and Musiime argued that the CHER results, combined with other recent findings, open up "new therapeutic perspectives."

In particular, they noted, children in the trial began treatment at a median age of about 7 weeks after birth. But the now-famous "Mississippi baby" was treated at 31 hours after birth; when her caregivers stopped treatment 18 months later, the virus did not rebound and she currently has no indication of active HIV infection.

"Even better results (than in the CHER trial) could be achieved if we could treat HIV-infected neonates earlier," they argued.

On the other hand, they cautioned, the full effects of treatment interruptions remain unclear -- sparing children the toxicity of antiretroviral therapy is a good thing "but we will need to be sure that this approach will not cause them any harm."

Cotton noted that currently only 28% of children with HIV are on therapy and added: "Our findings highlight the urgency of increasing early (within the first 3 months of life) testing and treatment of HIV-infected infants."

. Nearly 400 Infants Studied

He and colleagues enrolled 377 infants at a median age of 7.4 weeks. All still had a relatively robust immune system with a CD4 T-cell percentage of at least 25% (the median was 35%) and a plasma HIV RNA count of 5.7 log10 copies per mL.

The primary endpoint of the study was the time to failure of the initial treatment regimen or death.

After a median follow-up of 4.8 years, the investigators reported, infants in the deferred therapy arm needed to begin taking lifelong treatment on average 20 weeks after randomization.

On the other hand, those given 40 weeks of therapy were then able to remain off treatment, on average, for 33 weeks, while those who received the initial 96 weeks of treatment delayed long-term treatment by 70 weeks.

By the end of the trial, 24 infants (19%) in the 40-week arm and 40 (32%) in the 96-week arm were still well enough to remain off treatment, the researchers reported.

In the deferred therapy group, they reported, 48 of the 125 children (or 38%) reached the primary endpoint, including 23 (or 18%) who died.

In contrast, 32 of 126 infants in the 40-week group and 26 of 126 in the 96-week group (25% and 21%, respectively), reached the primary endpoint, including 11 deaths (or 9%) in each arm.

In the 40-week group, the hazard ratio for the primary endpoint, compared with deferred therapy, was 0.59 (95% CI 0.38-0.93, P=0.02). The hazard ratio in the 96-week arm was 0.47 (95% CI 0.27-0.76, P=0.002).

The cumulative probability of clinical disease progression or death by 3.5 years of follow-up was 41% in the deferred treatment group, 28% in the 40-week group, and 21% in the 96-week group, Cotton and colleagues reported.

Compared with deferred therapy, the hazard ratio for clinical progression over the entire period of follow-up was 0.53 (95% CI 0.34-0.82, P=0.005) for 40 weeks and 0.42 (95% CI 0.26-0.67, P=0.0003) for 96 weeks of initial therapy.

Cotton and colleagues cautioned that the study did not have an arm with early and continuous antiretroviral therapy. Differences between the two interruption arms, while numerically favoring the 96-week group, did not generally differ significantly because of small numbers, they added.

. The study had support from the National Institute of Allergy and Infectious Diseases, the Departments of Health of the Western Cape and Gauteng, South Africa, and GlaxoSmithKline. The researchers did not report any potential conflicts. The comment authors also said they had no conflicts.

By Michael Smith, North American Correspondent,

MedPage Today

The Lancet

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