Early Initiation of Combo Antiretrovirals Gaining Support

Pam Harrison

November 04, 2014

Evidence continues to support the initiation of combined antiretroviral therapy soon after HIV infection, researchers report.

In fact, the likelihood of the CD4/CD8 ratio normalizing was almost three times greater if antiretroviral therapy was initiated within 6 months of HIV infection than if it was delayed for more than 6 months, according to John Thornhill, MD, from Imperial College London in the United Kingdom, and his team.

They also report that for each month treatment was delayed after seroconversion, the likelihood of normalizing the ratio decreased by 2%.

"The CD4 cell count is a well-validated marker of disease progression, but the CD4/CD8 ratio may give you broader insight into immune dysfunction, particularly in patients with normal CD4 cell counts, where a low CD4/CD8 ratio is associated with immune dysfunction, such as T-cell activation, exhaustion, and immune senescence," Dr Thornhill told Medscape Medical News.

"This study definitely provides more evidence in favor of starting treatment as early as possible," he added.

The results were presented during the HIV Drug Therapy Congress in Glasgow, United Kingdom.

SPARTAC Trial

Dr Thornhill and colleagues used data from the SPARTAC trial and the UK Register of HIV Seroconverters to examine the effect of time from seroconversion to initiation of combination antiretrovirals on the CD4-CD8 ratio, after adjustment for sex, risk group, ethnicity, enrolment from an African site, and CD4 cell count and age at initiation of therapy.

Combination therapy was initiated in 468 patients a median of 3.37 months after the estimated seroconversion date. In the 309 patients in the early group, therapy was started within 6 months of seroconversion; in the 159 patients in the deferred group, treatment was initiated more than 6 months after seroconversion.

One year after the initiation of antiretrovirals, the CD4/CD8 ratio had normalized in more patients in the early group than in the deferred group (46.9% vs 12.6%).

The longer the period between seroconversion and the initiation of treatment, the less likely a normalized CD4/CD8 ratio would be achieved.

As expected, there was an association between CD4 cell count at the initiation of therapy and the normalization of CD4/CD8 ratio. There was also an association between normalization and the suppression of HIV RNA to below 400 copies/mL.

"It is very important to note that we are talking about primary HIV infection; we're not talking about chronic infection. What you are doing in this setting is controlling viremia quite quickly," Dr Thornhill explained.

By doing that, "you can prevent immune activation and the immune cascade that can lead to immune dysfunction," he added. "So it's really just stopping that process earlier."

Early treatment does appear to benefit individual patients, as data from this study support, said study researcher Sarah Fidler, MBBS, PhD, also from Imperial College London.

The other reason to start treatment early is to prevent the transmission of HIV to other partners, she added.

"Most clinicians and scientists would agree that from a purely immunologic point of view, it doesn't seem to be a good idea to have untreated viral replication in patients with HIV," Dr Fidler told Medscape Medical News.

"Although all information has to be correctly presented to patients to allow them to make an individual choice, it's the clinician's responsibility to let patients know that we have increasing levels of evidence that the sooner the treatment is started, the better the immunologic benefit, not only in terms of preventing an AIDs-defining illness, but for other non-AIDS-related morbidity and mortality events as well," she explained.

Normal CD4 Cell Counts

Most patients achieve normal CD4 counts (>500 cells/mm³) on modern combination therapy, but it is "widely accepted" that health is not fully restored despite normalization of CD4 cell counts, said Sergio Serrano-Villar, MD, from Hospital Universitario Ramon y Cajal in Madrid.

"When one looks at the CD4/CD8 ratio, it becomes apparent that many subjects on antiretroviral therapy who achieve normal CD4 counts show very heightened CD8 counts, resulting in a low CD4/CD8 ratio, whereas others normalize CD8 counts and achieve a normal CD4/CD8 ratio," Dr Serrano-Villar told Medscape Medical News.

"What we have seen is that during treated infection, the ratio correlates with ongoing T-cell activation, as well as surrogate markers of age-associated disease, and that it predicts non-AIDS events and associated mortality."

For example, in a recent study, Dr Serrano-Villar and colleagues analyzed a subset of treated individuals with CD4 cell counts below 500 cells/mm³ (PLoS One. 2014;9:e85798).

"In that subset of patients, we observed that a low ratio was still reflective of increased T-cell activation and T-cell senescence, and that it correlated with markers of innate immune activation and predicted non-AIDS morbidity and mortality," Dr Serrano-Villar reported.

The SPARTAC study also seems to confirm the results of Dr Thornhill and colleagues. In the small cohort of SPARTAC patients, the early initiation of antiretroviral therapy resulted in faster recovery of the CD4/CD8 ratio and a higher rate of CD4/CD8 ratio normalization than initiation deferred for more than 2 years after seroconversion.

"Many of these markers predict mortality independent of CD4 counts, and all of them can probably be encompassed in the vague term 'immune dysfunction'," Dr Serrano-Villar concluded.

"The best thing about the CD4/CD8 ratio is that it is already available in most clinics, and many have started to believe that it can become useful for clinical practice," he added.

Dr Thornhill, Dr Fidler, and Dr Serrano-Villar have disclosed no relevant financial relationships.

HIV Drug Therapy. Abstract 0112. Presented November 3, 2014.

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