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Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse PlannerNote that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.Patients with primary HIV infection receiving early treatment with five-drug highly active antiretroviral therapy (HAART) achieved lower cell-associated HIV-DNA levels and a better immune reconstitution than chronically infected patients on intensified long-term suppressive HAART. KUALA LUMPUR -- For patients in the early stages of HIV infection, initial treatment with five antiretroviral drugs, rather than three, may be a first step toward remission, a researcher said here.
In 2-year results from a 7-year prospective trial, such intense therapy resulted in a sharp decline in HIV DNA that is integrated into cells, according to Eva Wolf, PhD, of MUC Research in Munich, Germany.
But in patients with chronic HIV infection who were also given an intensified regimen, there was no change over time in the so-called cell-associated or proviral DNA, Wolf reported at the 7th International AIDS Society Meeting on HIV Pathogenesis, Treatment, and Prevention.
The drop in proviral DNA was accompanied by a reconstitution of the immune system, Wolf told MedPage Today, and may be the first step toward remission or a "functional cure" -- the ability to control HIV replication without drug therapy.
In a French cohort of patients treated early in the course of HIV infection -- the so-called Visconti cohort -- the level of cell-associated DNA appears to be an important predictor of such a functional cure, she said.
The proviral DNA is thought to be an important part of the HIV reservoir, which forms the basis for the ability of the virus to rebound when antiretroviral therapy is stopped.
The Visconti cohort includes 14 people who were treated in the first weeks of their infection with standard antiretroviral therapy. When they later stopped therapy for various reasons, they did not have a viral rebound, although HIV was still present.
Wolf and colleagues hypothesized that intensified therapy might have a similar effect, and to test the idea, they enrolled 20 patients with primary infection as well as 20 with chronic infection, who had been on successful antiretroviral therapy for at least 3 years.
The early patients were given five drugs -- two nucleoside reverse transcriptase inhibitors, a protease inhibitor, the entry inhibitor maraviroc (Selzentry) and the integrase inhibitor raltegravir (Isentress).
The chronically infected patients remained on their stable regimen, Wolf said, with the addition of maraviroc and raltegravir.
The primary outcome measures were successful interruption of HIV replication and depletion of the proviral DNA, measured as copies per million peripheral blood mononuclear cells.
After 2 years of the study, she reported, the chronic patients had a slight but nonsignificant increase in proviral DNA. On the other hand, those with primary infection had a median decline of 1.4 log10 copies per million cells (P<0.001).
Whether that is sufficient to lead to a functional cure is an open question. Wolf said, and she and colleagues are considering "pulsed treatment" to see if there is viral rebound in the absence of antiretroviral drugs.
Outside experts, though, cautioned that intensified treatment has been tried before without a clear benefit.
First , "you can't compare the groups" because it's already known that people with chronic disease don't see a marked reduction in proviral DNA with additional therapy, commented Sharon Lewin, MD, of Monash University in Melbourne, Australia, a leader in research aimed at curing HIV.
"They've taken people with an established reservoir, added in extra drugs (and found) no change in DNA because you're already at steady state," Lewin told MedPage Today.
Meanwhile, those with primary infection already are known to have a better response even with three-drug therapy, she noted, based on a study in 2012 in Thailand.
"If you really want to say the extra drugs made a difference, you'd compare three drugs and five drugs," she said.
In fact, there is so far no evidence that so-called mega-HAART makes a difference in the size of the proviral DNA reservoir in early infection, commented John Frater, MD, PhD, of Oxford University. Frater was one of the leaders of the so-called Spartac trial that invesigated the effects of therapy in the early stages of HIV infection using three standard drugs.
That trial showed a benefit of early treatment in terms of improving immune function, and delaying the time that patients would need to go back on therapy after stopping. But it's not clear that adding drugs would have had an additional benefit, he told MedPage Today.
He and colleagues are currently planning a trial in which raltegravir will be added to standard therapy in early infection -- but not because the investigators think it will markedly affect the reservoir compared with three drugs. Instead, Frater said, they hope the rapid decline in viral replication associated with raltegravir might "tip the balance" and help limit the establishment of the reservoir.
He added it's still not known how small the reservoir of proviral DNA has to be to allow patients to go off therapy and it is still not possible to measure the size of the reservoir accurately. "The errors in our assays are enormous," he said.
The study was supported by AbbVie; Merck, Sharp & Dohme; and Pfizer/ViiV Healthcare.
Wolf made no disclosures.
Lewin has reported grant support from Gilead and Merck.
Frater has not reported recent financial links with industry.
Primary source: International AIDS Society
Source reference:
Wolf E, et al "5-drug HAART during primary HIV infection leads to a reduction of proviral DNA levels in comparison to levels achievable during chronic infection" IAS 2013; Abstract MOPE097.
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