The new antiretroviral raltegravir (Isentress) is an effective first treatment for HIV and suppresses HIV replication far more rapidly than efavirenz, with fewer adverse events according to a study funded by the manufacturer

• Explain to interested patients that in this study, that raltegravir acted more quickly on HIV than efavirenz and with fewer adverse events.
• Note that the study was funded by Merck, the manufacturer of raltegravir.

Of patients given raltegravir as their first treatment for HIV, 86.1% saw their virus load (vRNA concentration) drop below 50 copies per milliliter of blood after 48 weeks, compared to 81.9% of patients given efavirenz, an older but commonly used drug (difference 4.2%, 95% CI -1.9 to 10.3)), according to results published online August 3 in The Lancet.

The viral suppression occurred more quickly for patients on raltegravir than on efavirenz (log-rank test P<0·0001), with 50% of the raltegravir group achieving virologic suppression by week four of treatment, compared with less than 20% of the efavirenz group.

Of the patients on raltegravir, 44% experienced adverse drug-related clinical adverse events, compared to 77% of those on efavirenz (95% CI -40.2 to -25, P<0·0001). For both drugs, less than 2% of patients experienced serious adverse events.

“Raltegravir-based combination treatment had rapid and potent antiretroviral activity, which was non-inferior to that of efavirenz at week 48,” Jeffrey L. Lennox, MD, of Emory University School of Medicine, and colleagues wrote. “Raltegravir is a well tolerated alternative to efavirenz as part of a combination regimen against HIV-1 in treatment-naive patients.”

Produced by Merck, raltegravir was approved by the U.S. Food and Drug Administration in October 2007, making it the first of a new class of drugs on the market known as “integrase inhibitors.” The drug works by disrupting the action of integrase, the enzyme that inserts HIV genetic material into human chromosomes.

Efavirenz, which was first approved in 1998, is a non-nucleoside reverse transcriptase inhibitor and works by inhibiting an enzyme vital for producing HIV viral DNA in host cells.

Previous studies have shown that use of raltegravir with optimum background therapy is effective and well tolerated in patients who have already undergone treatment for multidrug-resistant HIV-1 infection.

But the safety and efficacy of raltegravir in patients who have not yet begun treatment had only been explored in a much smaller study.

To study the use of raltegravir as a first medication for HIV patients, Lennox and colleagues enrolled 566 HIV patients from 67 study centers on five continents between Sept 14, 2006, and June 5, 2008.

The patients were at least 18 years old and had vRNA counts of at least 5,000 copies per milliliter blood.

At the beginning of the phase II trial, 297 patients had a vRNA concentration of more than 100,000 per milliliter and 47% had counts of 200 or fewer CD4 cells per milliliter.

Participants were randomly assigned to receive either 400 milligrams of oral raltegravir twice daily or 600 milligrams of oral efavirenz once daily. Both were taken in combination with tenofovir and emtricitabine, two other HIV drugs that are often administered along with efavirenz as part of a combination treatment approved by the FDA in 2006.

Of the participants, 281 received raltegravir, 282 received efavirenz and three were never treated.

Successful treatment with raltegravir was defined as the reduction of vRNA concentration to less than 50 copies per milliliter of blood at week 48 of the study.

The proportion of the patients reaching this endpoint in the raltegravir group had to be within 12% of that of the efavirenz group for raltegravir to be considered equivalent to efavirenz.

The authors noted efavirenz-based combination treatment can be given once daily as one pill, but that raltegravir must be taken twice daily, which might have effect on treatment adherence in clinical practice.

Given raltegravir’s fast-action and lower-risk of adverse events, however, the authors were bullish about the new drug.

In particular, they wrote, raltegravir may be warranted in cases of efavirenz-resistant HIV, or where efavirenz raises concerns of drug interactions, side effects or teratogenicity, its potential to cause physical abnormalities in an unborn fetus.

“Our findings that raltegravir-based combination treatment is effective and generally well tolerated in treatment-naive patients, compared with efavirenz, are supported by follow-up data to week 96 in a phase II study of treatment-naive patients,” Lennox and colleagues wrote.

“Raltegravir is an important additional drug for initial treatment of HIV-1 infection, and should be regarded as an alternative to efavirenz as part of a first-line combination regimen with tenofovir and emtricitabine in treatment-naive patients.”

In an accompanying editorial, Sean Emery, MD, of the National Centre in HIV Epidemiology 1and Clinical Research in Sydney, and Alan Winston, MD, of Imperial College London in London, wrote that raltegravir seems to have an edge over efavirenz in terms of safety and tolerability.

Moreover, Raltegravir seems to be free of clinical drug-drug interactions, is not likely to be vulnerable to transmitted HIV drug resistance and can increase the number of plausible drug regimens that could be used during an individual’s lifetime, they wrote.

“Unfortunately up to now, adverse side-effects and unfavourable drug-drug interactions have unerringly constrained progress with every antiretroviral drug class,” they wrote.

“However, today’s data are very encouraging for treatment and research. Raltegravir is an impressive drug and we hope other integrase inhibitors in development offer similar benefits.”

Primary source: The Lancet

Source reference:
Lennox J, et al. “Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial” The Lancet 2009; DOI:10.1016/S0140-6736(09)60918-1

CAPE TOWN, South Africa, July 20 — Patients in an experimental program suppressed human immunodeficiency virus (HIV) to undetectable levels over a full year of taking potent antiretroviral medications on a five-day on, two-day off (FOTO) schedule.

• The research was an experimental study that has not been replicated and all the patients in the study had suppressed viremia to be eligible for the study.
• Note 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.

Lead researcher Cal Cohen, MD, medical director of the Community Research Initiative of Boston, suggested that the long half-life of the drugs — efavirenz (Sustiva), tenofovir (Viread), and emtricitabine (Emtriva) — give patients the opportunity to take brief drug holidays without creating virologic rebound.

“I don’t consider this a structured treatment interruption study,” Dr. Cohen said in a poster presentation at the International AIDS Society conference here. “I prefer to look at this as another way of taking medication, in this case using the pharmacokinetic properties to structure treatment.”

Of the 60 patients in the study, he said, all have maintained HIV suppression for a year, some of them for as long as 18 months.

Half the patients are on the five-days-on, two-days-off (FOTO) regimen while the other 30 are taking their regimen daily.

All the patients had suppressed HIV, with viral loads undetectable using the 50 copies/mL assay at the time they began the study.

He said the number of patients in the study was sufficient to show that FOTO was not inferior to daily treatment.

Because the treatment uses fewer drugs, he said the participants who are on the FOTO regimen use 28% less medication than the patients taking the drugs on a daily basis.

“That represents a savings of about $5,000 a year,” Dr. Cohen said. “If you think about 100,000 people on this regimen, the costs savings would be phenomenal.”

However, he said he would not recommend the treatment for initial therapy.

“You have to get the virus suppressed first, and then make sure your patients are compliant in staying on the drugs and maintaining that suppression. Then you can consider the FOTO regimen,” he said.

Others were even more cautious.

“This study only has 60 patients,” noted Pedro Cahn, MD, chief of infectious diseases and director of Fundacion Huesped in Buenos Aires, Argentina. “We really cannot recommend this type of trial unless we can be certain that it would apply to a larger group of patients.”

Dr. Cahn suggested that the FOTO study benefits from use of the “right drugs among the right patients” and that replication of the trial might be difficult.

Dr. Cohen said that he is actively seeking to collaborate with other institutions in a major clinical trial to test his hypothesis.

Primary source: Conference Progamme 5^th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19-22 July 2009

Source reference:
Cohen C, et al “The FOTO study: The 48 week extension to assess durability of the strategy of taking efavirenz, tenofovir and emtricitabine Five days On, Two days Off (FOTO) each week in virologically suppressed patients,” Conference Progamme 5^th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19-22 July 2009. P. 49.