IAS: Integrase inhibitor raltegravir (MK-0518) potent, durable and more tolerable than efavirenz in treatment-naive at 48 weeks

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The investigational integrase inhibitor raltegravir (Isentress, formerly MK-0518) achieves similar efficacy to efavirenz (Sustiva) in treatment-naive patients up to 48 weeks, and appears to have a better lipid and tolerability profile, according the final results of a phase II study presented to the 4thIAS Conference in Sydney on Tuesday.

A related presentation demonstrated raltegravir’s potent ability to beat down the virus, which has reseachers questioning whether we need to re-evaluate our ideas of how highly active antiretroviral therapy (HAART) seeks and destroys HIV throughout the body.

Study design and main endpoints

The 48-week data, presented today by Dr Marty Markowitz of the Aaron Diamond AIDS Research Center in New York, follows up on 24-week data presented in 2006 to the Sixteenth International AIDS Conference in Toronto.

The study recruited 189 treatment-naïve patients, the majority of whom were non-white males, into four arms (containing between 38 and 41 individuals) each with a mean age between 34-37 years, a mean baseline viral load of between 4.6 and 4.8 log10 copies/ml and mean CD4 counts of between 271 and 338 cells/mm3.

Glossary

relapse

The return of signs and symptoms of a disease after a patient has been free of those signs and symptoms. 

virological relapse

When viral load can be measured after previously being undetectable.

diarrhoea

Abnormal bowel movements, characterised by loose, watery or frequent stools, three or more times a day.

treatment-naïve

A person who has never taken treatment for a condition.

naïve

In HIV, an individual who is ‘treatment naïve’ has never taken anti-HIV treatment before.

Participants were randomised to receive raltegravir at a dose of 100, 200, 400 or 600 mg twice daily or the standard 600mg once-daily dose of efavirenz (Sustiva) but also given twice daily with a placebo in a double-blinded fashion. All four arms also received tenofovir (Viread) and 3TC (lamivudine, Epivir).

After 48 weeks, all four arms showed a sustained decline in viral load of at least -2.2 log10 copies. Increases in CD4 cell counts were similar among groups, ranging between 144 to 221 cells/mm3. The percentage of participants receiving raltegravir who achieved a viral load below 50 copies/ml ranged from 83% in the 200 mg group to 88% in the 400 mg and 600 mg groups, compared with 87% among those receiving efavirenz.

Potency, virological failure and resistance

Participants receiving raltegravir achieved viral suppression sooner than those receiving efavirenz, though both groups had achieved similar suppression rates by 24 weeks. (See the ‘viral decay’ section below for more detail on this).

The study definition of virological failure was either:

  • >400 copies/ml at week 24 or early discontinuation (classified as a ‘non-response’).

or

  • >400 copies/ml after initial response to 1 log10 increase above nadir level (classified as a ‘virological relapse’).

A total of five individuals (out of 160; 3%) taking raltegravir and one (out of 38; 3%) taking efavirenz experienced virological failure. Only one individual – taking the lowest dose of raltegravir – was a ‘non-responder’. Compared to baseline, genotypic resistance mutations to raltegravir (V151I, N155H, D232D/N, and G163R/G), 3TC (M184M/I/V, K65K/R) and tenofovir (K65K/R) emerged on treatment.

Another four individuals on the 200mg dose of raltegravir experienced virological relapse. One individual had no new mutations – Dr Markowitz noted that this person admitted non-adherence for two weeks after initially denying it – another two experienced genotypic resistance to 3TC, and the fourth person acquired genotypic resistance to both raltegravir (N155H) and 3TC.

The individual experiencing virological relapse on efavirenz developed signature mutations to efavirenz (G190E), as well as 3TC and tenofovir.

Tolerability and toxicity

There were few discontinuations in any of the arms, although one individual did discontinue in the 600mg raltegravir arm after experiencing an elevation in the liver enzyme aspartate aminotransferase (AST). It was reported last year that this individual was also taking the anti-tuberculosis drug isoniazid, which can cause liver toxicity.

Rates of drug-related adverse events were broadly similar among the four arms. Diarrhoea was experienced by 12.5% of participants in the 600mg raltegravir arm compared with 10.5% in the efavirenz arm. This may have been dose-dependent, since diarrhoea was reported much less frequently in the other raltegravir arms.

On the other hand, CNS-related side-effects, such as dizziness, headache, abnormal dreams, and nightmares were reported far more frquently in the efavirenz arm than in the any of the raltegravir arms. By week 48, 13% of the participants on raltegravir compared with 29% of the participants on efavirenz experienced neuropsychiatric symptoms.

There were significant differences seen between the combined raltegravir arms and the efavirenz arm on total cholesterol (mean change -2.3 mg/dL vs. +20.7 mg/dL; p

Viral decay

In a related report based on the ten day monotherapy phase of the same study (Protocol 004), Dr John Murray from the National Centre in HIV Epidemiology and Clinical Research in Sydney, reported evidence from a related study that questions some long-standing ideas about how HAART goes about eliminating virus from the different HIV-infected compartments of the body.

Pioneering work after the introduction of protease inhibitors (PIs) during the mid-1990s showed that following the initiation of PI-based HAART, viral load initially drops very quickly, about 100-fold in 2 weeks. During this first phase of viral decay, it is thought that the drop is due to the clearance of free virus particles and the loss of active infected cells.

A second, slower phase of viral load decay then begins and is thought to represent the turnover of a longer-lived viral reservoir composed of cells with integrated virus.

Recording viral decay time in the raltegravir trial resulted in two observations that led the researchers to question this model. First, participants receiving raltegravir were more likely to achieve undetectable viral load than participants receiving efavirenz at several time points in the first 60 days. Second, median second phase viral load levels for the individuals taking raltegravir were reduced by 70% over the efavirenz group.

Based on its anti-integrase activity, Dr Murray told the conference that raltegravir should be most effective against virus that has not yet integrated into the host genome. With this in mind, he and his colleagues have now developed two hypotheses that could explain these faster, more potent effects.

Either the second phase of viral decay is due to the death of cells that are newly infected by other longer-lived infected cells, or the second phase is due to the activation of latently infected cells that contain unintegrated HIV DNA, he suggested.

Clinical implications

During the question and answer session that followed, Dr Markowitz was asked to speculate on the clinical relevance of raltegravir’s ability to achieve more rapid viral load declines compared with efavirenz.

“At this point,” he said, “it is far too early to say whether or not there’s going to be a clinical benefit, per se, of having raltegravir in the regimen compared with efavirenz.”

He noted that this was a small study that “was not designed to do very intensive viral dynamics” and that further studies were necessary to understand whether or not there would be a clinical benefit.

References

Markowitz M et al. Rapid onset and durable antiretroviral effect of raltegravir, a novel HIV-1 integrase inhibitor, as part of combination ART in treatment-naive HIV-1 infected patients: 48-week results. Fourth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, abstract TUAB104, Sydney, 2007.

Murray JM et al. The integrase inhibitor raltegravir alters viral delay kinetics of HIV, significantly reducing the second phase and challenging current hypotheses of viral replication. Fourth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, abstract TUAB103, Sydney, 2007.