Protease inhibitor to raltegravir switch maintains viral suppression, but NRTI resistance lowers efficacy

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People who switched from a suppressive boosted protease inhibitor to the integrase inhibitor raltegravir (Isentress) generally maintained undetectable viral load with improvements in blood lipid levels, according to a pair of studies presented this week at the Eighteenth International AIDS Conference in Vienna.

Once-daily raltegravir, however, did not work as well as twice-daily for people with pre-existing resistance to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs).


Jose Gatell, from Hospital Clinic Barcelona, and colleagues evaluated the safety and effectiveness of raltegravir amongst 282 study participants on a stable antiretroviral regimen containing a protease inhibitor boosted with ritonavir (Norvir), who had HIV RNA suppressed to less than 50 copies/ml. Patients had to have had an undetectable viral load for at least six months, but the median duration was much longer, closer to six years.

Participants were randomly assigned either to continue on their boosted protease inhibitor regimen or to switch to raltegravir, whilst staying on the same NRTI 'backbone'. The most common protease inhibitors at enrolment were lopinavir/ritonavir (Kaletra) and atazanavir (Reyataz), the latter of which causes fewer blood lipid abnormalities than other drugs in its class.



Fat or fat-like substances found in the blood and body tissues. Lipids serve as building blocks for cells and as a source of energy for the body. Cholesterol and triglycerides are types of lipids.

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.


A waxy substance, mostly made by the body and used to produce steroid hormones. High levels can be associated with atherosclerosis. There are two main types of cholesterol: low-density lipoprotein (LDL) or ‘bad’ cholesterol (which may put people at risk for heart disease and other serious conditions), and high-density lipoprotein (HDL) or ‘good’ cholesterol (which helps get rid of LDL).

virological suppression

Halting of the function or replication of a virus. In HIV, optimal viral suppression is measured as the reduction of viral load (HIV RNA) to undetectable levels and is the goal of antiretroviral therapy.


A blood fat (lipid). High levels are associated with atherosclerosis and are a risk factor for heart disease.


About three-quarters of participants were men and the median age was about 45 years. The current median CD4 T-cell count was high, at around 500 cells/mm3, but about one-third of patients had received an AIDS diagnosis. Nearly 40% had a history of prior treatment failure.

The researchers determined how many people maintained undetectable virus 48 weeks after switching to raltegravir, using an intent-to-treat analysis that counted participants who dropped out as treatment failures.

The study also looked at changes in levels of cholesterol and triglycerides. Protease inhibitors as a class are associated with changes in blood lipid profiles – elevated total and LDL 'bad' cholesterol plus decreased HDL 'good' cholesterol – that have been linked to increased cardiovascular risk.

The earlier SWITCHMRK studies found that, while people who switched from a protease inhibitor to raltegravir saw improved lipid levels, they were more likely to experience viral rebound. After these findings were reported, the SPIRAL Data and Safety Monitoring Board re-evaluated the study and recommended that it continue.

At week 48, the likelihood of remaining free of treatment failure (defined as two consecutive detectable viral loads, disease progression or study discontinuation) was high and similar in the two groups, 89% amongst participants who switched to raltegravir and 87% amongst those who stayed on a protease inhibitor.

Looking at proportions of patients free of virological rebound, the rates were even higher, 97% and 95%, respectively. The differences between the two arms were smaller than the pre-defined threshold, leading the researchers to conclude that raltegravir was non-inferior to boosted protease inhibitors.

Differences were larger, in favour of raltegravir, amongst participants with previous virological failure, use of prior suboptimal therapy (for example, NRTI monotherapy) and pre-existing drug-resistance mutations.

About 10% of participants assigned to either arm discontinued treatment prematurely for reasons including adverse events and virological failure. The types and frequencies of side-effects were similar in both groups, including 4% in both groups with severe adverse events.

As expected, participants who switched to raltegravir showed improved lipid profiles. The average triglyceride level fell by 23% in the raltegravir arm whilst rising by 5% in the protease inhibitor continuation arm. Total and LDL cholesterol decreased more than HDL amongst switchers, producing a more favourable total-to-LDL ratio.

Gatell noted that these blood fat improvements could have some clinical significance since fewer raltegravir recipients required lipid-lowering drugs.

With regard to the conflicting SWITCHMRK findings, he explained that whilst protease inhibitors performed about equally well in SWITCHMRK and SPIRAL, raltegravir did better in SPIRAL. One possible explanation is that SPIRAL participants were required to have longer minimum and medium durations of viral suppression, and longer suppression has been linked to better outcomes.

Nevertheless, he added, response rates in SPIRAL were very good in both arms, "among the highest ever seen in a switch study".


A second raltegravir switch study, however, turned up less promising findings.

As described by Eugenia Vispo from Hospital Carlos III in Madrid, the ODIS trial aimed to determine whether people with long-term viral suppression on a protease inhibitor-based regimen – again, below 50 copies/ml for at least six months – could safely switch to raltegravir taken once or twice daily.

Raltegravir is approved for twice-daily dosing, but its long intracellular half-life suggests less frequent dosing may be safe and effective.

A total of 222 participants were randomly assigned to switch from their current protease inhibitor to raltegravir, taken at either 400mg twice daily or 800mg once daily. Again lopinavir/ritonavir and atazanavir  were the most common protease inhibitors at study entry. After three months, patients with undetectable viral load in the twice-daily arm were randomised again to either stay on twice-daily therapy or switch to once-daily.

Here, about 65% of participants were men and the average age was 46 years; nearly half were coinfected with hepatitis C. The overall average CD4 cell count was 574 cells/mm3, but was significantly higher in the once-daily arm. About 70% had experienced prior virological failure and 40% had taken suboptimal regimens in the past.

More participants receiving raltegravir once daily experienced virological failure compared with the twice-daily recipients. This was true overall (6.4 vs 2.9%), and the effect was even more pronounced when looking at patients with prior suboptimal treatment (4.9 vs 0%), prior virological failure (8.7 vs 4.3%) or pre-existing NRTI resistance (17.7 vs 8.3%).

Although none of these differences reached statistical significance, safety monitors nevertheless halted the study ahead of schedule.

Statistical analysis (both univariate and multivariate) showed that prior existence of NRTI resistance mutations was the only factor that significantly predicted virological failure.

The researchers concluded that switching from protease inhibitors to raltegravir in patients with undetectable HIV RNA "effectively sustains viral suppression, as long as prior NRTI resistance had not been selected in the past". In this setting, they added, the efficacy of raltegravir "may not differ" when taken once or twice.

Taken together, these studies show that switching from a boosted protease inhibitor to raltegravir, especially with twice-daily dosing, is safe and effective for most people and can lead to lipid improvements that may lower the risk of cardiovascular disease. Caution is warranted, however, for patients with pre-existing NRTI resistance, who are more likely to experience loss of virological control.

Further information

View abstract and slides from this session on the official conference website.


Martinez E et al. Simplification of antiretroviral therapy by switching from ritonavir-boosted protease inhibitors to raltegravir in virologically suppressed HIV-1-infected patients (SPIRAL): a randomised open-label trial. Eighteenth International AIDS Conference, Vienna, abstract MOAB0103, 2010.

Vispo E et al. Simplification from protease inhibitors to once or twice daily raltegravir: the ODIS trial. Eighteenth International AIDS Conference, Vienna, abstract MOAB0102, 2010.