Comparing efavirenz to raltegravir

Efavirenz (Sustiva) is a commonly used drug in combination anti-HIV therapy that can be taken once daily. When efavirenz is co-formulated with the drugs tenofovir and FTC into one pill called Atripla, an entire regimen can be taken once daily.

Efavirenz can affect the central nervous system (CNS – the brain and spinal cord), and side effects from this drug in the first few weeks of use are common and can include the following:

• abnormal dreams
• sadness
• irritability
• nervousness
• lightheadedness
• difficulty sleeping

These CNS-related side effects usually diminish within the first two weeks of starting efavirenz-based regimens. A month after initiating therapy with efavirenz, most of these side effects should fade. But some efavirenz users continue to experience side effects even a year after having started therapy.

Raltegravir (Isentress) is the first anti-HIV integrase inhibitor. It is potent, generally well tolerated and has few interactions with other drugs.

Researchers at six hospital clinics in Switzerland conducted a randomized placebo-controlled study comparing the CNS side effects of efavirenz- and raltegravir-based regimens in volunteers who had been taking efavirenz for several years. Ultimately, they found that 51% of efavirenz users preferred to replace that drug with raltegravir. This switch was accompanied by improvements in stress and anxiety as well as lipid levels in the blood.

Study details

Researchers recruited 57 HIV-positive people—all of whom had been taking efavirenz-containing regimens and who were adherent and whose HIV viral load was suppressed in the blood—and randomly assigned them to one of two regimens:

• Raltegravir first: Participants received raltegravir 400 mg twice daily for two weeks along with placebo (fake) efavirenz
• Efavirenz first: Participants received efavirenz 600 mg once daily together with placebo raltegravir

All participants continued to take the nucleoside analogues (nukes)—such as abacavir + 3TC (Kivexa) or tenofovir + FTC (Truvada)—that they were taking before entering the study.

After two weeks, participants were switched from efavirenz to raltegravir, or vice versa.

Participants were regularly assessed for CNS symptoms and blood was drawn for analysis. After the 4th week, if they wished, participants could choose to remain either on efavirenz or raltegravir.

The trial was unblinded after four weeks, and at the 6th week, participants were interviewed about their drug preferences. Further monitoring continued for an additional six weeks, so the trial lasted for three months.

The average profile of participants when they entered the study was as follows:

• 74% males, 26% females
• age – 47 years
• length of time HIV positive – 10 years
• CD4+ count – 600 cells
• viral load – less than 20 copies/ml

Results

After four weeks in the study, 34 participants (64%) stated that they preferred one of the two drugs studied. The remaining 36% felt that for them the study drugs were equally tolerable.

Among the 34 people who told researchers that they preferred one of the study drugs over the other, the results were as follows:

• preferred efavirenz – 12 people (35%)
• preferred raltegravir – 22 people (65%)

Although nearly twice as many people preferred raltegravir to efavirenz, this difference trended to but did not achieve statistical significance.

At the 6th week of the study, participants had chosen the following treatments:

• continued taking efavirenz – 49%
• switched to raltegravir – 51%

CNS symptoms

Participants taking efavirenz reported feeling a greater degree of anxiety and stress than those taking raltegravir. Moreover, these differences were statistically significant.

Lipid levels

Efavirenz is associated with increased levels of fatty substances (lipids such as cholesterol and triglycerides) in the blood. When participants used raltegravir, abnormal lipid levels fell.

HIV levels

Monitoring to the 12th and final week of the study found that those participants who had switched to raltegravir continued to have viral loads less than 20 copies/ml.

Understanding the change

That about 51% of participants were willing to change efavirenz for raltegravir is remarkable, given that efavirenz is taken once daily and raltegravir needs to be taken twice a day. This suggests that efavirenz-related symptoms can persist and be bothersome for some people.

Emerging therapies

Over the coming months and years, more options will become available to HIV-positive people in high-income countries. First up will be rilpiverine (Endurant, formerly known as TMC278). This drug was recently approved in the U.S. and should be approved in Canada by the end of the summer. Rilpiverine is taken once daily and has fewer side effects than efavirenz. Rilpiverine will eventually be co-formulated into one pill with Truvada (tenofovir + FTC). This co-formulation of three drugs into one pill will make it the second triple combination that can be taken once daily.

Another option may be the integrase inhibitor elvitegravir. This drug is in the final stages of clinical trials prior to regulatory approval. Elvitegravir will need to be taken with a small dose of ritonavir or another booster such as cobicistat (GS-9350). Elvitegravir may be useful in some cases of raltegravir-resistant HIV.

Another drug entering the final stages of clinical trials is the integrase inhibitor 1349572 (or simply ’572). This drug is potent and may also be useful in some cases of raltegravir-resistant HIV. It is likely that ’572 will eventually be co-formulated into one pill together with Kivexa (abacavir + 3TC).

REFERENCES:

1. Nguyen A, Calmy A, Delhumeau C, et al. A randomized cross-over study to compare raltegravir and efavirenz (SWITCH-ER study). AIDS. 2011 May 17. [Epub ahead of print]
2. Métifiot M, Vandegraaff N, Maddali K, et al. Elvitegravir overcomes resistance to raltegravir induced by integrase mutation Y143. AIDS. 2011 Jun 1;25(9):1175-8.
3. Cohen C, Elion R, Ruane P, et al. Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV infection. AIDS. 2011 Mar 27;25(6):F7-12.