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Raltegravir looks promising for initial HIV therapy

Researchers are studying different anti-HIV drugs that have potent antiviral activity and potential for use in the initial therapy of HIV infection. One such drug is raltegravir, sold under the brand name Isentress.

Raltegravir represents a new group or class of anti-HIV medicines called integrase inhibitors. These drugs work by interfering with an enzyme that is needed to make new copies of HIV.

In Australia, Canada and the European Union, raltegravir is approved as part of combination therapy for treatment-experienced HIV positive people. Now it is being tested as part of combination therapy for use as initial HIV treatment.

In a trial called STARTMRK, HIV positive volunteers who had never been previously treated received either raltegravir or efavirenz (Sustiva, Stocrin) as part of combination therapy. In many treatment guidelines, efavirenz-based regimens are a preferred option for the initial therapy of HIV infection, so it was a logical choice to use this drug in this study. To reduce the possibility of bias when interpreting the results from this study, pharmacists who dispensed study medications also provided fake (placebo) raltegravir and efavirenz pills. Study participants and researchers did not know who received which drug until participants completed the study or dropped out.

After one year, researchers found that both regimens were very effective. Furthermore, in an editorial in the journal Lancet, other researchers commented that based on STARTMRK’s results “raltegravir seems to have an edge over efavirenz in terms of safety and tolerability.” More details about this study appear next.

Study details

Researchers planned for STARTMRK to last for two years. This report represents their analysis after one year. Researchers recruited volunteers from the following continents and countries:

• North America;
• South America;
• European Union;
• India;
• Thailand.

None of the volunteers were supposed to have used anti-HIV therapy before entering this study. Their average profile was as follows:

• 20% females, 80% males;
• age – 37 years old;
• 15% had AIDS;
• viral load – more than 70% had a viral load greater than 50,000 copies and almost 53% of all participants had a viral load greater than 100,000 copies;
• CD4+ count – 50% of participants had more than 200 cells;
• co-infection with hepatitis B or C viruses – 6%.

In addition to receiving raltegravir or efavirenz or placebo versions of these drugs, all participants received the following anti-HIV medicine:

• Truvada – a fixed-dose combination of tenofovir and FTC (emtricitabine).

After one year, researchers analysed data on 257 participants who received raltegravir and 247 who received efavirenz.

Results—Suppressing HIV and raising CD4+ counts

After one year, 86% of participants taking raltegravir and 82% taking efavirenz had viral loads below the 50-copy mark. This difference was not statistically significant and suggests that raltegravir is as effective as efavirenz for initial therapy of HIV infection.

Raltegravir’s antiviral activity was strong in STARTMRK. Significantly more participants taking raltegravir had their viral loads suppressed (below 50 copies) faster than people on efavirenz. Indeed, in just four weeks, raltegravir suppressed viral loads in 50% of people receiving this drug. In contrast, it took about 10 weeks before 50% of people using efavirenz had their viral load suppressed.

Participants taking raltegravir gained slightly more CD4+ cells than people on efavirenz (189 vs. 163).

Side effects

According to the study authors, “Most [participants] had at least one clinical adverse event during the study, of whom significantly more were on efavirenz rather than raltegravir.”

About 16% of participants taking raltegravir and 32% taking efavirenz had side effects that researchers described as “moderate-to-severe in intensity.” Such side effects included the following:

• dizziness;
• headache;
• abnormal dreams.

Focus on the brain

Efavirenz-related side effects on the brain are generally supposed to fade after the fourth week of therapy. However, in this double-blind placebo-controlled study, 20% of raltegravir users and 52% of efavirenz users had at least one neuropsychiatric symptom at the eighth week of the study.

After one year, the proportion of participants with at least one neuropsychiatric symptom was as follows:

• raltegravir users – 26%;
• efavirenz users – nearly 60%.

For most participants (60%) in both groups, these side effects were graded as “mild” by the study team. Only one participant with efavirenz-related neuropsychiatric side effects left the study.

Cancers and deaths

New or recurrent cancers occurred in both groups as follows:

• raltegravir – one person with Kaposi’s sarcoma (KS);
• efavirenz – nine people; six cases of KS, one case of anal cancer, one case of lymphoma and one case of bone cancer.

Two people died while taking raltegravir; one person from complications from KS and another from a stroke. Investigators determined that these complications were not due to exposure to raltegravir.

No one receiving efavirenz died during the study.

Results—Lab monitoring

In general, abnormal lab results of blood tests were more common among efavirenz users than people who took raltegravir, but this difference was not statistically significant.

Lipids—Cholesterol and triglycerides

A combination of long-term HIV infection, aging and, in some cases, anti-HIV medications can alter levels of fatty substances—cholesterol and triglycerides—in the blood. On average, one year after the study, levels of the following lipids in the blood rose to a greater extent in efavirenz users compared to people taking raltegravir:

• total cholesterol;
• good cholesterol (HDL-C);
• bad cholesterol (LDL-C);
• triglycerides.

Although the difference in the levels between the two study regimens was statistically significant, the actual changes in lipid levels were modest.

Hepatitis viruses

Hepatitis viruses affect the health of the liver and its ability to break down drugs. In cases of severe liver damage, reduced doses of anti-HIV medication must sometimes be used to reduce side effects. In STARTMRK, about 6% of participants were co-infected with hepatitis B or C. Side effects in these people were similar to those seen in people without these co-infections. Liver enzyme levels in co-infected people increased slightly during the study. Note that people in this study did not have severe liver disease; additional clinical trials are needed to assess the impact of raltegravir on people with severe liver disease.

Points to consider

The very promising results from STARTMRK have revealed that raltegravir-based regimens have similar effectiveness to efavirenz-based regimens for the initial treatment of HIV infection. These results occurred regardless of the initial viral load, CD4+ count or subtype of HIV. Also, raltegravir has fewer side effects than efavirenz.

For the future

The results from STARTMRK are particularly robust because this was a randomized double-blind placebo-controlled study. Raltegravir is already approved for the initial therapy of HIV infection in the United States. Regulatory authorities in Canada and the EU are considering authorizing the use of raltegravir in HIV positive people who have not been previously treated. If the safety of raltegravir is confirmed over the next several years and other countries make a decision to approve raltegravir for use in initial therapy, here are some possible impacts as outlined by reviewers in the journal Lancet:

• Doctors will have another, more tolerable option to offer HIV positive people considering initial therapy. This will increase the number of possible combinations available, particularly in high-income countries where governments subsidize access to these and other anti-HIV medicines.
• In the case of HIV positive women who may become pregnant, raltegravir is an important option because efavirenz can cause severe birth defects in monkeys. Moreover, birth defects have been documented in at least five children born to women who used efavirenz during the first three months of their pregnancy.
• Raltegravir does not, so far, have the potential for extensive drug interactions.

In STARTMRK, raltegravir was used at a dose of 400 mg twice daily with or without food. Efavirenz can be used once daily at a dose of 600 mg. The use of a twice-daily raltegravir regimen may be seen as a disadvantage by some doctors and their patients. Trials of once-daily raltegravir therapy are underway and their results are eagerly awaited.

—Sean R. Hosein

Created on: 09/04/2009

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