Maraviroc and Raltegravir: First Agents in 2 Novel Classes for Drug-Resistant HIV Infection

Internal Medicine World Report, November 2007, Volume 0, Issue 0

See also "First Integrase Inhibitor a Potent New Option" in this issue.

Although "in newly diagnosed patients multidrug-resistant virus is relatively rare," says Martin Markowitz, MD, there are currently tens of thousands of patients who have been infected with HIV for years and have developed resistance to many of the available antiretrovirals and have been running out of treatment options. "I would expect that it's at least 10% of the HIV-infected population," says Dr Markowitz, clinical director and staff investigator, Aaron Diamond AIDS Research Center, Rockefeller University, New York City.

The 2 New Drug Classes

This was the rationale for the expedited FDA review that led to the recent approval of a pair of first-in-class antiretrovirals for HIV-infected patients with drug-resistant disease.

Maraviroc (Selzentry; Pfizer), the first chemokine receptor antagonist, received FDA approval in August 2007. Unlike other antiretrovirals that attack virus inside white blood cells, maraviroc blocks the main route of virus entry into uninfected cells—chemokine receptor 5 (CCR5).

The second agent, raltegravir (Isentress; Merck), is the first integrase inhibitor to receive FDA approval (in October 2007). Until now, antiretroviral drugs could block only 2 of the 3 enzymes critical to the HIV replication process, protease and reverse transcriptase. Raltegravir inhibits the replication of the third enzyme—integrase.

"The successful targeting of integrase completes the trio" of the 3 enzymes involved in HIV replication, Dr Markowitz says. "Integrase inhibitors target an enzyme that is necessary for the virus to complete its life cycle?.it's a unique step in the life cycle of a retrovirus, and that's integration."

By preventing the integration of viral complementary DNA into the host DNA, integrase inhibitors help protect susceptible cells from becoming infected.

"The fact that it's a new target is very attractive, because raltegravir will have predictable activity across a wide range of isolates. It is almost independent of the treatment history of the patient," says Dr Markowitz.

The Paths to Approval

The FDA approval of raltegravir followed an analysis of pooled data from the first 24 weeks of 2 large, ongoing, randomized, placebo-controlled, phase 3 trials.

Martin Markowitz, MD

The trials included 699 treatment-experienced HIV-positive patients aged ≥16 years with HIV RNA >1000 copies/mL and documented resistance to ≥1 drugs in each of 3 classes: nucleoside reverse transcriptase inhibitor (NRTI); nonnucleoside reverse-transcriptase inhibitors (NNRTI), and protease inhibitors (PI).

Before randomization, optimized background therapy was chosen based on genotypic/phenotypic testing and the patient's antiretroviral therapy history. Participants were then randomly allocated (in a 2:1 ratio) to raltegravir, 400 mg twice daily, or placebo, both in combination with optimized background therapy.

Raltegravir is well tolerated. The most common adverse events reported in clinical trials were diarrhea, nausea, and headache. In addition, unlike many other antiretroviral agents, raltegravir appears to have minimal effects on lipids, an important consideration when treating patients long-term.

Maraviroc was also approved based on 24-week data from 2 ongoing placebo-controlled studies. Participants were 635 adults (aged 21-73 years) with CCR5-tropic HIV who had HIV-11 RNA >5000 copies/mL despite at least 6 months of therapy with at least 1 agent from 3 of 4 antiretroviral classes: NRTI, NNRTI, PI, and/or the fusion inhibitor enfuvirtide (Fuzeon). All patients received optimized background therapy during the trial.

After 24 weeks of treatment, 61% of the patients assigned to maraviroc 300 mg twice daily achieved an HIV RNA <400 copies/mL compared with only 28% of those in the placebo group.

Mean increase in CD4+ count was also higher with maraviroc&#8212;106.3 verus 57.4 cells/mm3.

A downside of maraviroc is the myriad adverse events that are associated with it; some of the more significant are constipation, pyrexia, upper respiratory tract infection, herpes infection, insomnia, cough, and rash.

Maraviroc includes a "black box" warning about the risk for hepatotoxicity, advising patients to seek immediate treatment if there is any evidence of a systemic allergic reaction (eg, pruritic rash, eosinophilia, elevated immunoglobulin E) or signs or symptoms of hepatitis.

Practical Applications

Raltegravir is currently indicated only in combination with optimized background therapy in treatment-experienced adults with HIV-1 infection who have evidence of viral replication and HIV strains that are resistant to >1 antiretroviral agent.

The indications for maraviroc are similar, except that it is restricted to individuals with CCR5-tropic HIV-1, which is present in about 50% to 60% of treatment-experienced patients.

Neither drug has been approved for treatment-na?ve patients.

Both agents are taken without regard to food. Both are to be taken twice daily, using a 400-mg tablet for raltegravir and a 300-mg tablet for maraviroc.

An ideal candidate for raltegravir, says Dr Markowitz, is "a patient who has been infected for a long time" and has been taking different regimens but has not yet used newer agents such as the PI tipranavir (Aptivus) and darunavir ethanolate (Prezista), or enfuvirtide. In such a patient, raltegravir should be combined with 1 or 2 other agents that the patient has not yet tried.

If the Trofile (HIV tropism) assay shows that the patient is susceptible to maraviroc, then "a combination of raltegravir, maraviroc, and one of the newer protease inhibitors would be highly desirable," says Dr Markowitz.

Raltegravir should not be used in patients who have already tried everything else. Doing so would virtually guarantee that you would be selecting for drug resistance in a relatively short time. In such patients, Dr Markowitz advises physicians to wait until new agents become available.

He stresses the importance of primary care physicians being involved in the management of HIV-infected patients. But when these patients are multidrug resistant, it is equally important to consult with specialists in the interpretation and management of resistance testing to improve patient outcomes. "I'm a firm believer that patients need primary care physicians, especially in areas where there might not be a lot of specialists around," says Dr Markowitz, adding, "If you're in a part of the country where it's really difficult for a patient to see a specialist, at least consult someone who is a specialist."

When it comes to antiretroviral selection, he emphasizes, "It is critical that the selection of the regimen that's used in combination with a new agent be done carefully and cautiously, with not only attention to the resistance test results, but also attention to all the drugs that the patient has taken in the past."

Saying that "it would be a crime to see a good drug like raltegravir be sacrificed because the healthcare provider doesn't make the right decision," Dr Markowitz enumerates some of the salient points to keep in mind:

  • Raltegravir is taken as 1 pill twice daily, making it attractive for treatment-experienced patients who must often take a plethora of drugs
  • Unlike other antiretroviral agents that are metabolized through the liver or kidney, raltegravir is glucuronidated, limiting its potential for drug?drug interactions
  • The manufacturer recommends that raltegravir be used with caution in combination with rifampin (Rifadin); Dr Markowitz would avoid this combination, as well as coadministration with dilantin (Phenytoin) and phenobarbital (Solfoton)&#8212;although no specific data are yet available on the latter 2 combinations
  • Raltegravir can be safely combined with all the other currently available antiretrovirals.

Even though there is a substantial reduction in raltegravir trough levels when coadministered with tipranavir, the activity of raltegravir does not appear to be affected. Dr Markowitz says that physicians should carefully read the drug interaction profile on the package insert.

Finally, after ordering resistance testing, recording a detailed treatment history, and obtaining Trofile assay results, physicians should either consult with an expert on the phone or via email or give these data to the patient to get an expert opinion. This will ensure that when you do use 1 of these 2 new drugs with an optimized regimen, that regimen is as good as it can be.

"Trust me, nobody has all the answers, but it's really important to move deliberately and not just use a new drug without really careful thought," says Dr Markowitz.

Both agents will cost around $10,000 per year, which is comparable to that of their competitors. The manufacturer of raltegravir is offering financial assistance to eligible patients.

Table. Drug-resistant HIV: raltegravir + background therapy vs placebo, at 24 wk

Outcome

Raltegravir,

400 mg bid

(n = 286)

Placebo

(n = 150)

Reached target HIV RNA,* %

&#160;<400 copies/mL

&#160;<50 copies/mL

&#160;

75.5

2.6

&#160;

39.3

33.3

CD4 cell count increase vs baseline,? cells/mm3

89

35

Discontinued therapy due to adverse events, %

2.0

1.4

Serious side effects, %

&#160;Diarrhea

&#160;Nausea

&#160;Headache

&#160;

3.7

2.2

2.41

&#160;

4.6

3.2

1.4

*Viral load <400 copies/mL, indicative of treatment response; <50 copies/mL, predictive of sustained response.

?At baseline, median CD4+ was 119 cells/mm3 in raltegravir group, 123 cells/mm3 in placebo group.

Source: Grinsztejn B, et al. Potent efficacy of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus: 24-week data. Abstract presented at the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 27-30, 2006; San Francisco, Calif.