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Entry Inhibitors
Maraviroc is an antiviral CCR5 co-receptor antagonist indicated for treatment-experienced adults infected with only CCR5-tropic HIV-1 who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. Use of this drug is not recommended in patients with dual/mixed or CXCR4 tropic HIV-1 as efficacy was not demonstrated in a Phase 2 study of this patient group and safety and efficacy have not been established in treatmentnaïve adult or pediatric patients. The recommended dose differs based on concomitant medications used. Dosing may be 150mg BID, 300mg BID or 600mg BID. Maraviroc comes with a black box warning of hepatoxicity with allergic features. In such cases, discontinuation of the medication should be considered with signs and symptoms of hepatitis, or with increased liver transaminases combined with a rash.
The drug should be used with caution in patients with increased cardiovascular risk,as myocardial ischemia and/or infarction were observed in patients. Immune reconstitution syndrome has been reported in patients treated with a combination antiretroviral therapy as well as increased risk of developing upper respiratory infections and herpes virus infections.There was no potential risk of malignancy due to maraviroc, but long-term follow-up is needed to assess this risk. The most common adverse events with twice daily therapy included cough, pyrexia, upper respiratory tract infections, rash, musculoskeletal symptoms, abdominal pains, and dizziness. Some of the less common side effects included Clostridium difficile colitis. Maraviroc is a substrate for cytochrome P4503A4 and so several antiretroviral agents have been shown to have relevant drug-drug interactions with it as shown below.15
Maraviroc Dosage Adjustments with Co-Administered
CYP3A Inhibitors or Inducers
| Reduce dose when given with strong CYP3A inhibitors (with or without CYP3A inducers) including PI (except tipranavir/ritonavir), delavirdine, ketoconazole, itraconazole, clarithromycin, telithromycin |
150 mg
twice daily |
| Use standard dose when given with NRTI, tipranavir/ritonavir, nevirapine, enfuvirtide and other drugs that are not strong CYP3A inhibitors or CYP3A inducers |
300 mg
twice daily |
| Increase dose when given with CYP3A inducers (without a strong CYP3A inhibitor) including efavirenz, rifampin, carbamazepine, phenobarbital, phenytoin |
600 mg
twice daily |
Administration of maraviroc with St. John’s Wort is not recommended as it will decrease maraviroc concentrations and lead to loss of virologic response and possible resistance. Maraviroc should be used with caution in patients with renal impairment and in patients with pre-existing liver dysfunction, or who are co-infected with hepatitis B or C. It can be taken with or without food.
Integrase Inhibitors
Integrase enzyme is required for HIV-1 replication. It catalyzes the irreversible process of integrating the viral DNA into the host cell’s DNA, called integration. The viral integrase enzyme is a target for antiviral therapy by integrase inhibitors. Raltegravir (formerly MK-0518) was recently approved by the FDA for the treatment of HIV-1 infection in treatment-experienced adult patients who have HIV-1 strains that are resistant to multiple antiretroviral agents. The safety and efficacy of raltegravir have not been established in treatmentnaïve adult patients or pediatric patients. The dosage is 400mg twice daily with or without food.16
Caution should be used during the initial phase of treatment, when patients may develop immune reconstitution syndrome. The most common side effects reported are diarrhea, nausea, headache, and pyrexia. Cancers like Kaposi’s sarcoma, lymphoma, squamous cell carcinoma, hepatocellur carcinoma, and anal cancer were reported in treatment experienced subjects, but it is unknown if these cancers were related to raltegravir use. The rates of AST and ALT abnormalities were higher in the subjects co-infected with hepatitis B and/or hepatitis C. It is metabolized by UGT1A1 glucuronidation pathway, and hence, caution should be used with rifampin or other strong inducers of UGT1A1. Less strong inducers like efavirenz, nevirapine, rifabutin, and St. John’s Wort may be used with raltegravir.15
The mutations that resulted in raltegravir resistance included an amino acid substitution at either Q148 (changed to H, K, or R) or N155 (changed to H) plus one or more substitutions (L74M/R, E92Q,T97A, e138A/K, G140A/S, V151I, G163R, H183P, Y226D/F/H, S230R and D232N). Another pathway to raltegravir resistance was seen with amino acid substitution at Y143C/H/R.15
BENCHMRK 1 and 2 studies confirmed the potency of raltegravir in treatment-experienced patients.16,17 Patients were randomized to raltegravir 400mg twice daily, or to placebo plus an OBR. At 16 weeks, 77% of patients in the raltegravir arms had HIV-1 RNA <400 copies/ml compared to 41-43% of placebo patients. CD4+ cell count response was also significantly higher in the raltegravir arms (83-86 cells/mm3) than in control as (31-40 cells/mm3). Data from BENCHMRK studies indicate that this drug will be beneficial in treatment-experienced patients when combined with at least one other active agent. Raltegravir does not require ritonavir boosting. Twice daily dosing will be a drawback, but the drug’s tolerability and lack of toxicity in studies will expand the options for sequential antiretroviral regimens.
CONCLUSION
As with any antiretroviral agent, the patient should be informed that neither maraviroc nor raltegravir is a cure for HIV infection, and that he or she can still develop opportunistic infections. These treatments do not lower the risk of passing HIV to other people through sexual contact or sharing needles, so they should continue to practice safer sex, and use barrier methods to lower the chance of sexual contact with any body fluids. Patients should remain under the care of a physician when using these drugs, and if they forget to take a dose, they should take the next dose of medication as soon as possible and then take their next scheduled dose at its regular time.15
Clinical
Trials
Phases |
In Phase I trials, researchers test an experimental drug or treatment in a small group to evaluate its safety in humans, determine a safe dosage range, and identify side effects.
In Phase II trials, the experimental study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety. A control group receives either a placebo or the standard treatment regimen.
In Phase III trials, the experimental study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely.
In Phase IV trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use. |
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OBR: Optimized background regimen
EAP: Expanded access programs provide new treatments that are “nearly approved” in Phase III clinical trials, to patients who have exhausted or are intolerant of approved therapies, in open studies or parallel tracks.
Maraviroc: Entry inhibitor approved for use in patients infected with HIV strains that are CCR5-tropic and resistant to multiple antiretroviral agents.
Raltegravir: Integrase inhibitor, approved for use in patients infected with HIV strains that are resistant to multiple antiretroviral agents.
Tropism assay: Test to determine whether patient has HIV that uses CCR5 and/or CXR4 as a co-receptor for entering CD4+ cells.
BENCHMRK 1 and 2 studies: Multi-center, triple-blind randomized Phase III studies to evaluate safety and efficacy of oral raltegravir twice daily vs placebo, each plus OBR, in HIV-infected patients with HIV resistant to three classes of oral ART.
MOTIVATE 1 and studies: Multi-center, double-blind randomized Phase III studies to evaluate safety and efficacy of maraviroc vs. placebo, each plus OBR, in HIV-infected patients with HIV resistant to three classes of oral ART, with only R5 HIV-1 detected at screening by Trofile assay |
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