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Role Of Newly Approved HIV Antitretrovial Agent by milliondollas(m): 6:34pm On Jan 21, 2015 |
1. Entry inhibitors: a. Enfuvirtide (FuzeonT20) b. Maraviroc (Selzentry – FDA approved CCR5 co- receptor antagonist for treatment-experienced HIV adults with only CCR5-tropic HIV-1 strains resistant to multiple antiretroviral agents. 2. Protease inhibitors: darunavir and tipranavir 3. Integrase inhibitors: raltegravir (Isentress) approved by FDA for HIV treatment-experienced adult with HIV strains resistant to multiple antiretroviral agents. There are three antiretroviral agents in development. 1. Entry inhibitors including TNX-355 and vicriviroc 2. Integrase inhibitors, including elvitegravir, and 3. A novel agent belonging to the maturation inhibitor class, bevirimat. The two classes of target for antiretroviral therapy that will be discussed here are the entry inhibitor maraviroc and the integrase inhibitor raltegravir. The use of tropism assays including Trofile and SensiTrop will be discussed to help clinicians make decisions of when to use the CCXR5 inhibitor in treatment-experienced patients. Mechanism of Entry Mechanisms of HIV entry involve attachment, triggering and fusion. Entry of the virus into the CD4+ cell involves binding of the viral gp120 envelope protein to the CD4 receptor on the host cell, followed by interactions with chemokine receptors, either CCR5 or CXCR4, which leads to fusion of the viral and cell membranes. (See “HIV Inhibition” figure, below.) HIV INHIBITION GRAPHIC Graphic Source: Clinical Care Options downloadable slideset: Understanding HIV Entry and Targets for Therapy;October 2007. Available at: www.clinicaloptions.com/tropism. ®Clinical Care Options 2007; reproduced with permission. HIV tropism HIV tropism is the ability of a given HIV strain to use CCR5 and/or CXCR4 as co- receptors for entering CD4+ cells.4 When protein on the virus binds to CCR5 or CXCR4, conformational changes occur that enable it to cause membrane fusion. Drugs that prevent these steps are referred to as entry inhibitors. The virus that enters the cell using the CCR5 co- receptor is termed R5 virus. Viruses that use CXCR4 co-receptor are termed X4 viruses. Viruses that can use either co-receptor are termed R5/X4 or dual tropic viruses.4 New HIV infections are almost always due to R5 viruses. The CCR5 antagonists have activity against R5 tropic virus only, and cannot be used for patients who have dual-mixed tropic (D/M) or X4 virus. In some patients, D/M and/or X4 viruses emerge years after infection. Most of the experience in clinical trials for assessing co-receptor tropism has been with one commercially developed assay, the Trofile.5 1) HIV RNA suppression – Phase IIb/III studies of maraviroc in treatment experienced patients and treatment-naïve patients with R5 virus have been presented. In MOTIVATE trials, triple class-resistant patients were randomized to maraviroc 150mg or 300mg daily or BID or to placebo, both combined with an optimized background regimen (OBR). At 24 weeks, twice the proportion of patients on maraviroc plus OBR vs. placebo plus OBR achieved the primary endpoint of HIV-1 RNA <400 copies/ml.6, 7 Use of maraviroc is not recommended in patients with D/M or X4 HIV-1, as efficacy was not demonstrated in a Phase II study, nor is its safety and efficacy established in treatment-naïve adult patients or pediatric patients.8 2) Tropism Shifting or Switching – In an HIV- positive patient, viral tropism is not fixed at primary infection, but may evolve towards CXCR4 use over time. In some patients only a small amount of CXCR4 may be present, possibly existing below the limits of detection by current technologies. This drug associated shift or switch in the population tropism will result in a change in the tropism call, e.g., from R5 to dual/mixed or X4 tropism. It has not yet been determined whether such a coreceptor antagonist associated switch/shift has an impact on disease progression over long-term follow-up. 3) Unmasking caused by co-receptor antagonist exposure – treatment with a co- receptor antagonist will suppress the majority R5 population revealing the underlying CXCR4 virus. 4) Resistance – the virus may develop phenotypic resistance to the CCR5 coreceptor antagonist, and this area is being explored.9 Several studies have used this assay to define the prevalence of co-receptor usage in various patient populations. Data from 8 cohorts, 3 of them treatment naïve-patients, and 5 of the treatment-experienced patients revealed that dual/mixed or X4 virus appears to be less prevalent among those with earlier stages of disease.6, 10-14 Even among treatment-naïve subjects, 12-19% of individuals had detectable D/ M or X4 virus.10,12 Therefore, it is necessary to assess each individual patient for viral tropism before the use of a CCR5 antagonist cells to alter the conformational state of the receptor. Monogram’s co-receptor assay, Trofile, identifies the tropism of a patient’s virus. The sensitivity to detect minority variant populations is 100% when X4 virus is 10% and is 85% when X4 virus is 5% with successful amplification and reliable results with viral load >1000 copies/ml.8 Another challenge for the use of maraviroc will be reimbursement for the cost of the tropism assay. The FDA has approved Pathway Diagnostics for the process of SensiTrop HIV Co-receptor Tropism Assay, a secondgeneration molecular based diagnostic HIV tropism assay, with a projected turn around time as fast as 2-4 days compared to the cell based assay development time of two weeks or more. Pathway describes this assay as highly sensitive in detecting CXCR4-tropic HIV in patient samples that contain as little as 1% CXCR4.10 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. |
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