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The FDA has approved use of specific medications in three classes of drugs for patients with multi-drug resistance. |
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
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| 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 |
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