Pilot Study Switching Individuals Receiving EFV With Continuing Central Nervous System Toxicity to TMC125
Condition: HIV
Study type: Interventional
Phase: Phase 3

Summary: 
      The purpose of the study is to examine the effect of switching from an antiretroviral
      combination that includes efavirenz (Susitiva®), in individuals experiencing
      efavirenz-related side effects, and replacing this with an investigational HIV medication
      called Etravirine (TMC125).

      The study will primarily investigate the effect of change in medication on your viral load
      (the levels of the HIV virus in your blood), on immunological parameters (CD4 count), on
      other safety parameters (such as cholesterol) your side effects and also on your quality of
      life.
    

Detailed description: 
      The majority of individuals who commence treatment for HIV in the UK start with a regimen
      that includes EFV in combination with other antiretrovirals. These regimens are convenient
      (once daily dosing) and highly efficacious. However EFV has several potential drawbacks
      including continued CNS toxicity, the potential for teratogenesis and a low barrier to the
      development of virological resistance. In the past the only alternative NNRTI available was
      nevirapine which appears to have a lower rate of virological success and is associated with
      potentially life threatening toxicities including hepatotoxicity and cutaneous toxicity
      including the Stevens-Johnson syndrome.

      Clinically controlled trials frequently reported undesirable nervous system side effects in
      patients receiving 600 mg EFV with other antiretroviral agents, including dizziness,insomnia,
      somnolence, impaired concentration and abnormal dreaming. CNS symptoms of moderate to severe
      intensity were experienced by 19.4% of patients compared to 9.0% of patients receiving
      control regimens. These symptoms were severe in 2.0% of patients receiving EFV 600 mg daily
      and in 1.3% of patients receiving control regimens. In clinical studies 2.1% of patients
      treated with 600 mg of EFV discontinued therapy because of nervous system symptoms.

      Nervous system symptoms usually begin during the first one or two days of therapy and often
      resolve after the first 2 -4 weeks. However in a significant proportion of individuals it
      continues with an adverse effect on quality of life. CNS toxicity may also worsen drug
      compliance. In a study of uninfected volunteers, a representative nervous system symptom had
      a median time to onset of 1 hour post dose and a median duration of 3 hours.

      Nervous system symptoms may occur more frequently when EFV is taken concomitantly with meals
      possibly due to increased EFV plasma. Dosing at bedtime seems to improve the tolerability of
      these symptoms and can be recommended during the first weeks of therapy and in patients who
      continue to experience symptoms although this is not always successful and may be associated
      with vivid or disturbing dreams. Dose reduction or splitting the daily dose has not been
      shown to provide benefit.

      Other adverse events associated with efavirenz include rash (5-26%, usually minor),increased
      cholesterol (20-40%) and triglycerides (6-11%), diarrhea (3-14%), nausea and hyperglycemia
      (2-5%). Serious psychiatric adverse events such as precipitation of psychosis, seizure,
      suicidal ideation, paranoia, mania and aggression have also been associated with use. These
      are seen in <1% taking EFV and are thought to be more likely in those with a history of
      mental illness/drug abuse or predisposition to psychological reactions.

      TMC125 is a diarylpyrimidine derivative that has proven efficacy against HIV-1 including
      activity in viral isolates with existing NNRTI signature mutations. Resistance to TMC125 also
      appears to develop less readily than to EFV and NVP. This has been attributed to its
      molecular structure. TMC125 has demonstrated safety and efficacy in short term studies in
      both treatment-naïve and NNRTI-resistant HIV-1 infected patients.

      Recently published results from phase 3 trials give further support to these findings with
      efficacy in reduction of HIV-1-RNA levels seen in patients with substantial NNRTI and PI
      resistance when treated with TMC125 plus an optimized background.

      TMC-125 is generally well tolerated and in particular has lower reported rates of CNS
      toxicity than EFV. Animal studies have shown a low risk of teratogenesis. The major toxicity
      of TMC125 has been skin rash which is usually self-limiting. In the repeated dose trials the
      adverse events (AEs) reported in more than 10% of all subjects were headache, somnolence,
      diarrhea, flatulence, nausea and vomiting, fatigue, fever, rash,and pruritus. Overall, AEs
      were mild to moderate in intensity, with no apparent doseresponse relationship. No consistent
      or clinically relevant changes in electrocardiogram (ECG) or vital signs were observed with
      single and repeated TMC125 dosing.

      TMC125 is a new NNRTI with proven efficacy against HIV-1 with several potential advantages
      over EFV including no CNS toxicity and a high barrier to the development of resistance. This
      study aims to investigate whether substitution of EFV with TMC125 leads to improvement of CNS
      toxicity with continued virological suppression and immunological reconstitution and whether
      this is associated with an improvement in quality of life.
    

Intervention name(s): Etravirine; Efavirenz
Intervention type(s): Drug; Drug
Intervention description(s): Four 100mg tablets daily for 12-24 weeks; One 600mg tablet daily
Other intervention name(s): TMC125; Brand Name: Intelence; TMC125; Brand Name: Intelence
Intervention MeSH terms: Efavirenz; Etravirine
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment