Tenofovir (DF) halts the replication of HIV in a slightly different way to other drugs and appears to have a better resistance profile than most, as Tracy Barnes explains.
Much of what we know about tenofovir (DF) is based on the clinical data utilised to support product licence applications. Tenofovir (DF) has only been available (on licence) in the UK since February this year, although an early access programme was started in March 2001.
Drug Name:
Tenofovir disoproxil fumarate (DF).
Drug Class:
Nucleotide reverse transcriptase inhibitor (NtRTI). Tenofovir (DF) is the only drug in this class licensed to treat HIV infection.
Brand Name:
Viread®
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How tenofovir (DF) works:
Tenofovir (DF) is a member of a new group of drugs referred to as nucleotide reverse transcriptase inhibitors (NtRTIs). This class of drug combats viral replication of HIV by blocking the essential transcription process of HIV genetic material (RNA) into DNA. Tenofovir (DF) is usually taken in combination with at least two other HIV antiretroviral drugs, and most commonly three other HIV antiretrovirals, by patients who have experienced virological failure with previous treatments.
History:
Tenofovir (DF) was formerly known as GS-4331-05 or PMPA. Tenofovir (DF) was first licensed in the US in October 2001 with the European licence granted on 7th February 2002. Tenofovir (DF) is licensed in Europe to be used with other antiretrovirals for the treatment of HIV-1 in patients over 18 years who are experiencing early virological failure.
The US license applies to the treatment of all HIV-1 patients over 18 years.
Combination therapy:
Tenofovir (DF) is an established effective component of combination antiretroviral therapy for those who have experienced early virological failure.
It has proven efficacy in reducing viral load in treatment-experienced people over both 24 and 48 weeks.
Even in the presence of HIV mutations which are resistant to all drug classes (PIs, NNRTIs and NRTIs), significant reductions in viral load have been achieved with tenofovir (DF).
At the recent World AIDS Conference in Barcelona, 48 week data was presented on tenofovir (DF) compared against d4T on a common background combination of 3TC and efavirenz in naïve patients.
The study showed that both regimens were equally effective in reducing viral load and that there were fewer mitochondrial and metabolic toxicities in the tenofovir (DF) arm.
Dosing:
Tenofovir (DF) is produced in a light blue, almond-shaped 245mg film-coated tablet. Each tablet contains 245 mg of tenofovir disoproxil (active ingredient) which is equivalent to 300 mg of tenofovir disoproxil fumarate (active ingredient + salt). Many studies have referred to 300mg tenofovir disoproxil fumarate which is the same dose as tenofovir disoproxil 245mg.
The recommended dose is one 245mg tenofovir disoproxil tablet which is taken once a day.
Dosing restrictions:
Tenofovir (DF) should be taken with food and as part of combination therapy.
As tenofovir DF is removed from the body by the kidneys, care should be taken if other renally-removed medications are also taken. Care should also be taken if tenofovir (DF) is taken with ddI as ddI levels may be increased.
No interaction studies have been performed with hormonal contraceptives.
Tenofovir (DF) should not be taken by anyone who has severe kidney function impairment.
Side effects:
Patients treated with tenofovir (DF) in combination with other antiretrovirals may experience the side effects common to most antiretrovirals. These are more likely to occur during the first few weeks after commencing treatment. The most frequently reported side effects of tenofovir (DF) are:
Diarrhoea
Vomiting
Flatulence
Nausea
In all studies focussing on the safety of tenofovir (DF), participants experienced no more side effects than those receiving antiretroviral regimens that did not include tenofovir (DF).
Pre-existing conditions:
Tenofovir (DF) is eliminated via the kidneys. For this reason tenofovir (DF) should not be used in patients with severely impaired kidney function. Tenofovir (DF) may be used in mild or moderately impaired kidney function, although monitoring of kidney function should be undertaken.
Paediatric use:
Tenofovir (DF) is not licensed for use in children.
Use during pregnancy:
There are no adequate and well-controlled studies of tenofovir (DF) in pregnant women. Therefore tenofovir (DF) is not recommended for use in fertile women unless effective contraception is used.
Tenofovir (DF) resistant HIV:
Clinical trials have demonstrated that resistance to tenofovir (DF) is rare and slow to develop.
In clinical studies the presence of 3 or more specific nucleoside (thymidine analogue) mutations inclusive of mutations at either 210 or 41 was associated with a reduced response to treatment.
Only one rare, signature resistance mutation has been identified in studies - K65R.
Future developments:
A paediatric development programme to identify an appropriate formulation and dosages is underway.
Safety and acceptability of an experimental topical microbicidal gel formulation of tenofovir to prevent vaginal transmission of HIV is also under investigation.
Results from animal studies have yielded promising results.
When tenofovir gel was applied to rhesus monkeys prior to and following vaginal exposure to the SIV virus, 100% protection from the virus was achieved.
