Tenofovir
Encyclopedia
Tenofovir disoproxil fumarate (TDF or PMPA), marketed by Gilead Sciences
under the trade name Viread, belongs to a class of antiretroviral drug
s known as nucleotide analogue reverse transcriptase inhibitor
s (NRTIs), which block reverse transcriptase
, an enzyme crucial to viral production.
form of tenofovir. Tenofovir is also available in a fixed-dose combination with emtricitabine
in a product with the brand name Truvada
for once-a-day dosing. Atripla
, a fixed-dose triple combination of tenofovir, emtricitabine and efavirenz
, was approved by the FDA on 12 July 2006 and is now available, providing a single daily dose for the treatment of HIV.
at the Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic
(IOCB) in Prague
, and Erik DeClercq, Rega Institute for Medical Research
, Catholic University of Leuven
, Belgium.
Tenofovir was approved by the U.S. Food and Drug Administration (FDA) on October 26, 2001 for the treatment of HIV, and on August 11, 2008 for the treatment of chronic hepatitis B.
Fortunak's graduate student Adrian Williams tested different methods to improve this step. A catalyst, TBAB (tetrabutylammonium bromide) sped up the reaction and thinned the oatmeal-like mixture into something "like milk," Williams said. But unexpectedly, it made the product more stable, which substantially increased the yield. This lowered the cost by about 20%.
-resistant HBV.
Tenofovir has also been implicated in causing renal toxicity, particularly at elevated concentrations.
Tenofovir can cause acute renal failure
, Fanconi syndrome
, proteinuria
or tubular necrosis. These side effects are due to accumulation of the drug in proximal tubule
s. Tenofovir can interact with didanosine
by increasing didanosine's concentration. It also decreases the concentration of atazanavir
sulfate.
gave either tenofovir or a placebo
to 936 high-risk women in Cameroon
, Ghana
and Nigeria
. While the results show signs that the tenofovir group contracted HIV at a reduced rate, the researchers cautioned against drawing conclusions from the study because the sample size was so small.
In July 2010, a vaginal gel containing tenofovir was shown to reduce HIV infection rates by 39 percent in the CAPRISA 004
trial conducted in South Africa.
In July 2011, a placebo-controlled trial in Africa of daily tenofovir was shown to reduce HIV infection rates by 62%.
Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes therapeutics. For many years since the company was founded, the company concentrated primarily on antiviral drugs to treat patients infected with HIV, hepatitis B or influenza. In 2006, Gilead acquired two...
under the trade name Viread, belongs to a class of antiretroviral drug
Antiretroviral drug
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART...
s known as nucleotide analogue reverse transcriptase inhibitor
Reverse transcriptase inhibitor
Reverse-transcriptase inhibitors are a class of antiretroviral drug used to treat HIV infection, tumors, and cancer. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase enzyme that retroviruses need to reproduce.-Mechanism:...
s (NRTIs), which block reverse transcriptase
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
, an enzyme crucial to viral production.
Drug forms
Tenofovir disoproxil fumarate is a prodrugProdrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
form of tenofovir. Tenofovir is also available in a fixed-dose combination with emtricitabine
Emtricitabine
Emtricitabine , with trade name Emtriva , is a nucleoside reverse transcriptase inhibitor for the treatment of HIV infection in adults and children....
in a product with the brand name Truvada
Truvada
Tenofovir/emtricitabine, trademark Truvada, is a fixed-dose combination of two antiretroviral drugs used for the treatment of HIV. It consists of 300 milligrams of tenofovir and 200 milligrams of emtricitabine. By combining the two agents into one tablet, it reduces the pill burden and increases...
for once-a-day dosing. Atripla
Atripla
Emtricitabine/tenofovir/efavirenz is a fixed-dose combination drug for the treatment of HIV infection. It combines Gilead Sciences's tenofovir and emtricitabine with Bristol-Myers Squibb's efavirenz into a fixed-dose pill...
, a fixed-dose triple combination of tenofovir, emtricitabine and efavirenz
Efavirenz
Efavirenz is a non-nucleoside reverse transcriptase inhibitor and is used as part of highly active antiretroviral therapy for the treatment of a human immunodeficiency virus type 1....
, was approved by the FDA on 12 July 2006 and is now available, providing a single daily dose for the treatment of HIV.
History
Tenofovir was discovered through a collaborative research effort between Antonín HolýAntonín Holý
Antonín Holý is a Czech scientist. He specialises in the field of chemistry and cooperated on the development of important antiretroviral drugs used in the treatment of HIV and hepatitis B. He was involved in the creation of the most effective drug in the treatment of AIDS...
at the Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic
Academy of Sciences of the Czech Republic
The Academy of Sciences of the Czech Republic was established in 1992 by the Czech National Council as the Czech successor of the former Czechoslovak Academy of Sciences. The Academy is the leading non-university public research institution in the Czech Republic...
(IOCB) in Prague
Prague
Prague is the capital and largest city of the Czech Republic. Situated in the north-west of the country on the Vltava river, the city is home to about 1.3 million people, while its metropolitan area is estimated to have a population of over 2.3 million...
, and Erik DeClercq, Rega Institute for Medical Research
Rega Institute for Medical Research
The Rega Institute for Medical Research is a Belgian scientific establishment that is part of the Catholic University of Leuven in central Belgium...
, Catholic University of Leuven
Katholieke Universiteit Leuven
The Katholieke Universiteit Leuven is a Dutch-speaking university in Flanders, Belgium.It is located at the centre of the historic town of Leuven, and is a prominent part of the city, home to the university since 1425...
, Belgium.
Tenofovir was approved by the U.S. Food and Drug Administration (FDA) on October 26, 2001 for the treatment of HIV, and on August 11, 2008 for the treatment of chronic hepatitis B.
Increased yield
A difficult step in the manufacture of tenofovir is near the end, when the mixture is "like oatmeal, making it very difficult to stir," said Joseph Fortunak, who left Abbott Laboratories to teach at Howard. That slows the next reaction, a problem because the intermediary is highly unstable and decomposes, thus lowering the yield.Fortunak's graduate student Adrian Williams tested different methods to improve this step. A catalyst, TBAB (tetrabutylammonium bromide) sped up the reaction and thinned the oatmeal-like mixture into something "like milk," Williams said. But unexpectedly, it made the product more stable, which substantially increased the yield. This lowered the cost by about 20%.
Indications
Tenofovir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults. This indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in controlled studies of tenofovir in treatment-naive and treatment-experienced adults. There are no study results demonstrating the effect of tenofovir on the clinical progression of HIV. It also has activity against wild-type and lamivudineLamivudine
Lamivudine is a potent nucleoside analog reverse transcriptase inhibitor .It is marketed by GlaxoSmithKline with the brand names Zeffix, Heptovir, Epivir, and Epivir-HBV.Lamivudine has been used for treatment of chronic hepatitis B at a lower dose than for treatment of HIV...
-resistant HBV.
Adverse effects and drug interactions
The most common side effects associated with tenofovir include nausea, vomiting, diarrhea, and asthenia. Less frequent side effects include hepatotoxicity, abdominal pain, and flatulence.Tenofovir has also been implicated in causing renal toxicity, particularly at elevated concentrations.
Tenofovir can cause acute renal failure
Acute renal failure
Acute kidney injury , previously called acute renal failure , is a rapid loss of kidney function. Its causes are numerous and include low blood volume from any cause, exposure to substances harmful to the kidney, and obstruction of the urinary tract...
, Fanconi syndrome
Fanconi syndrome
Falconi syndrome is a disease of the proximal renal tubules of the kidney in which glucose, amino acids, uric acid, phosphate and bicarbonate are passed into the urine, instead of being reabsorbed. Fanconi syndrome affects the proximal tubule, which is the first part of the tubule to process fluid...
, proteinuria
Proteinuria
Proteinuria means the presence of anexcess of serum proteins in the urine. The protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine , retrograde ejaculation, pneumaturia due to a fistula, or drugs such as pyridium.- Causes...
or tubular necrosis. These side effects are due to accumulation of the drug in proximal tubule
Proximal tubule
The proximal tubule is the portion of the duct system of the nephron of the kidney which leads from Bowman's capsule to the loop of Henle.-Structure and appearance:...
s. Tenofovir can interact with didanosine
Didanosine
Didanosine is sold under the trade names Videx and Videx EC. It is a reverse transcriptase inhibitor, effective against HIV and used in combination with other antiretroviral drug therapy as part of highly active antiretroviral therapy .-History:The related pro-drug of didanosine,...
by increasing didanosine's concentration. It also decreases the concentration of atazanavir
Atazanavir
Atazanavir, marketed under the trade name Reyataz by Bristol Myers, is an antiretroviral drug of the protease inhibitor class...
sulfate.
Therapeutic drug monitoring
Tenofovir may be measured in plasma by liquid chromatography. Such testing is useful for monitoring therapy and to prevent drug accumulation and toxicity in patients with renal or hepatic impairment.HIV risk reduction
A 2006 trial by Family Health InternationalFamily Health International
Family Health International is a public health and development organization dedicated to improving living standards of the world's most vulnerable people. Family Health International has 2,500 staff conducting research and implementing programs in fifty-five countries...
gave either tenofovir or a placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
to 936 high-risk women in Cameroon
Cameroon
Cameroon, officially the Republic of Cameroon , is a country in west Central Africa. It is bordered by Nigeria to the west; Chad to the northeast; the Central African Republic to the east; and Equatorial Guinea, Gabon, and the Republic of the Congo to the south. Cameroon's coastline lies on the...
, Ghana
Ghana
Ghana , officially the Republic of Ghana, is a country located in West Africa. It is bordered by Côte d'Ivoire to the west, Burkina Faso to the north, Togo to the east, and the Gulf of Guinea to the south...
and Nigeria
Nigeria
Nigeria , officially the Federal Republic of Nigeria, is a federal constitutional republic comprising 36 states and its Federal Capital Territory, Abuja. The country is located in West Africa and shares land borders with the Republic of Benin in the west, Chad and Cameroon in the east, and Niger in...
. While the results show signs that the tenofovir group contracted HIV at a reduced rate, the researchers cautioned against drawing conclusions from the study because the sample size was so small.
In July 2010, a vaginal gel containing tenofovir was shown to reduce HIV infection rates by 39 percent in the CAPRISA 004
CAPRISA 004
CAPRISA 004 is the name of a clinical trial conducted by CAPRISA. This particular study was the first to show that a topical gel could reduce a person's risk of contracting HIV. The gel used in the study contained a microbicide.-Background:...
trial conducted in South Africa.
In July 2011, a placebo-controlled trial in Africa of daily tenofovir was shown to reduce HIV infection rates by 62%.