Tenofovir disoproxil fumarate

Tenofovir disoproxil fumarate (Viread) is an antiviral drug that is approved for the treatment of HIV infection. It is able to reduce the amount of HIV in the blood, help prevent or reverse damage to the immune system and reduce the risk of AIDS-related illnesses. It is also a treatment for hepatitis B.

Tenofovir belongs to the nucleotide reverse transcriptase inhibitor (NtRTI) class of drugs. Like the nucleoside analogue reverse transcriptase inhibitors (NRTIs), NtRTIs inhibit an enzyme called reverse transcriptase, which is essential to the process of viral replication.

There are now two formulations of tenofovir, each one available in several combination products. The original formulation is known as tenofovir disoproxil fumarate (TDF) and is marketed as Viread, as a generic product and in fixed-dose combination tablets.

The newer formulation is known as tenofovir alafenamide (TAF) and is available in several fixed-dose combination tablets. See Tenofovir alafenamide – detailed information for further details of this formulation.

Both TDF and TAF were developed by Gilead Sciences Inc.

TDF is available in several fixed-dose combination tablets:

• A tablet containing 200mg emtricitabine and 300mg TDF. It may be marketed under the name Truvada, but generic versions are also available. This combination has also been approved for use as pre-exposure prophylaxis for prevention of HIV infection. See Emtricitabine/tenofovir disoproxil fumarate (Truvada) – detailed information for further information.
• A tablet containing 600mg efavirenz, 200mg emtricitabine, and 300mg TDF. It may be marketed under the name Atripla, but generic versions are also available. See Efavirenz/emtricitabine/tenofovir disoproxil fumarate (Atripla) – detailed information for further information.
• Eviplera is a fixed-dose tablet combining 25mg rilpivirine, 200mg emtricitabine, and 245mg TDF. See Eviplera for further information.
• Stribild is a fixed-dose combination tablet containing 150mg of elvitegravir, 150mg of cobicistat, 200mg of emtricitabine and 245mg of TDF. See Stribild – detailed information for further information.
• Delstrigo is a fixed-dose combination tablet containing 100mg of doravirine, 300mg of lamivudine and 245mg of TDF. See Delstrigo for further information.

Effectiveness

TDF is an effective antiviral agent that can reduce HIV viral load.

It was approved on the basis of the results of Study 903, in which over 600 people who had not previously used antiretroviral therapy were randomised to receive TDF or stavudine, plus lamivudine and efavirenz. Intent-to-treat analysis showed that both arms had similar virological outcomes, with 76% of people in the tenofovir arm achieving viral load below 50 copies/ml as compared to 80% in the stavudine arm. Equivalence was also demonstrated at weeks 96 and 144. At week 144, the mean increase in CD4 cell count was 263 cells/mm³ in the tenofovir arm and 283 cells/mm³ in the stavudine arm. (Gallant)

TDF has also been tested for first-line use in combination with emtricitabine. See Emtricitabine/tenofovir disoproxil fumarate (Truvada) – detailed information for further details.

Several intensification studies have shown that adding TDF to an existing regimen can provide benefit in treatment-experienced people with detectable viral load. In Study 907, 550 treatment-experienced people with detectable viral load were randomised to add TDF or placebo to their treatment regimen. In the tenofovir arm, 22% reached viral load below 50 copies/ml after 24 weeks, compared to 1% in the placebo group. After one year, the average viral load reduction was 0.57 log₁₀ in the tenofovir arm. (Squires, 2003)

Tenofovir is also active against hepatitis B and is recommended as a component of HIV treatment for anyone who is co-infected with hepatitis B.

Taking it

The standard dose of TDF when not dosed in a combination tablet is one 200mg tablet once a day, taken with or without food.

Side effects

Common side effects of TDF are:

• diarrhoea, vomiting, nausea, abdominal pain, feeling bloated, flatulence
• dizziness, feeling weak, headache
• rash
• decreases in phosphate in the blood, increases in liver enzymes.

Reduced kidney function or acute kidney toxicity are rare side effects of TDF. Fanconi syndrome, in which the small tubes in the kidneys that absorb electrolytes and minerals become damaged, is a rare side effect. Observational cohort studies have confirmed that acute renal toxicity is rare, affecting only around 1 to 4% of patients. (Scott) (Padilla)

Reduced kidney function, measured by elevations in creatinine levels, or reduced glomerular filtration rate, has been observed in several large studies of people taking TDF. (Harris; Kirk) But the clinical implications are uncertain; a systematic review and meta-analysis of studies concluded that people taking TDF did not have an increased risk of chronic kidney disease or end-stage renal failure requiring dialysis. (Cooper)

More detailed analyses have concluded that TDF-associated kidney toxicity is more common in people who have pre-existing renal insufficiency or who are also taking other drugs that can damage the kidneys. (Izzedine) (El Sahly) (Moreno)

Combining TDF with the anti-HIV drugs ritonavir (Norvir), ritonavir-boosted lopinavir (Kaletra) atazanavir (Reyataz) or didanosine (Videx / VidexEC) may also be a risk factor for kidney damage. (Zimmerman)

Reports have suggested that TDF-related kidney impairment is reversible, with renal function returning to normal soon after TDF therapy is stopped.

Although kidney damage is now regarded as a rare side effect of TDF, anyone on TDF who begins to experience symptoms of extreme thirst, frequent urination, confusion, or muscular weakness should report these symptoms to their doctor immediately.

Experts have emphasised the importance of regular monitoring of blood levels of creatinine and electrolytes in patients receiving TDF.

TDF use as HIV treatment or pre-exposure prophylaxis has been associated with reduced bone mineral density. A systematic review and meta-analysis found that TDF was associated with greater bone mineral loss when compared to other drugs and this effect was more pronounced when used as HIV treatment than as PrEP. Nonetheless, TDF treatment was not associated with a higher incidence of osteoporosis or fracture. (Baranek)

However, another systematic review and meta-analysis, looking at cross-sectional and longitudinal studies of antiretroviral treatment, found that treatment with TDF was not associated with an increased risk of reduced bone mineral density or osteopenia/osteoporosis. Low bone mineral density was associated with low CD4 cell count and established risk factors for reduced bone mineral density including low body mass and older age. (Goh)

The newer formulation of the drug, tenofovir alafenamide (TAF) was developed, in part, to address concerns about kidney and bone health. Studies have shown consistently that people taking TAF had less reduction in kidney function or bone density loss than people taking TDF. It is unclear if these reductions in laboratory measurements of kidney function and bone density will translate into long-term reductions in kidney damage or fewer fractures. See Tenofovir alafenamide – detailed information.

Resistance

The development of resistance to tenofovir after treatment failure is rare. Tenofovir can be recycled in second-line treatment after failure of first-line treatment if the K65R reverse transcriptase mutation is not present. The K65R mutation causes resistance to TDF and cross-resistance to lamivudine and abacavir. (Brenner)

Drug interactions

Tenofovir disoproxil fumarate (TDF) should not be used with the following drugs:

• tenofovir alafenamide
• adefovir dipivoxil
• didanosine

If TDF is used at the same time as other medicines that are known to cause kidney toxicity, there may be an increased risk of kidney side effects. Weekly monitoring of kidney functioning is advisable if use of the following drugs cannot be avoided:

• aminoglycosides
• amphotericin B
• cidofovir
• foscarnet
• ganciclovir
• interleukin-2
• non-steroidal anti-inflammatory drugs (NSAIDs)
• pentamidine
• tacrolimus
• vancomycin.

Regular monitoring of kidney function should take place when TDF/emtricitabine is used in combination with a boosted protease inhibitor or with direct-acting antiviral treatment for hepatitis C, owing to the potential for these agents to boost levels of tenofovir.

Pregnancy

An analysis of data submitted to the Antiretroviral Pregnancy Registry found no indication that TDF (Viread) use by HIV-positive pregnant women, either during the first trimester or later in pregnancy, was associated with an increased risk of birth defects. The registry collects reports from healthcare providers worldwide about adverse outcomes amongst infants born to women taking anti-HIV drugs during pregnancy. (Squires, 2009)

Three systematic reviews found no evidence of an increased risk of adverse birth outcomes, side-effects or congenital abnormalities as a result of exposure to TDF during pregnancy. (Nachega; Wang; Mofenson) The British HIV Association recommends the use of TDF as a preferred option for antiretroviral treatment during pregnancy in combination with other HIV drugs.

Children

Tenofovir disoproxil fumarate is approved for use in children aged 12 years and over. Reduced strength tablets are available for 6-12 year olds and granules for 2-12 year olds.