Tenofovir is an acyclic nucleotide analogue of adenosine used in combination with other agents in the therapy of the human immunodeficiency virus (HIV) and as single agent in hepatitis B virus (HBV) infection. Tenofovir does not appear to be a significant cause of drug induced liver injury.


Tenofovir (ten of' oh vir) is an acyclic nucleotide analogue of adenosine, but is poorly absorbed orally. For this reason, the prodrug is used, either tenofovir disoproxil fumarate or more recently tenofovir alafenamide, which are well absorbed from the intestines, rapidly hydrolyzed to tenofovir intracellularly and then phosphorylated to the active form, tenofovir diphosphate. Tenofovir diphosphate is a competitive inhibitor of the HIV reverse transcriptase (and the HBV polymerase) and is also incorporated into the nascent DNA strand causing chain termination. Tenofovir disoproxil fumarate (TDF) was approved for use in HIV infection in the United States in 2001 and for use in hepatitis B in 2008. Tenofovir alafenamide (TAF) was approved in 2015 for use both in HIV and HBV infection. Clinical indications include treatment and prevention of HIV infection, usually in combination with other reverse transcriptase, protease or integrase inhibitors. Tenofovir is also approved for use in chronic hepatitis B as a single agent. TDF is available generically and under the brand name Viread in 300 mg oral tablets. TAF is available under the brand name Vemlidy in 25 mg tablets. Both TDF and TAF are also available in various fixed combinations with other antiviral agents for use in treatment of HIV infection, usually in a single oral daily dose that is often referred to as a “single tablet regimen” (STR) which is extremely helpful in insuring compliance with HIV therapy. Examples of some of the single tablet regimen combinations and their brand names and doses are given in the Table below. The recommended daily dose of TDF in adults is 300 mg and of TAF is 25 mg, the lower dose of TAF being considered important in decreasing long term side effects, particularly those on phosphate metabolism and bone and kidney effects. Side effects of tenofovir are not common but can include asthenia, diarrhea, flatulence, nausea and vomiting, headache, renal dysfunction and rash. Rare but potentially severe adverse events associated with long term therapy include lactic acidosis and liver failure when given with other antiretroviral agents, severe withdrawal flares of hepatitis B upon discontinuation of tenofovir therapy, osteoporosis, and phosphate wasting proximal tubular dysfunction, renal tubular acidosis and renal failure. The bone and renal effects of tenofovir are believed to be less common with TAF than TDF.

Table: Tenofovir Combination Single Tablet Regimens Approved for HIV Therapy*


Like all nucleoside analogues used as therapy of hepatitis B, tenofovir can cause transient increases in serum aminotransferases during or after therapy. These abnormalities appear to be due to an exacerbation or flare of the underlying hepatitis B. Three types of flares due to nucleoside analogue therapy have been described: transient flares during initiation of therapy (treatment flares), flares occurring in association with development of antiviral resistance (breakthrough flares) and flares occurring in the few months after stopping therapy (withdrawal flares). Treatment flares generally arise during the first few months of starting therapy, are usually mild, asymptomatic and self-limited and do not require dose modification or interruption of therapy. Breakthrough flares generally follow the development of antiviral resistance and subsequent rise in HBV DNA levels during nucleoside analogue therapy. Breakthrough flares can be symptomatic and severe. Because tenofovir is associated with a very low rate of antiviral resistance (<1% after 4 years), no convincing cases of breakthrough hepatitis have been linked to its use. Finally, sudden discontinuation of antiviral therapy is capable of causing a hepatitis B withdrawal flare. Withdrawal flares can be severe and several instances of acute liver failure resulting in death or the need for liver transplantation have been reported after stopping nucleoside analogue therapy. The rate of such flares after withdrawal of tenofovir therapy has not been clearly defined.

Tenofovir appears to have little or no direct hepatotoxicity. In patients without HBV and HIV infection, given tenofovir as a part of preexposure prevention, minor serum ALT and AST elevations are more frequent than with placebo, but are rarely above 5 times ULN (<1%). There have been no convincing reports of acute, clinically apparent liver injury attributable to tenofovir, although the combination of tenofovir and didanosine appears to lead to liver injury, with microvesicular fatty liver disease and lactic acidosis more commonly than didanosine with other antiretrovirals, perhaps because of drug-drug interactions. Tenofovir may also predispose to serum aminotransferase elevations during efavirenz therapy, again possibly because of drug-drug interactions.

Likelihood score: C (has been associated with flares of hepatitis when it is withdrawn and rarely with a sudden antiviral effect early during therapy and finally linked to episodes of lactic acidosis due to its effects on drug levels of other nucleosides that can cause lactic acidosis).

Mechanism of Injury

The majority of cases of lactic acidosis and hepatic failure in patients receiving tenofovir appear to be due to didanosine, stavudine or zidovudine coadministration. Addition of tenofovir to an antiretroviral regimen including didanosine concurrently can increase didanosine concentrations by up to 60%, thus amplifying its potential to cause mitochondrial injury. Tenofovir by itself appears to have little hepatotoxic potential.

Outcome and Management

The minor ALT elevations associated with initiation of tenofovir therapy in chronic hepatitis B are usually asymptomatic and transient. Care should be taken in stopping tenofovir therapy in patients with chronic HBV infection. If administered concurrently with tenofovir, didanosine should be reduced in dosage and patients monitored carefully.

Agents used in therapy of HBV infection include adefovir, emtricitabine, entecavir, lamivudine, telbivudine, tenofovir, interferon alfa and peginterferon.

Drug Class: Antiviral Agents, Antiretroviral Agents, Hepatitis B Agents

Other Drugs in the Subclass, Nucleoside Analogues: Abacavir, Adefovir, Didanosine, Emtricitabine, Entecavir, Lamivudine, Stavudine, Telbivudine, Zidovudine


Case 1. Lactic acidosis arising during therapy with didanosine after addition of tenofovir.(1)

A 45 year old woman with HIV infection and chronic hepatitis C developed vomiting, abdominal pain, and obtundation 8 weeks after the addition of tenofovir to her long term antiretroviral regimen of stavudine and didanosine. Tenofovir was used to replace nevirapine, which was discontinued because of minor serum enzymes elevations which then returned to initial values. On admission, she was jaundiced and disoriented and had tender hepatomegaly. Serum bilirubin was 12.6 mg/dL, ALT 157 U/L, and an international normalized ratio (INR) was 2.1. She had lactic acidosis with blood pH of 7.24 and lactate levels of 16.4 mmol/L. Imaging of the liver suggested fatty infiltration. Antiretrovirals were discontinued, but the lactic acidosis and hepatic failure worsened and she died two days after admission.

Key Points


Acute microvesicular hepatic steatosis with liver failure and lactic acidosis is a syndrome associated with several medications including the nucleoside analogues, particularly didanosine, stavudine and zidovudine. A similar syndrome occurs with intravenous tetracycline, aspirin (Reyes syndrome) and valproate, but the timing and course is different for those agents (shorter latency period), probably because they directly affect function of mitochondria rather than by causing functional failure by inhibition of mitochondrial replication and mitochondrial depletion. Mitochondria have a half-life of several weeks, so that inhibition of mitochondrial replication would be expected to lead to severe dysfunction (mitochondrial failure) after 2 to 3 months. Both didanosine and stavudine have been linked to many cases of hepatic steatosis and lactic acidosis and the addition of tenofovir appears to increase the risk of this complication. This syndrome has not been reported with the use of tenofovir alone. Other risk factors for hepatic steatosis with lactic acidosis include presence of underlying liver disease (such as hepatitis C), obesity and alcohol use.

Case 2. Transient flare of hepatitis B with initiation of tenofovir therapy.(2)

A 29 year old Asian-American woman was started on the combination of tenofovir and emtricitabine (Truvada) in a clinical trial of therapy of HBeAg-positive hepatitis B and developed a doubling of serum ALT levels to ~14 times the upper limit of normal within two weeks of starting therapy. At the same time, HBV DNA levels had fallen by four log10 IU (352 million to 36,160 IU/mL), but she remained HBsAg and HBeAg positive. Serum direct and total bilirubin levels increased slightly, but remained in the normal range. She had no symptoms of hepatitis and reported no other side effects. Tests for hepatitis A, C and D showed no evidence of de novo infection with these viruses. She was taking no other medications or herbal products. The dose of tenofovir and emtricitabine was not changed and, subsequently, her serum aminotransferase levels fell into the normal range and HBV DNA to undetectable. After 36 weeks of treatment, she became HBeAg-negative but did not develop anti-HBe. At one year, histologic evidence of inflammation and fibrosis had improved, but she remained HBsAg-positive and was continued on therapy.

Key Points

Laboratory Values


A minor flare in hepatitis is not uncommon with initiation of antiviral therapy of hepatitis B and should not lead to dose modification, if HBV DNA levels are decreasing and no other cause for acute liver injury can be found. The flare of hepatitis probably represents an immunological reaction to the sudden decrease in HBV replication and may actually be a favorable sign, predictive of a serological and virological response (loss of HBeAg during treatment which occurred at 36 weeks).



Tenofovir (Tenofovir disoproxil fumarate) – Generic, Viread®

Tenofovir (Tenofovir alafenamide) – Generic, Vemlidy®


Antiviral Agents

COMPLETE LABELING (Tenofovir disoproxil fumarate)

COMPLETE LABELING (Tenofovir alafenamide)

Product labeling at DailyMed, National Library of Medicine, NIH



Rivas P, Polo J, de Górgolas M, Fernández-Guerrero ML. Drug Points: Fatal lactic acidosis associated with tenofovir. BMJ. 2003;327:711. [PMC free article: PMC200801] [PubMed: 14512477]
Case from the National Institutes of Health, Tenofovir Study Patient A2.


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