Fatal lactic acidosis associated with tenofovir

[Guest guest]

BMJ 2003;327:711 (27 September)

Drug points: Fatal lactic acidosis associated with tenofovir

Pablo Rivas, medical doctor1, Polo, medical doctor1, de

Górgolas, medical doctor1, L Fernández-Guerrero, medical doctor1

1 Division of Infectious Diseases, Fundación Jiménez Díaz, Universidad

Autónoma de Madrid, Avda Reyes Católicos 2, 28040, Madrid, Spain

Correspondence to: P Rivas pablorivasg@...

Recently introduced, tenofovir disoproxil is the first nucleotide analogue

for treating HIV-1 infection.1 We report a fatal case of lactic acidosis

during treatment with tenofovir.

A 45 year old woman presented with vomiting, abdominal pain, and

obtundation. She was HIV positive and had been recently treated with a

combination of didanosine, stavudine, and nevirapine and had chronic

hepatitis C. Because concentrations of liver enzymes had increased eight

weeks before admission, nevirapine was stopped; concentrations then returned

to initial values. Admitting doctors prescribed enteric coated didanosine

(250 mg a day), stavudine (30 mg twice a day), and tenofovir (300 mg a day).

Three days before admission she had developed vomiting, abdominal pain, and

then confusion and obtundation. On admission she was jaundiced and

disoriented, and we felt tender hepatomegaly. Laboratory values were serum

aspartate aminotransferase 2.35 µkat/l (normal range 0.18-0.58 µkat/l),

serum alanine aminotransferase 2.68 (0.08-0.72) µkat/l, total bilirubin

215.46 (1.71-22.23) µmol/l, amylase 9.35 (0-1.67) µkat/l, lipase 57.58

(1.9-4.77) µkat/l, international normalised ratio for prothrombin time 2.12,

blood pH 7.24, Pco2 2.38 (4.66-5.99) kPa, sodium bicarbonate 11.4 (22-26)

mmol/l, and lactic acid 16.38 (0.6-1.7) mmol/l. Computed tomography showed

fatty infiltration of the liver and slight enlargement of pancreas.

We discontinued antiretrovirals and gave her bicarbonate, vitamin K,

thiamin, and riboflavin. Unfortunately, lactic acidosis worsened; she

developed severe bleeding and died 36 hours later.

Tenofovir is being increasingly used even though its safety is not certain.2

Because of its low affinity for mitochondrial DNA polymerase , tenofovir may

be less toxic to mitochondria than nucleoside analogues and less likely to

cause hyperlacticacidaemia.3 4 But we believe that tenofovir was central to

the onset of hyperlacticacidaemia because the woman died soon after taking

the drug.

The woman had taken stavudine and didanosine without side effects. Tenofovir

may have directly caused lactic acidosis or may have affected the toxicity

of the other drugs. Taking tenofovir and didanosine together can increase

didanosine concentrations by 60%, leading to hyperlacticacidaemia.5 Patients

who take tenofovir and didanosine should be closely monitored. Doses of

didanosine should allow for simultaneous use of tenofovir.

--------------------------------------------------------------------------------

Funding: None.

Competing interests: None declared.

References

FDA approves Viread for HIV-1 infection. FDA Consum 2002;36: 5.

Cheng A, Barriere S, Coackley DF, Chen SS, Wulfsohn M, Toole JJ. Safety

profile of Tenofovir DF in antiretroviral treatment-experienced patients

from randomized, double-blind, placebo-controlled clinical trials. 14th

International AIDS Conference, Barcelona, July 2002. (Abstract No

TuPeB4460.)

Birkus G, Hitchcock MJ, Cihlar T. Assessment of mitochondrial toxicity in

human cells treated with tenofovir: comparison with other nucleoside reverse

transcriptase inhibitors. Antimicrob Agents Chemother 2002;46:

716-23.[Abstract/Free Full Text]

Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase

inhibitor-induced mitochondrial toxicity. Clin Ther 2000;22:

685-708.[CrossRef][iSI][Medline]

Kearney BP, Damle B, Plummer A, Sayre J, Zhang X, K, et al. Tenofovir

DF (TDF) and Didanosine EC (ddI EC): investigation of pharmacokinetic (PK)

drug-drug and drug-food interactions. 14th International AIDS Conference,

Barcelona, July 2002. (Abstract No LbPeB9026.)

(Accepted June 4, 2003)

[Guest guest]

BMJ 2003;327:711 (27 September)

Drug points: Fatal lactic acidosis associated with tenofovir

Pablo Rivas, medical doctor1, Polo, medical doctor1, de

Górgolas, medical doctor1, L Fernández-Guerrero, medical doctor1

1 Division of Infectious Diseases, Fundación Jiménez Díaz, Universidad

Autónoma de Madrid, Avda Reyes Católicos 2, 28040, Madrid, Spain

Correspondence to: P Rivas pablorivasg@...

Recently introduced, tenofovir disoproxil is the first nucleotide analogue

for treating HIV-1 infection.1 We report a fatal case of lactic acidosis

during treatment with tenofovir.

A 45 year old woman presented with vomiting, abdominal pain, and

obtundation. She was HIV positive and had been recently treated with a

combination of didanosine, stavudine, and nevirapine and had chronic

hepatitis C. Because concentrations of liver enzymes had increased eight

weeks before admission, nevirapine was stopped; concentrations then returned

to initial values. Admitting doctors prescribed enteric coated didanosine

(250 mg a day), stavudine (30 mg twice a day), and tenofovir (300 mg a day).

Three days before admission she had developed vomiting, abdominal pain, and

then confusion and obtundation. On admission she was jaundiced and

disoriented, and we felt tender hepatomegaly. Laboratory values were serum

aspartate aminotransferase 2.35 µkat/l (normal range 0.18-0.58 µkat/l),

serum alanine aminotransferase 2.68 (0.08-0.72) µkat/l, total bilirubin

215.46 (1.71-22.23) µmol/l, amylase 9.35 (0-1.67) µkat/l, lipase 57.58

(1.9-4.77) µkat/l, international normalised ratio for prothrombin time 2.12,

blood pH 7.24, Pco2 2.38 (4.66-5.99) kPa, sodium bicarbonate 11.4 (22-26)

mmol/l, and lactic acid 16.38 (0.6-1.7) mmol/l. Computed tomography showed

fatty infiltration of the liver and slight enlargement of pancreas.

We discontinued antiretrovirals and gave her bicarbonate, vitamin K,

thiamin, and riboflavin. Unfortunately, lactic acidosis worsened; she

developed severe bleeding and died 36 hours later.

Tenofovir is being increasingly used even though its safety is not certain.2

Because of its low affinity for mitochondrial DNA polymerase , tenofovir may

be less toxic to mitochondria than nucleoside analogues and less likely to

cause hyperlacticacidaemia.3 4 But we believe that tenofovir was central to

the onset of hyperlacticacidaemia because the woman died soon after taking

the drug.

The woman had taken stavudine and didanosine without side effects. Tenofovir

may have directly caused lactic acidosis or may have affected the toxicity

of the other drugs. Taking tenofovir and didanosine together can increase

didanosine concentrations by 60%, leading to hyperlacticacidaemia.5 Patients

who take tenofovir and didanosine should be closely monitored. Doses of

didanosine should allow for simultaneous use of tenofovir.

--------------------------------------------------------------------------------

Funding: None.

Competing interests: None declared.

References

FDA approves Viread for HIV-1 infection. FDA Consum 2002;36: 5.

Cheng A, Barriere S, Coackley DF, Chen SS, Wulfsohn M, Toole JJ. Safety

profile of Tenofovir DF in antiretroviral treatment-experienced patients

from randomized, double-blind, placebo-controlled clinical trials. 14th

International AIDS Conference, Barcelona, July 2002. (Abstract No

TuPeB4460.)

Birkus G, Hitchcock MJ, Cihlar T. Assessment of mitochondrial toxicity in

human cells treated with tenofovir: comparison with other nucleoside reverse

transcriptase inhibitors. Antimicrob Agents Chemother 2002;46:

716-23.[Abstract/Free Full Text]

Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase

inhibitor-induced mitochondrial toxicity. Clin Ther 2000;22:

685-708.[CrossRef][iSI][Medline]

Kearney BP, Damle B, Plummer A, Sayre J, Zhang X, K, et al. Tenofovir

DF (TDF) and Didanosine EC (ddI EC): investigation of pharmacokinetic (PK)

drug-drug and drug-food interactions. 14th International AIDS Conference,

Barcelona, July 2002. (Abstract No LbPeB9026.)

(Accepted June 4, 2003)

[Guest guest]

BMJ 2003;327:711 (27 September)

Drug points: Fatal lactic acidosis associated with tenofovir

Pablo Rivas, medical doctor1, Polo, medical doctor1, de

Górgolas, medical doctor1, L Fernández-Guerrero, medical doctor1

1 Division of Infectious Diseases, Fundación Jiménez Díaz, Universidad

Autónoma de Madrid, Avda Reyes Católicos 2, 28040, Madrid, Spain

Correspondence to: P Rivas pablorivasg@...

Recently introduced, tenofovir disoproxil is the first nucleotide analogue

for treating HIV-1 infection.1 We report a fatal case of lactic acidosis

during treatment with tenofovir.

A 45 year old woman presented with vomiting, abdominal pain, and

obtundation. She was HIV positive and had been recently treated with a

combination of didanosine, stavudine, and nevirapine and had chronic

hepatitis C. Because concentrations of liver enzymes had increased eight

weeks before admission, nevirapine was stopped; concentrations then returned

to initial values. Admitting doctors prescribed enteric coated didanosine

(250 mg a day), stavudine (30 mg twice a day), and tenofovir (300 mg a day).

Three days before admission she had developed vomiting, abdominal pain, and

then confusion and obtundation. On admission she was jaundiced and

disoriented, and we felt tender hepatomegaly. Laboratory values were serum

aspartate aminotransferase 2.35 µkat/l (normal range 0.18-0.58 µkat/l),

serum alanine aminotransferase 2.68 (0.08-0.72) µkat/l, total bilirubin

215.46 (1.71-22.23) µmol/l, amylase 9.35 (0-1.67) µkat/l, lipase 57.58

(1.9-4.77) µkat/l, international normalised ratio for prothrombin time 2.12,

blood pH 7.24, Pco2 2.38 (4.66-5.99) kPa, sodium bicarbonate 11.4 (22-26)

mmol/l, and lactic acid 16.38 (0.6-1.7) mmol/l. Computed tomography showed

fatty infiltration of the liver and slight enlargement of pancreas.

We discontinued antiretrovirals and gave her bicarbonate, vitamin K,

thiamin, and riboflavin. Unfortunately, lactic acidosis worsened; she

developed severe bleeding and died 36 hours later.

Tenofovir is being increasingly used even though its safety is not certain.2

Because of its low affinity for mitochondrial DNA polymerase , tenofovir may

be less toxic to mitochondria than nucleoside analogues and less likely to

cause hyperlacticacidaemia.3 4 But we believe that tenofovir was central to

the onset of hyperlacticacidaemia because the woman died soon after taking

the drug.

The woman had taken stavudine and didanosine without side effects. Tenofovir

may have directly caused lactic acidosis or may have affected the toxicity

of the other drugs. Taking tenofovir and didanosine together can increase

didanosine concentrations by 60%, leading to hyperlacticacidaemia.5 Patients

who take tenofovir and didanosine should be closely monitored. Doses of

didanosine should allow for simultaneous use of tenofovir.

--------------------------------------------------------------------------------

Funding: None.

Competing interests: None declared.

References

FDA approves Viread for HIV-1 infection. FDA Consum 2002;36: 5.

Cheng A, Barriere S, Coackley DF, Chen SS, Wulfsohn M, Toole JJ. Safety

profile of Tenofovir DF in antiretroviral treatment-experienced patients

from randomized, double-blind, placebo-controlled clinical trials. 14th

International AIDS Conference, Barcelona, July 2002. (Abstract No

TuPeB4460.)

Birkus G, Hitchcock MJ, Cihlar T. Assessment of mitochondrial toxicity in

human cells treated with tenofovir: comparison with other nucleoside reverse

transcriptase inhibitors. Antimicrob Agents Chemother 2002;46:

716-23.[Abstract/Free Full Text]

Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase

inhibitor-induced mitochondrial toxicity. Clin Ther 2000;22:

685-708.[CrossRef][iSI][Medline]

Kearney BP, Damle B, Plummer A, Sayre J, Zhang X, K, et al. Tenofovir

DF (TDF) and Didanosine EC (ddI EC): investigation of pharmacokinetic (PK)

drug-drug and drug-food interactions. 14th International AIDS Conference,

Barcelona, July 2002. (Abstract No LbPeB9026.)

(Accepted June 4, 2003)

[Guest guest]

BMJ 2003;327:711 (27 September)

Drug points: Fatal lactic acidosis associated with tenofovir

Pablo Rivas, medical doctor1, Polo, medical doctor1, de

Górgolas, medical doctor1, L Fernández-Guerrero, medical doctor1

1 Division of Infectious Diseases, Fundación Jiménez Díaz, Universidad

Autónoma de Madrid, Avda Reyes Católicos 2, 28040, Madrid, Spain

Correspondence to: P Rivas pablorivasg@...

Recently introduced, tenofovir disoproxil is the first nucleotide analogue

for treating HIV-1 infection.1 We report a fatal case of lactic acidosis

during treatment with tenofovir.

A 45 year old woman presented with vomiting, abdominal pain, and

obtundation. She was HIV positive and had been recently treated with a

combination of didanosine, stavudine, and nevirapine and had chronic

hepatitis C. Because concentrations of liver enzymes had increased eight

weeks before admission, nevirapine was stopped; concentrations then returned

to initial values. Admitting doctors prescribed enteric coated didanosine

(250 mg a day), stavudine (30 mg twice a day), and tenofovir (300 mg a day).

Three days before admission she had developed vomiting, abdominal pain, and

then confusion and obtundation. On admission she was jaundiced and

disoriented, and we felt tender hepatomegaly. Laboratory values were serum

aspartate aminotransferase 2.35 µkat/l (normal range 0.18-0.58 µkat/l),

serum alanine aminotransferase 2.68 (0.08-0.72) µkat/l, total bilirubin

215.46 (1.71-22.23) µmol/l, amylase 9.35 (0-1.67) µkat/l, lipase 57.58

(1.9-4.77) µkat/l, international normalised ratio for prothrombin time 2.12,

blood pH 7.24, Pco2 2.38 (4.66-5.99) kPa, sodium bicarbonate 11.4 (22-26)

mmol/l, and lactic acid 16.38 (0.6-1.7) mmol/l. Computed tomography showed

fatty infiltration of the liver and slight enlargement of pancreas.

We discontinued antiretrovirals and gave her bicarbonate, vitamin K,

thiamin, and riboflavin. Unfortunately, lactic acidosis worsened; she

developed severe bleeding and died 36 hours later.

Tenofovir is being increasingly used even though its safety is not certain.2

Because of its low affinity for mitochondrial DNA polymerase , tenofovir may

be less toxic to mitochondria than nucleoside analogues and less likely to

cause hyperlacticacidaemia.3 4 But we believe that tenofovir was central to

the onset of hyperlacticacidaemia because the woman died soon after taking

the drug.

The woman had taken stavudine and didanosine without side effects. Tenofovir

may have directly caused lactic acidosis or may have affected the toxicity

of the other drugs. Taking tenofovir and didanosine together can increase

didanosine concentrations by 60%, leading to hyperlacticacidaemia.5 Patients

who take tenofovir and didanosine should be closely monitored. Doses of

didanosine should allow for simultaneous use of tenofovir.

--------------------------------------------------------------------------------

Funding: None.

Competing interests: None declared.

References

FDA approves Viread for HIV-1 infection. FDA Consum 2002;36: 5.

Cheng A, Barriere S, Coackley DF, Chen SS, Wulfsohn M, Toole JJ. Safety

profile of Tenofovir DF in antiretroviral treatment-experienced patients

from randomized, double-blind, placebo-controlled clinical trials. 14th

International AIDS Conference, Barcelona, July 2002. (Abstract No

TuPeB4460.)

Birkus G, Hitchcock MJ, Cihlar T. Assessment of mitochondrial toxicity in

human cells treated with tenofovir: comparison with other nucleoside reverse

transcriptase inhibitors. Antimicrob Agents Chemother 2002;46:

716-23.[Abstract/Free Full Text]

Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase

inhibitor-induced mitochondrial toxicity. Clin Ther 2000;22:

685-708.[CrossRef][iSI][Medline]

Kearney BP, Damle B, Plummer A, Sayre J, Zhang X, K, et al. Tenofovir

DF (TDF) and Didanosine EC (ddI EC): investigation of pharmacokinetic (PK)

drug-drug and drug-food interactions. 14th International AIDS Conference,

Barcelona, July 2002. (Abstract No LbPeB9026.)

(Accepted June 4, 2003)