| |
| |
| •
| Randomized,
double-blind, 24-week study
| | •
| Compared
FTC/d4T to 3TC/d4T with either NVP or EFV
| | •
| 36/385
(9.4%) in NVP stratum developed severe hepatotoxicity: 33 in first 4 weeks
| | •
| No
hepatotoxicity in EFV stratum
| | •
| Incidence
in females 2x males (12% vs. 6%; p<0.03)
| |
|
|
| •
Hepatotoxicity may also be associated with antiretroviral therapy. How big of
a risk is it, and are certain agents implicated more?
• Bartlett
and colleagues have examined the issue of severe liver toxicity in patients receiving
a regimen consisting of two NRTIs and one NNRTI.1 This was a randomized, double-blind,
24-week study.
• They compared the combination of emitricitabine,
commonly known as FTC, and d4T to 3TC and d4T. Each of these combinations had
NNRTIs added to them, either nevirapine or efavirenz.
• A total
of 36 out of 385 patients in the nevirapine stratum developed severe hepatotoxicity.
The majority of these cases, 33, occurred during the first four weeks of therapy.
No liver toxicity occurred in the efavirenz stratum.
• Interestingly,
the incidence of hepatotoxicity was two times greater for female patients than
it was for male patients.
• Based on their results, Bartlett and
colleagues recommend that liver enzymes should be monitored closely in patients
receiving nevirapine along with other antiretroviral agents. This is particularly
important during the first eight weeks of therapy.
Reference:
1. Bartlett J and the FTC 302 Study Investigators. Severe liver toxicity in patients
receiving two nucleoside analogues and a non-nucleoside reverse transcriptase
inhibitor. Program and abstracts of the 8th Conference on Retroviruses and Opportunistic
Infections, Chicago, IL; February 4-8, 2001.
| |
| | |
| •
| Prospective
study of 298 patients with new NNRTI regimens (NVP-202, EFV-96)
|
| •
| AST
and ALT taken before/during therapy
| | •
| HCV
and HBV routinely performed
| | •
| 41/298
(13.8%) developed severe hepatotoxicity
| | •
| Incidence
rate similar for NVP and EFV
| | •
| Chronic
HCV or HBV did not increase risk
| |
|
| | •
The risk of hepatotoxicity has also been investigated in relationship to chronic
viral hepatitis.
• Sulkowski and colleagues conducted a prospective
study of 298 patients who were prescribed new NNRTI regimens containing either
nevirapine or efavirenz.1
• AST and ALT levels were evaluated before
and during antiretroviral therapy. They defined severe hepatotoxicity as grade
3 or 4 changes according to standard toxicity criteria.
• A total
of 41 patients developed severe hepatotoxicity, 33 receiving nevirapine and 8
receiving efavirenz. However, the incidence rate was similar for both agents.
The higher number of cases with nevirapine was attributed to longer time on therapy.
Only a CD4 cell response of greater than 50 cells/_L was independently associated
with severe hepatotoxicity.
• Chronic hepatitis C or hepatitis
B virus infection was not associated with an increased risk of severe toxicity.
Therefore, it is not necessary to withhold NNRTI therapy from patients with chronic
viral hepatitis.
Reference:
1. Sulkowski M, Mehta S, Thomas
D, Moore R. Hepatotoxicity associated with NNRTI use: role of drugs and chronic
viral hepatitis. Program and abstracts of the 8th Conference on Retroviruses and
Opportunistic Infections, Chicago, IL; February 4-8, 2001. Abstract 618..
| |
|
| •
| Hepatotoxicity
associated with NRTI/HU searched for among FDA AERS data
|
| •
| 34
cases found with any NRTI/HU (31 ddI)
| | | -
| 11/18
(61%) of ddI/d4T/HU cases fatal
| | | -
| 4/16
(25%) of other NRTI/HU cases fatal | | •
| 73
cases found with ddI/d4T without HU
| | | -
| 25/73
(34%) cases fatal
| |
|
| | •
A final study has investigated cases of hepatotoxicity associated with the combination
of hydroxyurea and NRTIs.
• Boxwell and Toerner searched data from
the FDA’s Adverse Effect Reporting System for reports of hepatotoxicity associated
with the use of any NRTI with hydroxyurea at doses of up to 1 gram per day.1
• They found 34 cases, 31 of which were associated with ddI use. Out
of 18 cases found for the combination of ddI + d4T + hydroxyurea, 11 were fatal.
Of the 16 cases associated with other NRTI/hydroxyurea combinations, four were
found to be fatal.
• Another 73 cases of hepatotoxicity were found
in patients using the combination of ddI + d4T without concomitant hydroxyurea.
• In conclusion, using hydroxyurea with NRTI combinations may increase
the risk of death from hepatotoxicity. Liver toxicity associated with NRTI therapy,
combined with hydroxyurea’s ability to enhance intracellular incorporation
of NRTIs, may be responsible for this effect. A fatal outcome may be further enhanced
with the combination of ddI + d4T + hydroxyurea. Given these risks, any patient
receiving hydroxyurea with any NRTI combinations should be aggressively monitored
for liver toxicity.
Reference:
1. Boxwell D, Toerner J. Fatal
hepatotoxicity associated with combination hydroxyurea and nucleoside reverse
transcriptase inhibitors (NRTIs): cases from the FDA adverse event reporting system
(AERS). Program and abstracts from the 8th Conference on Retroviruses and Opportunistic
Infections, Chicago, IL; February 4-8, 2001. Abstract 617. |
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