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  AIDS 2002 Barcelona
Barcelona, Spain July 7-12 2002
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Nevirapine Hepatotoxicity
Reported by Jules Levin
  Boerhinger Ingelheim reported at the Intl AIDS Conference Barcelona on the Viramune Hepatic Safety Project, a study they conducted.
The potential for drug-induced liver injury or elevations in liver enzymes has emerged as one of the most important adverse reactions associated with HIV treatment. At the 2002 Human Retrovirus Conference conducted in February several studies reported that end-stage liver disease is the leading cause of death in HIV, and the rate has increased in the last few years from 5% to 8%.
These concerns have been increased because many HIV-infected individuals also have hepatitis -- an estimated 40% of HIV-infected patients also have hepatitis C and/or B. Among HIV-infected persons who were infected by IVDU it's estimated that 50-90% also have Hepatitis C and it's been estimated that about 10% of HIV-infected persons also have Hepatitis B. There has been too little research into better understanding the relative contributions of HIV, HAART, the individual ant-HIV drugs, other drugs used in HIV, and liver disease to the risk for harm to the liver; particularly in patients dually infected with HIV and hepatitis.
For patients with elevated liver enzymes (ALT) before starting HAART or patients with HCV or HBV, the chances for experiencing further elevations of ALT after starting HAART are increased.
These concerns weigh on the minds of patients and doctors. Some patients are reluctant to begin therapy over concern about the effect of HAART on their liver. Some patients stop HAART, without telling their doctors, because their ALT increased or because they are simply worried about the effect of HAART on the liver. Some doctors at times unwarrantedly withhold HAART from patients with hepatitis over concern of the effect on the liver.
Having hepatitis is another crucial factor in considering treatment for HIV and having HIV is crucial in considering treatment for hepatitis. Several studies show HIV accelerates HCV progression. In certain circumstances, it may be preferable to treat the hepatitis before the HIV. Treating the hepatitis first may make HAART more tolerable, and response to HCV therapy may be better when HCV & HIV are in the earlier stages of disease progression. Treating HCV first may make patients more comfortable with HAART and improve adherence to HAART. As well, patients can be treated for both HCV & HIV simultaneously.
Anti-HIV drugs are processed through the liver, and can have an effect of raising liver enzymes. The relationship between elevated ALT and subsequent clinical liver injury or the effect on the liver in hepatitis-infected patients remains unclear and is likely variable between individuals. Just as we don't understand why HIV progresses at different rates for different individuals, we don't clearly understand why HCV progresses more quickly for some. There are some risk factors that can increase progression such as excessive alcohol drinking and fatty liver. Fatty liver can result from excessive fat deposits in liver, which may result from elevated cholesterol & triglycerides in the blood. Since HCV therapy can improve liver function, treating HCV first may have an effect on increases in cholesterol & triglycerides that can result from HAART.
Doug Mayers, from Boerhinger Ingelheim, reported at Barcelona on this study whose purpose he stated was to characterize the hepatic safety of NVP as fully as possible and to identify possible risk factors for hepatotoxicity.
This study looked at 2545 patients in 9 controlled and 8 uncontrolled studies including NVP that were conducted between 1991-2001. Mayers reported they also reviewed a number of observational cohort studies: TARGET, CHORUS, ICONA, ATHENA, ACTG. 1912 patients in these studies were looked at as controls, they did not receive NVP.
The average number of days exposed to NVP was 340. Of the 2545 patients receiving NVP, 633 were female, 680 were black, 141 hispanic. Two independent case-selection rules were used to try to ensure identification of all potential clinical hepatic events: all hepatic and billary adverse event reported terms; all extra-hepatic or systemic terms consistent with liver disease (within 14 days of elevated ALT/AST >2 times upper limit of normal). The endpoints for this study were ALT/AST 5 times the upper limit of normal (ULN), symptomatic hepatic events (rash-associated adverse events, all other symptomatic hepatic events). Mayers reported all cases were cross-reviewed by internal and external experts blinded to the treatment patients received.
Probability of Developing Asymptomatic ALT/AST 5 Times ULN
--ALT/AST >5x ULN in controlled studies, asymptomatic and symptomatic: 8.8% (n=153) for patients taking NVP; 6.2% for patients not taking NVP (risk Ratio 1.5, p<.01); 10% for patients receiving NVP in all trials (controlled & uncontrolled). Mayers mentioned that the risk for developing ALT/AST elevations may vary by the patient group. For example, the rates of elevated ALT/AST were greater in study FTC-302 in Africa.
--symptomatic ALT/AST >5x ULN in the controlled studies: 5.8% for patients receiving NVP and 5.5% for patients not receiving NVP. 6.3% for all patients receiving NVP in all studies (controlled & uncontrolled).
--Mayers reported patients taking NVP had an increased risk for developing these ALT/ALT elevations (>5x ULN) during the first 6 weeks of therapy compared to patients not taking NVP; but after the first 6 weeks the rates for risk were comparable for patients receiving NVP or not receiving NVP
Factors that increased risk for developing 5x ULN liver enzymes:
--ALT/AST >2.5x ULN before starting therapy increased risk 4.3 times for developing symptomatic or asymptomatic ALT/AST elevations >5 times ULN
--gender was not reported as a risk factor in developing 5x ULN liver enzyme elevations, but was reported as increasing risk by 3.2 times for women for developing rash-associated hepatic events
--Mayers reported race was a weak & inconsistent risk factor
--baseline CD4 count, analyzed at different intervals, was a weak & inconsistent risk factor: for males >400 cd4s, increased risk was 1.6 times (P<.02), for females >250 cd4s increased risk of 1.3 times (p=.27)
--Mayers reported they found that the overall rate for developing >5x AST/ALT ULN was comparable to other drugs. But as stated above the risk was greater during the first 6 weeks of therapy when taking NVP
Non-Rash Associated Events
--HBV coinfection increased risk 3.9 fold (p<.01)
--Mayers reported HCV coinfection not a risk factor
Risk of Developing Symptomatic Hepatic Events
--During the first 6 weeks of therapy, the risk was greater for patients taking NVP
--after the first 6 weeks, the rate of symptomatic events was similar for patients taking NVP as for patients not taking NVP
--46% of symptomatic hepatic events were associated with rash and almost all occurred in the first 4-6 weeks of therapy
Rash-Associated Hepatic Events Risk Factors
--increased risk of 11 times for patients receiving NVP (p<.01)
--female gender, 3.2 times increased risk (p<.01)
--cd4 count >250 in females increased risk 10 times (p<.01)
--cd4s >400 in males increased risk 6.4 times (p<.01)
--rash-associated hepatic events not associated with elevated baseline ALT/AST; there were too few events to establish a relationship with HBV/HCV infection.
--other non-rash-associated hepatic events had a risk profile similar to asymptomatic ALT/AST elevations >5x ULN.
In a chart showing results from observational cohort studies (n=2198), nelfinavir showed the lowest risk compared to all the other drugs for patients developing 5x ALT/AST ULN. This is data from specified observational studies and does not necessarily prove that nelfinavir is safer than the other drugs regarding ALT elevations or the effect on the liver in coinfected patients. We need studies to examine and prove these types of things. And these types of studies are not being conducted. What regimens are safer for patients with liver disease? We need studies examining this question.
Treatment Actions During Double-Blind Period in All Patients Developing >5x ULN ALT/AST
--immediate discontinuation for hepatic reasons; 14% in NVP patients; 15% controls (patients not taking NVP)
--treatment continued without interruption: 35% for NVP patients; 46% for controls - successful 100% with NVP, 87% with controls
--interruption, recovery, and reintroduction of blinded treatment: 42% NVP, 26% controls - successful 81% NVP; 77% controls
Mayers reported symptomatic hepatic events in NVP clinical trials were rarely serious and improved on withdrawal of study drugs. Fulminant hepatic events were rare in clinical trials (0.1%).
Mayer summarized that most drug related hepatic events are asymptomatic elevations of ALT/AST, associated with HBV/HCV coinfection, elevated baseline ALT/AST, and complicated by other medications, herbs, and alcohol
Mayers reported the data from this analysis suggest:
--risk for NVP associated hepatic events is greatest during the first 6 weeks. The information reported above show there is an increased risk during the first 6 weeks of therapy for patients on NVP compared to patients not on NVP
--maintain increased clinical and laboratory surveillance in the following groups: HCV & HBV coinfected patients; patients with elevated baseline ALT/AST >2.5 to 5x ULN
--discontinue NVP permanently for ant symptomatic hepatic event (consistent with rash management guidelines for rash-associated events)
--interrupt treatment when ALT/AST is >5x ULN: evaluate for new or underling liver disease; NVP may be reintroduced on a case-by-case basis with heightened clinical and lab vigilance based on clinical needs and judgement