3 Nevirapine Studies Reporting on Liver Enzyme Elevations & Clinical Hepatitis

Three studies on nevirapine and its affect on liver enzyme tests and hepatitis were reported in Glasgow. None of the 3 studies reported baseline LFT values. Ian Sanne reported from the study conducted in South Africa and a 9.4% rate of grade 4 liver enzyme elevations (ALT, AST, alkaline phosphatase, and total bilirubin) for those taking nevirapine.

Martinez reported on a cohort of patients who received NVP and reported a 15% incidence of 3-fold increase in ALT or AST with one case of clinical hepatitis without HCV present. There were 6 cases of clinical hepatits when the patient had HCV. He reported only on elevations in GGT or ALT & AST. Martinez concluded despite the ALT or AST elevations they were mainly asymptomatic.

In the third study, Pedro Cahn reported on a large study (BI study 1090) in which 2200 patients with <200 CD4s were randomized to receive either NVP+2 nukes or 2 nukes. The median time on blinded study drug was 13 months. Follow-up was 2 years. He reported only on ALT and AST, and 3.2% receiving NVP+2 nukes had Grade 4 ALT or AST elevations vs 2.0% receiving 2 nukes. 8.2% in both arms had Grade 3/4 ALT or AST elevations. 2.8% (NVP) vs 1.4% (2 nukes) had what they called expanded hepatitis diagnosis (clinical hepatitis + infectious hepatitis). Ongoing analysis is exploring hepatitis co-infection and its role.

Martinez concluded that monitoring LFTs with NVP did not seem justifed but Cahn and Sanne concluded LFTs should be monitored.

European regulators have changed the nevirapine label to caution and advise about potential NVP related liver toxicities. In the US new product labels will be issued reflecting the same concerns. Boerhinger Ingleheim, the manufacturer of NVP, has issued a Dear Doctor Warning letter. You can read this letter and Patient and Prescription label changes at the NATAP web site:  

http://www.natap.org/Nevirapine/Nevirapine_pdfs.html

Severe liver toxicity in patients receiving 2 nukes and a NNRTI

Ian Sanne from South Africa reported on behalf of the FTC-302 Clinical Investigators and the Independent Clinical Steering Committee. FTC-302 is a randomized, placebo-controlled, double-blinded study comparing FTC to 3TC in a background of d4T and either nevirapine (NVP) (screening HIV RNA <100,000 copies/ml) or efavirenz (EFV) (screening HIV RNA >100,000 copies/ml). The study was conducted in 468 treatment-naÔveÝ patients in South Africa (385 in NVP arm and 83 in EFV arm). 59% of the patients were female and 87% were Black. HIV RNA was 4.6 and CD4 was about 350. The two arms were blinded so you don't know which arm was FTC or 3TC, but all patients received d4T. I do not think any report was made by Sanne of baseline LFTs.

• Grade 3 hepatotoxicity was defined as >5-10 times the upper limit of normal (ULN) for alklaline phosphatase, ALT, and AST.

• Grade 3 total bilirubin was defined as >2.5-5 x ULN.

• Grade 4 hepatotoxicity was defined as >10 x ULN and bilirubin as >5 x ULN. 

At week 32, there were 34 cases of grade 3/4 hepatotoxicities in Arm B and 24 in Arm A. Of the 58 with grade 3/4 outcome 50 of 58 (86%) occurred within the first 4 weeks. 4 of 58 (7%) were HbsAg positive at screening and had no evidence of active hepatitis. 2 of 58 3.5%) had serologic evidence of HCV prior to hepatotoxicity. 9 of 36 Grade 4 patients (26%) had rash which was temporarily associated with hepatotoxicity. 18 of 36 Grade 4 patients (44%) had GI symptoms. 4 of 38 (11%) Grade 4 patients had jaundice. In the program abstract Sanne reports 9.4% (n=36) at week 24 had grade 4 elevations on liver enzymes (this includes ALT, AST, alkaline phosphatase, and total bilirubin).in the NVP arm and none in the EFV arm. In the slide presentation (32 weeks) Sanne reported hepatotoxicities were observed in 58/385 (15%) of NVP treated and 0/88 EFV patients. At week 32, there were 16% grade 3/4 liver enzyme elevations in Arm B and 12% in Arm A. Sanne reported there was no significant difference between arms A & B.

Sanne also reported in the program abstract that at week 24 there was no difference between Blacks and non-Blacks in developing hepatotoxicity. Within the NVP treated patients the incidence was twice as high in females (19% vs 9%). Two patients died of liver failure, one of whom was HbsAg positive. Both patients were receiving NVP+d4T. I think he said no other factors were predictive of hepatotoxicity. He recomeneded liver enzymes in patients receiving NVP should be monitored closely particularly within the first 8 weeks of initiating therapy.

Nevirapine-induced liver toxicity: a prospective cohort study

E. MartÌnez¹, J.A. Arnaiz², A. Cruceta¹, J.B. PÈrez-Cuevas¹, A. Mocroft³, X. CarnȲ and J.M. Gatell¹

1.  Dept. of Infectious Diseases, Hospital Clinic, Barcelona, Spain;
2.. Clinical Pharmacology Unit-Hospital ClÌnic, Barcelona, Spain;
3.  HIV Research Unit, Royal Free Medical School, London, UK

Background:
Nevirapine (NVP) is a potent and reasonably well tolerated NNRTI. Recently, a warning has been added to the product information advising to monitor liver function tests (LFT) during first weeks of therapy.

Objective:
To assess the incidence of LFT abnormalities and clinical hepatitis associated with NVP-containing HAART within a prospectively followed cohort of HIV-infected patients.

Methods:
All consecutive patients who initiated a NVP-containing HAART from 9/97 to 5/00. The databases with clinical data and laboratory results (ASAT, ALAT, GGT, alkaline phosphatase (AP), bilirubin, serology for HBV and HCV) were matched. 

Results:
NVP was prescribed to 706 of the 4352 patients of the clinical database. 610 had baseline information, underwent at least one further clinical laboratory evaluation and were included in the study. Median follow-up and exposure to NVP were 12 and 9 months respectively. Twelve patients (2%) died, 32 (5.2%) were lost to follow-up while on NVP and 239 (39%) stopped NVP before the end of the study. 13/610 patients (2%) stopped NVP for liver toxicity and the remaining for other reasons, mainly virological failure (13%) or skin toxicity (9%). The number and proportions of patients with a 3-fold increase in ALAT, ASAT or GGT and Kaplanñ Meier estimates at different time points are shown in the table below.

There were seven cases of clinical hepatitis (incidence rate: 1.2 cases per 100 person-years), but 6 of them in patients with chronic liver disease due to HCV, developing from 20 to 270 days (median 60) after initiating NVP. There were no cases of fulminant hepatitis or deaths due to liver failure. Independent risk factors for 3-fold increase of ALAT  or ASAT were elevated baseline ALAT (P =0.013), seropositivity for HCV (P =0.0024) and duration of exposure to antiretrovirals (P =0.022). 

Conclusion:
NVP was generally well tolerated. Clinical hepatitis seldom appeared and other underlying factors might be related. Abnormalities in ALAT or ASAT increased steadily along first year of therapy, but they were mainly asymptomatic. LFT monitoring during first 1ñ 2 months of therapy does not seem to be justified.

Hepatic safety with nevirapine (NVP) and two nucleosides in patients with advanced HIV infection, from a placebo (PBO) controlled clinical endpoint trial (1090)

P. Cahn¹ , M. Johnson², R. Nusrat³, D. Hall³ , P. Robinson³ and the 1090 Study Team¹

1.  Foundacion Huesped, Buenos Aires, Argentina;
2.  Royal Free Hospital, London, UK;
3.  Boehringer-Ingelheim Pharmaceuticals, Ridgefield, Connecticut, USA

Background:
Study 1090 was a clinical endpoint study of NVP versus PBO, in patients with advanced HIV infection (<200 CD4s). In addition to NVP or PBO all 2200 patients received 3TC and 1 additional nuke. This international trial was conducted from December 1995 through July 1998 and offers the opportunity to examine the incidence of hepatic adverse events (AEs) due to NVP and/or background therapies, in patients from diverse regions and ethnicities.

Methods:
Adult HIV infected patients with < 200 CD4+ cells were randomized to receive NVP or PBO, plus double nucleoside (nuc) background therapy. Patients were to remain on assigned therapy until a confirmed HIV endpoint occurred, and then could switch to open label NVP+ background therapy. All patients were to be followed for 24 months, regardless of changes in therapy. Clinical and laboratory safety and treatment exposure data were recorded prospectively and evaluated for the time when patients were on blinded NVP/PBO.

• In the poster the incidence of LFT elevations were listed:
     Grade 1-- 33% vs 35% NVP vs 2 nukes respectively);
     Grade 2-- 17% 16%; 
     Grade 3-- 5% vs 6.2%; 
     Grade 4-- 3.2% vs 2%.
• Hepatic events: 9.1% NVP (n=102) vs 7.2% (n=81), p=0.092 Serious hepatic events: 1.2% n=14 (NVP) vs 0.6% n=7 (PBO), p=0.142
• Serious hepatic events + Grade 4 LFTs: 3.5% NVP (n=39) vs 2.4% PBO (n=27), p=0.128
• Increased baseline LFTs consistently predicted higher rate of hepatic events for NVP and PBO groups
  --for any hepatic event (risk ratio: 2.11, p=0.0009)
  --expanded hepatitis diagnosis (clinical+infectious hepatitis-- risk ratio: 2.84, p=0.038)
  --serious hepatitis event (risk ratio: 13.1, p=0.017)
  
• Gender, race, and geographic region were not consistently associated with increased risk of hepatic events
• About 60% of patients in NVP and PBO arms exhibited elevated LFTs at some point during study

Conclusion:
Hepatic events are encountered in HIV-infected patients taking NVP and non-NVP containing regimens. Understanding potential risk factors (such as HCV and elevated baseline LFTs) and clinically appropriate caution should help to minimize important HEs in patients receiving combination antiretroviral therapy.