Abrahams, M

Boulle, A

Chu, K

Ford, N

Goemaere, E

Hilderbrand, K

Mathee, S

English

MSF Field Research

Nevirapine-Induced Hepatotoxicity: Incidence, Risk Factors, and Associated 
Mortality in a Primary Care ART Programme in South Africa
6
0
3
Kathryn Chu1, Andrew Boulle2, Nathan Ford1,2, Katherine Hilderbrand1,2, Eric Goemaere1, Musaed Abrahams1, Shaheed Mathee3
& Gilles Van Cutsem*1,2
Ph: +27-21-3645490
Fx: +27-21-3617051
gillesvancutsem@gmail.com
Médecins Sans Frontières
South Africa
1.
Fax: +27-21-406-6764
University of Cape Town
Ph:   +27-21-406-6711
andrew.boulle@uct.ac.za
http://www.ideu.uct.ac.za
2.
School of Public Health and Family Medicine
Table 1: Patient characteristics at initiation of ART
Discussion and conclusions
Risk Factors of  Hepatotoxicity and Mortality
 The overall incidence of HT in this cohort was lower than reported in clinical trials.
 HT resolved despite continuing NVP in a subset of patients.
 Low CD4 count and gender were not found to be associated with HT contrary to previous studies.
 Most hepatotoxic events occurred during the first 8 weeks on ART.
 ALT screening according to protocol was only accomplished in a small proportion of patients. This
highlights the difficulties in implementing serial ALT monitoring in a high burden resource-limited setting.
In this context, ALT measurements are usually prompted by clinical symptoms.
 Serial ALT monitoring is likely to be even less feasible in settings with less resources than South Africa.
Objectives
Background
Baseline Characteristics
Incidence of Hepatotoxicity
Table 2: Grade of Alanine Aminotransferase on Nevirapine Based Antiretroviral Therapy
Background Nevirapine (NVP) is used by more than 60% of patients on first line antiretroviral therapy
(ART) in low-income countries. One of the primary concerns with NVP is associated severe hepatotoxicity
(HT). International guidelines recommend frequent screening of alanine transferase (ALT) serum levels.
This is often not feasible in resource limited settings. We describe the incidence, risk factors, and
associated mortality of NVP-associated HT in a primary care antiretroviral therapy (ART) programme in
Khayelitsha, South Africa.
Methods Prospective cohort study of all treatment-naïve adults initiating NVP-based ART in Khayelitsha
from November 2002 to December 2006. We used Kaplan-Meier analyses to estimate time to HT and
mortality, and Cox proportional hazards regression to model risk factors of HT and mortality. Logistic
regression was used to determine factors associated with HT at baseline. HT was defined as ALT above 5
times the upper limit of normal.
Results 1831 adults were initiated on NVP-based ART during the study period. 382 (21.1%) were male.
The median baseline CD4 count was 112 cells/ µl. South African guidelines were recommending ALT
measurements at 0, 2, 4, 8, 12, and 24 weeks. Only 6.9% of patients had ALT measured according to
protocol. A baseline CD4 count below 50 cells/µl was associated with baseline HT (OR 16.5, 95% CI: 1.8-
151.3). 26 (1.4%) of 1831 patients developed HT. The incidence of early hepatotoxicity on protocol was
1.9% (18/911) compared to 0.9% (8/920) off protocol (p=0.045). Of those that were on protocol, 12 (1.3%)
developed HT by 4 weeks, 4 (0.4%) between 4- 8 weeks, and 2 (0.2%) between 8-12 weeks. Of the 8 who
inadvertently continued NVP, all resolved their HT. The median time to HT was 56 days (IQR 28-121).
Three (0.16%) patients died. All had discontinued NVP and had been restarted on efavirenz.
Conclusion The overall incidence of HT in this cohort was lower than reported in clinical trials. HT at
baseline and female gender were not found to be associated with HT contrary to previous studies. HT
resolved despite continuing NVP in a subset of patients. ALT screening according to protocol was only
accomplished in a small proportion of patients. This highlights the difficulties in implementing serial ALT
monitoring in a high burden resource limited setting. In this context, ALT measurements are usually
prompted by clinical symptoms. Further research into the sensitivity of symptoms is needed to determine
whether clinical criteria alone should be recommended to monitor HT in resource poor settings.
ABSTRACT
Nevirapine (NVP) is used by more than 60% of patients on first line antiretroviral therapy  
in low income countries. One of the primary concerns with NVP is associated severe 
hepatotoxicity (HT).  International guidelines recommend frequent screening of alanine 
transferase (ALT) serum levels.  This is often not feasible in resource limited settings. 
Setting: Khayelitsha, South Africa
The objectives of this study were to describe the incidence, risk factors, and associated
mortality of NVP-associated hepatotoxicity in a primary care antiretroviral therapy (ART)
programme in Khayelitsha, South Africa.
Grade of Hepatotoxicity Time to Hepatotoxicity
Baseline Characteristics Total Cohort
Total on NVP 1831
Males 387 (21)
Age on starting NVP based ART, years 32 (28-37)
Baseline CD4+ count, cell/µl 112 (57-164)
Baseline viral load, log10 copies 5.0 (4.5-5.5)
WHO clinical staging on starting ART
   Stage 1 161 (9)
   Stage 2 198 (11)
   Stage 3 930 (51)
   Stage 4 542 (230)
Weight on starting ART, kg 60 (53-69)
Follow-up time on NVP-based ART, months 13 (6-22)
6 month mortality 77 (4.2)
* Patients with at least a baseline and a 4 week ALT measurement
Continous variables are given as medians (interquartile range).  
Ordinal and discrete variables are given as n(%).  NVP, Nevirapine.  
ART, antiretroviral therapy.   WHO, World Health Organization. 
Total*
On Protocol 1444 (78.9) 911 (49.7) 368 (20.1) 127 (6.9) 2850  
ALT Grade  
Grade 0 1314 (90.3) 779 (85.6) 321 (87.2) 105 (82.7) 2519 (88.4)
Grade 1 110 (7.6) 86 (9.4) 33 (9.0) 17 (13.4) 246 (8.6)
Grade 2 13 (0.9) 32 (3.5) 9 (2.4) 3 (2.4) 57 (2.0)
Grade 3 6 (0.4) 5 (0.6) 3 (0.8) 2 (1.6) 16 (0.6)
Grade 4 2 (0.1) 9 (0.1) 2 (0.5) 0 (0.0) 13 (0.5)
*Total visits while on protocol 
8 weeks 12 weeks 4 weeks Baseline
Ordinal and discrete variables are given as n(%).  ALT, alanine aminotransferase.  ALT grade 0: < 1.25x upper limit of normal (ULN); grade 1: 1.25-2.5x ULN; 
grade 2: 2.6-5.0x ULN, grade 3: 5.1-10x ULN; grade 4: > 10x ULN.  
Table 3: Risk Factors of Mortality
HR 95% CI p HR 95% CI p
Males 1.12 (0.64-1.97) 0.693 1.40 (0.78-2.53) 0.265
Age on starting NVP based ART, years 1.00 (0.98-1.04) 0.490 1.01 (0.99-1.04) 0.299
Baseline CD4 count<50 cell/µl 3.80 (2.42-5.93) <0.001 3.88 (2.47-6.07) <0.001
Concurrent TB infection 0.93 (0.54-1.62) 0.807
PMTCT 0.81 (0.60-1.10) 0.184
Hepatotoxicity 2.65 (0.83-8.44) 0.098 2.4 (0.77-7.74) 0.215
Grade 3 or 4 ALT at baseline 3.48 (0.48-25.06) 0.215
*Analysis restricted to the first 6 months
Univariate Multivariate
NVP, Nevirapine. ART, antiretroviral therapy.WHO, World Health Organization.  TB, tuberculosis.  PMTCT, preventing 
 The proportion of early hepatotoxicity on protocol was 1.9% (18/911) and 0.9% 
(8/920) off protocol (p=0.045).
 Of those that were on protocol, 12 (1.3%) developed HT by 4 weeks, 4 (0.4%) 
between 4- 8 weeks, and 2 (0.2%) between 8-12 weeks.
 Of the 26 patients with early HT, 8 (30.7%) inadvertently continued NVP-based
ART. All had grade 3 HT which subsequently resolved without treatment
modification.
 Of the 18 who stopped NVP, 17 (94.4%) were switched to efavirenz (EFV) 
based-ART. Of these, 2 (11.8%) developed further HT on EFV; 1 resolved 
spontaneously and one had to stop ART.
 Eleven (0.6%) additional patients developed late hepatotoxicity (after 12 weeks) 
between 121-891 days.
 Treatment naïve HIV + individuals over 16 years on NVP-based ART from November 2002 until 
the end of December 2006 were included.
 Women who had previously received NVP-based therapy via the prevention of mother to child 
transmission (PMTCT) program were included. 
 Serum ALT was graded using criteria established by the AIDS Clinical Trial Group : 
grade 0: < 1.25x upper limit of normal (ULN); grade 1: 1.25-2.5x ULN; grade 2: 2.6-5.0x ULN, 
grade 3: 5.1-10x ULN; grade 4: > 10x ULN. Early hepatotoxicity was defined as an increase in 
ALT from grade 0-2 at baseline to grade 3 or 4 within 102 days of starting ART. 
 Sequential ALT measurements – at baseline, 4, 8, and 12 weeks- were defined as “on protocol”. 
Patients who had at least a baseline and a 4 week ALT were considered in the “ALT protocol” 
cohort for description of baseline characteristics.
 There was no association 
between gender, age, baseline 
CD4 count less than 50 cells/µl, 
baseline viral load, concurrent 
TB infection, history of 
participation in PMTCT, or 
baseline weight <60 kilograms 
and hepatotoxicity (data not 
shown).
 Three patients with early 
hepatotoxicity died. All had 
grade 4 HT.
 CD4 less than 50 cells/µl was 
associated with mortality.
 From November 2002 to December 2006, 3728 
individuals were initiated on ART in Khayelitsha. 
 Of these,1831 (49%) were started on NVP-based 
ART.
 911 (50%) patients were “on protocol” with at least 
a baseline and a 4 week ALT measurement. 
Department of Health
Provincial Government of the Western Cape
Ph: +27-21-4832518
3.
Directorate HIV/AIDS and TB
Figure 1:  Time to Hepatotoxicity on Protocol
 Median time to HT was 32 (IQR 28-58) days

Nevirapine-Induced Heratotoxicity: Incidence, Risk Factors and Associated Mortality in a Primary Care ART Programme in South Africa

Nevirapine-Induced Heratotoxicity: Incidence, Risk Factors and Associated Mortality in a Primary Care ART Programme in South Africa

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