Overall, 217 [38.3%, 95% confidence interval (CI): 34.4 to 42.4] participants developed hepatotoxicity, with 61 (10.8%, 95% CI: 8.5 to 13.6) participants experiencing severe hepatotoxicity. Among men, 144 (36.8%, 95% CI: 32.2 to 41.7) participants experienced hepatotoxicity; of those, 31 (7.9%, 95% CI: 5.6 to 11.0) were judged to be severe cases. Among women, 73 (41.7%, 95% CI: 34 to 49.1) participants developed hepatotoxicity; of those 30 (17.1%, 95% CI: 12.3 to 23.4) were judged to be severe. Among those who experienced hepatotoxicity, the peak ALT and AST levels occurred at week 4, compared with other follow-ups. Women had higher prevalence of hepatotoxicity (P = 0.002). More women developed severe hepatotoxicity than men (P = 0.001).
As shown in Table 2, in the multivariable model, CD4 cell count and hepatitis C viral antibody serostatus were independent predictors of hepatotoxicity. Baseline CD4 cell count more than 250 cells per microliter was an independent risk factor for hepatotoxicity in Chinese men [adjusted RR = 1.22 (95% CI:, 1.04 to 2.44)] and women [adjusted RR = 1.72 (95% CI: 1.20 to 2.46)]. Regimen 1 (ddI + AZT + NVP) was associated with more risk of hepatotoxicity compared with the other 2 regimens [adjusted RR = 1.36 (95% CI: 1.09 to 1.69)].
Severe hepatotoxicity was more likely in both men and women with CD4 >250 cells per microliter. About 13.7% men and 24.6% women with CD4 >250 cells per microliter developed severe hepatotoxicity, compared with 5.9% men (P = 0.01) and 13.2% women (P = 0.05) with CD4 <250 cells per microliter developed severe hepatotoxicity. Among 61 patients with severe hepatotoxicity, 49 recovered after discontinuation of NVP and the rest were lost to follow-up after 12 weeks.
Twenty-one patients developed rash and 14 patients developed fever during our study. Nine (42.9%) patients with rash had concomitant hepatotoxicity, 4 (19.0%) with severe hepatotoxicity. Nine (64.3%) patients with fever had hepatotoxicity, 2 (14.3%) were severe. There were no reported deaths due to liver failure in our population.
Current Chinese guidelines recommend that women with a CD4 cell count more than 250 cells per microliter and men with a CD4 cell count more than 400 cells per microliter avoid NVP-containing ART regimens. In this study, we found that CD4 cell count more than 250 cells per microliter was an independent risk factor for hepatotoxicity in both men and women. Our findings suggest that we may need to reconsider prescribing NVP to all Chinese patients with a CD4 cell count more than 250 cells per microliter regardless of sex. Given that NVP is recommended as a first-line antiretroviral agent by official Chinese treatment guidelines, the impact on the population at large is likely to be significant.
Racial differences, study methodology, and other differences in study populations may each play a role in explaining these findings. The exact mechanism of NVP-related hepatotoxicity and its relationship with CD4 cell count is still not fully understood. NVP-related hepatotoxicity may be immune mediated. Antunes et al15 showed that metabolic activation of NVP into a form called 2-hydroxy NVP could induce the formation of DNA protein covalent adducts in vivo, which might play a role in NVP-related hepatotoxicity. Clinically, however, patients did not benefit from anti-inflammatory therapy.16 There may also be racial differences in drug metabolism. Finally, the impact of drug–drug interactions must be accounted for. In our study, the combination of ddI, AZT, and NVP was associated with a higher rate of hepatotoxicity compared with other drug combinations.
The prevalence of hepatotoxicity in our study is consistent with findings from most other reports. In an US study which included patients from different racial/ethnic groups (including white, African American, Hispanic, and Asian), the prevalence of hepatotoxicity (defined as ALT or AST higher than 5 × ULN) from 200 mg twice daily oral doses of NVP was 8.8% overall.4 That study was underpowered to detect significant racial differences. A comprehensive summary by Dieterich et al17 on clinical trials from the United States, Italy, the Netherlands, Australia, Canada, Argentina, and South Africa found a prevalence of NVP-related hepatotoxicity of 10%. The prevalence in another study from South Africa was 17%. The higher prevalence in the latter study may reflect a difference in study population as patients with baseline CD4 cell count <200 cells per microliter were excluded.18 At the same time, several studies reported a lower rate of hepatotoxicity. One study from Boehringer Ingelheim Company, although disputed by several peers,19 reported a prevalence of 5.8%.4 Another study from Africa showed prevalence of grade 3–4 hepatotoxicity at 1.3%, which might be due to a lower baseline CD4 cell count and normal baseline AST/ALT of the studies population.20
Other predictors of hepatotoxicity found in our analysis are consistent with published studies. An increased prevalence of hepatotoxicity and severe hepatotoxicity in women is consistent with findings from several other studies.19,21 Similarly, HCV coinfection were previously reported to be independent predictors of hepatotoxicity with NVP use.22 The lack of association between hepatitis B virus coinfection and hepatotoxicity was observed in our previous study13 and several others.23–25
This study has several strengths. The data were derived from a randomized controlled trial, which tends to minimize the potential for confounding. The trial was a multicenter study that included a broad representation of the Chinese population thereby enhancing external validity. Our study, however, has several limitations. First, we used a limited number of tests to define liver toxicity. Although these tests are sensitive measures of liver damage, we did not assess other measures of hepatic function, such as serum alkaline phosphatase, gamma-glutamyl transpeptidase, and albumin levels, and we did not confirm these findings histologically. Second, we could not assess for all causes of liver damage, but given that the parent study was randomized, it is unlikely that this bias was differential among groups. Third, we excluded pregnant women from enrollment to this study, and we could not generalize our finding to pregnant women directly. However, based on our findings, and what we know about the risks of NVP-induced hepatotoxicity in pregnant women whose CD4 counts are greater than 250 cells per microliter, it seems reasonable to assume that our recommendations apply to that population as well. Finally, the sample size was relatively small. As such, lack of associations may reflect limited power rather than a true null finding.
In conclusion, CD4 cell count more than 250 cells per microliter was an independent risk factor for both hepatotoxicity and severe hepatotoxicity when using NVP-containing antiretroviral regimens in Chinese men and women. Additional studies are needed to confirm these findings. Current Chinese national treatment guidelines may need to reflect this increased risk in both sexes. Based on our findings, we suggested the following changes be considered as a way to minimize hepatoxicity: (1) efavirenz, the alternate nonnucleoside reverse transcriptase inhibitor, may be used as the first-line agent for ART-naive patients with CD4 cell counts >250 cells per microliter and in those who are coinfected with hepatitis B virus and/ or HCV; (2) The combination regimen of ddI + AZT + NVP seems to be associated with greater risk of hepatotoxicity, and consideration should be made to no longer recommend it as a first-line regimen.
The authors thank the study participants for their cooperation. The following clinical institutions or hospitals participated in this study: Peking Union Medical College Hospital, Beijing Youan Hospital, Beijing Ditan Hospital, Zhengzhou Sixth People’s Hospital, Tangdu Hospital, Guangzhou Eighth People’s Hospital, Shanghai Public Health Clinical Center, Shenzhen Third People’s Hospital, Fuzhou Infectious Diseases Hospital, Yunnan AIDS Care Center, Kunming Third People’s Hospital, and Honghe First People’s Hospital. The authors are grateful to Ang Li, from Columbia University College of Physicians and Surgeons for his insightful comments and editorial support; and to Weidong Zhang, MD, PhD, director of the department of epidemiology, School of Public Health, Zhengzhou University for his kind assistance in data analysis.
1. Li T, Dai Y, Kuang J, et al.. Three generic nevirapine
-based antiretroviral treatments in Chinese HIV/AIDS patients: multicentric observation cohort. PLoS One. 2008;3:e3918.
2. Zhang F, Li T, Wang Y, et al.. National Guide for Free Antiviral Treatment Of HIV Patients. Beijing, China: People's Medical Publishing House; 2007.
3. Viramune tablets and oral suspension, US [package insert]. Ingelheim, German: Boehringer Ingelheim; 2006.
4. Stern JO, Robinson PA, Love J, et al.. A comprehensive hepatic safety analysis of nevirapine
in different populations of HIV infected patients. J Acquir Immune Defic Syndr. 2003;34(suppl 1):S21–S33.
5. Torti C, Costarelli S, De Silvestri A, et al.. Analysis of severe hepatic events associated with nevirapine
-containing regimens: CD4+ T-cell count and gender in hepatitis C seropositive and seronegative patients. Drug Saf. 2007;30:1161–1169.
6. Lyons F, Hopkins S, Kelleher B, et al.. Maternal hepatotoxicity
as part of combination antiretroviral therapy in pregnancy. HIV Med. 2006;7:255–260.
7. Peters PJ, Stringer J, McConnell MS, et al.. Nevirapine
was not predicted by CD4 count >/=250 cells/μL among women in Zambia, Thailand and Kenya. HIV Med. 2010;11:650–660.
8. Bottaro EG, Huberman MJ, Iannella MC, et al.. Nevirapine
-associated toxicity in clinical practice in Buenos Aires, Argentina. J Int Assoc Physicians AIDS Care (Chic). 2010;9:306–312.
9. Chu KM, Boulle AM, Ford N, et al.. Nevirapine
-associated early hepatotoxicity
: incidence, risk factors, and associated mortality in a primary care ART programme in South Africa. PLoS One 2010;5:e9183.
10. Phanuphak N, Apornpong T, Teeratakulpisarn S, et al.. Nevirapine
-associated toxicity in HIV-infected Thai men and women, including pregnant women. HIV Med. 2007;8:357–366.
11. Peters PJ, Polle N, Zeh C, et al.. Nevirapine
and rash among HIV-infected pregnant women in Kenya. J Int Assoc Physicians AIDS Care (Chic). 2012;11:142–149.
12. Marazzi MC, Germano P, Liotta G, et al.. Safety of nevirapine
-containing antiretroviral triple therapy regimens to prevent vertical transmission in an African cohort of HIV-1-infected pregnant women. HIV Med. 2006;7:338–344.
13. Wang H, Li Y, Zhang C, et al.. Immunological and virological responses to cART in HIV/HBV co-infected patients from a multicenter cohort. AIDS. 2012;26:1755–1763.
15. Antunes AM, Novais DA, Da SJ, et al.. Synthesis and oxidation of 2-hydroxynevirapine, a metabolite of the HIV reverse transcriptase inhibitor nevirapine
. Org Biomol Chem. 2011;9:7822–7835.
16. Bonnet F, Lawson-Ayayi S, Thiebaut R, et al.. A cohort study of nevirapine
tolerance in clinical practice: French aquitaine cohort, 1997–1999. Clin Infect Dis. 2002;35:1231–1237.
17. Dieterich DT, Robinson PA, Love J, et al.. Drug-induced liver injury associated with the use of nonnucleoside reverse-transcriptase inhibitors. Clin Infect Dis. 2004;38(suppl 2):S80–S89.
18. Sanne I, Mommeja-Marin H, Hinkle J, et al.. Severe hepatotoxicity
associated with nevirapine
use in HIV-infected subjects. J Infect Dis. 2005;191:825–829.
19. Baylor MS, Johann-Liang R, Hepatotoxicity
associated with nevirapine
use. J Acquir Immune Defic Syndr. 2004;35:538–539.
20. Kalyesubula R, et al.. Hepatotoxicity
from first line antiretroviral therapy: an experience from a resource limited setting. Afr Health Sci. 2011;11:16–23.
21. Wit FW, Weverling GJ, Weel J, et al.. Incidence of and risk factors for severe hepatotoxicity
associated with antiretroviral combination therapy. J Infect Dis. 2002;186:23–31.
22. Labarga P, Soriano V, Vispo ME, et al.. Hepatotoxicity
of antiretroviral drugs is reduced after successful treatment of chronic hepatitis C in HIV-infected patients. J Infect Dis. 2007;196:670–676.
23. Ocama P, Castelnuovo B, Kamya MR, et al.. Low frequency of liver enzyme elevation in HIV-infected patients attending a large urban treatment centre in Uganda. Int J STD AIDS. 2010;21:553–557.
24. Palmon R, Koo BC, Shoultz DA, et al.. Lack of hepatotoxicity
associated with nonnucleoside reverse transcriptase inhibitors. J Acquir Immune Defic Syndr. 2002;29:340–345.
25. Mbougua JB, Laurent C, Kouanfack C, et al.. Hepatotoxicity
and effectiveness of a nevirapine
-based antiretroviral therapy in HIV-infected patients with or without viral hepatitis B or C infection in Cameroon. BMC Public Health. 2010;10:105.
Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
nevirapine; CD4 lymphocyte count; drug toxicity; hepatotoxicity