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Nevirapine-associated toxicity in HIV-infected Thai menand women, including pregnant women N Phanuphak,1 T Apornpong,1 S Teeratakulpisarn,1 S Chaithongwongwatthana,2 C Taweepolcharoen,2 S Mangclaviraj,2 SLimpongsanurak,2 T Jadwattanakul,3 P Eiamapichart,3 W Luesomboon,3 A Apisarnthanarak,4 A Kamudhamas,4 ATangsathapornpong,4 C Vitavasiri,5 N Singhakowinta,6 V Attakornwattana,6 R Kriengsinyot,2 P Methajittiphun,3 KChunloy,4 W Preetiyathorn,5 T Aumchantr,6 P Toro,7 EJ Abrams,7 W El-Sadr7 and P Phanuphak11The Thai Red Cross AIDS Research Centre, Bangkok, Thailand, 2King Chulalongkorn Memorial Hospital, Bangkok,Thailand, 3Queen Sawangwattana Memorial Hospital, Chonburi, Thailand, 4Thammasat University Hospital, Pathumthani,Thailand, 5Police General Hospital, Bangkok, Thailand, 6Queen Sirikit Hospital, Chonburi, Thailand, and 7InternationalCenter for AIDS Care and Treatment Programs, Mailman School of Public Health, Columbia University, New York, NY, USA ObjectivesThe aim of the study was to determine the incidence of, and risk factors for, nevirapine(NVP)-associated hepatotoxicity and rash in HIV-infected Thai men and women, includingpregnant women, receiving NVP-containing highly active antiretroviral therapy (HAART).
MethodsNVP-containing HAART was prescribed to eligible men and women enrolled in the Prevention ofMother-To-Child Transmission of HIV (PMTCT) and MTCT-Plus programmes. All pregnant womenreceived zidovudine (ZDV)/lamivudine (3TC)/NVP from 414 weeks of gestational age if their CD4cell count was 200 cells/mL or from 428 weeks if their CD4 cell count was 4200 cells/mL.
Patients followed for at least 8 weeks after starting HAART or until delivery were included in theanalyses.
ResultsOf 409 patients, 244 were pregnant women, 87 were nonpregnant women and 78 were men.
Hepatotoxicity occurred in 15.6% of all patients. Men had a significantly higher rate ofasymptomatic hepatotoxicity (P 5 0.021). Pregnant women receiving HAART for PMTCT (92% hadCD4 cell counts 4250 cells/mL) had a significantly higher rate of symptomatic hepatotoxicity(P 5 0.0003) than pregnant women receiving HAART for therapy. Rash occurred in 16.1% of allpatients. The patients’ sex and baseline CD4 cell count were not associated with the risk ofhepatotoxicity or rash. NVP was discontinued in 4.2% and 6.8% of patients because ofhepatotoxicity and rash, respectively.
ConclusionsThe incidence of NVP-related hepatotoxicity and rash in Thai adults is similar to incidences reportedfor other populations. While larger studies are needed, our data support continued use ofNVP-containing regimens as first-line treatment in developing countries for HIV-infected patients,including pregnant women. Pregnant women with high CD4 cell counts may experience higher ratesof symptomatic hepatotoxicity and thus require careful clinical and laboratory monitoring.
Keywords: hepatotoxicity, nevirapine, pregnancy, rash, risk factors Received: 4 May 2006, accepted 27 March 2007 Nevirapine (NVP) is the preferred nonnucleoside reverse Correspondence: Dr Nittaya Phanuphak, The Thai Red Cross AIDS Research transcriptase inhibitor in first-line antiretroviral regimens Centre, 104 Rajdumri Road, Pathumwan, Bangkok, Thailand 10330. Tel:1 662 253 0996; fax: 1 662 253 0998; e-mail: in resource-limited settings because of its low cost and its availability in generic and fixed dose combination HAART from 428 weeks of gestation until delivery and formulations [1]. Hepatotoxicity and rash are the two most zidovudine (ZDV)/lamivudine (3TC) was continued for common treatment-limiting toxicities [2]. Symptomatic 1 week postpartum. Pregnant HIV-infected women with hepatotoxicity has been reported in 1.0–4.9% of adults [2– CD4 cell counts 200 cells/mL or 350 cells/mL at World 10], while the incidence of all hepatotoxicities ranges Health Organization (WHO) stage of disease42 were widely from 3.2 to 12.0% [2–5,9–11]. In addition to provided with NVP-containing HAART regimens for coinfection with viral hepatitis and elevated baseline therapy during pregnancy (usually starting from 414 transaminase levels, a number of factors have been weeks gestation) and indefinitely following delivery (the associated with NVP-related hepatotoxicity [3,5,11–13], ‘therapy’ group). Similarly, other HIV-infected nonpreg- including female sex, high baseline CD4 cell count, high nant women and men eligible for HAART using the same NVP blood level, alcohol abuse and certain human eligibility criteria as described for pregnant women above leucocyte antigen (HLA) types [2–5,9,11–14]. NVP-related were prescribed NVP-containing HAART for therapy.
rash has been reported in 4.3–36% of adults [8–10,13,15– Various programmes were responsible for HIV care and 24], but Stevens–Johnson syndrome is relatively infre- the treatment described above. The Thai Red Cross AIDS quent, occurring in fewer than 1% of adults on treatment Research Centre (TRCARC) established the Prevention of [10,13,19,24]. Similar risk factors to those for NVP-related Mother-To-Child Transmission of HIV (PMTCT) programme hepatotoxicity have been identified, including female sex, under the patronage of Her Royal Highness Princess high baseline CD4 cell count, low baseline HIV-1 RNA and Soamsawali in February 1996 using funds donated by the Thai public to obtain antiretrovirals for poor HIV-infected While NVP is a useful antiretroviral drug given its pregnant Thai women. In addition, patients were enrolled convenience in administration, low pill burden, lack of in the MTCT-Plus initiative beginning on 1 February 2003.
food restriction and overall good safety profile, there is The MTCT-Plus initiative, described in detail elsewhere increasing concerns regarding reports of severe toxicities, ( [36], is a woman-centred, fa- particularly the higher observed risk of serious liver mily-orientated, multidisciplinary HIV care and treatment toxicity in adults with higher CD4 cell counts, particularly programme initiated and co-ordinated by the International women with CD4 cell counts 4250 cells/mL [25]. NVP- Center for AIDS Care and Treatment Programs (ICAP) at the containing highly active antiretroviral therapy (HAART) Columbia University Mailman School of Public Health. The regimens, however, have also been used increasingly in latter programme, in order to expand the programme at developing countries in HIV-infected pregnant women for TRCARC, enrolled pregnant women as well as postpartum prevention of mother-to-child transmission (PMTCT) of women with their HIV-exposed infants and other HIV- HIV rather than the use of single dose NVP during labour.
infected family members, mainly HIV-infected male Results from several studies have demonstrated the safety partners of the women enrolled. Patients received either of NVP-containing regimens during pregnancy [26–32] ZDV or stavudine (d4T) plus 3TC and NVP. All patients both prior to and since the reports of severe cases of started NVP-based regimens with the recommended lead-in dose of NVP 200 mg every 24 h for 14 days followed The conflicting data on the safety of NVP-containing thereafter by NVP 200 mg every 12 h.
regimens coupled with the recognized advantages of NVP For pregnant women on HAART, regular laboratory as a component of a HAART regimen motivated us to monitoring for hepatotoxicity was conducted according to conduct an assessment of our experience of using NVP- a specific schedule. Thus, serum alanine aminotransferase containing HAART regimens in a diverse population of (ALT) and aspartate aminotransferase (AST) measurements patients. We describe the incidence and risk factors for were obtained at baseline, at weeks 2, 4, 6 and 8, and then NVP-related toxicities among HIV-infected Thai pregnant every 4 weeks until delivery. An ALT/AST value of 42 times the upper limit of normal (ULN) was a contra-indication for the initiation of a NVP-containing regimen.
For these pregnant women on HAART, toxicity manage-ment included discontinuation of either NVP or the entire Patients with HIV infection were prescribed NVP-contain- regimen if ALT or AST increased to 42.5 times ULN or rash ing HAART regimens from a variety of programmes and for more severe than grade I occurred. Efavirenz (EFV)- or various indications. Pregnant HIV-infected women with nelfinavir (NFV)-containing regimens were options for CD4 cell counts 4200 cells/mL were prescribed NVP- pregnant women with abnormal baseline ALT/AST values containing HAART for PMTCT until delivery (the ‘PMTCT’ or who had to switch from NVP-containing regimens as a group). This involved the provision of NVP-containing r 2007 British HIV Association HIV Medicine (2007) 8, 357–366 For nonpregnant women and men receiving NVP- the baseline characteristics of all patients. Analysis of containing HAART regimens, ALT and AST were measured variance (ANOVA) and the Kruskal–Wallis test were used to at baseline. No regularly scheduled laboratory monitoring compare continuous outcomes among more than two was required. However, laboratory tests were obtained groups and least significant difference (LSD) was used for according to the physician’s judgement, either because of pairwise multiple comparisons. The Student t-test and abnormal baseline values or if indicated based on patient Mann–Whitney U-test were used to compare two groups.
symptoms or signs. ALT/AST values of 45 times ULN at The percentage differences in each outcome were evaluated baseline and during follow-up were a contraindication for by w2 test and Fisher’s exact test. The log rank test was used initiation of NVP-containing HAART and an indication to to compare the incidence rate between two groups. The Cox stop HAART during follow-up, respectively. Patients had regression model was the multivariate analysis used to clinic visits at weeks 2, 4, 6 and 8 and then every 2 months.
determine risk factors for NVP-related hepatotoxicity and Telephone follow-up at weeks 1, 3, 5 and 7 and at months 3 NVP-related rash, adjusting for baseline variables. Mean and 5 was used to assess side effects and adherence to values were used to group predictive factors. The hazard medications. EFV or other protease inhibitor (PI)-contain- ratio for each independent variable was determined from ing regimens were options for patients who needed to the Cox regression model. A P-value of 0.05 was switch from NVP-containing regimens.
regarded as indicating statistical significance. All tests Pregnant women, postpartum women and men were and confidence intervals (CIs) were considered to be included in the analyses presented here if they were on a significant at a P-value 0.05 (two-sided).
NVP-containing HAART regimen and had at least 8 weeksof follow-up after starting the regimen or until delivery, NVP-related toxicities were graded according to the Of 409 patients included in this study, 244 were pregnant AIDS Clinical Trial Group Protocol Management Handbook women, 87 were nonpregnant women and 78 were men.
Table for Grading Severity of Adult Adverse Experiences Their baseline characteristics are shown in Table 1.
Nonpregnant women had a lower mean body weight (53.4 kg) than men (61.8 kg) (Po0.001). Mean body massindex (BMI) values were comparable among groups.
Pregnant women had the highest median CD4 cell counts Statistical Product and Service Solutions (SPSS) for (277 cells/mL compared with 152 cells/mL in nonpregnant Windows was used to perform all statistic analyses (SPSS, women and 136 cells/mL in men; Po0.001). Among Chicago, IL). Descriptive analyses were used to examine pregnant women, 133 (54.5%) had CD4 cell counts 4250 NVP-related hepatotoxicity and NVP-related rash and cells/mL and 76 (31.1%) had CD4 cell counts 4400 cells/mL.
demographic variables. Frequency and percentage distri- Except for three nonpregnant women and seven men, all bution were used for qualitative variables, while mean and nonpregnant women and men had CD4 cell counts 250 standard deviation were used for quantitative variables for cells/mL. All patients with a CD4 count 4400 cells/mL in Table 1 Baseline characteristics of 409 adults receiving nevirapine-based antiretroviral therapy wValues significantly different from those of other groups by least significant difference.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; PMTCT, prevention of mother-to-child transmission.
r 2007 British HIV Association HIV Medicine (2007) 8, 357–366 our study were pregnant women. Men had higher mean PMTCT had higher rates of symptomatic hepatotoxicity baseline ALT/AST values (Po0.001). A hepatitis B virus [16.0 (95% CI 6.6–25.4) versus 2.5 (95% CI À 0.4 to 5.4) per surface antigen (HBsAg) result was available for 106 100 person-years, respectively; P 5 0.0003], rash-asso- pregnant women (43.4%), and three of these 106 (2.8%) ciated hepatotoxicity [10.2 (95% CI 2.7–17.7) versus 0.8 (95% CI À 0.9 to 2.5) per 100 person-years, respectively; Twenty-six pregnant women (10.6%) were tested for P 5 0.0003], grade I/II symptomatic hepatotoxicity [10.2 anti-hepatitis C virus (HCV) antibody; two of these 26 (95% CI 2.7–17.7) versus 1.7 (95% CI 0.0–3.4) per 100 person-years, respectively; P 5 0.005], and grade III/IV Of 244 pregnant women, 142 (58.2%) were on HAART symptomatic hepatotoxicity [5.8 (95% CI 0.1–11.5) versus for PMTCT (CD4 cell count range 211–1169 cells/mL) while 0.8 (95% CI – 0.9 to 2.5) per 100 person-years, respectively; 102 (41.8%) qualified for HAART for therapeutic treatment P 5 0.023] compared with pregnant women on NVP-based (CD4 cell count range 2–252 cells/mL). Among these, 33 (13.5%) started HAART before 27 weeks of gestation.
Asymptomatic hepatotoxicity occurred in 15.4% of Pregnant women had a shorter mean follow-up time on patients who had at least two ALT/AST tests (95% CI HAART (41 weeks compared with 80 weeks in nonpregnant 11.5–18.5), or at a rate of 17.9 (95% CI 12.7–23.1) per 100 women and 79 weeks in men; Po0.001), as 58.2% of those person-years. Men had higher proportions and higher rates who received HAART for PMTCT discontinued it after of asymptomatic hepatotoxicity (Po0.001 and P 5 0.021, respectively) and grade I/II asymptomatic hepatotoxicity Toxicities of any type and grade occurred in 29.1% of (P 5 0.001 and P 5 0.042, respectively).
Pregnant women on NVP-based HAART for PMTCT had a shorter mean time to onset of asymptomatic hepatotoxi-city than those on NVP-based HAART for therapy (4.6 versus 14.3 weeks, respectively; P 5 0.042).
Differential laboratory monitoring among patient groupsresulted in a significantly higher percentage of pregnant women (90%) who had at least two ALT/AST testscompared with the other groups (Po0.001; data not Table 3 presents data on the development of rash among shown). Only 39% of nonpregnant women and 50% of participants. Rash of any grade occurred in 16.1% of men had at least two ALT/AST tests. The median number of patients (95% CI 12.6–19.7), or at the rate of 18.1 (95% CI tests carried out was higher (4) in pregnant women than in 13.7–22.5) per 100 person-years [14.3% of pregnant nonpregnant women (1) and in men (1) (Po0.001; data not women (95% CI 9.9–18.8), or 21.3 (95% CI 14.3–28.4) per shown). The median time between tests was shorter 100 person-years; 21.8% of nonpregnant women (95% CI (2 weeks) in pregnant women than in nonpregnant women 13.0–30.7), or 18.3 (95% CI 13.1–26.5) per 100 person- (7 weeks) and in men (6 weeks) (Po0.001; data not shown).
years; and 15.4% of men (95% CI 7.2–23.6), or 12.4 (95% Twenty patients (4.9%) had abnormal baseline ALT/AST values, including three pregnant women with values 42 P 5 0.404, respectively]. Grade III/IV rash occurred in 5.1% of all patients (95% CI 3.0–7.3) or at a rate of 5.8 Table 2 shows data on 64 patients who developed either (95% CI 3.3-8.3) per 100 person-years [3.7% of pregnant symptomatic or asymptomatic hepatotoxicity (15.6% of all women (95% CI 1.3–6.1), or 5.5 (95% CI 1.9–9.1) per 100 patients). Symptomatic hepatotoxicity including rash- person-years; 6.9% of nonpregnant women (95% CI associated hepatotoxicity occurred in 4.6% of patients 1.5–12.3), or 5.8 (95% CI 2.9–8.7) per 100 person-years; (95% CI 2.6–6.7%) or at the rate of 4.4 (95% CI 2.4–6.4) per and 7.7% of men (95% CI 1.6–13.7), or 6.2 (95% CI 1.2– 100 person-years. Pregnant women had a higher rate of 11.2) per 100 person-years; P 5 0.415 and P 5 0.404, symptomatic hepatotoxicity than nonpregnant women [7.5 respectively]. Stevens–Johnson syndrome occurred in six (95% CI 3.6–11.4) versus 1.5 (95% CI À 0.6 to 3.6) per 100 patients. Mean time to onset of all rash was 2.3 weeks, with person-years, respectively; P 5 0.018], with higher rates of no significant differences among groups.
both rash-associated hepatotoxicity [4.3 (95% CI 1.3–7.3)versus 0.8 (95% CI À 0.7 to 2.3) per 100 person-years, Risk factors for NVP-related hepatotoxicities matic hepatotoxicity [4.8 (95% CI 1.7–8.0) versus 0.8 In univariate analysis, high baseline CD4 cell count (95% CI–0.7 to 2.3) per 100 person-years, respectively; (Po0.001), CD4 cell count ! 250 cells/mL (P 5 0.001), P 5 0.039]. Pregnant women on NVP-based HAART for and CD4 cell count ! 400 cells/mL (P 5 0.003) were r 2007 British HIV Association HIV Medicine (2007) 8, 357–366 r 2007 British HIV Association HIV Medicine (2007) 8, 357–366 Table 3 Characteristics of nevirapine-related rash (n 5 66) PMTCT, prevention of mother-to-child transmission; PY, person-years; SJS, Stevens–Johnson syndrome.
Table 4 Multivariate analyses of risk factors for nevirapine (NVP)-related hepatotoxicity and nevirapine-related rash (n 5 409; rate per 100 person-years) ALT, alanine aminotransferase; CI, confidence interval; HAART, highly active antiretroviral therapy; PMTCT, prevention of mother-to-child transmission;Ref., reference value.
significant risk factors for all-grade hepatotoxicity, but analyses resulted in similar conclusions regarding the none of these was significant in multivariate analysis.
development of NVP-related hepatotoxicity and NVP- Pregnancy status, gestational age at HAART initiation, BMI related rash, as stated above (data not shown).
and baseline mean ALT/AST were not associated with NVP-related hepatotoxicity either in univariate or in multi- Table 5 describes management of NVP-related toxicity.
Overall, 74% of patients who experienced any hepatotoxi- city were able to continue NVP therapy. Among 13 adults In univariate and multivariate analyses, the patients’ sex, who experienced grade III/IV and/or symptomatic hepato- pregnancy status, gestational age at HAART initiation, toxicity (10 pregnant women, one nonpregnant women and BMI, baseline CD4 count ( ! 250 or ! 400 cells/mL) and two men), two (15%) continued NVP, seven (54%) were baseline ALT/AST were not significantly associated with changed to EFV-containing regimens, and four (31%) In order to assess whether use of a shorter follow-up Fifty-seven per cent of the 66 patients who developed a period for the analyses might enable us to capture more rash of any grade were able to continue NVP treatment.
toxicities, separate analyses were carried out in patients Among 21 patients with grade III/IV rash (nine pregnant with a minimum follow-up period of 2 weeks. These women, six nonpregnant women and six men), four (19%) r 2007 British HIV Association HIV Medicine (2007) 8, 357–366 Table 5 Management of nevirapine (NVP)-related toxicities Grade III/IV and/or symptomaticContinued NVP were able to continue NVP, 13 (62%), including six patients with Stevens–Johnson syndrome, were changed to EFV-containing regimens, and four (19%) stopped HAART.
The incidence of NVP-related hepatotoxicity (15.9%) in our Among 119 patients (29.1% of the total) with either study of adult men and women, including pregnant hepatic or rash toxicities of any grade, 83 patients (69.7%) women, was high compared with values reported pre- were able to continue NVP. These included three pregnant viously (3.2–12.0%). However, the overall incidence of women who could continue on NVP although they had symptomatic hepatotoxicity, 4.6%, was similar to pre- ALT/AST values of more than 2.5 times ULN. Of 36 patients viously reported rates (1.0–4.9%). Unexpectedly, we found (8.8% of the total) who discontinued NVP, 27 (75%) a higher rate of asymptomatic hepatotoxicity in men switched to EFV, one (2.8%) switched to PIs, and eight compared with pregnant and nonpregnant women, with a (22.2%) discontinued NVP without changing to other significantly higher rate of grade I/II asymptomatic antiretroviral drugs (three pregnant women, one nonpreg- hepatotoxicity, although men in our study were tested nant woman and one man discontinued HAART, while only according to the physician’s judgement and we would three pregnant women discontinued NVP only). Among 27 expect to find lower rates of asymptomatic hepatotoxicity patients who switched to EFV, 24 were able to continue EFV, two patients with NVP-related grade III and IV rash Pregnant women on NVP-based HAART for PMTCT had had recurrent rash after switching, and one patient with an earlier onset of asymptomatic hepatotoxicity. Pregnant NVP-related rash-associated hepatotoxicity had rising women had a higher rate of symptomatic hepatotoxicity, ALT/AST values after switching. Hepatotoxicity led to including rash-associated hepatotoxicity and grade I/II NVP discontinuation in 4.2% and rash led to NVP symptomatic hepatotoxicity, than nonpregnant women.
discontinuation in 6.8% of patients.
More aggressive laboratory monitoring in our pregnant Seventeen pregnant women switched from NVP to EFV women might have contributed to these higher rates of secondary to toxicity at a mean gestational age of 32 weeks (range 18–39 weeks). No congenital abnormalities were Pregnant women on NVP-based HAART for PMTCT also found in infants born to this group of women.
r 2007 British HIV Association HIV Medicine (2007) 8, 357–366 rash-associated hepatotoxicity, and grade I–IV sympto- Baseline HIV-1 RNA and NVP levels were not available and matic hepatotoxicity than pregnant women on NVP-based thus could not be assessed as risk factors for development HAART for therapy. Although in univariate analysis high baseline CD4 cell count, CD4 cell count ! 250 cells/mL and It should also be noted that a minimum follow-up period CD4 cell count ! 400 cells/mL were significant risk factors of 8 weeks (or until delivery in pregnant women) was used for hepatotoxicity, we did not find any association between in this study. We realized that using a shorter follow-up sex, pregnancy status, gestational age at HAART initiation, period for the analyses might enable us to capture more or baseline CD4 cell count and the incidence of hepato- toxicities, but separate analyses in patients with a minimum follow-up period of 2 weeks resulted in similar Female sex and high baseline CD4 cell count were conclusions regarding the development of NVP-related previously identified as risk factors for NVP-related hepatotoxicity, especially in rash-associated hepatotoxicity NVP was discontinued in 4.2 and 6.8% of our patients [3,4]. Our inability to demonstrate an association between because of hepatotoxicity and rash, respectively. Although CD4 cell count and incidence of hepatotoxicity in this we expected a higher discontinuation rate in our patients, study may be related to the relatively modest size of our as a large proportion were women and particularly cohort and the low median CD4 cell count outside the pregnant women (in whom discontinuation of NVP is pregnant women group; 35.0% of all patients had CD4 recommended for hepatotoxicity or rash more severe than counts ! 250 cells/mL and 18.8% had CD4 counts ! 400 grade I) [19], our rates were within the previously reported cells/mL. In addition, as our study might not be sufficiently range of 3.2–26% [15–20,22–24,39]. Twenty-four of 27 powered to detect differences, caution in the interpretation patients who required discontinuation of NVP were of the risk for NVP-related hepatotoxicity in pregnant successfully switched to EFV; 11 of 12 (91.7%) who had women on HAART for PMTCT is warranted, given a high liver dysfunction and 19 of 21 (90.5%) who had rash. This upper 95% CI limit of 16.6 in this group.
rate was at the high end of the range previously reported Abnormal baseline transaminase levels and coinfection (47.4–91.2% of patients who experienced NVP-related with hepatitis B and C viruses have been reported to be rash) [15,18,40]. It is important to highlight the importance independent risk factors for antiretroviral-associated he- of careful follow-up of patients who develop NVP-related hepatotoxicity or rash, including those who are switched [3,5,12,13]. Very few patients in our cohort had abnormal baseline transaminase levels and only small proportions The results of our study support the findings of previous were tested for hepatitis B and C. Therefore, we were unable studies on the overall safety of NVP when used as a to demonstrate an association of these factors. In addition, component in a HAART regimen for pregnant women as relevant data were not collected, we were unable to [26–32]. However, they are not in agreement with the very assess the effect of other risk factors that have been high rates of hepatotoxicity, including one maternal death reported to be associated with NVP-related hepatotoxicity from fatal hepatotoxicity, reported in the PACTG 1022 such as alcohol intake, high NVP blood levels and certain study [35]. Baseline CD4 cell count 4250 cells/mL was identified as a significant risk factor for fulminant hepatitis The incidence of NVP-related rash in our study (16.1%) in this study. Similarly, Gonzalez-Garcia et al. found CD4 was also within the range reported by others (4.3–36.0%).
cell counts 4250 cells/mL to be a risk factor for both NVP- Our findings do not support the previously reported high incidence of NVP-related rash in Asian patients [38] and pregnancy [28]. Ende et al. found that being naı¨ve to the rates were lower than those reported in Thai patients antiretroviral therapy was a significant risk factor [31], who participated in the 2NN study [15]. However, the whereas Joy et al. reported a relationship between NVP incidence of Stevens–Johnson syndrome in our patients hepatotoxicity and late trimester use [41]. Timmermans (1.5%) was higher than reported previously (0.3–1.0%). In et al. also found NFV- or NVP-based antiretroviral therapy univariate and multivariate analyses, we did not find any (ART) regimens to be associated with more frequent side association of sex, pregnancy status, gestational age at effects in pregnant than in nonpregnant women [42].
HAART initiation, or baseline CD4 cell count with the Although we found that our pregnant women had a higher incidence of rash. However, our study was probably not rate of symptomatic hepatotoxicity than nonpregnant sufficiently powered to find differences and, given an women, and that pregnant women who received NVP- upper 95% CI limit of 6.5 for NVP-related rash in patients based HAART for PMTCT (92% had CD4 counts ! 250 with CD4 counts ! 400 cells/mL who were all pregnant cells/mL) experienced a higher rate of symptomatic (but not women, this finding should be interpreted with caution.
asymptomatic) hepatotoxicity than those who received r 2007 British HIV Association HIV Medicine (2007) 8, 357–366 NVP-based HAART during pregnancy for therapy, we were 3 Dieterich DT, Robinson PA, Love J, Stern JO. Drug-induced unable to confirm the other associations mentioned above liver injury associated with the use of nonnucleoside in this cohort of pregnant Thai women receiving NVP- reverse-transcriptase inhibitors. Clin Infect Dis 2004; 38 While attention has been particularly directed to the 4 Baylor MS, Johann-Liang R. Hepatotoxicity associated with safety of NVP during pregnancy, more information is nevirapine use. J Acquir Immune Defic Syndr 2004; 35: needed on the safety of other antiretroviral drugs in pregnant women. PI-based regimens, especially regimens 5 Stern JO, Robinson PA, Love J, Lanes S, Imperiale MS, Mayers containing NFV, are used as the first-line regimen in DL. A comprehensive hepatic safety analysis of nevirapine in pregnant women in settings where resources are available.
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Our study has several strengths. These include the 7 Martinez E, Blanco JL, Arnaiz JA et al. Hepatotoxicity in diversity of the patient population, the largest number of HIV-infected patients receiving nevirapine-containing women on NVP-containing HAART during pregnancy antiretroviral therapy. AIDS 2001; 15: 1261–1268.
reported to date, the prospective follow-up according to a 8 Pujari SN, Patel AK, Naik E et al. Effectiveness of generic predetermined schedule of visits, and the utilization of fixed-dose combinations of highly active antiretroviral therapy a standardized toxicity grading system. However, the study for treatment of HIV infection in India. J Acquir Immune Defic also has limitations. These include the limited size of the cohort, the limited duration of follow-up, and the low 9 Martin AM, Nolan D, James I et al. Predisposition to nevirapine median CD4 cell counts, which may limit the ability to hypersensitivity associated with HLA-DRB1*0101 and assess higher CD4 cell counts as a risk factor for NVP- abrogated by low CD4 T-cell counts. AIDS 2005; 19: 97–99.
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