Nevirapine-associated toxicity in HIV-infected Thai men and women, including pregnant women

ORIGINAL RESEARCH

Nevirapine-associated toxicity in HIV-infected Thai menand women, including pregnant womenN 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 Phanuphak1

1The 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

Introduction

Nevirapine (NVP) is the preferred nonnucleoside reversetranscriptase inhibitor in first-line antiretroviral regimensin resource-limited settings because of its low cost and its

Correspondence: Dr Nittaya Phanuphak, The Thai Red Cross AIDS ResearchCentre, 104 Rajdumri Road, Pathumwan, Bangkok, Thailand 10330. Tel:1 662 253 0996; fax: 1 662 253 0998; e-mail: [email protected]

r 2007 British HIV Association HIV Medicine (2007), 8, 357–366

357

availability in generic and fixed dose combinationformulations [1]. Hepatotoxicity and rash are the two mostcommon treatment-limiting toxicities [2]. Symptomatichepatotoxicity has been reported in 1.0–4.9% of adults [2–10], while the incidence of all hepatotoxicities rangeswidely from 3.2 to 12.0% [2–5,9–11]. In addition tocoinfection with viral hepatitis and elevated baselinetransaminase levels, a number of factors have beenassociated with NVP-related hepatotoxicity [3,5,11–13],including female sex, high baseline CD4 cell count, highNVP blood level, alcohol abuse and certain humanleucocyte antigen (HLA) types [2–5,9,11–14]. NVP-relatedrash has been reported in 4.3–36% of adults [8–10,13,15–24], but Stevens–Johnson syndrome is relatively infre-quent, occurring in fewer than 1% of adults on treatment[10,13,19,24]. Similar risk factors to those for NVP-relatedhepatotoxicity have been identified, including female sex,high baseline CD4 cell count, low baseline HIV-1 RNA andhigh NVP blood level [16–20].

While NVP is a useful antiretroviral drug given itsconvenience in administration, low pill burden, lack offood restriction and overall good safety profile, there isincreasing concerns regarding reports of severe toxicities,particularly the higher observed risk of serious livertoxicity in adults with higher CD4 cell counts, particularlywomen with CD4 cell counts 4250 cells/mL [25]. NVP-containing highly active antiretroviral therapy (HAART)regimens, however, have also been used increasingly indeveloping countries in HIV-infected pregnant women forprevention of mother-to-child transmission (PMTCT) ofHIV rather than the use of single dose NVP during labour.Results from several studies have demonstrated the safetyof NVP-containing regimens during pregnancy [26–32]both prior to and since the reports of severe cases ofhepatotoxicity [33–35].

The conflicting data on the safety of NVP-containingregimens coupled with the recognized advantages of NVPas a component of a HAART regimen motivated us toconduct an assessment of our experience of using NVP-containing HAART regimens in a diverse population ofpatients. We describe the incidence and risk factors forNVP-related toxicities among HIV-infected Thai pregnantwomen, nonpregnant women and men.

Methods

Patients with HIV infection were prescribed NVP-contain-ing HAART regimens from a variety of programmes and forvarious indications. Pregnant HIV-infected women withCD4 cell counts 4200 cells/mL were prescribed NVP-containing HAART for PMTCT until delivery (the ‘PMTCT’group). This involved the provision of NVP-containing

HAART from 428 weeks of gestation until delivery andzidovudine (ZDV)/lamivudine (3TC) was continued for1 week postpartum. Pregnant HIV-infected women withCD4 cell counts � 200 cells/mL or � 350 cells/mL at WorldHealth Organization (WHO) stage of disease42 wereprovided with NVP-containing HAART regimens fortherapy during pregnancy (usually starting from 414weeks gestation) and indefinitely following delivery (the‘therapy’ group). Similarly, other HIV-infected nonpreg-nant women and men eligible for HAART using the sameeligibility criteria as described for pregnant women abovewere prescribed NVP-containing HAART for therapy.

Various programmes were responsible for HIV care andthe treatment described above. The Thai Red Cross AIDSResearch Centre (TRCARC) established the Prevention ofMother-To-Child Transmission of HIV (PMTCT) programmeunder the patronage of Her Royal Highness PrincessSoamsawali in February 1996 using funds donated by theThai public to obtain antiretrovirals for poor HIV-infectedpregnant Thai women. In addition, patients were enrolledin the MTCT-Plus initiative beginning on 1 February 2003.The MTCT-Plus initiative, described in detail elsewhere(http://www.mtctplus.org) [36], is a woman-centred, fa-mily-orientated, multidisciplinary HIV care and treatmentprogramme initiated and co-ordinated by the InternationalCenter for AIDS Care and Treatment Programs (ICAP) at theColumbia University Mailman School of Public Health. Thelatter programme, in order to expand the programme atTRCARC, enrolled pregnant women as well as postpartumwomen with their HIV-exposed infants and other HIV-infected family members, mainly HIV-infected malepartners of the women enrolled. Patients received eitherZDV or stavudine (d4T) plus 3TC and NVP. All patientsstarted NVP-based regimens with the recommended lead-indose of NVP 200 mg every 24 h for 14 days followedthereafter by NVP 200 mg every 12 h.

For pregnant women on HAART, regular laboratorymonitoring for hepatotoxicity was conducted according toa specific schedule. Thus, serum alanine aminotransferase(ALT) and aspartate aminotransferase (AST) measurementswere obtained at baseline, at weeks 2, 4, 6 and 8, and thenevery 4 weeks until delivery. An ALT/AST value of 42times 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 entireregimen if ALT or AST increased to 42.5 times ULN or rashmore severe than grade I occurred. Efavirenz (EFV)- ornelfinavir (NFV)-containing regimens were options forpregnant women with abnormal baseline ALT/AST valuesor who had to switch from NVP-containing regimens as aresult of NVP-related toxicities.

358 N Phanuphak et al.

r 2007 British HIV Association HIV Medicine (2007) 8, 357–366

For nonpregnant women and men receiving NVP-containing HAART regimens, ALT and AST were measuredat baseline. No regularly scheduled laboratory monitoringwas required. However, laboratory tests were obtainedaccording to the physician’s judgement, either because ofabnormal baseline values or if indicated based on patientsymptoms or signs. ALT/AST values of 45 times ULN atbaseline and during follow-up were a contraindication forinitiation of NVP-containing HAART and an indication tostop HAART during follow-up, respectively. Patients hadclinic visits at weeks 2, 4, 6 and 8 and then every 2 months.Telephone follow-up at weeks 1, 3, 5 and 7 and at months 3and 5 was used to assess side effects and adherence tomedications. EFV or other protease inhibitor (PI)-contain-ing regimens were options for patients who needed toswitch from NVP-containing regimens.

Pregnant women, postpartum women and men wereincluded in the analyses presented here if they were on aNVP-containing HAART regimen and had at least 8 weeksof follow-up after starting the regimen or until delivery,whichever occurred earlier.

NVP-related toxicities were graded according to theAIDS Clinical Trial Group Protocol Management HandbookTable for Grading Severity of Adult Adverse Experiences[37].

Statistical analysis

Statistical Product and Service Solutions (SPSS) forWindows was used to perform all statistic analyses (SPSS,Chicago, IL). Descriptive analyses were used to examineNVP-related hepatotoxicity and NVP-related rash anddemographic variables. Frequency and percentage distri-bution were used for qualitative variables, while mean andstandard deviation were used for quantitative variables for

the baseline characteristics of all patients. Analysis ofvariance (ANOVA) and the Kruskal–Wallis test were used tocompare continuous outcomes among more than twogroups and least significant difference (LSD) was used forpairwise multiple comparisons. The Student t-test andMann–Whitney U-test were used to compare two groups.The percentage differences in each outcome were evaluatedby w2 test and Fisher’s exact test. The log rank test was usedto compare the incidence rate between two groups. The Coxregression model was the multivariate analysis used todetermine risk factors for NVP-related hepatotoxicity andNVP-related rash, adjusting for baseline variables. Meanvalues were used to group predictive factors. The hazardratio for each independent variable was determined fromthe Cox regression model. A P-value of � 0.05 wasregarded as indicating statistical significance. All testsand confidence intervals (CIs) were considered to besignificant at a P-value � 0.05 (two-sided).

Results

Of 409 patients included in this study, 244 were pregnantwomen, 87 were nonpregnant women and 78 were men.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(277 cells/mL compared with 152 cells/mL in nonpregnantwomen and 136 cells/mL in men; Po0.001). Amongpregnant women, 133 (54.5%) had CD4 cell counts 4250cells/mL and 76 (31.1%) had CD4 cell counts 4400 cells/mL.Except for three nonpregnant women and seven men, allnonpregnant women and men had CD4 cell counts � 250cells/mL. All patients with a CD4 count 4400 cells/mL in

Table 1 Baseline characteristics of 409 adults receiving nevirapine-based antiretroviral therapy

Characteristic

Women

Men Total P-value

Pregnant

PMTCT Therapy Nonpregnant

n (%) 142 (34.7) 102 (24.9) 87 (21.3) 78 (19.1) 409 (100.0)Mean body weight (kg) 60.9 58.2 53.4 61.8 58.3 o 0.001*

Mean BMI (kg/m2) 24.7 28.3 22.2 22.0 24.4 0.274CD4 count (cells/mL) 413.5w 135.5 152 136 187 o 0.001[median (range)] (211–1169) (2–252) (3–388) (0–1070) (0–1169)Mean ALT (U/L) 17.3 19.7 20.8 31.8w 21.1 o 0.001Mean AST (U/L) 18.8 21.2 25.0 33.5w 23.1 o 0.001Mean follow-up (weeks) 26w 62w 80 79 57 o 0.001

*Nonpregnant women versus men.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.

NVP toxicity in men and women 359


our study were pregnant women. Men had higher meanbaseline ALT/AST values (Po0.001). A hepatitis B virussurface antigen (HBsAg) result was available for 106pregnant women (43.4%), and three of these 106 (2.8%)tested positive.

Twenty-six pregnant women (10.6%) were tested foranti-hepatitis C virus (HCV) antibody; two of these 26(7.7%) tested positive.

Of 244 pregnant women, 142 (58.2%) were on HAARTfor PMTCT (CD4 cell count range 211–1169 cells/mL) while102 (41.8%) qualified for HAART for therapeutic treatment(CD4 cell count range 2–252 cells/mL). Among these, 33(13.5%) started HAART before 27 weeks of gestation.Pregnant women had a shorter mean follow-up time onHAART (41 weeks compared with 80 weeks in nonpregnantwomen and 79 weeks in men; Po0.001), as 58.2% of thosewho received HAART for PMTCT discontinued it afterdelivery.

Toxicities of any type and grade occurred in 29.1% ofthese adult patients (119 of 409).

NVP-related hepatotoxicity

Differential laboratory monitoring among patient groupsresulted in a significantly higher percentage of pregnantwomen (90%) who had at least two ALT/AST testscompared with the other groups (Po0.001; data notshown). Only 39% of nonpregnant women and 50% ofmen had at least two ALT/AST tests. The median number oftests carried out was higher (4) in pregnant women than innonpregnant women (1) and in men (1) (Po0.001; data notshown). The median time between tests was shorter(2 weeks) in pregnant women than in nonpregnant women(7 weeks) and in men (6 weeks) (Po0.001; data not shown).Twenty patients (4.9%) had abnormal baseline ALT/ASTvalues, including three pregnant women with values 42times ULN.

Table 2 shows data on 64 patients who developed eithersymptomatic or asymptomatic hepatotoxicity (15.6% of allpatients). Symptomatic hepatotoxicity including rash-associated hepatotoxicity occurred in 4.6% of patients(95% CI 2.6–6.7%) or at the rate of 4.4 (95% CI 2.4–6.4) per100 person-years. Pregnant women had a higher rate ofsymptomatic hepatotoxicity than nonpregnant women [7.5(95% CI 3.6–11.4) versus 1.5 (95% CI � 0.6 to 3.6) per 100person-years, respectively; P 5 0.018], with higher rates ofboth rash-associated hepatotoxicity [4.3 (95% CI 1.3–7.3)versus 0.8 (95% CI � 0.7 to 2.3) per 100 person-years,respectively; P 5 0.0498] and grade I/II sympto-matic hepatotoxicity [4.8 (95% CI 1.7–8.0) versus 0.8(95% CI–0.7 to 2.3) per 100 person-years, respectively;P 5 0.039]. Pregnant women on NVP-based HAART for

PMTCT had higher rates of symptomatic hepatotoxicity[16.0 (95% CI 6.6–25.4) versus 2.5 (95% CI � 0.4 to 5.4) per100 person-years, respectively; P 5 0.0003], rash-asso-ciated hepatotoxicity [10.2 (95% CI 2.7–17.7) versus 0.8(95% CI � 0.9 to 2.5) per 100 person-years, respectively;P 5 0.0003], grade I/II symptomatic hepatotoxicity [10.2(95% CI 2.7–17.7) versus 1.7 (95% CI 0.0–3.4) per 100person-years, respectively; P 5 0.005], and grade III/IVsymptomatic hepatotoxicity [5.8 (95% CI 0.1–11.5) versus0.8 (95% CI – 0.9 to 2.5) per 100 person-years, respectively;P 5 0.023] compared with pregnant women on NVP-basedHAART for therapy.

Asymptomatic hepatotoxicity occurred in 15.4% ofpatients who had at least two ALT/AST tests (95% CI11.5–18.5), or at a rate of 17.9 (95% CI 12.7–23.1) per 100person-years. Men had higher proportions and higher ratesof asymptomatic hepatotoxicity (Po0.001 and P 5 0.021,respectively) and grade I/II asymptomatic hepatotoxicity(P 5 0.001 and P 5 0.042, respectively).

Pregnant women on NVP-based HAART for PMTCT hada shorter mean time to onset of asymptomatic hepatotoxi-city than those on NVP-based HAART for therapy (4.6versus 14.3 weeks, respectively; P 5 0.042).

NVP-related rash

Table 3 presents data on the development of rash amongparticipants. Rash of any grade occurred in 16.1% ofpatients (95% CI 12.6–19.7), or at the rate of 18.1 (95% CI13.7–22.5) per 100 person-years [14.3% of pregnantwomen (95% CI 9.9–18.8), or 21.3 (95% CI 14.3–28.4) per100 person-years; 21.8% of nonpregnant women (95% CI13.0–30.7), or 18.3 (95% CI 13.1–26.5) per 100 person-years; and 15.4% of men (95% CI 7.2–23.6), or 12.4 (95%CI 5.4–19.4) per 100 person-years; P 5 0.437 andP 5 0.404, respectively]. Grade III/IV rash occurred in5.1% of all patients (95% CI 3.0–7.3) or at a rate of 5.8(95% CI 3.3-8.3) per 100 person-years [3.7% of pregnantwomen (95% CI 1.3–6.1), or 5.5 (95% CI 1.9–9.1) per 100person-years; 6.9% of nonpregnant women (95% CI1.5–12.3), or 5.8 (95% CI 2.9–8.7) per 100 person-years;and 7.7% of men (95% CI 1.6–13.7), or 6.2 (95% CI 1.2–11.2) per 100 person-years; P 5 0.415 and P 5 0.404,respectively]. Stevens–Johnson syndrome occurred in sixpatients. Mean time to onset of all rash was 2.3 weeks, withno significant differences among groups.

Risk factors for NVP-related hepatotoxicities

In univariate analysis, high baseline CD4 cell count(Po0.001), CD4 cell count � 250 cells/mL (P 5 0.001),and CD4 cell count � 400 cells/mL (P 5 0.003) were



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significant risk factors for all-grade hepatotoxicity, butnone of these was significant in multivariate analysis.Pregnancy status, gestational age at HAART initiation, BMIand baseline mean ALT/AST were not associated with NVP-related hepatotoxicity either in univariate or in multi-variate analysis (Table 4).

Risk factors for NVP-related rash

In univariate and multivariate analyses, the patients’ sex,pregnancy status, gestational age at HAART initiation,BMI, baseline CD4 count (� 250 or � 400 cells/mL) andbaseline ALT/AST were not significantly associated withNVP-related rash (Table 4).

In order to assess whether use of a shorter follow-upperiod for the analyses might enable us to capture moretoxicities, separate analyses were carried out in patientswith a minimum follow-up period of 2 weeks. These

analyses resulted in similar conclusions regarding thedevelopment of NVP-related hepatotoxicity and NVP-related rash, as stated above (data not shown).

Management of NVP-related toxicities

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 adultswho experienced grade III/IV and/or symptomatic hepato-toxicity (10 pregnant women, one nonpregnant women andtwo men), two (15%) continued NVP, seven (54%) werechanged to EFV-containing regimens, and four (31%)discontinued HAART.

Fifty-seven per cent of the 66 patients who developed arash of any grade were able to continue NVP treatment.Among 21 patients with grade III/IV rash (nine pregnantwomen, six nonpregnant women and six men), four (19%)

Table 4 Multivariate analyses of risk factors for nevirapine (NVP)-related hepatotoxicity and nevirapine-related rash (n 5 409; rate per 100 person-years)

Factor

NVP-related hepatotoxicity NVP-related rash

n (%) Hazard ratio (CI) P-value n (%) Hazard ratio (CI) P-value

Patient groupNonpregnant women 5 (11.1) 1 (Ref.) 19 (28.8) 1 (Ref.)Pregnant women, PMTCT 13 (28.9) 2.4 (0.4, 16.6) 0.369 20 (30.3) 0.3 (0.1, 1.4) 0.130Pregnant women, therapy 11 (24.4) 0.6 (0.1, 2.7) 0.509 15 (22.7) 0.5 (0.2, 1.4) 0.215Male 16 (35.6) 1.4 (0.4, 5.6) 0.601 12 (18.2) 0.7 (0.3, 1.6) 0.349Baseline ALT (U/mL)o 21.5 14 (48.3) 1 (Ref.) 34 (66.7) 1 (Ref.)� 21.5 15 (51.7) 2.2 (0.9, 5.1) 0.055 17 (33.3) 1.1 (0.6, 2.0) 0.840CD4 group (cells/mL)o 250 32 (71.1) 1 (Ref.) 46 (69.7) 1 (Ref.)� 250 13 (28.9) 0.8 (0.2, 4.0) 0.815 20 (30.3) 1.2 (0.3, 5.0) 0.767o400 39 (86.7) 1 (Ref.) 53 (80.3) 1 (Ref.)� 400 1 pregnancy 6 (13.3) 1.1 (0.3, 3.5) 0.863 13 (19.7) 2.3 (0.8, 6.5) 0.123Gestational age at HAART initiation� 27 weeks 4 (8.9) 1 (Ref.) 4 (6.1) 1 (Ref.)� 27 weeks 41 (91.1) 1.0 (0.2, 5.0) 0.946 62 (93.9) 1.1 (0.3, 4.1) 0.830

ALT, alanine aminotransferase; CI, confidence interval; HAART, highly active antiretroviral therapy; PMTCT, prevention of mother-to-child transmission;Ref., reference value.

Table 3 Characteristics of nevirapine-related rash (n 5 66)

Grading

Women [n (%, per 100 PY)]

Men[n (%, per100 PY)]

Total[n (%, per100 PY)]

P-value(%, per100 PY)

P-value(preg vsnonpreg)(%, per100 PY)

P-value(PMTCT vstherapy)(%, per100 PY)

Pregnant

PMTCT Therapy Nonpregnant

I/II 14 (9.9, 23.4) 12 (11.8, 11.5) 13 (14.9, 12.5) 6 (7.7, 6.2) 45 (11.0, 12.3) 0.475, 0.462 0.384, 0.241 0.677, 0.666III/IV (six SJS) 6 (4.2, 10.0) 3 (2.9, 2.9) 6 (6.9, 5.8) 6 (7.7, 6.2) 21 (5.1, 5.8) 0.415, 0.404 0.234, 0.176 0.738, 0.610Total 20 (14.1, 33.5) 15 (14.7, 14.3) 19 (21.8, 18.3) 12 (15.4, 12.4) 66 (16.1, 18.1) 0.437, 0.404 0.146, 0.093 0.891, 0.897Time to onset (weeks) 2.5 (1, 4) 2.8 (1, 10) 1.9 (1, 6) 2.2 (1, 5) 2.3 (1, 10) 0.492 0.163 0.700[mean (range)]

PMTCT, prevention of mother-to-child transmission; PY, person-years; SJS, Stevens–Johnson syndrome.



were able to continue NVP, 13 (62%), including six patientswith Stevens–Johnson syndrome, were changed to EFV-containing regimens, and four (19%) stopped HAART.

Among 119 patients (29.1% of the total) with eitherhepatic or rash toxicities of any grade, 83 patients (69.7%)were able to continue NVP. These included three pregnantwomen who could continue on NVP although they hadALT/AST values of more than 2.5 times ULN. Of 36 patients(8.8% of the total) who discontinued NVP, 27 (75%)switched to EFV, one (2.8%) switched to PIs, and eight(22.2%) discontinued NVP without changing to otherantiretroviral drugs (three pregnant women, one nonpreg-nant woman and one man discontinued HAART, whilethree pregnant women discontinued NVP only). Among 27patients who switched to EFV, 24 were able to continueEFV, two patients with NVP-related grade III and IV rashhad recurrent rash after switching, and one patient withNVP-related rash-associated hepatotoxicity had risingALT/AST values after switching. Hepatotoxicity led toNVP discontinuation in 4.2% and rash led to NVPdiscontinuation in 6.8% of patients.

Seventeen pregnant women switched from NVP to EFVsecondary to toxicity at a mean gestational age of 32 weeks(range 18–39 weeks). No congenital abnormalities werefound in infants born to this group of women.

Discussion

The incidence of NVP-related hepatotoxicity (15.9%) in ourstudy of adult men and women, including pregnantwomen, was high compared with values reported pre-viously (3.2–12.0%). However, the overall incidence ofsymptomatic hepatotoxicity, 4.6%, was similar to pre-viously reported rates (1.0–4.9%). Unexpectedly, we founda higher rate of asymptomatic hepatotoxicity in mencompared with pregnant and nonpregnant women, with asignificantly higher rate of grade I/II asymptomatichepatotoxicity, although men in our study were testedonly according to the physician’s judgement and we wouldexpect to find lower rates of asymptomatic hepatotoxicityin this group.

Pregnant women on NVP-based HAART for PMTCT hadan earlier onset of asymptomatic hepatotoxicity. Pregnantwomen had a higher rate of symptomatic hepatotoxicity,including rash-associated hepatotoxicity and grade I/IIsymptomatic hepatotoxicity, than nonpregnant women.More aggressive laboratory monitoring in our pregnantwomen might have contributed to these higher rates oftoxicities.

Pregnant women on NVP-based HAART for PMTCT alsohad a higher rate of symptomatic hepatotoxicity,

Table 5 Management of nevirapine (NVP)-related toxicities

Nevirapine-related toxicity

Female

Pregnant Nonpregnant Male Total

HepatotoxicityContinued NVP 26 (68.4%) 7 (87.5%) 15 (78.9%) 48 (73.8%)Discontinued NVP 12 (31.6%) 1 (12.5%) 4 (21.1%) 17 (26.2%)Switched to EFV 7 (18.4%) 1 (12.5%) 4 (21.1%) 12 (18.5%)Total 38 (100%) 8 (100%) 19 (100%) 65 (100%)Grade III/IV and/or symptomaticContinued NVP 2 (20%) 0 0 2 (15%)Discontinued NVP 8 (80%) 1 (100%) 2 (100%) 11 (85%)Switched to EFV 4 (40%) 1 (100%) 2 (100%) 7 (54%)Total 10 (100%) 1 (100%) 2 (100%) 13 (100%)RashContinued NVP 18 (51.4%) 12 (63.2%) 8 (66.7%) 38 (57.6%)Discontinued NVP 17 (48.6%) 7 (36.8%) 4 (33.3%) 28 (42.4%)Switched to EFV 13 (37.1%) 5 (26.3%) 3 (25.0%) 21 (31.8%)Total 35 (100%) 19 (100%) 12 (100%) 66 (100%)Grade III/IVContinued NVP 1 (11%) 1 (17%) 2 (33%) 4 (19%)Discontinued NVP 8 (89%) 5 (83%) 4 (67%) 17 (81%)Switched to EFV 5 (56%) 5 (83%) 3 (50%) 13 (62%)Total 9 (100%) 6 (100%) 6 (100%) 21 (100%)All toxicitiesContinued NVP 42 (64.6%) 18 (69.2%) 23 (82.1%) 83 (69.7%)Discontinued NVP 23 (35.4%) 8 (30.8%) 5 (17.9%) 36 (30.3%)Switched to EFV 17 (26.2%) 6 (23.1%) 4 (14.3%) 27 (22.7%)Total 65 (100%) 26 (100%) 28 (100%) 119 (100%)

EFV, efavirenz.



rash-associated hepatotoxicity, and grade I–IV sympto-matic hepatotoxicity than pregnant women on NVP-basedHAART for therapy. Although in univariate analysis highbaseline CD4 cell count, CD4 cell count � 250 cells/mL andCD4 cell count � 400 cells/mL were significant risk factorsfor hepatotoxicity, we did not find any association betweensex, pregnancy status, gestational age at HAART initiation,or baseline CD4 cell count and the incidence of hepato-toxicity in multivariate analysis.

Female sex and high baseline CD4 cell count werepreviously identified as risk factors for NVP-relatedhepatotoxicity, especially in rash-associated hepatotoxicity[3,4]. Our inability to demonstrate an association betweenCD4 cell count and incidence of hepatotoxicity in thisstudy may be related to the relatively modest size of ourcohort and the low median CD4 cell count outside thepregnant women group; 35.0% of all patients had CD4counts � 250 cells/mL and 18.8% had CD4 counts � 400cells/mL. In addition, as our study might not be sufficientlypowered to detect differences, caution in the interpretationof the risk for NVP-related hepatotoxicity in pregnantwomen on HAART for PMTCT is warranted, given a highupper 95% CI limit of 16.6 in this group.

Abnormal baseline transaminase levels and coinfectionwith hepatitis B and C viruses have been reported to beindependent risk factors for antiretroviral-associated he-patotoxicity, including NVP-related hepatotoxicity[3,5,12,13]. Very few patients in our cohort had abnormalbaseline transaminase levels and only small proportionswere tested for hepatitis B and C. Therefore, we were unableto demonstrate an association of these factors. In addition,as relevant data were not collected, we were unable toassess the effect of other risk factors that have beenreported to be associated with NVP-related hepatotoxicitysuch as alcohol intake, high NVP blood levels and certainpharmacogenetic factors [9,11,14].

The incidence of NVP-related rash in our study (16.1%)was also within the range reported by others (4.3–36.0%).Our findings do not support the previously reported highincidence of NVP-related rash in Asian patients [38] andthe rates were lower than those reported in Thai patientswho participated in the 2NN study [15]. However, theincidence of Stevens–Johnson syndrome in our patients(1.5%) was higher than reported previously (0.3–1.0%). Inunivariate and multivariate analyses, we did not find anyassociation of sex, pregnancy status, gestational age atHAART initiation, or baseline CD4 cell count with theincidence of rash. However, our study was probably notsufficiently powered to find differences and, given anupper 95% CI limit of 6.5 for NVP-related rash in patientswith CD4 counts � 400 cells/mL who were all pregnantwomen, this finding should be interpreted with caution.

Baseline HIV-1 RNA and NVP levels were not available andthus could not be assessed as risk factors for developmentof NVP-related rash [16,17].

It should also be noted that a minimum follow-up periodof 8 weeks (or until delivery in pregnant women) was usedin this study. We realized that using a shorter follow-upperiod for the analyses might enable us to capture moretoxicities, but separate analyses in patients with aminimum follow-up period of 2 weeks resulted in similarconclusions regarding the development of NVP-relatedtoxicities.

NVP was discontinued in 4.2 and 6.8% of our patientsbecause of hepatotoxicity and rash, respectively. Althoughwe expected a higher discontinuation rate in our patients,as a large proportion were women and particularlypregnant women (in whom discontinuation of NVP isrecommended for hepatotoxicity or rash more severe thangrade I) [19], our rates were within the previously reportedrange of 3.2–26% [15–20,22–24,39]. Twenty-four of 27patients who required discontinuation of NVP weresuccessfully switched to EFV; 11 of 12 (91.7%) who hadliver dysfunction and 19 of 21 (90.5%) who had rash. Thisrate was at the high end of the range previously reported(47.4–91.2% of patients who experienced NVP-relatedrash) [15,18,40]. It is important to highlight the importanceof careful follow-up of patients who develop NVP-relatedhepatotoxicity or rash, including those who are switchedfrom NVP to EFV.

The results of our study support the findings of previousstudies on the overall safety of NVP when used as acomponent in a HAART regimen for pregnant women[26–32]. However, they are not in agreement with the veryhigh rates of hepatotoxicity, including one maternal deathfrom fatal hepatotoxicity, reported in the PACTG 1022study [35]. Baseline CD4 cell count 4250 cells/mL wasidentified as a significant risk factor for fulminant hepatitisin this study. Similarly, Gonzalez-Garcia et al. found CD4cell counts 4250 cells/mL to be a risk factor for both NVP-related hepatotoxicity and NVP-related rash duringpregnancy [28]. Ende et al. found that being naı̈ve toantiretroviral therapy was a significant risk factor [31],whereas Joy et al. reported a relationship between NVPhepatotoxicity and late trimester use [41]. Timmermanset al. also found NFV- or NVP-based antiretroviral therapy(ART) regimens to be associated with more frequent sideeffects in pregnant than in nonpregnant women [42].Although we found that our pregnant women had a higherrate of symptomatic hepatotoxicity than nonpregnantwomen, and that pregnant women who received NVP-based HAART for PMTCT (92% had CD4 counts � 250cells/mL) experienced a higher rate of symptomatic (but notasymptomatic) hepatotoxicity than those who received



NVP-based HAART during pregnancy for therapy, we wereunable to confirm the other associations mentioned abovein this cohort of pregnant Thai women receiving NVP-based HAART.

While attention has been particularly directed to thesafety of NVP during pregnancy, more information isneeded on the safety of other antiretroviral drugs inpregnant women. PI-based regimens, especially regimenscontaining NFV, are used as the first-line regimen inpregnant women in settings where resources are available.However, one death from fatal hepatotoxicity has beenreported in a pregnant woman receiving a NFV-basedHAART regimen [43], and more recently 24% of 17pregnant women on NFV had at least one elevatedtransaminase measurement [44].

Our study has several strengths. These include thediversity of the patient population, the largest number ofwomen on NVP-containing HAART during pregnancyreported to date, the prospective follow-up according to apredetermined schedule of visits, and the utilization ofa standardized toxicity grading system. However, the studyalso has limitations. These include the limited size of thecohort, the limited duration of follow-up, and the lowmedian CD4 cell counts, which may limit the ability toassess higher CD4 cell counts as a risk factor for NVP-related toxicities, especially in nonpregnant women andmen, as well as the differential laboratory monitoring ofpregnant women versus other patient groups. This lastlimitation may have affected our ability to detect the truerate of asymptomatic hepatotoxicity as well as differencesbetween men and women in this cohort.

In summary, we found NVP to be safe even when used asa component of HAART in pregnant women. However,pregnant women with high CD4 cell counts who receiveNVP-based HAART for PMTCT may experience higher ratesof symptomatic hepatotoxicity and thus require carefulclinical and laboratory monitoring. Further studies areneeded to better define the risk factors for severehepatotoxicity, to identify methods for monitoring patientsto ensure their safety, and to assess the safety of otherregimens during pregnancy.

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Nevirapine-associated toxicity in HIV-infected Thai men and women, including pregnant women

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