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Sex Differences in Nevirapine Rash

  1. Susan J. Bersoff-Matcha1,
  2. William C. Miller2,
  3. Judith A. Aberg3,
  4. Charles van der Horst2,
  5. H. James Hamrick Jr.2,
  6. William G. Powderly1, and
  7. Linda M. Mundy1
  1. 1 Washington University School of Medicine, St. Louis, Missouri
  2. 2 University of North Carolina at Chapel Hill, San Francisco
  3. 3 University of California, San Francisco
  1. Reprints or correspondence: Dr. L. M. Mundy, Washington University School of Medicine, 660 South Euclid, Campus Box 8051, St. Louis, MO 63141 (lmundy{at}imgate.wustl.edu).
 
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Abstract

Nevirapine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) that has the most common treatment limiting side effect of rash. Severe rash has been observed in 3% of patients taking nevirapine in clinical trials, 85% of whom were men. In a multicenter, retrospective cohort study of all patients who received nevirapine over a 5-year period, severe rash was noted in 9 of 95 women and 3 of 263 men (risk ratio [RR], 8.31; 95% confidence interval [CI], 2.3–30.0; P = .005). Women were more likely to discontinue nevirapine therapy because of rash (RR, 4.5; 95% CI, 1.9–10.5; P = .0005). After adjusting for age and baseline CD4 cell count in multivariate analysis, women had a 7-fold increase in risk for severe rash and were 3.5 times more likely to discontinue nevirapine therapy. In women of reproductive age for whom contraception may occur, nevirapine remains the NNRTI of choice. Recognition of sex differences in this severe adverse event will be important in prescribing nevirapine.

Nevirapine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) that has proven to be an effective component of highly active antiretroviral therapy (HAART) used in the treatment of HIV type 1 [1–5]. Because of its long half-life, nevirapine can be given as part of a twice-daily dosing regimen [1, 6–9], requiring only 1 pill for each dose. In addition, it has good penetration into the CNS, making it an attractive option for patients with HIV-associated CNS disease [10].

In general, nevirapine has a favorable safety profile, with major severe adverse events that include fever, oral ulcers, and elevated hepatic transaminases [11]. Yet the most common treatment-limiting side effect has been rash. Early clinical studies reported the incidence of rash to be as high as 32%–48% [3, 7] when patients received full-dose nevirapine from the outset of treatment. Subsequently, dose escalation of 200 mg every day for 2 weeks, then 400 mg every day has been shown to effectively reduce the incidence of rash in patients initiating nevirapine therapy [12]. Aggregate data from 1752 patients who participated in 33 nevirapine clinical trials revealed a rash rate of 17% [8]. Overall, 6% of the patients in these studies had to discontinue the drug because of the rash, and 0.5% of patients developed Stevens-Johnson syndrome, whereas sex-specific rates of severe cutaneous eruptions were not addressed [8].

In our clinical experience with nevirapine, we have noted more frequent and severe side effects in women who have been treated with this drug. The goal of our study was to determine whether women are more likely to develop severe rash than men who take nevirapine and to determine the risk factors that may lead to the development of severe side effects.

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Methods

Study population and study design. We conducted a retrospective cohort study of all patients aged ⩾13 years who received an antiretroviral regimen that included nevirapine at the 3 study sites from September 1993 through September 1998. The study sites included Washington University Medical School Infectious Diseases clinic and AIDS Clinical Trials Units (ACTU), where patients were identified through a search of electronic medical records and ACTU records; University of North Carolina at Chapel Hill Infectious Diseases Clinic and ACTU, where patients were identified through a search of pharmacy records and ACTU records; and University of California, San Francisco, San Francisco General Hospital, where patients were identified by a daily survey of all patients seeking care at the HIV primary care and subspecialty clinics at San Francisco General Hospital.

To be included in the study, patients had to have been on nevirapine therapy for at least 30 days (unless the drug had to be discontinued before 30 days of therapy for a severe cutaneous adverse event), and 1 documented follow-up visit had to have occurred at least 30 days after the initiation of nevirapine therapy. Patients were excluded if they were started on nevirapine at an outside institution; if they took the medication <30 days; if there was no documented follow-up after the initiation of nevirapine therapy; or if they had undergone sex reassignment surgery. At each study site, nevirapine dose escalation was routinely prescribed during the defined study period.

Data collection. All sites used a standardized data extraction form. Demographic data, immunologic parameters, and concurrent medical therapies were recorded. The grading of rash was prospectively assigned for ACTU enrollees and retrospectively assigned for patients who were not in the trial. The extracted data were entered into a database by use of Epi Info software, version 6.0 (USD).

Study definitions. The primary outcome of interest was the occurrence of severe rash within 90 days of initiation of therapy. All cutaneous eruptions occurring within the first 90 days were ascribed to nevirapine. The grading scheme according to the AIDS Clinical Trial Group Protocol Management Handbook Table for Grading Severity of Cutaneous Eruptions [13] was used; this scheme is as follows: (1) grade 1, erythema with or without pruritus; (2) grade 2, a diffuse erythematous macular or maculopapular cutaneous eruption or dry desquamation with or without pruritus or typical target lesions without blistering, vesicles, or ulcerations in the lesions; (3) grade 3, 1 of the following clinical presentations: urticaria; diffuse erythematous macular or maculopapular cutaneous eruption or moist desquamation with or without pruritus together with any of the 4 constitutional findings possibly related to the drug (i.e., 2-fold increase above baseline alanine aminotransferase or aspartate aminotransferase but at least 5-fold increase above the upper limit of aspartate aminotransferase or alanine aminotransferase elevation; fever with a temperature >39°C; blistering, vesiculation, or both of cutaneous eruptions; or any site of mucosal lesions considered related to study drug without other etiology, such as herpes simplex or aphthous ulcer); angioedema; exfoliative dermatitis (defined as severe widespread erythema and dry scaling of the skin and generalized superficial lymphadenopathy, with other constitutional findings possibly related to study drug such as fever or weight loss); or diffuse rash and serum sickness-like reactions defined as clinical symptom complex manifested as fever, lymphadenopathy, edema myalgia, arthralgia, or a combination; and (4) grade 4, diffuse cutaneous eruptions usually starting on the face, trunk, or back, often with prodromal symptoms plus one of the following: cutaneous bullae, sometimes confluent with widespread sheetlike detachment of skin (Nikolsky's sign), Stevens-Johnson syndrome, erythema multiforme major, or toxic epidermal necrolysis, or 2 or more anatomically distinct sites of mucosal erosion or ulceration not due to another cause (e.g., herpes simplex). Severe rash was defined as grade 3 and grade 4 cutaneous eruptions when we used this grading scheme. Skin biopsies were not required for categorization of rash. The secondary outcome of interest was discontinuation of nevirapine therapy because of rash.

Patients were defined as receiving opportunistic infection prophylaxis if they were receiving prophylaxis for Pneumocystis carinii pneumonia or Mycobacterium avium complex. Women were defined as receiving contraceptive hormones if they were using medroxyprogesterone (Depo-Provera), levonorgestrel (Norplant), or oral contraceptives.

Statistical analysis. Statistical analyses were performed with Stata, version 5.0 (Stata). Statistical significance for initial bivariate analyses was assessed by Fisher's exact test for categorical variables and the 2 sample t-test for continuous variables. We calculated cumulative incidences and RRs of the rash-related outcomes over 90 days. Ninety-five percent CIs for the cumulative incidences and RRs were calculated with exact methods. Our target sample size was based on the ability to detect a RR of 4.0 with estimated cumulative incidences of severe rash of 12% among women and 3% among men with α = .05 and power equal to 0.80.

Potentially confounding demographic, behavioral, and clinical variables were initially assessed for significant relationship to the rash outcomes. Variables that were related to these outcomes were then assessed for a significant association to sex with P ⩽.15 as the α level in these analyses. Factors assessed in these analyses included age, race, CD4 cell count historical nadir, CD4 cell count at initiation of therapy, HIV virus load at initiation of therapy, tobacco use, alcohol use, injection drug abuse, the use of individual antiretroviral drugs, the use of individual drugs for prophylaxis against opportunistic infections, and the use of 50 additional medications.

We performed multivariate analyses controlling for the identified potentially confounding variables with a generalized linear model (binomial family, log link function). This model provides a direct estimate of the risk (cumulative incidence) and RR [14]. The analyses were repeated with logistic regression, with similar results. Given the overestimation of the RR by the OR obtained with logistic regression, only the multiplicative risk model is presented.

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Results

Characteristics of study population. From the 3 sites, 358 (77%) of 464 patients were eligible for the study. A total of 106 patients met the exclusion criteria and were excluded: nevirapine prescribed at another institution (34 patients), missing charts (26), no follow-up after nevirapine therapy was initiated (24), nevirapine taken <30 days (10), nevirapine never actually taken by patient (10), congenital HIV (1), and sex reassignment surgery (1). The final study population included 95 women (27%) and 263 men (73%). There was no statistically significant difference in rates of rash among the 3 sites. Several differences between sexes were noted (table 1). Women were younger and more of them were African-American. A greater proportion of women had high CD4 cell counts at initiation of therapy, and higher nadir CD4 cell count. A greater proportion of men smoked tobacco. Differences were noted in the concurrent use of other antiretroviral agents. A greater proportion of men had taken ritonavir (11% vs. 3%, P = .021), saquinavir (11% vs. 4%, P = .042), stavudine (27% vs. 18%, P = .073), didanosine (13% vs. 6%, P = .089), and indinavir (19% vs. 12%, P = .112) within 2 weeks of the initiation of nevirapine.

Table 1
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Table 1

Characteristics of study population of 358 patients infected with HIV and grouped by sex.

Relationship of sex and rash. The overall cumulative incidence of severe rash during the first 90 days of nevirapine therapy was 3.4% (95% CI, 1.7–5.8). Among women, the risk of severe rash was 9.5%, compared with 1.1% in men during the first 90 days of therapy (RR, 8.3; 95% CI, 2.3–30; P = .005). Women were also more likely to discontinue nevirapine therapy because of rash: 13.7% (95% CI, 7.5–22.3) discontinued therapy, compared with 3% (95% CI, 1.3–5.9) of men (RR, 4.5; 95% CI, 1.9–10.5; P ⩽.001).

The difference between men and women was less striking when any rash in the first 90 days of therapy was considered as the outcome. A total of 15 (15.8%) women developed a rash, compared with 22 (8.4%) men (P = .05). All 4 patients with grade 4 rash had Stevens-Johnson syndrome. Rash tended to be more severe in women when we assessed it by use of ACTG rash severity scale. There was no significant difference in the time to development of rash (table 2).

Table 2
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Table 2

Apparent nevirapine-associated rash by sex among 358 patients infected with HIV.

Relationship of demographic and clinical factors with rash. Several factors in addition to gender were associated with the development of severe rash or discontinuation of therapy. In bivariate analyses, higher CD4 cell count at initiation of therapy and higher nadir CD4 cell count were strongly associated with severe rash and discontinuation of therapy (table 3). Age <35 years was associated with discontinuation of nevirapine therapy, but less strongly with severe rash. HIV virus load was not significantly associated with either rash outcome. The use of prophylaxis for opportunistic infections was associated with a decreased risk for severe rash and discontinuation of therapy. No cases of severe rash were observed in any of the 10 patients treated with prednisone or the 23 patients treated with diphenhydramine. The use of any antihistamine (128 patients) also appeared protective, but it did not attain statistical significance. We examined the contribution of contraceptive hormones to the severity of rash. Of 23 women taking contraceptive hormones, 4 (17%) developed severe rash compared with 5 (7%) of 72 women not receiving contraceptive hormones (RR, 2.5; 95% CI, 0.7–8.6; P = .21). No relationship was observed between discontinuation of nevirapine therapy and contraceptive hormones (table 3).

Table 3
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Table 3

Unadjusted risk ratios for severe rash and discontinuation of nevirapine therapy.

Relationship of sex and rash—multivariate analysis. After assessment of the relationship of variables to both outcome and sex, we identified age (⩽35 years vs. >35 years), CD4 cell count at initiation of therapy (⩽200 cells/mm3 vs. >200 cells/mm3), and nadir CD4 cell count (⩽200 cells/mm3 vs. >200 cells/mm3) as potential confounding variables. CD4 cell count at initiation of therapy and nadir CD4 cell count were highly correlated; these variables were entered in separate multivariate models. The use of opportunistic infection prophylaxis was associated with both rash and sex, but it was protective for rash and therefore was not included in the multivariate modeling.

In a multiplicative risk model adjusting for age and CD4 cell count at initiation of therapy, the adjusted RR for the development severe rash comparing women with men was 7.3 (95% CI, 2.0–27.1; P = .003). Similar results were obtained when adjusting for age and nadir CD4 cell count (RR, 6.8; 95% CI, 1.8–25.8; P = .005). For discontinuation of nevirapine therapy, the RR for sex was 3.5 (95% CI, 1.5–8.2; P = .005), adjusting for age and CD4 cell count at initiation. Similar results were obtained when adjusting for age and nadir CD4 count cell (RR, 3.4; 95% CI, 1.4–8.3; P = .006).

Higher CD4 cell counts were associated with increased risk of severe rash and discontinuation of therapy that approached statistical significance. For severe rash, people with CD4 cell count at initiation of therapy of >200 cells/mm3 were at 2.9 times the risk (95% CI, 0.8–10.4; P = .112) of people with CD4 cell counts of ⩽200 cells/mm3, after adjustment for age and sex. There were no sex differences in time to onset of rash (figure 1). For discontinuation of therapy, the adjusted RR for CD4 counts at initiation of therapy was 2.5 (95% CI, 0.97–6.2; P = .057). Similar results were observed for nadir CD4 cell count.

Figure 1
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Figure 1

Comparison of time to onset of rash in men and women with human immunodeficiency virus taking nevirapine.

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Discussion

Analysis of our data indicates that severe rash is significantly more common among women receiving nevirapine therapy. Although the mechanism of nevirapine rash remains unclear, this adverse event has been noted since the outset of clinical trials with this drug. This risk of severe mucocutaneous reactions associated with nevirapine appears to be among the highest reported for any HIV drug approved by the US Food and Drug Administration (FDA). It would be useful, therefore, to know the risk factors, if any, that may predict which patients are at the greatest risk for developing severe nevirapine rash.

Although studies have shown that nevirapine rash does not correlate well with nevirapine plasma levels [8], only 1 other study to date has attempted to analyze the risk factors that may contribute to the development of nevirapine rash [15]. This study identified CD4 cell counts of <100 cells/mm3 and concurrent use of fluconazole as potential risk factors for development of rash, whereas no correlation between rash and the use of trimethoprim-sulfamethoxazole (TMP-SMZ) or amoxicillin-clavulanate was identified, as had previously been suspected. Overall, the study concluded that there were no reliable predictors of nevirapine-associated rash. This study had limitations, however, because the study population was predominantly white (83%) and male (88%), and involved only bivariate analyses.

In our cohort, rash was noted in patients with higher CD4 cell counts and was not significantly associated with age, race, or concurrent medications. Our study also has recognized limitations common to retrospective designs, the predominant one being the potential for bias in the grading of rash in patients not enrolled in ACTU trials. Although possible, we believe this is unlikely, given the rigorous ACTG criteria used for grading this adverse cutaneous event.

Before approval by the FDA in June 1996, nevirapine was evaluated in 7 published clinical studies [1–3, 6, 7, 16, 17]. In these studies, 36 (10%) of 358 patients developed a rash while on nevirapine, in whom 29 the rash was severe enough to warrant discontinuation of therapy. Data were available for 296 men and 52 women, with no distinction in rash episodes by sex. Since FDA approval was granted, there have been 20 reported cases of nevirapine-associated Stevens-Johnson syndrome and 3 possibly associated deaths [18]. It has recently been suggested in an uncontrolled study that short-course glucocorticoid therapy at the time nevirapine is initiated may be effective in preventing rash [19]. In the cohort we studied, there were 10 patients (3 women and 7 men) who were receiving glucocorticoids at the time nevirapine was started, 2 of whom (both men) developed a grade 1 rash.

Sex disparity for mucocutaneous reactions to nevirapine is not unprecedented, and several previous studies have also identified sex differences in skin reactions to drugs [20]. The Boston Collaborative Drug Surveillance Program reported generalized morbilliform drug exanthems, urticaria, and generalized pruritus in >2% of all medical inpatients, with the overall rate for women being 50% higher than that for men [21]. In a follow-up report by the same group a decade later, the overall rate of cutaneous reactions was again found to be just over 2%, with the incidence in women 35% higher than that for men [22]. Additional studies have identified women as more likely to develop cutaneous reactions after exposure to several commonly prescribed drugs [23–25], including TMP-SMZ [26], ampicillin [27], pyrimethamine-sulfadoxine (Fansidar) [28], and warfarin [29].

The results of our study should be interpreted cautiously because of the small number of people who experience severe rashes. Although the difference between men and women was substantial, we cannot be certain that this difference was not explained by other factors. In our multivariate analyses, we were only able to control for 2 other factors: age and CD4 cell counts, expressed as dichotomous variables. Furthermore, it was difficult to determine with certainty whether concomitant use of other medications could have contributed to the observed differences.

Why women seem to have a higher propensity for cutaneous reactions to nevirapine and other commonly prescribed medications is unclear. What is certain is that for rash, adverse drug reaction rates cannot be extrapolated between sexes. Adequate sex representation is needed for evaluating medications known to have skin rash as a side effect. Because women are the fastest growing demographic group contracting HIV in the United States [30], it will continue to be important to recruit sufficient numbers into the clinical trials of new drugs so that sex differences in clinical efficacy, adverse events, and plausible interventions can be better characterized.

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Footnotes

  • Financial support: HRSA SPNS (grant BRU-900125-02-0); National Institutes of Health (grants AI-25903, AI-25867, and RR00046); Washington University AIDS Clinical Trials Unit, University of North Carolina Center for AIDS Research grant P30HD3726; Holderness Foundation; Independent Clinical Trials Unit at the University of California at San Francisco Positive Health Program, SFGH AIDS Program.

  • Received April 4, 2000.
  • Revision received May 30, 2000.
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  1. Clin Infect Dis. (2001) 32 (1): 124-129. doi: 10.1086/317536
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