In our cohort, 78% discontinued or altered their regimens during an average follow-up time of 4.2 years (SD ± 2.7) (Table 3). After 12 months of follow-up, about half of women (53.0%) and men (54.4%) discontinued/changed their initial regimen, with no significant differences seen when stratified by gender and race (African American females: 53.8%; African American males: 53.4%; white females: 50.0%; white males: 55.2%). Overall, women and men were equally likely to discontinue or change regimens. At the time of change/discontinuation, 1 of 3 women (34%) and men (31.1%) had achieved undetectable virus levels (<50 copies/mL). Although the number of regimens per year did not differ by gender, women experienced more days off therapy than men (Table 3). Furthermore, black women reported the highest number of days off regimen per year, 51.2 days per year followed by white women, 41.0 days per year; black men, 37.3 days per year; and white men, 31.4 days per year.
The most common reason for δART regimens was virologic failure (composite variable); about 50% of both men and women had virologic failure documented as one of the reasons for changing regimens (Fig. 1). Individuals who started NNRTI-HAART instead of NRTI-HAART [adjusted odds ratio (OR), 0.46; 95% confidence interval (CI): 0.24 to 0.88] had lower rates of δART due to virologic failure. Individuals on other ARVs had a higher probability of discontinuing a regimen for virologic failure than those on NRTI-HAART (adjusted OR, 13.10, 95% CI: 5.55 to 30.96). As one of the reasons for virologic failure, although numbers involved were small, more men than women discontinued/changed their regimen due to documented resistance (6.9% vs. 2.4%, P = 0.04).
Women were more likely (44%) than men (36%) to discontinue/change their regimen because of reported nonadherence to treatment (composite variable) (adjusted OR, 1.44; 95% CI: 0.85 to 2.42). Individuals who started on NNRTI-HAART (adjusted OR, 0.44; 95% CI: 0.22 to 0.88) compared with those on NRTI-HAART were significantly less likely to discontinue their regimen because of documented poor adherence, whereas individuals on other ARVs (adjusted OR, 2.32; 95% CI: 1.53 to 3.95) were more likely to discontinue their regimens due to nonadherence to treatment. Patients who reported intravenous drug use as the mode of HIV transmission were significantly more likely to discontinue treatment for adherence reasons (adjusted OR, 2.13; 95% CI: 1.15 to 3.95) than those who did not, whereas older patients were less likely to discontinue their treatment due to nonadherence (adjusted OR, 0.96; 95% CI: 0.94 to 0.98).
Multivariate logistic regression analyses demonstrated that women were more likely to δART for neurologic (adjusted OR, 1.82; 95% CI: 0.98 to 3.39) and dermatologic symptoms (adjusted OR, 2.88; 95% CI: 1.01 to 8.18), for constitutional symptoms (adjusted OR, 2.23; 95% CI: 1.10 to 4.51), and for other concurrent medical conditions (adjusted OR, 2.03; 95% CI: 1.00 to 4.12) (composite variables) (Fig. 1). Within the composite category of neurologic reasons (Table 1 for definition of composite variables), 15% of women vs. 7% of men discontinued their regimen because of peripheral neuropathy (P = 0.002), whereas about 2% of women vs. 0.4 % of men changed/discontinued their treatment due to experiencing vertigo or dizziness (P = 0.04). Within the composite category of constitutional symptoms, 9% of women and 4% of men discontinued because of weight loss (P = 0.02) and/or fatigue (P = 0.05). Within the composite category of central nervous system related, psychiatric reasons, women were more likely to discontinue because of depression than men (7% vs. 4%, P = 0.07). In addition, although the difference was not statistically significant, women tended to discontinue/change regimens more often for rash (7.9% vs. 4.5%, P = 0.09). As expected, women were more likely to change/discontinue ART due to pregnancy (4.3%) or delivery (2.4%) of a child (categorized as a concurrent medical condition).
Time to discontinuation/change of the first regimen was not significantly different for men and women even after adjusting for race, type of regimen, and CD4 count at start of regimen. The only independent factor that had an effect on time to discontinuation/change of the first regimen was the type of regimen that was prescribed (Table 4).
In the presented cohort of 631 HAART-naive patients receiving outpatient care in a single urban clinic in the Southeast of the United States, women and men were equally likely to discontinue or change their initial HAART regimen, regardless of race, types of regimens, and CD4 count at therapy initiation. However, women spent more time off therapy than men, and the data suggest that women were more likely to discontinue or change their regimens due to neurologic, dermatologic, or constitutional toxicities or more specifically due to symptoms, such as rash, peripheral neuropathy, fatigue, weight loss, and feelings of vertigo/dizziness.
Previous studies have reported conflicting results with regard to the association of gender and discontinuation of therapy. A study by Mocroft et al8 reported that women were less likely to discontinue HAART than men, whereas d'Arminio Monforte et al7 reported that women were more likely to discontinue therapy due to toxicities. Differences between these studies in the characteristics of their populations, the types of regimens, and the definition of adverse event outcomes might explain some of the conflicting results. For example, African American women have been shown to be more likely to discontinue ART than white women.5 However, despite the high proportion of African American women (78% of women) in our cohort, we did not see a difference in discontinuation by gender or race.
Although general differences in ARV therapy response have been described for both men and women,7,10,15 specific reasons for discontinuation or change of therapy as documented by the provider and how they differ by gender have not been reported in detail. When focusing on specific ARVs or side effects, previous studies have shown gender-specific differences in ARV side effects, such as rash16 and depression.17 However, these studies were focusing on specific adverse events as outcomes of interest, rather than exploring the relative contributions of different events to the overall discontinuation rates. No studies to our knowledge have investigated the association of gender differences in therapy discontinuation due to peripheral neuropathy, fatigue, or weight loss, although the importance of these side effects as predictors of therapy failure has been established.10 In our study, these were documented more frequently for women than men as reasons for therapy discontinuation or change.
Although we identified significant gender differences in reasons for discontinuation or change of therapy, gender differences in the toxicities described may be also explained by other factors that were significantly different between men and women, that is, race and progression of HIV disease as shown by VL and CD4 count. Both race and CD4 counts have been described as predictors of adverse events in response to therapy, such as efavirenz or nevirapine.18,19
Women were more likely to discontinue or change their medications than men due to poor adherence although this difference was not significant in multivariate analysis. In particular, providers were more likely to report that women self discontinued their medicine-this might explain why women were found to be more days off therapy than men. The number of days off therapy was higher in black women than white women and higher than in white and black men. This emphasizes the importance of strengthening ART adherence strategies and interventions especially in African American women. Previous studies have also found that nonadherence to ART among women was associated with African American race. Other factors included suffering from depression, reluctance to take medications openly at home, and socioeconomic status.5,20 Although we did not evaluate socioeconomic status or barriers to ART adherence, women in our study were more likely to be African American and to have depression as a reported cause of regimen discontinuation.
The only reason for discontinuation/change in therapy that seemed to be more frequent in men than women was viral resistance. Because women were more likely to be nonadherent and to have more days off therapy than men, this difference may be more likely related to primary drug resistance of the transmitted virus rather than a response to the therapy administered. Although most cohort studies have not identified gender as a predictor for primary drug resistance in recently infected patients,21-24 the Canadian HIV strain and drug resistance surveillance program reported a higher frequency of primary drug resistance in white, male, homosexual populations than any other population group. In our study, white homosexuals accounted for the majority of the male patient population, therefore, it is plausible that the resistance observed in men was primary rather than secondary to suboptimal ARV adherence. However, we did not have data that allowed us to distinguish between primary and secondary drug resistance, nor was resistance testing administered systematically.
Although we found no differences in the discontinuation rate by gender, we found that type of regimen was associated with time to initial therapy change or discontinuation. In particular, in comparison to PI-based regimens, NNRTI-based regimens fared the best in delaying the time to regimen change. Therefore, depending on the type of regimen administered, rates of discontinuation may be found to be higher in women than in men. In our study, ART types did not differ significantly by gender, with about 33% of individuals being on PI-based regimens, 33% being on NNRTI-based regimens, and 9% being on NRTI-based regimens.
The design of this study had several limitations, which need to be considered when interpreting the results. Adverse events leading to discontinuation/change of therapy were those reported by providers and were retrospectively summarized for this study. Therefore, some information on reasons for discontinuation/change may be missing or misclassified in the medical records reviewed. However, all reasons for change/discontinuation were documented by rigorously reviewing the entire record of each patient to minimize the extent of missing information. Furthermore, questionable records were discussed with the providers for clarification. Only adverse events/reasons that led to discontinuation/change of therapy were documented for this study; therefore, the frequency of adverse events as a response to therapy may be higher assuming that not every adverse event will lead to therapy change/discontinuation. Therefore, this study did not investigate the overall frequency of specific drug toxicities by gender.
In conclusion, given the increasing predominance of women and in particular African American women in the HIV infected population, documented therapy gaps in women, especially African Americans, is a matter of concern and warrants further detailed investigation. Interventions targeting the prevention of the described adverse events and toxicities need to be developed to minimize therapy discontinuation in women. Such interventions will also have an indirect positive effect on adherence patterns given that toxicities might lead to suboptimal adherence to therapy. As suggested by Ofotokun and Pomeroy,25 individualized drug dosages based on drug plasma levels may reduce the disparities in adverse drug events and thus in discontinuation of therapy. Therefore 2 types of interventions may be needed-one at the provider level-adjusting drug dosage levels to avoid adverse events in response to therapy-and another on the patient level-providing education and resources to stress and support adherence to ART, especially among women who lack the support for taking their medications in their daily life.
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Keywords:© 2009 Lippincott Williams & Wilkins, Inc.
antiretroviral therapy discontinuation; antiretroviral therapy change; gender; HIV; HAART; women