In the presented cohort of 631 HAART-naïve patients receiving outpatient care in a single urban clinic in the Southeast of the US, 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 suggests 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 regards to the association of gender and discontinuation of therapy, A study by Mocroft et. al. 8
reported that women were less likely to discontinue HAART than men, whereas Monforte et. al. 7
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.
Whereas 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 rash 16
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.
While 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, i.e., 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 non-adherence to ART among women was associated with African American race. Other factors included suffering from depression, reluctance to take medications openly at home, and socio-economic status 5, 20
. While we did not evaluate socio-economic 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 appeared to be more frequent in men than women was viral resistance. Since women were more likely to be non-adherent 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.
While 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 differed 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 in order 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 et. al. 25
, individualized drug dosages based on drug plasma levels may reduce the disparities in adverse drug events and thus in discontinuation of therapy. Therefore two 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.