We noted important differences between men and women with respect to signs and symptoms in the 2 cohort groups. There was no difference between the sexes when we looked at more easily quantifiable metrics such as abnormal laboratory values, serious adverse events, and newly established diagnoses. More women than men had a suboptimal virological response and experienced VF, primarily reflecting more women than men experiencing VF without new drug resistance mutations. Of note, all participants in this study experienced VF twice before study entry. Data from treatment programs in LMIC suggest that women are more likely to access therapy and, in contrast to the findings of our study, achieve virological suppression on their first regimens. Importantly, in our study, more women than men had an NVP-based first-line regimen, a regimen that is more likely to lead to VF than an efavirenz-based regimen. Drivers of regimen failure are complex and include both biological and personal factors. For example, historical use of single-dose NVP for the prevention of vertical transmission has led to significant NNRTI resistance in women; in 2019, the WHO reported levels of pretreatment drug resistance nearly twice as high among women as among men.
We do not have good data on access to PI-based therapy in LMIC. The excess in pretreatment resistance, documented above, may mean that more women than men require second-line regimens. In addition, individuals experiencing VF of a second regimen may represent a specific subset of people that have problems with adherence and may be different from those initiating ART. Importantly, we do not have data on stigma or mental health issues that may affect women's adherence differently than men's.
Despite these limitations, we believe that there is an important biological basis for treatment failure in women. Specifically, the contrast in patterns for women and men between "signs and symptoms" (subjective measure of tolerability) and "diagnoses" and "laboratory abnormal values" (objective measures of tolerability) is important because it may represent sex differences in the experience of treatment. It is possible that clinicians are less likely to make changes in the face of subjective tolerability especially when regimen choices are limited.
Our study raises the possibility that tolerability issues may be driving incomplete adherence to ART in women referred for third-line therapy, with important clinical consequences. In our study, women who continued their PI-based regimens experienced more grade ≥3 signs and symptoms than men, but this was not the case for grade ≥3 diagnoses or laboratory values. Moreover, women experienced VF more frequently than men, and more women had a suboptimal virological response at week 48 than men. More women than men experienced VF without new resistance mutations which strongly suggests nonadherence to PI-based regimens in this setting.
Differences in tolerability between the sexes may also be driving the findings in cohort A. More women than men entered cohort A (which had the least resistance at screening) after having experienced treatment failure with both an NNRTI- and a PI-based regimen. Consistent with current standard of care in LMIC, where treatment options are limited, our study required the continuation of the PI-based regimen with an emphasis on adherence counseling and support. The individuals in cohort A remained on their second-line ART regimen with only minor modifications. Cohort A was likely enriched for individuals who had past incomplete adherence, resistance, or tolerability issues. We are unable to determine which of these factors or combination of factors was responsible for the increased number of women in cohort A, a limitation of our study.
Tolerability issues that might lead to treatment discontinuation have been reported in a variety of settings. In a cross-sectional survey of self-reported nonadherence, men were more likely to report forgetting to take their medications, while women were more likely to report adverse events. Important sex differences in ART tolerability have been reported, and a higher rate of adverse events that lead to treatment discontinuation in women has been documented with nearly all ART classes. NVP has a well-described hepatic toxicity in women, leading to recommendations that its use be limited in women with CD4 counts >250 cells/mm3. Women are more likely than men to develop a rash when exposed to efavirenz. Nausea and vomiting have featured prominently in several reports relating to ritonavir use.[9,10] The women in our study commonly experienced gastrointestinal complaints, consistent with known toxicities of ritonavir.
Sex differences in drug metabolism have been described which may lead to differences in tolerability. Ritonavir clearance is noted to be slower in women, leading to concentrations approximately a third higher than in men after adjustment for body weight. A large prospective clinical trial identified higher concentrations and a slower clearance of atazanavir (given with ritonavir) in women than in men. The authors suggested that this might have been responsible for greater rates of VF in women than men; ritonavir concentrations in that study were not measured. Sex differences have been reported in the metabolism of other drugs as well: Intracellular concentrations of the active triphosphate moiety of both zidovudine and lamivudine may be higher in women than men, and saquinavir (when given with ritonavir) concentrations were shown to be higher in women.[13,14] It has been postulated that differences in metabolism are related to drug exposure with plasma drug concentrations in women being higher because of women's smaller size. In our study, adjustment for weight did not affect the findings, but it may be that body composition played an important role. Additionally or alternatively, the basis for higher ritonavir concentrations in women may be metabolic and/or genetic. Ritonavir is a substrate and inhibitor of cytochrome P-450 3A and P-glycoprotein, as are atazanavir and saquinavir. The oral clearance of verapamil, also a mixed CYP3A and P-glycoprotein substrate, was shown to be slower in women than in men. Sex-specific differences in expression/function of CYP3A and P-glycoprotein, therefore, could provide a pharmacokinetic basis for higher ritonavir concentrations in women and thereby, a pharmacodynamic basis for those higher concentrations to result in poorer tolerance in women.
Women comprise more than half of all those with HIV infection, and most women with HIV live in LMIC. Therapy for HIV is lifelong, and adherence to life-long therapy is a challenge for all PLH. Interventions designed to improve adherence may need to be tailored to specific populations and stages during the life span. Even with the planned widespread use of dolutegravir, it is likely that boosted PIs may be required at some stages of life.
Our analysis identified a potentially modifiable biological determinant of incomplete adherence in women. If tolerability is indeed a more important driver of incomplete adherence for women, interventions designed to improve tolerability may improve outcomes and reduce treatment failure. In our study, it is possible that lower grade signs and symptoms may have been responsible for differences in adherence and differences in outcomes between men and women. We could not fully assess the effect of intolerance in PLH assigned to cohort A because we tracked more severe adverse events and not lower grade adverse events. Future studies should proactively monitor low-level adverse events that could be addressed by more aggressive management, including treatment switches, to prevent failure due to incomplete adherence from poor tolerability. Personalized or targeted drug selections and dose modifications may also be required. Certainly, simpler and better tolerated regimens such as those that include dolutegravir could be helpful.
One of the key strengths of our study was the large proportion of women across several countries which allowed us to look critically at this information. This was a planned secondary analysis, but the study was not specifically designed to evaluate differences between men and women. In addition, the cohorts were not randomized, a potential limitation; however, the finding of "subjective intolerance" was noted across all cohorts. As such, we may have identified a potentially modifiable determinant of nonadherence in women. Understanding the specific reasons for incomplete adherence will allow targeted interventions aiming to improve adherence and HIV-related outcomes. Attention to the sex differences in the experience with ART will allow for prompt identification of emerging toxicities and mitigation of those toxicities.
Supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1 AI068634, UM1 AI068636, and UM1 AI106701. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
C.G. wrote this article in her capacity as an NIH employee, but the views expressed in this article do not necessarily represent those of the NIH. R.G. has funding P30 AI 045008: R.G. serves on a DSMB for a Pfizer drug unrelated to HIV treatment. Remaining author has no conflict of interest to disclose.
The trial is registered with ClinicalTrials.gov, number NCT01641367.
J Acquir Immune Defic Syndr. 2020;84(2):203-207. © 2020 Lippincott Williams & Wilkins