This study is novel in its use of a validated PN screen to measure the incidence of PN in an incipient cohort of patients initiating ART in a resource-limited setting. Patients diagnosed with PN at baseline were significantly less likely to start on D4T-based regimens, suggesting that the screening tool helped clinicians make beneficial treatment decisions. Using the PN screening tool, we report for the first time that women were ~10 times more likely than men to develop PN during the first year after ART was initiated.
Previous studies in HIV-infected patients receiving ART in sub-Saharan Africa have not found an increase in risk of PN among women, although none used an incipient cohort to study the incidence of PN, the BPNS tool, or the same definition of PN as we did in the current work [2
]. Furthermore, studies conducted in resource-rich countries on PN among HIV-infected patients receiving ART have low female enrollment, limiting their power to evaluate sex differences [18
]. A recent cross-sectional study conducted in 2 Asian countries and in Australia that did use the BPNS for the diagnosis of PN in HIV-infected patients receiving ART did not find a sex difference [21
]. In fact, they found that women were less likely to have PN in Indonesia and Malaysia and equally likely in Australia. Differences in study design (cross-sectional vs longitudinal) and racial characteristics of the cohort may account for this discrepancy. Studies from resource-rich settings have shown that women tolerate NRTI-containing regimens less well than men [22
]. A recent study found that women discontinued ART for PN more often than men [22
]. The reason for greater adverse events in women has not been clearly shown; however, suggested mechanisms for sex differences have included differences in weight or BMI and hormonal changes that may affect drug distribution and metabolism [25
]. In our study, women were more likely to be younger, more anemic and have slightly higher BMI than men. Although we did not identify anemia as an independent risk factor for PN overall, there was a trend toward a higher risk of PN in adults with hemoglobin levels of 5.5–8.9 g/dL than in those with levels of 10.7–16.9 g/dL. Furthermore, the hazard ratio for developing PN among women decreased from 9.6 to 7.4 when hemoglobin levels were controlled for. It is possible that anemia may be a marker for other risk factors unmeasured in this study, such as general micronutrient deficiencies. Larger studies using the BPNS should be conducted in resource-limited settings to better identify modifiable risk factors for PN in HIV-infected men and women, such as iron, vitamin B12, and other deficiencies.
We did not find the expected association between development of PN and initiation of ART with a D4T-based regimen. Furthermore, patients in our study developed PN despite our use of the recommended weight-based dosing for D4T. This result supports continued vigilance in routine monitoring for the development of PN among ART-treated patients, even with the revised 2010 WHO guidelines for ART, which no longer recommend D4T as first-line therapy [26
The use of the BPNS in routine care may help to identify PN earlier and prevent disability. As we have reported elsewhere, clinical and medical officers in our busy urban clinic in Kenya easily integrated the BPNS into patient visits [13
]. Use of the screening tool by trained clinicians added 5 min to patient visits. Our experience suggests that the BPNS can be a useful tool for routine care of HIV-infected patients in resource-limited settings, although the optimal frequency of testing is unclear. However, previous work has shown that if PN does occur in HIV-infected patients, it does so within the first year after the start of ART, and if PN did not develop during the first year, it was less likely to occur in subsequent years [27
]. Therefore, in resource-limited settings, it may be sufficient to limit screening for PN to the first year of ART.
Limitations of our study include a small sample size that reduced our statistical power to detect weaker associations. In addition, several known risk factors for PN were not assessed, including alcohol use, micronutrient status, hepatitis C status, syphilis, thyroid disorders, and renal dysfunction. Because we did not have data on adherence to ART, we cannot determine the impact of higher rates of PN among women on nonadherence to a medication regimen. Selection bias is a concern and may partially explain our finding that women developed PN more frequently than men. However, it is unlikely to explain this finding completely. Because enrollment occurred among consecutive eligible patients beginning ART, the demographic makeup of the study cohort was similar to the HIV cohort of patients at the clinic as a whole (60% female), and the 27 patients excluded from analysis due to lack of follow-up screens were similar in sex and age to the analyzed population.