Failure on second-line ART with PI mutations and gender
Our study showed that the majority of the cases were males (67.1%) (Table 1), and were more likely to fail on second-line ART with PI mutations (p=0.001). This is in agreement with other studies conducted in developing countries that have shown that male HIV patients are more likely to present to HIV care facilities with advanced disease as compared to their female counterparts [23, 24]. Moreover, studies conducted in Ethiopia and South Africa have cited advanced HIV/AIDS as a critical predictor for failure on second-line ART [25, 26]. Furthermore, research has shown that males are more prone to virological failure while on second-line ART than females [27, 28], attributable to poor adherence and higher odds of alcohol consumption while on ART [29, 30]. However, our findings are contrasted by a South African study, which showed that 60% of patients who failed second-line ART with PI mutations were women [31]. That said, our findings continue to highlight male HIV positive patients as a key vulnerable population that needs special attention if we are to maintain them on second-line ART over an extended period.
Age and failure on second-line ART with PI mutations
A study by Chimbetete et al. (2018) found that younger patients (< 24 years of age) were associated with lower odds of PI mutations at failure on second-line ART [20]. However, our study did not find any statistical difference concerning age and failure on second-line ART with PI mutations. We recommend more studies to understand the factors behind younger HIV/AIDS patients on second-line ART having lower odds of PI mutations at failure.
HIV/TB Coinfection and Second-line ART failure with PI mutations
Concomitant Tuberculosis treatment while on second-line ART was higher among cases (67%) and significantly associated with second-line failure with PI mutations (p=<0.001). Our findings are in line with a study conducted by Rossouw et al. 2015, which found that children on Tuberculosis treatment while on second-line ART were more likely to fail on second-line therapy with PI mutations [21]. This is attributable to factors such as higher pill burden [32, 33], HIV/TB coinfection being associated with advanced HIV/AIDS [34], and the fact that Rifabutin is not readily available in the resource-limited settings as a replacement for Rifampicin which is known to reduce the pharmacookinetic levels of PIs and consequently their their efficacy [35, 36]. Our study calls on HIV care providers to provide more personalized attention, counseling, and support to patients concurrently on TB and second-line ART as they are at a high risk of failure with PI mutations. Furthermore, HIV clinical care specialists have to weigh options of initiating patients with TB on PIs carefully.
Type of second-line ART with failure on second-line ART with PI mutations
Patients who had “other” PIs like saquinavir and nelfinavir had higher odds of failure on second-
line ART with PI mutations (p=0.029) compared to counterparts on Alluvia or Atazanavir. This
could be associated with the higher pill burden of “other” PIs like saquinavir [37] and their low
genetic barrier to resistance and reduced bioavailability [38]. We recommend to HIV clinical care
specialists to give priority to prescribing PIs of higher genetic barrier resistance, and periodically
review and assess patients on PIs such as saquinavir for resistance.
Significance of the study
To our knowledge, this study is the first endeavor to investigate the factors associated with failure on second-line ART with PI mutations in Uganda. The study was conducted within an HIV care provision setting, which reflects ground reality, and our measures were based on WHO standards for assessing failure on second-line ART. Due to existing data management mechanisms for data validity at JCRC, data used for this study was relatively good and reliable. More importantly, we employed a robust data collection system and trained all staff involved in the data collection and management process to minimize errors and ensure the quality and validity of results.
Study Limitations
Our study had a couple of limitations. First, we excluded 69 (45%) files under the “case” arm, and 68 (21%) files under the “control” arm due to incompleteness, which could have affected the findings. Howver, we worked with data of over 50% of the whole population of interest which is generalisable. Second, there might have been original data entry errors since our analysis was solely based on routinely collected project data. Third, our study was conducted within the limitations of case-control studies, with the odds ratios unstable as reflected by the wide confidence intervals. This was minimised by increasing the power of the study. Finally, based on available data, we could not assess poor adherence. That said, our findings provide a platform for more extensive longitudinal studies to understand further the underlying factors and co-factors for second-line ART failure with PI mutations within low-income settings.