Virological failure among people living with HIV receiving second ... - BMC Infectious Diseases

Our cross-sectional study found that around one-sixth of participants met criteria for VF on second-line ART at a large tertiary ART center in western India. In addition, our analysis identified significant associations between VF and lower time-updated CD4 count (≤ 350 cells/mm³), present OI and low weight (< 51 kg). Overall, this study adds to the limited evidence on second-line VF and associated factors in India.

The prevalence of VF in our study population is consistent with that reported in the only other study from north India on second-line ART associated VF [3]. However, our estimate was obtained using a larger sample size from a different geographical region in India with higher HIV prevalence. Additionally, compared to the study from north India that included data only till 2012, the data we use is updated to 2015. Our prevalence estimate is also consistent with reports of VF from other LMICs, although varying definitions of VF across studies, makes it challenging to directly compare the burden of second-line associated VF across countries [9].

Similar to previous studies, our analysis indicates that low CD4 count at the time of VL testing is associated with VF [9, 10]. The cross-sectional nature of our data precludes us from commenting on the directionality of this association. The WHO has recommended that in situations where VL measurement is routinely available and PLHIV are clinically stable on ART, VL be exclusively used to monitor second-line ART treatment outcomes [16]. However, in many LMICs, the regularity of VL testing remains suboptimal. A recent study from Asia of 31,346 PLHIV (with > 60% of the data originating from India) showed that VL testing was performed less than annually in > 50% of PLHIV [17]. At present, NACO recommends CD4 monitoring among adult PLHIV on second-line ART with CD4 count < 350 cells/mm³ in addition to 6-monthly VL testing [6, 7]. Given the implementational challenges of regular VL testing in India, CD4 count measurement will continue to remain an important aspect of monitoring PLHIV on second-line ART and may be useful to identify PLHIV at potential risk of VF.

The presence of an OI at the time of diagnosis of VF was associated with second-line failure in our cohort. However, as this was a cross-sectional study, it was not possible to assess whether OIs were the cause or effect of VF. As in previous studies from India, TB was the most common OI [18, 19]. As per NACO guidelines, PLHIV diagnosed with TB are treated with rifabutin-based antituberculosis therapy, and the additional pill burden could affect adherence in this subset of PLHIV [20]. Our analysis indicates suboptimal adherence to ART among half of PLHIV with second-line VF and an OI. These findings suggest that patients with active TB on second-line ART may require additional adherence support.

We found that lower weight at first-line failure was associated with second-line VF. A study from Ethiopia reported that weight loss after starting second-line ART was associated with treatment failure [21]. The measurement of weight is easy and inexpensive to perform. Therefore, in LMICs, where the burden of HIV is high and resources are limited, it may be of value for future studies to better understand the role of weight as a predictor of treatment response to second-line ART.

There are several limitations to our study findings. A major limitation is that we used a data set that does not include DTG-based second-line therapy. Currently 80% of PLHIV at BJGMC-SGH ART center receiving second-line ART are on PI-based regimens, making these findings relevant to a majority. Moreover, as recently as September 2022, there were DTG stockouts across India increasing the reliance on PI-based second-line regimens [22]. As already mentioned, to our knowledge, this remains the most updated dataset from India to describe VF among those receiving second-line ART. Future analyses should work on updating our findings. We used a single VL measurement to define VF. WHO defines second-line treatment failure as plasma VL above 1000 copies/mL on two consecutive measurements within 3 months along with adherence support [23]. However, our study definition was based on published literature, allowing us to compare our findings to similar previous studies. We found no association with adherence; a primary factor for VF in previous studies [8]. We were able to characterize adherence only at cut-off levels of < 95% and ≥ 95%, as recommended by NACO. Therefore, it is possible that very few participants had truly low adherence (i.e., adherence levels < 80%) which resulted in the non-significant adjusted association with VF. Additionally, pill counting may not be the optimal method to measure adherence to second-line ART. The use of two non-invasive methods or plasma therapeutic drug concentration levels may be better adherence assessment measures [24]. We did not perform HIV genotyping to determine resistance to second-line drugs, on those with VF. However, in a study of 47 PLHIV from Mumbai (150 km from Pune), relative to drug resistance, decreased adherence was observed to be a more crucial factor for second-line associated VF [25]. This further highlights the need for better and more granular adherence measures among PLHIV receiving second-line ART. Our study is cross-sectional, limiting the exploration of causal relationships. Future longitudinal analyses are required to address this limitation. Lastly, our findings may be generalizable only to western India and more specifically Pune. We advocate for studies from different regions of India to corroborate our findings.

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