BMC Infectious Diseases| BMC Infectious Diseases

Our cross-sectional study revealed that approximately one-sixth (or 1.6%) of participants met criteria to receive VF on second-line treatment at a large tertiary 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). This study adds to the evidence of second-line VF in India and other associated factors.

The prevalence of VF in our study population matches that reported in the only study from north India with second-line ART and VF. [3]. Our estimate was made using a larger sample of people from a different region in India, with a higher HIV prevalence. The data we use are also updated to 2015, unlike the north Indian study that only included data from 2012 Our prevalence estimate is consistent also with reports from other LMICs on VF. However, there are many definitions of VF that vary across studies making it difficult to compare the burdens of second-line associated and VF across countries. [9].

Similar to other studies, our analysis shows that low CD4 counts at the time VL testing are associated with VF. [9, 10]. Because our data is cross-sectional, we cannot comment on the directionality. VL should only be used to monitor second-line ART outcomes in cases where VL measurement is routinely possible and PLHIV are clinically stable. This is according to the WHO. [16]. However, VL testing continues to be suboptimal in many LMICs. 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 the 6-monthly VL testing [6, 7]. Given the challenges in implementing regular VL testing in India (which is difficult to do), CD4 count measurement will remain an important aspect to monitor PLHIV on second line ART. It may also be useful to identify PLHIV at risk of VF.

Our cohort showed a higher rate of second-line failure when there was an OI present at the time of diagnosis. It was impossible to determine whether OIs were a cause or effect of VF because this was a cross sectional study. Similar to previous studies in India, TB was also the most common OI. [18, 19]. According to NACO guidelines, PLHIV with TB are treated using rifabutin-based antituberculosis treatment. This could lead to adherence problems in this subset. [20]. Our analysis revealed that half of the PLHIV patients who have received second-line VF and an oral infusion (OI) are not adhering to ART. These results suggest that patients with active TB who are on second-line ART may need additional adherence support.

Lower weight at first-line failure was associated to second-line VF, according to our findings. Study from Ethiopia found that treatment failure was associated with weight loss after first-line failure. [21]. It is simple and cheap to measure your weight. It may prove useful in LMICs where HIV prevalence is high and resources are scarce to measure weight to better understand how it affects second-line ART response.

Our study findings are not without limitations. One limitation of our study is the lack of DTG-based second-line treatment. Currently, 80% of PLHIVs at BJGMC–SGH ART centre receiving second-line ART are on PI based regimens. This makes these findings relevant to a large majority. DTG stockouts were reported in India as recently September 2022, increasing the dependence on PI-based second line regimens. [22]. As we have already stated, this is the most up-to-date dataset from India that describes VF among people who are receiving second-line treatment. Future analyses will be required to update our findings. To define VF, we used one VL measurement. 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]. Our study definition was based in published literature. We were able to compare our findings with other studies. We did not find any association with adherence, which was a primary factor 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. Pill counting may not be the best method to determine adherence to second-line treatment. It may be more beneficial to use two non-invasive methods of measuring adherence or plasma therapeutic drug levels. [24]. On those with VF, we did not do HIV genotyping to determine their resistance to second-line medications. 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 highlights the need to improve and refine adherence measures for PLHIV who are receiving second-line ART. Our study is not cross-sectional and cannot explore causal relationships. This limitation will be addressed by future longitudinal analyses. Our findings may also be limited to western India, and more specifically Pune. We recommend studies from other regions of India to confirm our findings.