In multivariate analysis, the risk of virological breakthrough in the 6-month period following a diagnosis of TB was associated with over twice the risk of virological breakthrough compared with person-time without a TB diagnosis (IRR: 2.3, 95% CI: 1.7 to 3.2, P < 0.001). The 6-month period before TB diagnosis or time more than 6 months after TB diagnosis were not associated with increased risk of virological breakthrough after adjustment for other risk factors (IRR: 0.8, 95% CI: 0.5 to 1.3, and IRR: 0.9 95% CI: 0.7 to 1.1, respectively) (Fig. 3).
A sensitivity analysis similarly found increased adjusted risks of virological breakthrough and failure (IRR: 2.3, 95% CI: 1.6 to 3.3, P < 0.001, and IRR 3.1, 95% CI: 1.9 to 5.2, P = 0.002, respectively) in the 6 months after microbiologically confirmed diagnosis of incident TB but not in the periods either preceding or more than 6 months after TB diagnosis.
An exploratory analysis was also performed of the association between prevalent TB and virological failure. As previously, only person-time following initial virological suppression was included and to provide adequate person-time for analysis, a 12-month period was considered. In adjusted analysis, the risks of virological breakthrough or failure following prevalent TB were greater during the first 12 months of ART compared with >12 months after starting ART (IRR: 1.7, 95% CI: 1.0 to 2.8, P = 0.053 and IRR: 1.4, 95% CI: 0.9 to 2.0, P = 0.072, respectively).
Few studies have reported data on virological breakthrough and failure rates during ART in sub-Saharan Africa.19 The high cumulative proportion of patients experiencing virological breakthrough and failure in this study may reflect the long duration of follow-up, and rates are consistent with data from other studies elsewhere in the world.20–23 Virological breakthrough differs from virological failure in that the majority of patients experiencing breakthrough will virologically suppress following adherence interventions.17 The significance of virological breakthrough has yet to be clearly defined, and a better understanding and correlation with clinical outcomes is needed. There is conflicting evidence as to whether low-level viremia (commonly defined as 50–400 copies/mL) during ART is associated with virological failure.24–28 Blips of increasing magnitude (eg, >500 copies/mL), however, have been associated with virological failure and resistance.29 Virological breakthrough in this study was conservatively defined as >1000 copies per milliliter and was thus unlikely to be because of stochastic variation and represented patients at increased risk of virological failure, resistance, and poor clinical outcomes.
In this study, PI-based ART regimens were associated with increased risk of virological breakthrough and failure before but not after adjustment for other risk factors. This is most likely because of PI-based regimens being used as second-line treatment, most commonly following virological failure. However, there was some evidence of an independent association between NVP-based ART regimens and poor virological outcomes. This could be a direct association with NVP; existing studies have shown NVP-based regimens to have inferior virological outcomes compared with EFV- or PI-based regimens, especially in the context of rifampicin-based TB treatment, although a recent randomized trial found no difference.37–41 Alternatively, the relationship could be confounded by pregnancy (for which data were not available and adjustment was not made) as NVP-based regimens were mostly prescribed for women who were pregnant or at risk of pregnancy. Pregnancy has been independently associated with worse virological outcomes.41
The findings of this study have several implications for ART programs. First, further research is needed to explore the mechanisms underlying the association between incident TB and poor virological outcomes and to identify appropriate interventions. However, there is also an immediate need to recognize that patients with TB during ART are at increased risk of poor virological outcomes and should, therefore, be prioritized for virological monitoring where possible and increased adherence support. The adherence support system used in this cohort has previously been shown to be associated with successful virological suppression in approximately two thirds of patients with virological breakthrough as also reported in this analysis.17 During the period of this study, HIV care and TB treatment were provided by separate nonintegrated services, which compromises efficient delivery of care as described elsewhere.30,31 Delivery of care for patients with HIV-associated TB must be strengthened, colocated, and integrated. Finally, adjunctive interventions are needed to prevent incident TB during ART, including the use of isoniazid preventive therapy and effective infection control measures in health care facilities.5,42,43
Strengths of this study include the large sample size, long median duration of follow-up, completeness of the dataset, high frequency of CD4 and VL testing, availability of time-updated ART regimen data, high proportion of microbiologically confirmed TB diagnoses, and the use of multiple-event analysis techniques. Although the observational design of the study has inherent limitations, including the inability to establish a direct causal relationship between TB and virological breakthrough and failure, the routine programmatic conditions may improve the generalizability of the findings. The lack of data on treatment adherence and side-effects are a limitation as we were unable to explore these as potential mechanisms. Although this study cannot exclude VL > 1000 copies per milliliter being a risk factor for incident TB, the strong temporal relationship and lack of association between time preceding TB diagnosis and VL breakthrough do not support this explanation. Although other opportunistic infections not accounted for in this study may also be implicated in virological failure, most opportunistic infections are strongly related to CD4 cell count, which was adjusted for. There may be other social and biological risk factors for poor virological outcomes that were not possible to quantify or adjust for in this study. Although the LTFU rate (18.9% over a median follow-up of 5.2 years) was considerably lower than that of other ART programs in sub-Saharan Africa,44 some may have had unascertained TB. However, patients LTFU from this cohort in fact do not have poor prognostic characteristics45 and do not have higher TB incidence rates before LTFU.10
In conclusion, this study shows an association between TB occurring during ART and virological breakthrough and virological failure, and this association is strongly time dependent. Patients developing TB during ART may benefit from targeted VL monitoring, intensified treatment support, and adherence interventions that may be best delivered through integrated TB-HIV services. Further research into the underlying mechanisms and potential solutions is needed.
The authors are grateful to the staff and patients of the Hannan Crusaid ART Clinic in Gugulethu, Cape Town, South Africa.
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