'Alarming' rates of second-line HIV treatment failure in sub-Saharan Africa

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BloodThe number of people failing second-line antiretroviral treatment (ART) is reaching “alarming” levels in Sub-Saharan Africa (SSA), with failure more common in the first 12-18 months after treatment initiation, among children, and among those residing in countries in the southern part of SSA.

In a systematic review and meta-analysis, researchers at the Haramaya University, Harar, Oromia, Ethiopia; and the University of Technology Sydney in Australia found that the analysis also revealed that treatment failure was associated with suboptimal ART adherence, a higher viral load reading at baseline, a lower peak CD4 count, and among those with advanced HIV as defined by the World Health Organisation (WHO) classification.

ART has been transformational for people living with HIV, changing living with the virus to a manageable chronic illness. But as more people access treatment for life, problems arise as increasing numbers of people experience treatment failure.

Defining treatment failure requires a viral load test alongside other clinical and immunological biomarkers. In SSA and other low-resourced settings, cost and operational challenges mean that these are not always performed to inform specific patient treatment actions. This means that some people may be unnecessarily switched to second- or third-line treatment regimes when a viral load test may indicate persevering with that current regime.

HIV treatment failure involving second-line regimens has very narrow options for further switching. This is a serious concern in resource-limited settings where financial restraints may limit availability of multiple options. Therefore, the optimal use of first- and second-line therapy is crucial in SSA.

The investigators sought to understand the pooled estimates for second-line HIV treatment failure and the factors associated with treatment failure in SSA. They identified a total of 33 studies including 18,550 participants and analysing 19,988.45 person-years (PYs). Person-years is a measure of incidence and is the sum of the amount of time contributed by study participants in the follow-up period.

The pooled estimate for rate of second-line HIV treatment failure was reported as 15.0 per 100 person-years (PYs) of follow-up. Failures ranged from 1.0/100 PYs to 40.0/100 PYs in the studies included in the analysis.

Researchers then compared patient groups (children, adults, mixed age-groups); regions in SSA (southern Africa, eastern Africa, western Africa, mixed regions of SSA); and type of second-line ART (PI-based ART, ritonavir-boosted PI-based ART) across three points in time in the follow-up after second-line ART initiation (less than 12 months, 12–18 months, above 18 months).

The incidence of treatment failure was highest in the 12 to 18-month period of follow-up among children (19.0/ 100PYs) and among patients in southern SSA (18.0/100 PYs).

The analysis also revealed certain factors that influence treatment failure. Having a high baseline viral load increased the likelihood of treatment failure by 5.67-fold, while advanced clinical stage of HIV at baseline increased it by 3.27-fold, low peak CD4 cell counts at baseline (<100 cells/mm3) by 2.80-fold, and suboptimal adherence by 1.92-fold.

Also linked to second-line treatment failure were prolonged delays in switching prior therapy, tuberculosis co-treatment, and other patient factors including younger age, depressive symptoms, being underweight, and traditional medicine use.

In their conclusion, the authors note that given the findings, second-line treatment approaches should look to quickly and aggressively suppress viral load, strive for rapid immune recovery and excellent treatment adherence. Viral load monitoring and more frequent clinical follow-ups can help to support rapid identification and intervention for cases of failure.

They commented, “Countries in the SSA should develop strategies and guidelines related to containment of second-line HIV treatment including intensive adherence support and intervention as routine clinical practice especially for patients with slow response to the therapies.”

Background: Increased second-line antiretroviral therapy (ART) failure rate narrows future options for HIV/AIDS treatment. It has critical implications in resource-limited settings; including sub-Saharan Africa (SSA) where the burden of HIV-infection is immense. Hence, pooled estimate for second-line HIV treatment failure is relevant to suggest valid recommendations that optimize ART outcomes in SSA.
Methods: We retrieved literature systematically from PUBMED/MEDLINE, EMBASE, CINAHL, Google Scholar, and AJOL. The retrieved studies were screened and assessed for eligibility. We also assessed the eligible studies for their methodological quality using the Joanna Briggs Institute’s appraisal checklist. The pooled estimates for second-line HIV treatment failure and its associated factors were determined using STATA, version 15.0 and MEDCALC, version 18.11.3, respectively. We assessed publication bias using Comprehensive Meta-analysis software, version 3. Detailed study protocol for this review/meta-analysis is registered and found on PROSPERO (ID: CRD42018118959).
Results: A total of 33 studies with the overall 18,550 participants and 19,988.45 person-years (PYs) of follow-up were included in the review. The pooled second-line HIV treatment failure rate was 15.0 per 100 PYs (95% CI: 13.0–18.0). It was slightly higher at 12–18 months of follow-up (19.0/100 PYs; 95% CI: 15.0–22.0), in children (19.0/100 PYs; 95% CI: 14.0–23.0) and in southern SSA (18.0/100 PYs; 95% CI: 14.0–23.0). Baseline values (high viral load (OR: 5.67; 95% CI: 13.40–9.45); advanced clinical stage (OR: 3.27; 95% CI: 2.07–5.19); and low CD4 counts (OR: 2.80; 95% CI: 1.83–4.29)) and suboptimal adherence to therapy (OR: 1.92; 95% CI: 1.28–2.86) were the factors associated with increased failure rates.
Conclusion: Second-line HIV treatment failure has become highly prevalent in SSA with alarming rates during the 12–18 month period of treatment start; in children; and southern SSA. Therefore, the second-line HIV treatment approach in SSA should critically consider excellent adherence to therapy, aggressive viral load suppression, and rapid immune recovery.

Dumessa Edessa, Mekonnen Sisay, Fekede Asefa

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