Viral loads’ study reveals new cohort at risk of therapy failure

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In a large South African cohort study, a team of researchers from the University of the Witwatersrand (Johannesburg, Gauteng, South Africa) collaborating with the Ndlovu Research Consortium (Groblersdal, Limpopo), the National Health Laboratory Service (SA), the University of California San Diego, and the University Medical Centre Utrecht (The Netherlands) found that low level viremia in treated HIV-patients is an important risk factor for treatment failure.

The findings of the study indicate that the current World Health Organisation (WHO)-defined threshold for virological failure fails to identify a large subset of patients who are at increased risk of poor outcomes of ART and that that clinical interventions should take place at lower viral loads than those proposed by the current WHO guidelines.

“Sustainable virological suppression is an important part of the 90-90-90 targets defined by UNAIDS. This study shows that patients with LLV are at risk for therapy failure.” says Dr. Francois Venter, WHRI, Witwatersrand University. “A strong message from WHO regarding the risk of virological failure after LLV could motivate clinicians to act when LLV is encountered. “

The monumental response to the global HIV epidemic has led to an unprecedented amount of patients on antiretroviral therapy (ART). The goal of antiretroviral therapy (ART) in HIV positive patients is to suppress the amount of HIV in the blood (also known as viral load).

From the start of the ART roll-out, South Africa has invested in laboratory capacity enabling routine viral load monitoring of all patients on ART. The implementation of viral load monitoring was largely done in accordance with WHO ART guidelines, which advice annual routine monitoring and a threshold of 1000 copies/mL to define virological failure.

In clinical guidelines for high income settings, cut-offs for therapy failure are lower and clinical intervention is already required above 50 copies/mL. Suppression below 50 copies prevents disease progression towards Aids, prevents selection of resistance and lowers the risk of transmission of the virus to others.

The unique South African large-scale programmatic viral load monitoring program yields unique insights into crucial aspects of WHO ART guidelines, such as their current definition for virological failure. A study of over 70 000 patients attending 57 HIV treatment facilities has shown that patients presenting with detectable viral loads below the lenient 1000 copies/mL threshold are at an increased risk to develop virological failure that is, >1000 copies/mL.

A quarter of the patients in this cohort who were on first-line ART experienced one or more episodes of LLV. Compared to patients with virological suppression, that is with <50 copies/ml, patients with LLV were threefold more prone to develop failure of ART. In patients with LLV of the highest range (400-999 copies/mL) this risk increased to nearly fivefold, the risk to change to second line therapy was even more pronounced to 13 times.

Important conclusions can be drawn from this study. The findings indicate that the current WHO-defined threshold for virological failure fails to identify a large subset of patients who are at an increased risk of poor outcomes of ART.

Dr Sergio Carmona, National Health Laboratory Services at Witwatersrand University, Johannesburg, adds that viral load monitoring remains key to determining ART success. “This study provides clear evidence that clinical interventions should take place at lower viral loads than those proposed by the current WHO guidelines. We need to support the scale-up of viral load testing in low- and middle-income countries as well as encourage adherence to ARVs and close follow-up of viral load results.”

A more active approach to low level viremia is essential to prevent virological failure and subsequent selection of resistance. Such an approach should be implemented prior the introduction of integrase inhibitors which are the cornerstone of ART globally to preserve this powerful treatment for the coming decades.

Background: Antiretroviral therapy (ART) that enables suppression of HIV replication has been successfully rolled out at large scale to HIV-positive patients in low-income and middle-income countries. WHO guidelines for these regions define failure of ART with a lenient threshold of viraemia (HIV RNA viral load ≥1000 copies per mL). We investigated the occurrence of detectable viraemia during ART below this threshold and its effect on treatment outcomes in a large South African cohort.
Methods: In this observational cohort study, we included HIV-positive adults registered between Jan 1, 2007, and May 1, 2016, at 57 clinical sites in South Africa, who were receiving WHO-recommended ART regimens and viral load monitoring. Low-level viraemia was defined as the occurrence of at least one viral load measurement of 51–999 copies per mL during ART. Outcomes were WHO-defined virological failure (one or more viral load measurement of ≥1000 copies per mL) and switch to second-line ART. Risks were estimated with Cox proportional hazard models.
Findings: 70 930 patients were included in the analysis, of whom 67 644 received first-line ART, 1476 received second-line ART, and 1810 received both. Median duration of follow-up was 124 weeks (IQR 56–221) for patients on first-line ART and 101 weeks (IQR 51–178) for patients on second-line ART. Low-level viraemia occurred in 16 013 (23%) of 69 454 patients, with an incidence of 11·5 per 100 person-years of follow-up (95% CI 11·4–11·7), during first-line ART. Virological failure during follow-up occurred in 14 380 (22%) of 69 454 patients on first-line ART. Low-level viraemia was associated with increased hazards of virological failure (hazard ratio [HR] 2·6, 95% CI 2·5–2·8; p<0·0001) and switch to second-line ART (HR 5·2, 4·4–6·1; p<0·0001]) compared with virological suppression of less than 50 copies per mL. Risk of virological failure increased further with higher ranges and persistence of low-level viraemia.
Interpretation: In this large cohort, low-level viraemia occurred frequently and increased the risk of virological failure and switch to second-line ART. Strategies for management of low-level viraemia need to be incorporated into WHO guidelines to meet UNAIDS-defined targets aimed at halting the global HIV epidemic.

Lucas E Hermans, Michelle Moorhouse, Sergio Carmona, Diederick E Grobbee, L Marije Hofstra, Douglas D Richman, Hugo A Tempelman, Willem D F Venter, Annemarie MJ Wensing

The Lancet Infectious Diseases article summary

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