Significant health gains from faster switching to second-line ART in sub-Saharan Africa

Switching to second-line antiretroviral therapy (ART) after a single viral load measurement above 1000 copies/ml has the potential to save lives, avert a significant burden of AIDS-related illnesses and help achieve the 90-90-90 target, according to the results of a modelling study published in AIDS.

Current World Health Organization (WHO) ART guidelines recommend that people taking first-line efavirenz-based ART with a viral load above 1000 copies/ml should only switch to second-line protease inhibitor-based therapy if their viral load remains above 1000 copies/ml three months later and after receiving enhanced adherence support.

But research by Dr Amir Shroufi and colleagues from Médecins Sans Frontières and University College London showed that switching immediately after a viral load measurement above 1000 copies/ml would not only increase the proportion of people starting second-line treatment but also substantially reduce the burden of AIDS-related illness and death, as well as the prevalence of non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. It would help meet the virological suppression component of the 90-90-90 target (90% of people with HIV diagnosed; 90% of diagnosed people on ART; 90% of ART-treated people virally suppressed) to end the AIDS epidemic.

“As a step towards reducing unnecessary mortality associated with delayed second-line ART switch, defining failure of first-line efavirenz-based regimens as a single viral load of more than 1000 copies/ml should be considered,” write the authors.

WHO now recommends routine viral load monitoring to identify individuals who are experiencing first-line ART treatment failure. But patients only switch to more expensive protease inhibitor-based second-line ART if their viral load remains elevated in a confirmatory test three months later and after receiving enhanced adherence support.

However, there are several potential problems with this approach. Only a minority of people experiencing an elevation in viral load to over 1000 copies/ml subsequently re-suppress while remaining on first-line ART, in part because up to 90% have NNRTI resistance. Many programmes fail to switch failing patients promptly with delays of a year or more widely reported. Such delays lead to avoidable HIV transmissions, AIDS-related illness and death.

Investigators therefore wanted to see if switching treatment immediately after a single viral load test above 1000 copies/ml would overcome these problems.

They therefore used the HIV Synthesis Model (a well-established individual-based simulation model of HIV transmission, disease progression, effect of ART and resistance-risk), to compare the merits of the existing WHO guidance and simplified switching.

The model was based on the demographics and HIV epidemic in Malawi, but it was repeated 500 times to take account of the full range and extent of the HIV epidemic in sub-Saharan Africa.

The results clearly showed the benefits of simplified switching (using a single elevation in viral load above 1000 copies to define NNRTI-based first-line treatment failure).

Over a three-year period, it would lead to an 18% decrease in AIDS-related mortality among people with a viral load above 1000 copies while on ART (fall in incidence from 3.1 to 2.5 per 100 person-years).

The simplified strategy reduced by almost a third the six-month incidence of AIDS-defining illnesses among people on ART and a viral load above 1000 copies/ml.

In a country with 10 million adults and 8.8% HIV prevalence, use of the simplified switch strategy would avert 1322 AIDS-related deaths over three years. This would mean that 10,125 AIDS deaths would be prevented in South Africa annually.

There would also be a significant increase in the number of people switching to second-line therapy before developing drug resistance. Modelling for a country of 10 million showed that there would be 301 switches annually without resistance when using the existing WHO guidelines. This increased to 7285 switches with the simplified strategy.

The proportion of people with resistance who switched to second-line treatment would increase from 48% using the baseline scenario to 65% using a single viral load measurement.

There would also be a small but significant (3%) increase in the overall proportion of ART-treated people who were virally suppressed, therefore surpassing the third of the 90-90-90 targets needed to end AIDS.

“The likelihood of an increase in switching is not implausible given that the single switch strategy reduces the number of steps necessary to switch and the observed delays at every step of the current strategy,” comment the investigators.

Reductions in the cost of protease inhibitors and the adoption of more tolerable dolutegravir-based regimens as second-line therapy would also make simplified switching more affordable and acceptable for patients.

“As the cost of second-line regimes decline, a change of strategy to define failure of efavirenz-based first-line ART after a single viral load value more than 1000 copies/ml should be considered, allowing faster switch to second-line boosting effort to achieve the 3^rd 90 and reducing AIDS-related deaths,” conclude the researchers.

Shroufi A et al. Simplifying switch to second-line antiretroviral therapy: predicted effect of defining failure of first-line efavirenz-based regimens in sub-Saharan Africa by a single viral load more than 1000 copies/ml. AIDS, online edition, doi: 10.1097/QAD.0000000000002234 (2019).