Resistance testing is unlikely to improve the effectiveness of second-line HIV treatment in resource-limited settings and the introduction of routine HIV drug resistance testing is not a high priority, investigators from a large international study have concluded in a report in the journal The Lancet HIV.
Instead, their findings and those of other recent research reports point to the need to prioritise adherence support, the scale-up of viral load testing and prompt action when test results show a rebound in viral load.
The findings, from the EARNEST study of second-line antiretroviral treatment in Africa, show that even when people have predicted resistance to two of the three drugs in their second-line drug combination, they are still highly likely to achieve and maintain an undetectable viral load, suggesting that the drugs still exert enough activity to prevent viral rebound.
Resistance testing in lower-income settings
Resistance testing is used in higher-income settings to select drugs for second- or third-line treatment, especially those of the nucleoside analogue class. Resistance testing plays less of a role in choosing second-line treatment regimens nowadays because the greater range of available drug classes makes it easier to put together a regimen of active drugs. Determining a patient’s drug resistance profile remains critical after the failure of a second- or third-line drug regimen.
In lower-income settings, resistance testing is used largely for surveillance, to check if drug-resistant virus is being transmitted and to determine the prevalence of resistance to various drugs. Resistance testing requires laboratory conditions that may exist only in central hospitals or research laboratories, so it is not carried out routinely. The cost of a resistance test is also a major barrier to routine use.
The World Health Organization (WHO) has advised that resistance testing is not essential in lower-income settings, and that for the time being, the risk of drug resistance can be monitored at national level by using five early warning indicators: how many people pick up medication on time; how many people are retained in care, and how many are virally suppressed, 12 months after starting treatment; drug stock-outs; and, the proportion of people on treatment who get a viral load test (coverage).
If these measures began to show a rising risk of transmissible drug-resistant virus, countries would be urged to consider changing treatment regimens or taking other steps to minimise the impact of resistance. WHO is drawing up guidance on how to respond to a rise in drug resistance this year.
The EARNEST study and second-line treatment
The EARNEST study compared three approaches to second-line antiretroviral treatment in sub-Saharan Africa. The study compared switching to a ritonavir-boosted protease inhibitor and two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs), to a boosted protease inhibitor and the integrase inhibitor raltegravir, or protease inhibitor monotherapy following 12 weeks of induction therapy with raltegravir and boosted protease inhibitor.
The study found no significant difference in viral suppression rates between the protease inhibitor + NRTI group and the protease inhibitor + integrase inhibitor group, but found protease inhibitor monotherapy to be inferior to both.
In a further analysis, study investigators have now looked at the impact of having active NRTIs – drugs to which there is no evidence of resistance – in the second-line regimen. The analysis looked at 391 of the 426 people who had received NRTIs in the study and whose baseline resistance data available. On the basis of detectable resistance mutations, the researchers predicted which drugs would be active in the study population. Fifty-nine per cent were predicted to have no active NRTIs available. In 77% of these people, their second-line regimen consisted of tenofovir and lamivudine or emtricitabine. Thirty-three per cent were predicted to have one active drug available, and in 88% of these people, the second-line regimen consisted of tenofovir and lamivudine or emtricitabine.
After almost three years of follow-up, 89% of those receiving a boosted protease inhibitor and no predicted-active NRTIs had a viral load below 400 copies/ml, compared to 81% of those who received a boosted protease inhibitor and raltegravir (both of which should have been active drugs)(p = 0.02). There was no significant difference in viral suppression between people who received one or no active NRTIs (81% vs 89%, p = 0.30). Furthermore, multivariate analysis showed that greater evidence of drug activity (measured by a drug susceptibility score) was associated with a reduced likelihood of viral suppression (odds ratio 0.61, 95% CI 0.46-0.81, p = 0.001).
The findings are surprising but the researchers say they are confident that their findings are robust, due to the large number of participants and the length of follow-up.
A lack of employment was more strongly associated with lack of viral suppression (OR 0.39, 95% CI 0.21-0.72, p = 0.003). So too were non-adherence and higher baseline viral load, after adjusting for other confounding factors.
The researchers say that drugs with predicted resistance are probably still having an effect, for example by prolonged concentrations in cells and because of the impact of some NRTI resistance mutations on HIV’s ability to copy itself accurately, without mutations. The development of these NRTI mutations may stop protease inhibitor mutations from emerging, the authors speculate.
Implications
The researchers say that selecting NRTIs that are well-tolerated and easy to take might have more impact than routine resistance testing. They urge the need for “critical thinking around the benefits to be gained, if any, before new elements of care are introduced into the public health approach, even if they are considered as standard practice in high-income settings.”
Recently published research from a trial conducted in West Africa, and findings from a study of once or twice-daily dosing in sub-Saharan Africa, India and Brazil, show that drug resistance in both trials was strongly associated with high viral load after failure of first-line treatment. In the second study (PEARLS), just over half of people with one viral load measurement over 1000 copies/ml went on to resuppress their viral load after adherence counselling.
Researchers on the PEARLS study found that a scoring system based on weight, age, time on treatment and the degree of viral rebound would result in only 0.5% of people with rebound being switched to a new regimen unnecessarily. However, the sensitivity of this scoring system was low (28%), which means that around seven out of ten people with drug resistance would experience a delay in switching if the scoring system alone were used. The research group says that its scoring system will allow some people to be switched immediately, without the need for confirmatory viral load testing or adherence evaluation. They say that further research is needed to validate the risk score and to look at the financial and health trade-offs between switching people unnecessarily to more expensive second-line regimens or leaving people on failing treatment for longer.
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Scoring algorithm |
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Age less than 30 |
1 point |
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BMI > 25 |
2 points |
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< 7 months on treatment |
3 points |
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7-12 months on treatment |
2 points |
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First rebound VL 10,000-100,000 copies/ml |
4 points |
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First rebound VL > 100,000m copies/ml |
2 points |
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If scoring 9 points or above: switch immediately |
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If scoring below 9 points: review adherence & carry out confirmatory viral load 3-6 months later |
References
Paton N et al. Nucleoside reverse transcriptase inhibitor cross-resistance and outcomes from second-line therapy in the public health approach: an observational analysis within the randomised, open-label, EARNEST trial. The Lancet HIV, advance online publication, 8 May 2017. Free full text available: http://dx.doi.org/10.1016/S2352-3018(17)30065-6
Guichet E et al. High viral load and multidrug resistance due to late switch to second-line regimens could be a major obstacle to reach the 90-90-90 UNAIDS objectives in Sub-Saharan Africa. AIDS Research Human Retroviruses 32(12):1159-1162, 2016
Rutstein SE et al. Predicting resistance as indicator for need to switch from first-line antiretroviral therapy among patients with elevated viral loads: development of a risk score algorithm. BMC Infect Dis16:280, 2016. Free full text available: doi: 10.1186/s12879-016-1611-2