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 in a large international study have concluded.
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, writes Keith Alcom writes for AidsMap.
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 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 Organisation (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 led by Professor Nicholas Paton, at the Yong Loo Lin School of Medicine at the National University of Singapore and the MRC Clinical Trials Unit at University College London, 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 were available.
On the basis of detectable resistance mutations, the researchers predicted which drugs would be active in the study population – 59% were predicted to have no active NRTIs available. In 77% of these people, their second-line regimen consisted of tenofovir and lamivudine or emtricitabine – 33% 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.
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, just over half of people with one viral load measurement over 1000 copies/ml went on to re-suppress 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.
Background: Cross-resistance after first-line antiretroviral therapy (ART) failure is expected to impair activity of nucleoside reverse-transcriptase inhibitors (NRTIs) in second-line therapy for patients with HIV, but evidence for the effect of cross-resistance on virological outcomes is limited. We aimed to assess the association between the activity, predicted by resistance testing, of the NRTIs used in second-line therapy and treatment outcomes for patients infected with HIV.
Methods: We did an observational analysis of additional data from a published open-label, randomised trial of second-line ART (EARNEST) in sub-Saharan Africa. 1277 adults or adolescents infected with HIV in whom first-line ART had failed (assessed by WHO criteria with virological confirmation) were randomly assigned to a boosted protease inhibitor (standardised to ritonavir-boosted lopinavir) with two to three NRTIs (clinician-selected, without resistance testing); or with raltegravir; or alone as protease inhibitor monotherapy (discontinued after week 96). We tested genotypic resistance on stored baseline samples in patients in the protease inhibitor and NRTI group and calculated the predicted activity of prescribed second-line NRTIs. We measured viral load in stored samples for all patients obtained every 12–16 weeks. This trial is registered with Controlled-Trials.com (number ISRCTN 37737787) and ClinicalTrials.gov (number NCT00988039).
Findings: Baseline genotypes were available in 391 (92%) of 426 patients in the protease inhibitor and NRTI group. 176 (89%) of 198 patients prescribed a protease inhibitor with no predicted-active NRTIs had viral suppression (viral load Interpretation: Genotypic resistance testing might not accurately predict NRTI activity in protease inhibitor-based second-line ART. Our results do not support the introduction of routine resistance testing in ART programmes in low-income settings for the purpose of selecting second-line NRTIs.
Nicholas Paton, Cissy Kityo, Jennifer Thompson, Immaculate Nankya, Leonard Bagenda, Anne Hoppe, James Hakim, Andrew Kambugu, Joep J van Oosterhout, Mary Kiconco, Silvia Bertagnolio, Philippa J Easterbrook, Peter Mugyenyi, A Sarah Walker