Analysis: Tenofovir resistance ‘surprisingly common’

Resistance to the commonly prescribed antiretroviral drug tenofovir is ‘surprisingly common’, according to findings published in the Lancet Infectious Diseases last week.

What does the study say?

The study, TenoRes, reviewed data on drug resistance from HIV treatment trials and cohorts between 1998 and 2015. In their meta-analysis, they included 44 relevant studies, including 1,926 patients from 36 countries who failed their first-line tenofovir-based treatment regimen.

The study has four key findings relating to prevalence, risk and transmission of tenofovir resistance.

1. Prevalence of tenofovir resistance varies between regions

In sub-Saharan Africa, up to 60% of people who failed their treatment had tenofovir-resistant strains of HIV. By contrast, only 20% of those analysed in Europe had the resistant strains.

They estimated that 7.5% to 17.5% of people treated with tenofovir in sub-Saharan Africa would develop drug resistance in their first year of treatment.

2. Starting treatment late increases odds of tenofovir resistance

Across all regions, people were 50% more likely to become resistant to tenofovir if treatment was started when their immune system was already compromised. That is, at a CD4 count of less than 100 cells/mm3.

3. Lamivudine or nevirapine increases odds of tenofovir resistance

The odds of resistance increased by 50% when the patient was on lamivudine or nevirapine with tenofovir.

Tenofovir is a nucleotide reverse-transcriptase inhibitor (NRTI) normally prescribed in combination with a cytosine analogue (lamivudine or emtricitabine), and a non-nucleotide reverse-transcriptase inhibitor (NNRTI) (efavirenz or nevirapine).

Of all the people with tenofovir resistance – 83% also had cytosine analogue resistance, 78% had a major NNRTI resistance, and 65% had both. This leaves a lot of people at risk of having their regimens partially or completely compromised.

4. No difference in viral loads between people with tenofovir resistance and without

Patients with tenofovir resistance had a viral load that was no lower than those without resistant strains. They were also just as infectious, meaning transmission of tenofovir-resistant strains is highly possible.

It was previously thought that drug resistant strains were less effective at spreading between people.

Tenofovir resistance – why is it important?

Tenofovir is the main NRTI backbone drug recommended by the World Health Organisation (WHO) for people starting HIV treatment. It is highly effective, with older NRTIs like stavudine being phased out.

“It is a very potent drug with few side effects, and there aren't any good alternatives that can be deployed using a public health approach,” says Dr. Ravi Gupta, of University College London, lead author of the study.

Tenofovir is also used as a fixed-dose combination with emtricitabine to make Truvada – the only drug approved for use as a pre-exposure prophyaxis (PrEP) to prevent HIV transmission.

In light of the results, the authors state that the use of tenofovir in a combination therapy is ‘potentially fragile’, as all drugs within the tenofovir-backed regimen can be compromised by one amino-acid gene mutation, resulting in partial or total drug resistance.

Understanding how prevalent tenofovir resistance is, and then stopping it, is vital for ensuring people benefit from effective treatment regimens and stay healthy.

The viral load effect

As tenofovir resistance was highest in sub-Saharan Africa, the authors hypothesised that a lack of viral load testing was a key reason for this.

In high-income countries, patients had their viral load tested 3 to 4 times a year. This means that treatment failure can be caught earlier – and before gene mutations occur. Interventions such as support with treatment adherence and tweaking the drug regimen can result in a more effective treatment outcome.

Optimising treatment regimens

Given the prevalence of drug resistance, the authors call for better surveillance of resistance and optimisation of treatment regimens, particularly in low-income countries.

Testing for resistance to key drugs before treatment initiation would help by ‘avoiding use of partly active treatment regimens’, but is largely unaffordable and uncommon in low-income settings.

In addition to the increased risk of tenofovir resistance when used with nevirapine, nevirapine is associated with adverse effects compared to efavirenz. Efavirenz is now the preferred NNRTI option by WHO, but nevirapine is still used in countries where guidelines have not been fully rolled out.

The use of lamivudine over emtricitabine also highlights treatment optimisation issues. The authors note that lamivudiune has previously been found to be more prone to virological failure. They remark that the difference between the two is becoming less important in high-income countries, where the use of another type of HIV drug, integrase inhibitors, are now recommended as a third agent. 

Subtype C

The authors also found viral subtypes to influence treatment failure – notably subtype C, more commonly seen in sub-Saharan Africa.

In a Lancet comment linked to the article, Mark A. Wainberg of McGill University AIDS Centre said it was a worry, “limited availability of integrase inhibitors in such settings for use in first-line therapy despite the fact that their use is now recommended by almost all treatment guidelines, will potentially exacerbate this problem [of drug resistance].”

Other regional factors were highlighted that could influence treatment failure in sub-Saharan Africa, including drug stock-outs and ‘other indicators of quality HIV services’.

Nowhere without testing

Given that the risk of tenfovoir resistance is higher when treatment is started late, expanding access and uptake of HIV testing is a critical strategy to limiting drug resistance, said Wainberg.

There’s a need to identify those who don’t know they have HIV, and put them on treatment as soon as possible while they are still healthy. This limits the likelihood of treatment failure, but is also beneficial for their own health and wellbeing, to prevent onward transmission by keeping their viral load down, and to help achieve UNAIDS 90-90-90 targets.

Increasing access to testing is vital, but alongside ongoing efforts to improve adherence, which the study shows is fundamental for the prevention of drug resistance. Also of importance are efforts to improve access to viral load testing, to help guide and inform treatment regimen planning, and developing low cost drug-resistance screening tools, to again guide treatment prescribing and prevent treatment failure. 

The study is the largest ever to look at tenofovir resistance after treatment failure – but the small sample size of patients and the global scale of the study highlight the need for further research.

In his comment, Wainberg said that drug resistance was an “unavoidable outcome of the successful HIV drug rollout programmes that have helped to save millions of lives.”

The authors noted that improving quality of HIV care and viral load monitoring could curb drug resistance – but the problem for low-income countries remains a very real one.