The challenge of HIV drug resistance as prevalence exceeds 10%
As HIV drug resistance increases in low- and middle-income countries, getting people onto antiretroviral treatment means little in the long run if treatment programming is not also strengthened.
Resistance to key antiretroviral drugs continues to rise across many low- and middle-income countries (LMICs), according to the most up-to-date estimates published in the Lancet Infectious Diseases this month.
In 2016, pre-treatment HIV drug resistance to non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs reached 11% in Southern Africa, 10.1% in East Africa, 7.2% in West and Central Africa, and 9.4% in Latin America and the Caribbean among people starting, or re-initiating first-line antiretroviral treatment (ART).
According to the analysis, rates of pre-treatment drug resistance are increasing rapidly year-on-year. The researchers found that between 2001 and 2016, the odds of drug resistance increased annually by 23% in Southern Africa, 17% in East, Western and Central Africa, and 11% in Asia, Latin America and the Caribbean.
The stats are alarming, as NNRTIs are widely used across low- and middle-income countries and form part of the World Health Organization (WHO) recommended first-line treatment regime. But just a single mutation can result in resistance to two commonly prescribed drugs in the NNRTI class – nevirapine and efavirenz – and options for newer drugs and other drug classes remain relatively limited in these settings because of costs and procurement challenges.
It is clear that without appropriate action, drug resistance can threaten treatment options, increase treatment programme costs, and if left untreated, the level of virus that is resistant to drugs can increase in the body to the extent that it can be transmitted to others.
The research analysed 56,000 people initiating ART over two decades in 63 countries – the largest systematic review on pre-treatment drug resistance, and included previously unpublished data from the WHO and other studies.
Drug resistance to other drug classes remained universally low or unchanged, although statistically significant increases in resistance to nucleoside reverse transcriptase inhibitor (NRTI) drugs in East and Southern Africa were reported, but overall prevalence still remained low (below 5% in all regions in 2016).
Thankfully, resistance to the commonly prescribed NRTI, tenofovir, was infrequent in the analysis – but continued surveillance of this is needed to ensure this continues.
Unsurprisingly, drug resistance was more likely to occur in people who had been exposed to ART previously (known as acquired drug resistance), such as women who had taken ART as part of a prevention of mother-to-child transmission programme, or those re-starting first-line treatment for a second time.
The risk of virological failure in this group was three times higher than those who reported no previous experience of ART. This is likely to become an increasing concern in LMICs, as 10% to 30% of people starting ART in these settings are thought to have been previously exposed.
According to the authors, the statistics provide “the first robust evidence that people with disclosed previous antiretroviral drug exposure at the time of treatment initiation […] are substantially more likely to have viruses resistant to both NNRTIs and NRTIs compared with people who report being antiretroviral-drug naive, in whom we infer resistance as being due to transmitted drug resistance.”
New WHO guidelines published this summer now call for countries to consider alternative treatment regimes when drug resistance surpasses 10% nationally. In these instances, dolutegravir is the preferred drug of choice – an integrase inhibitor with a high barrier to resistance. The statistics confirm that many countries have now reached this threshold and should consider making the change.
While this roll-out may be slow, prioritising those known to have been on treatment previously is critical to ensuring treatment success, as the analysis shows.
Some countries such as Kenya, Botswana and Brazil have already started to roll-out dolutegravir-based first-line treatment, but in an accompanying comment in the Lancet, Sabine Yerly and Alexandra Calmy said: “Caution should be exercised when assuming that these new agents alone will solve the problem, particularly in situations where children and adolescents currently bear the burden of drug resistance.”
“Treatment resistance indicators have turned to red in several countries, highlighting the risk that the extraordinary achievement of providing effective ART worldwide will not be sustained.”
Indeed, as more people access treatment and drug resistance trends continue to rise, it is the strengthening of HIV treatment programme quality that will have the best results, preventing the emergence and transmission of HIV drug resistance.
This includes access to the most effective drugs, as well as regular viral load monitoring for treatment success and timely switching to alternative regimes when needed.
Yerly and Calmy conclude, “Multiple approaches and the commitment and leadership of all internal policy-makers and national governments remain essential.”