HIV drug resistance: a new threat for low- and middle-income countries
With 17 million people now accessing antiretroviral treatment worldwide, HIV drug resistance has the potential to unravel progress towards the Fast-Track target of ending AIDS by 2030.
The public health approach to HIV is centred on ‘Treat All’ – meaning every person living with HIV is able to access the HIV treatment they need. The effectiveness of this approach for keeping people living with HIV alive and healthy, and also for reducing the onward transmission of HIV, is evidenced in falling mortality rates and stabilised or falling new infection rates in many countries around the world.
But as the number of people accessing antiretroviral treatment (ART) increases, a rise in the number of cases of HIV drug resistance (HIVDR) is inevitable and already being seen in some places. This means an increase in the number of people living with HIV who carry strains of HIV that are resistant, in varying degrees, to one or more classes or types of HIV drug.
Those with drug resistant HIV can experience poor virological outcomes, leading to treatment failure. The effect of an epidemic of HIVDR could undermine the positive gains made from increasing treatment access, and could set us back in the fight to end AIDS by 2030.
Nowhere is this concern greatest than in low- and middle-income countries (LMICs), where studies have shown significant increases in HIV drug resistance since the rollout of antiretroviral treatment.
These increases are driven largely by resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) in sub-Saharan Africa. Here, studies have shown that in the first ten years (2001-2011) of mass treatment roll-out, NNRTI resistance increased by 36% per year in East Africa, and by 23% in southern Africa.1
The surprisingly common resistance to the nucleoside reverse transcriptase inhibitor (NRTI), tenofovir, is also worrying across sub-Saharan Africa. Here, up to 60% of people who failed their tenofovir-based treatment regimens had tenofovir resistant strains of HIV – compared to just 20% in Europe.2
Tenofovir-based regimens are the recommended first-line treatment course by the World Health Organization (WHO), taken with either lamivudine or emtricitabine, and an NNRTI - usually efavirenz.
In high-income countries, tenofovir-based regimens are commonly prescribed with second generation protease or integrase inhibitors, in place of NNRTIs, primarily because of the high genetic barrier to resistance these classes have over NNRTIs. These more expensive drugs are not widely available in sub-Saharan Africa, and where they are, are generally reserved for those with no other treatment options.
A number of LMICs have also reported high levels of drug resistance in people who have no experience of HIV treatment – suggesting that transmitted HIV drug resistance could become a major concern.3
The high rates of HIVDR in LMICs is generally attributed to the lack of access to viral load testing, which indicates treatment success. Regular viral load testing can detect failing treatment early and before too many viral mutations occur, meaning changes in therapy can be minimal and less costly.
Drug resistance testing (genotypic and phenotypic testing), which looks for specific drug-resistant mutations in the genetic makeup of HIV, are even less available in LMICs.
These tests are expensive, require significant laboratory infrastructure, take several weeks to produce, and produce results which are complex to interpret, and are therefore not recommended by the World Health Organization (WHO) for use in LMICs. But they come as standard in high-income countries for people just starting ART, and for those experiencing virological failure, as a means to select the optimum combination of drugs for treatment success.
From 2012, tenofovir replaced older drugs zidovudine (AZT) and stavudine (d4T) as the primary NRTI backbone for first-line treatment. Many programmes have been unable to offer viral load or resistance testing before switching people to tenofovir – these single-drug substitutions have led to higher levels of HIVDR among NNRTIs - and, crucially, the NRTI tenofovir.4
Barriers to diagnostics for HIVDR remain a significant challenge for LMICs, and further research and development is needed to find more affordable point-of-care technologies to monitor levels of drug resistance.
But while increasing access to this type of testing is important, high rates of HIVDR in LMICs are also attributed to less than optimal adherence rates and drug interruptions caused by stock-outs, affecting people’s ability to stick to an essential drug taking regime.
In response, the WHO developed a set of ‘Early Warning Indicators’ (EWIs) in 2004, which are strong predictors of HIV drug resistance. These give countries a practical and cost-effective tool to monitor drug resistance, enabling them to make changes to programming where necessary to improve levels of HIVDR.
The EWIs include prescribing ART correctly and according to international or national guidelines; loss to follow-up and ART retention after 12 months; on-time pill pick up; on-time appointment keeping; pharmacy stock-outs, as well as viral load suppression. A WHO report released last year (2016) showed that while there are significant variations across and even within countries, urgent attention is needed to decrease levels of loss to follow-up, support retention, maximise adherence and prevent drug stock-outs.
A WHO report released last year (2016) showed that while there are significant variations across and even within countries, urgent attention is needed to decrease levels of loss to follow-up, support retention, maximise adherence and prevent drug stock outs.
What is clear is that the importance of identifying gaps in ART programming and service delivery cannot be underestimated as efforts to scale-up treatment access are pushed globally. 'Treat All' must be accompanied with quality standards in treatment delivery.
The WHO will be releasing a Global Action Plan (GAP) on HIVDR in February at the 2017 Conference for Opportunistic Infections and Retroviruses (CROI), providing a roadmap to guide global and national approaches to HIVDR over the next five years.