Malaria

Antimalarial drug resistance in the Greater Mekong Subregion: How concerned should we be?

Q&A with Dr Pedro Alonso, Director of the Global Malaria Programme

29 September 2017

A recent letter published in The Lancet Infectious Diseases1 reported on the presence of a drug-resistant lineage (strain) of malaria parasites in south Viet Nam that is responsible for “alarming rates of failure” of dihydroartemisinin-piperaquine, a first-line antimalarial medicine. The lineage, first identified in Cambodia in 2008, has now become the dominant lineage in some parts of the region. This letter builds on data published2 earlier in the year.

Following the publication of this letter, several news organizations reported on the rapid spread of a “dangerous” malaria parasite that “cannot be killed with the main anti-malaria drugs” – a parasite they describe as “super malaria”.


How concerned is WHO about the so-called “super malaria” parasite in South-East Asia?

First, let me emphasize that the term “super malaria” has not been adequately defined; the scientific and public health community does not recognize this term.

The problem of multidrug resistance in the Greater Mekong Subregion (GMS), including in Viet Nam, has been well known to WHO for a number of years. In 2014 and 2015, 4 studies conducted by Viet Nam’s National Malaria Control Programme (NMCP), in collaboration with WHO, already demonstrated high treatment failure rates with dihydroartemisinin-piperaquine (DP)3 ranging from about 26% to 46%. The Lancet letter confirms data published earlier this year by the NMCP Viet Nam and WHO and gives us a clearer picture of the genetic background of the parasites responsible for these high treatment failure rates.

While we are obviously concerned by multidrug resistance in Viet Nam, we are very encouraged by 2 recent developments. First, in September 2016, Viet Nam’s NMCP changed its policy for first-line treatment of malaria, replacing DP (in provinces where DP is failing) with artesunate-mefloquine, an effective treatment against the drug-resistant strain of malaria parasites reported in the Lancet letter. Secondly, the NMCP, under the auspices of WHO, has been testing a new artemisinin-based combination therapy (ACT) called artesunate-pyronaridine; preliminary data show that the drug has a very high efficacy rate, even in areas in Viet Nam that contain the drug-resistant strain.

Moreover, it is important to note that since 2008, when artemisinin resistance was first detected in the GMS, there has been a major decline in the rate of malaria cases and deaths. According to WHO estimates, malaria case incidence in GMS countries fell by 54% between 2012 and 2015. Malaria death rates fell by 84% over the same period. Last year, there were approximately 200 malaria deaths and less than 300 000 cases reported in the 5 GMS countries. Insufficient access to prompt diagnosis and treatment (and not drug resistance) remains the major risk factor for malaria-related deaths in this subregion.

Finally, parasite resistance to antimalarial medicines is a serious problem. But we must not create unnecessary alarm. Providing timely access to malaria prevention, diagnosis and treatment should be our primary focus.

Some news reports claim that the drug-resistant strain of malaria parasites detected in Viet Nam cannot be killed by current antimalarial medicines. Is this accurate?

No. The newly adopted first-line treatment in Viet Nam, artesunate-mefloquine, remains highly efficacious against this strain as does the new ACT artesunate-pyronaridine. Up until now, we have had effective treatment options for all malaria parasites that have been detected globally.

What is the likelihood that drug-resistant malaria will spread from the GMS to India and Africa?

In December 2016, at the request of the Malaria Policy Advisory Committee (MPAC), WHO’s top advisory committee for malaria, an Evidence Review Group (ERG) analysed the body of evidence on the emergence and spread of multidrug-resistant P. falciparum in the GMS over the last decade. A full report of this ERG meeting is available on the WHO website as well as the subsequent endorsement of the report by MPAC in March 2017.

While the group recognized that the risk of drug-resistant malaria spreading to India and Africa cannot be discounted, the broad consensus was that drug-resistant parasites were more likely to emerge independently in other parts of the world than to spread directly from the GMS.

It is difficult, however, to estimate this risk with any level of precision. In some cases, resistance to antimalarial medicines (like chloroquine) has spread to other regions. In other cases (as with mefloquine), it has not.

Could resistance to artemisinin-based combination therapies in the GMS have the same consequences that resistance to chloroquine did several decades ago?

Again, it would be difficult to make a prediction with any high degree of confidence. However, there are several important considerations to bear in mind.

First, when chloroquine resistance emerged in Africa in the 1980s, malaria control across the continent was very limited. As an example, the proportion of the population sleeping under a bednet was less than 1%.

Fortunately, since then, the malaria landscape has changed dramatically. With the massive roll-out of effective vector control,4 improved case management through diagnostics and combination therapies, improvements to health systems, increased monitoring of drug efficacy and clear guidance on policy changes, the consequences of drug-resistant malaria – should it ever reach India or Africa – are likely to be less severe today than those observed with chloroquine in the 1980s.

Secondly, we expect that – with investments in research and development – new tools, including new medicines, will enable us to overcome the challenge of multidrug resistance in the Greater Mekong Subregion.

Does WHO consider the threat of antimalarial drug resistance a public health emergency of international concern?

Not at this time. A public health emergency of international concern (PHEIC), as defined in the International Health Regulations (IHR), is an “extraordinary event.” These regulations were designed to address acute (as opposed to chronic) public health conditions. The public health community has known of the emergence and spread of multidrug resistance in this subregion for many years and is addressing it through the work of national malaria control and elimination programmes.

Meeting in both 2012 and 2014, the Technical Expert Group on Drug Resistance and Containment concluded that artemisinin resistance does not constitute a PHEIC because the conditions for PHEIC are not met. These conclusions were endorsed by MPAC.

What is WHO doing to stop the spread of antimalarial drug resistance in the Greater Mekong?

WHO has coordinated and led global efforts to counter artemisinin resistance from the very beginning, providing technical guidance and mobilizing partners to action. In 2013, WHO launched the Emergency response to artemisinin resistance (ERAR) in the Greater Mekong Subregion, a high-level plan of attack to contain the spread of drug-resistant parasites and to provide life-saving tools for all populations at risk of malaria.

In 2015, GMS Ministers of Health adopted the WHO Strategy for malaria elimination in the Greater Mekong Subregion (2015-2030) . The plan aims to eliminate P. falciparum malaria from the subregion by 2025 and all species of human malaria by 2030. Priority action is targeted to areas where multidrug resistant malaria has taken root. This subregional strategy is fully aligned with the goals and targets of the WHO Global Technical Strategy for Malaria 2016-2030, adopted by the World Health Assembly in May 2015.

With technical guidance from WHO, all GMS countries have developed national malaria elimination plans. Providing access to prevention, diagnosis and treatment for all populations at risk of malaria is a key priority. Monitoring drug efficacy and strengthening surveillance systems are other core elements of our work. Other priorities in this subregional effort are described in detail in a report published last November.

WHO’s work in the GMS is a collaborative effort involving technical teams based at 6 country offices, at regional offices in New Delhi and Manila, at a special regional hub in Phnom Penh, and at WHO’s Geneva headquarters. It is a unique initiative in view of the human resources deployed and the level of integration across many layers of the Organization.

WHO is leading the elimination effort in the GMS with the support of a number of partners, including the Global Fund to Fight AIDS, Tuberculosis & Malaria, the Bill & Melinda Gates Foundation, USAID, and the Australian Department of Foreign Affairs and Trade.

We are winning the battle. We are on the right track. The massive reductions in disease and death reported in GMS countries are a testament to the sustained progress that has been achieved along the path toward elimination in this subregion. It is only through eliminating this parasite that we will do away – once and for all – with the problem of drug resistance in this subregion.

Drug resistance in the Greater Mekong Subregion: a brief history

The GMS has long been the epicentre of antimalarial drug resistance. Parasites resistant to chloroquine were first detected in the late 1950s along the Cambodia–Thailand border. Resistance of P. falciparum malaria parasites to artemisinin was first confirmed along the Cambodia–Thailand border in 2008. To date, artemisinin resistance has been detected in 5 countries of the GMS: Cambodia, Lao People’s Democratic Republic (PDR), Myanmar, Thailand and Viet Nam.

Resistance to ACT partner drugs has also emerged in some areas of the GMS. Treatment failure with dihydroartemisinin-piperaquine (DP) was reported in Cambodia as early as 2009 and, more recently, in Lao PDR. Four studies conducted by Viet Nam’s NMCP in 2014 and 2015 demonstrated high treatment failure rates for the drug DP.

When artemisinin resistance was first confirmed along the Cambodia–Thailand border in 2008, WHO took immediate action to contain its spread. A coordinated regional effort to eliminate malaria transmission in the GMS is critical to protecting the efficacy of existing antimalarial medicines.

Key definitions: ACTs and artemisinin resistance

Artemisinin and its derivatives are very effective medicines known for their ability to swiftly reduce the number of parasites in the blood of patients with malaria. Artemisinin-based combination therapies (ACTs) are recommended by WHO as the first-line treatment for uncomplicated P. falciparum malaria. Over the last 15 years, expanded access to ACTs in malaria-endemic countries has played an important role in reducing the global burden of malaria.

ACTs combine artemisinin with one of several partner drugs. The role of artemisinin is to dramatically reduce the number of parasites in the bloodstream during the first 3 days of treatment. The role of the partner drug is to eliminate any remaining parasites thereafter.

Artemisinin resistance is defined as a delay in the clearance of parasites from the bloodstream following treatment with an ACT. Currently, most patients with delayed parasite clearance are still cured by ACTs provided the partner drug remains effective. As such, protecting the efficacy of artemisinin and its partner drugs is critically important.


Notes:
[1] Spread of a single multidrug resistant malaria parasite lineage (PfPailin) to Vietnam (http://dx.doi.org/10.1016/S1473-3099(17)30524-8)
[2] The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study (http://dx.doi.org/10.1016/S1473-3099(17)30048-8)
[3] DP, an artemisinin-based combination therapy, is the first-line treatment for uncomplicated P. falciparum malaria in some parts of the Greater Mekong Subregion.
[4] According to the World Malaria Report 2016, nearly 60% of the population in Africa is now protected from malaria through either insecticide-treated nets or indoor residual spraying.