Elements dictating the fate of artemisinin combination therapy in India

Over the course of its existence in India, Artemisinin combination therapy (ACT), has emerged as the titular tool at mankind’s disposal to counter falciparum malaria related mortalities. The dramatic slide in reported deaths due to Plasmodium falciparum is a testament to ACT’s efficacy. However, a closer look reveals the successes so far achieved with ACT to be only a smokescreen. A large majority of the patients in the more remote and backward regions of India, still remain bereft of ACT, which might be the reason for the startling malaria mortality figures reported by the community surveillances. In our manuscript, we have laid focus on the key facets of the Indian health care system that has purportedly played a central role in the present successes with ACT. Further, we have highlighted as to how these key elements, for instance, health workers like Accredited Social Health Activists (ASHAs), sub-centers, supply chain of ACT can be improved upon further so as to ensure that ACT is able to reach the truly needy.

Keywords: ACT, accredited social health activist, prescribing practice, sub-center, supply chain

It was in April 2001, in riposte to the global emergence of the multi-drug resistant Plasmodium falciparum (MDR Pf), that the World Health Organization (WHO) introduced Artemisinin Combination Therapy (ACT).^[1] However, it was not until 2007 that the Indian authorities warmed up to WHO’s suggestions.^[2] ACT implementation, took its first baby steps in India, when 117 of the most endemic districts, where drug resistance was at its worst, adopted ACT as the first line of defense against MDR Pf.^[3] Despite the initial tentativeness, it was not long before ACT came to be adopted universally across the country. The results so observed have been dramatic. Malaria associated reported fatalities have dwindled down from 1,311 in 2007 to 562 in 2014.^[4] Arguments can be made in favor of other interventions like rapid diagnostic kits (RDKs) also laying claim to this stellar feat. However, there can be no disputing the fact that ACT has been at the forefront in our fight against malaria, to especially curtail the fatalities.Conversely, till date, India accounts for 60% of the malaria associated deaths in Southeast Asia.^[5] The under-5 year mortality rate in India is second only to the sub-Saharan African nations.^[6] These statistics hint that despite all the successes so achieved by ACT, there might be a few shortcomings at some level in its current form of implementation. Hence, it is our endeavor here to critically appraise the few key elements in the story of ACT’s application in India that could potentially determine whether ACT becomes the success it was intended to be.

The first step towards curtailing malaria associated deaths involved acknowledging the disease burden in the country. At the turn of the century, the promulgation by the authorities of scaling down malaria related mortalities by a margin of 50% by the end of the decade, set the tone for the future anti-malaria endeavors.^[7] It was well-understood by the establishment that in order to achieve a semblance of success, the anti-malaria program needed to be shored up financially. The paltry sum of US$ 21, that is, India’s public health care expenditure per capita in 2001,^[8] indicated the perennial state of neglect that had then come to engulf the healthcare sector in India. Moreover, in light of then wide-spread prevalence and high malaria related mortality, expenditure of a mere 116 crore rupees for the national anti-malaria program was an embarrassment.^[9] More so for a country that was slowly, but surely emerging as a global leader at the turn of the century. And it jolted the authorities into action. Thereafter, ensued a period of increased public expenditure for anti-malaria measures, especially since the year 2007. A 13% increment so observed in malaria related expenses from X^th to the XIth five-year plan, only further attests to the fact that the establishment had woken up to the threat posed by malaria.^[10] Homing in on to ACT, a tremendous leap has been observed in its procurement ever since 2007. As per the National Vector Borne Disease Control Program’s (NVBDCP’s) report in 2009, the proportion of expenditure on ACT packs, out of the total malaria related expenses was expected to rise progressively from 22% to 30% over 2009-2015.^[9] More relevantly, the report predicted that ACT’s share of the cost of all anti-malarial drugs procured and dispensed over the same period would experience a significant hike from 46% to 67%.^[9] These statistics only substantiate the perception that the observed expansion in ACT procurement and dispensation since 2007, may have been central to the decline in malaria related mortalities.

In the backdrop of this perceived notion, it makes for an interesting reading that India still accounts for a large chunk of the malaria associated deaths across Southeast Asia. More alarming is the fact that though in terms of the actual amount there has been an upward movement, the overall proportion of malaria related expenditures in NVBDCP’s budget has experienced downsizing.^[9] This decline could be attributed to the siphoning of the erstwhile malaria related allocations to counter the increasing burden of other vector borne diseases. The emergence of diseases like dengue, have stolen the spotlight away from malaria in the recent years. In addition to this, studies indicate that the actual expenditure has trailed the allocated resources to malaria control endeavors, in a large manner.^[9],[10] This is indicative of bureaucratic red-tape that seems to be slowing down the flow of funds from the top down. As of today, when India stands on the cusp of stepping from the pre-elimination stage into the malaria elimination stage, India can ill-afford to draw its attention away from malaria. If Indian authorities dither in their effort to curb malaria now, it could so easily translate into a situation akin to ‘Out of sight, out of mind’. This would be catastrophic and could lead to the re-emergence of malaria with a vengeance. It can be argued in favor of present ACT implementation strategy that the actual mortality numbers may prove minuscule in comparison to India’s vast population. However, it would be pertinent to remember that these numbers represent only the tip of the iceberg. The mortality numbers quoted here refer to the small proportion of cases and deaths being reported in the formal health sector. The true picture of malaria cases and fatalitiesis revealed only once the surveillance data is extrapolated to the whole community. If one is to go by the recently published World Malaria Report 2015, the prevalence of malaria infection stands at an astounding 10-26 million (estimated from surveillance) in India.^[11] Even more alarming is the estimated exorbitant mortality figures of 2,300-55,000.^[11] The impression we get from these epidemiological survey numbers is that though ACT may have achieved significant successes, it is yet to completely reach the truly needy.

It is our belief that this could probably be due to a significant lacuna that exists at the lower levels of our health care system, in terms of infrastructural and work-force deficit.

ASHAs

Training our sights on the man-power shortfall, it is our opinion that the role of grass-roots level health workers in effective implementation of ACT in India is highly under-rated. To understand this, one has to remember that a huge chunk of the cases and fatalities arise from the 150 odd moderate to highly endemic districts, which incidentally are some of the most backward and remote places in India.^[12] The regions in question are often plagued by a serious shortage of basic amenities of life, for instance potable water. Hence, the availability of higher levels of health care facilities still remains a far-fetched dream in these regions. This props up further, the role of a community health worker like ASHA as being part of the village community, they are easily accessible even in the most remote and backward of the places. In addition, the fact that the treatment rendered by these health workers comes without any cost, makes them an enticing point of health care delivery for the severely impoverished in these regions. Realizing the potential of ASHAs in dispensing rapid and effective healthcare, an active recruitment and promotion campaign has been underway since 2005. The promise of financial incentives and emoluments combined with the social prestige that goes hand in hand with the job of an ASHA, seems to have been effective in propelling their numbers to 0.860 million in 2014.^[13] Nonetheless, the present figures are still short of the intended mark of 1 ASHA per village or per 1000 population.^[14] It is not just the quantitative deficit, but also the qualitative shortcomings in ASHA’s training that seems to be hurting their ability to counter malaria related deaths. The recent studies have indicated that the awareness among ASHAs about the malaria drug policy changes and case management skills seems to be way short of the desired level.^[15],[16] Hence it could be suggested, keeping in mind the nominal education level of ASHAs, a concerted effort should be made to improve their training, with special focus laid on malaria case management and age-wise ACT prescription. Post-training follow-up, structured supervisory visits and close monitoring of their performances, could go a long way in helping ASHA provide better medical services. In turn, this could translate into better control over malaria related deaths at the grass-roots level.

Sub-centers

Besides ASHAs, it is the sub-centers that play a singular role in our health care system. Being in a position, where they act as an interface between the ASHAs and the primary health care centers (PHCs), sub-centers can help ensure effective delivery of ACTs to the needy population, in a big way. Hence, the 1.6% spike seen in their numbers over the period of 2005-12 may be one of the biggest factors in reducing the malaria related mortalities during the same period.^[17] Moreover, bearing their significance in mind, it is ideal if the sub-centers are situated in a prominent location in the region, thus making them easily recognizable and accessible. Interestingly, the number of sub-centers located within the government facilities increased by 1.5 times over the period of 2005-2012.^[17] Simultaneously, the sub-centers being rented out of obscure private buildings also slid down from 50,338 to 35,936 during the same period.^[17] By locating within the government facilities, it is intended that the sub-centers should not remain deprived of the basic amenities needed for a medical facility to function. Despite all these attempts, it is startling to note that about a quarter of the existing sub-centers suffer from water and electricity shortages and 7% remain inaccessible for a large part of the year.^[17] In addition, sub-centers are often plagued by workforce shortfalls. Despite the observed 56% increase in the number of auxiliary nurse mid-wives within the sub-centers, the deficits of male health workers in the sub-centers throughout the country stood at an alarming 64% as per India’s rural health statistics in 2012. The situation is comparatively better in case of female health workers. However, the deficit still remains significant.^[17] The heavy work-force shortfalls at the sub-centers should ring the alarm bells as it is the sub-centers that often act as the next recourse after the ASHAs for the impoverished who are plagued by malaria. Without properly trained personnel to effectively manage falciparum malaria cases using ACT, the point of opening a sub-center is rendered moot. Thus, in light of these shortfalls, both on workforce and infrastructure fronts, it is highly unlikely that the malaria cases, especially in the tribal and remote areas receive proper treatment, especially ACTs. The story runs on similar lines in case of PHCs and community health centers (CHCs) as well. However, in our opinion, PHCs and CHCs being higher levels of health care than sub-centers, are unlikely to have as great an impact as sub-centers, on improving the reach of ACT among the poor. Hence, we have limited our discussion to sub-centers in this segment.

Another factor that seems to be compounding the issue of the delivery of effective anti-malaria treatment in the form of ACTs is the issue of stock-outs. To rectify the situation at the ground level, fixed norms for ACT availability were drawn up.^[9] It was mandated that each ASHA would have to maintain 2 combi-blister packs of ACTs for each age-group at any given point of time.^[9] In a similar manner, sub-centers and other higher level facilities were expected to maintain pre-fixed number of ACTs for each age group at all times. Further, in order to ensure a steady stream of supply of ACTs to the grass-roots level, few innovative strategies were adopted. Prominent among them were the ‘Voluntary Pooled Procurement’ (VPP) method through the procurement support service (PSS) provided for by the Global Fund for AIDS, Tuberculosis and Malaria (GFATM) as well as the process of ‘Emergency Procurement’ via international outlets like WHO, aimed at short term replenishments (usually for 6 months).^[9] In addition, the seriousness of the government in tackling stock-outs could be seen by the decentralization of the procurement process for a one-time buffer stock of 25% of the total requirement, which would be needed to ensure an un-interrupted supply of resources, especially during seasonal upsurges in cases.^[9] Further, in a bid to maintain the quality of the ACTs, inspections and quality monitoring by independent agencies as agreed upon by the authorities and the provider agency, would be carried out in pre- and post-procurement stages.^[9] Procurement asides, a few steps were planned to bolster the delivery system. Standard operating procedures (SOPs) for storage and inventory of ACTs were prepared and disseminated to the states.^[9] An independent professional agency, that is, Strategic Alliance Management Services (SAMS) was engaged with the aim of improving upon the transparency and efficacy of the supply chain.^[9] Various strategies like first expiry, first out (FEFO) and first in, first out (FIFO), maintaining stock registers and periodic physical checks, improved security measures, regular visits by the SAMS to the states and districts for reviewing the supply chain and fixing the bottlenecks, seemed to be other notable inclusions in the establishment’s plans for strengthening the supply chain.^[9] To ensure prioritization of the most ravaged areas, distribution of ACTs was to be carried out as per the situation on the ground reported by the local, state or central officers during their visits to the peripheries.^[9] To keep close tabs on the supply and utilization of ACTs, a regular indent system was worked out.^[9]

However, the ground reality as attested by various studies in high disease burden states like Odisha^[16] and Jharkhand^[18] does not seem to reflect favorably upon this impressive list of modifications to the anti-malaria program with respect to ACT supply and utilization.The examples of Odisha and Jharkhand assume immense significance in light of the fact that until 2014 November, figures revealed both these states to account for 48% and 25% of the reported malaria cases and mortalities respectively.^[19] This would suggest that being the largest contributors to the disease burden in India, these two states would be the center of attention for all anti-malaria endeavors. However, the results of an elegant study conducted in Odisha in 2012 should sound off alarm bells for the concerned authorities. It was observed that despite being adequately trained in malaria case treatment, grass-roots level health workers like ASHAs and ANMs referred a huge chunk of their patient population to the higher centers. The investigators homed on to the non-availability of ACTs as the primary reason for this unhealthy trend. Further, paucity of ACTs on a similar scale was observed at higher level health centers as well. More alarming was the issue of the long duration of ACT stock-outs, especially for the younger age-groups. The scenario was no different in Jharkhand as well. Interestingly, a lion’s share of the population in the states with the highest burden of malaria cases comprises of the tribal population residing within the remote and backward areas.^[20] Further, it has been observed overall that the tribal population in India is probably contributing to 60% of the Plasmodium falciparum cases.^[21] This would suggest that the current ACT supply strategies may not be the right way to move forward in these highly under-developed regions. In cognizance of this gaping lacuna, innovative strategies, for instance, collaboration with the Ministry of Tribal Affairs, local non-government organizations (NGOs), community based organizations and other private sector organizations may be the need of the hour. Toeing this line of thought, the government in its National Framework for Malaria Elimination 2016-2030, has introduced a Tribal Malaria Action Plan (TMAP) that aims at scouring out cases more aggressively using mobile surveillance systems, on the spot species specific treatment, follow-up of cases to ensure complete treatment and timely referral of severe cases to higher centers.^[12] Though indicative of an honest intention, it remains to be seen in the years to come as to how effectively can this program reach the tribal population.

Besides, eco-geographical factors, there are other elements mitigating the success of ACT implementation in India. In light of the emergence of resistance to Artemisinin in the latter part of the last decade, WHO called for banning of prescription of Artemisinin as a monotherapy. With the Indian authorities complying with this directive in 2009,^[22] it was hoped that ACT would go on to replace Artemisinin as the first line of defense against falciparum malaria. However, the poor awareness of the national anti-malarial drug policies translating into continued prescription of Artemisinin as a monotherapy has stunted the growth of ACT implementation, especially in the private sector. The practice of Artemisinin monotherapy prescription is further bolstered by the unregulated sale of oral Artemisinins in the private retail sector.^[23] This has largely been possible due to the transgressions of the Indian Pharmaceutical companies. As recently in January 2014, WHO reported about 11 Indian pharmaceutical companies targeting the private sector that have repeatedly ignored WHO’s appeals and have continued in their merry way of producing oral Artemisinin to satisfy their baser goal of profiteering.^[23] Besides, ACT in India is available primarily as co-formulated blister packs and not as fixed dose combinations (FDC).^[24] This lends itself perfectly to the unhealthy trend of Artemisinin monotherapy prescription. It can be suggested that in an effort to improve the awareness among the prescribers of the national malaria drug policy, regular sensitization programs in the form of seminars and continued medical educations (CMEs) should be carried out. Involvement of the elderly physicians in policy making decisions is another innovative yet an inclusive technique of combating irregular anti-malarial prescribing practices. Improving upon the packaging of the drugs, preferably as a FDC could also prevent Artemisinin monotherapy prescribing. Further, measures like pre-deciding the time-frame of phasing out oral Artemisinin drugs from the market and imposing punishments on the offending companies, cessation of new approvals of oral Artemisinin-based monotherapies, suspension of import and export licenses of companies exclusively marketing oral Artemisinin-based monotherapies, active recall of oral Artemisinins from the market, could go a long way in completely wiping out oral Artemisinin.^[25] When combined together with a wide-scale deployment of ACT, these measures could help in improving the reach of ACTs in India.

The high cost of ACTs too, does itself no favors in its endeavor to reach the truly needy. It has to be understood that a large chunk of the malaria sufferers in India belongs to the socio-economically backward communities. The perennial shortfall of ACTs seen with the grass-roots level health workers and the other higher public health facilities, for instance the sub-centers and the primary health center (PHC), forces them to look to the private health-care sector for access to anti-malarial medications. However, the ACTs in the private sector are priced at about 4-5 times that of chloroquine.^[26] The non-affordability of ACTs by the patients leads to the dispensation of improper anti-malarial drugs by the private health-care dispensers, thus further stunting the expansion of ACT implementation program. Various initiatives have been undertaken by the authorities besides the provision of free anti-malarial drugs by the health workers and at the public health facilities. Prominent among them is the Jan-AushadhiYojna program initiated in 2008, aimed primarily at boosting the availability of quality and affordable medicines for the poor and the disadvantaged.^[27] However, the intended figure of one Jan-Aushadhi store (JAS) per district has remained a far-fetched dream till date.^[27] As per the government’s report in 2013, a disappointing 147 out of the proposed 630 JAS had been opened, of which only 84 remained functional.^[27] Moreover, the disputes over jurisdiction between the state and central authorities have only added to the confusion and stifled the expansion of this scheme.^[27] The capacity of the JAS to cater to the needs of the poor has been hampered by the limited medicine supply from the Central Pharma Public Sector Undertakings (CPSUs).^[27] Various other factors at play here, for instance, lack of awareness about these stores amongst the prescribers as well as the patients, continued prescription of branded medicines has mitigated the success of this scheme.^[27] Hence, it would appear that the Jan-AushadhiYojna intended to complement the free anti-malarial drug schemes, already in place in various states and increase the availability of affordable anti-malarial drugs for the poor, seems to have failed miserably. However, it has been envisaged by the government in the recent years that adopting measures like aggressive media campaigns promoting JAS, co-ordinating with the state governments to avoid wastage of resources and preventing duplication of efforts, promoting the prescription of generic medicines via educating health professionals, could help turn around the fortunes of Jan-Aushadhi scheme.^[27] It is our opinion that other steps like enlisting the help of non-government organisation s (NGOs), expanding the list of Essential Drug List (EDL), limiting the margin of profits for manufacturers, wholesale retailers and reduction on taxes and duties on raw materials, the prices of not only anti-malarials, but other drugs as well can be slashed away drastically. This could ultimately go a long way in reducing the proportion of the Indian populace seeking medical care in the private sector and simultaneously improve upon the utilisation of public health facilities as well.

Finally, to conclude, it would serve the authorities in good measure, to take a look at the manner in which the malarial parasite has managed to evade every anti-malarial drug till date. In light of this, the effective and rational use of ACT gains immense significance as it exploits the innate ability of a combination therapy to mitigate the chances of development of resistance and also effectively eliminate the parasite. Thus, for India to achieve its targets of malaria elimination by 2030, the authorities would be better served now, if more attention is drawn away from the endeavor of developing newer drugs towards improving upon the utilisation of ACT by taking cognizance of the key elements pointed out in our manuscript. ACT is still a novelty and an extremely effective one at that. Let us help ACT fulfil its promise to mankind.

Acknowledgements

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Financial support and sponsorship

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Conflicts of Interest

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1755-6783.205588