What's going on in India?

In India, more than 23 million people are currently infected with lymphatic filariasis (LF).1,2 Most live in urban LF “hotspots” with low sanitation and poor hygiene.3,4 Under the National Vector Borne Disease Control Program (NVBDCP), the Government of India (GOI) has been implementing Mass Drug Administration (MDA) as an intervention against LF in the form of triple drug preventive chemotherapy (PC) administered to the susceptible population. MDA consumption coverage has often been suboptimal, especially in hotspots, and one of the most important reasons is lack of acceptance. Because LF PC has been traditionally dispensed as loose tablets from shared bottles, and on regular paper without labels or instructions,4 beneficiaries often do not trust the medicines distributed by the health care workers.5 The phenomenon seems to be more acute in urban slums, where health systems are weaker.6 Bend Biomedical's work here is a response to the call for steps to be taken to attain more effective treatment coverage in these areas.6

Lucknow, Uttar Pradesh, India

India has already missed three LF elimination targets – one in 2015, one in 2017, and one in 2021. A World Health Organization (WHO) worker recently noted that if current trends are any indication, India will not be able to eliminate the disease sooner than 2029,7 even with triple therapy.

Hotspots in India are slums where residual lymphatic filariasis gathers. The most endemic states of India are Uttar Pradesh and Bihar.

The current approach of PC in India is for most tablets to be from shared bottles without instructions. As a result, there is a lack of trust. The consequences are effective coverage between only 23.0% and 50.3%4 in urban slums. Because the free drugs are being supplied to governments at no cost, the makers are unwilling to change the packaging or otherwise improve products, and they are reluctant to allow the product to leave their direct control to be blister-packaged elsewhere.

Bend Biomedical is developing and manufacturing generic blister packs for LF MDA to improve acceptance in slum areas of India. After development, we plan to initially manufacture 60 million blister-packed tablets of ivermectin (IVM), 45 million blister-packed tablets of diethylcarbamazine citrate (DEC), and 15 million blister-packed caplets of albendazole (ALB).

Our model makes blister packs that are WHO “prequalified generic” and an improvement from existing bottled drugs in use now. India already uses blister packs for leprosy (NLEP, National Leprosy Eradication Programme) and tuberculosis (NTEP, National Tuberculosis Elimination Programme). We suggest using blister packs for filariasis (ELF, Elimination of Lymphatic Filariasis).

Second, we are adding color to the ordinarily white tablets to help differentiate pills for people who cannot read. Third, we are individually labeling the medicine and providing informative literature inside the cartons to include drug purpose, instructions, and possible side effects, in the appropriate languages (English and Hindi).

In addition to treating lymphatic filariasis (51 million currently infected worldwide), our blister-packed LF medicines alone or in combination can treat two other MDA diseases: onchocerciasis (25 million) and soil-transmitted helminthiases (ancylostomiasis, ascariasis, and trichuriasis, combined >1 billion). The same drugs can be used for PC for these diseases, and one or more are prescribed8 for mansonelliasis, oesophagostomiasis, scabies, strongyloidiasis, and tropical pulmonary eosinophilia.9a

The benefits of blister packaging these drugs extend beyond providing labels and instructions. Blister packaged medicines are perceived as trustworthy. They are moisture-protected, tamper-proof, child safe, individually labeled, and environmentally friendly, in comparison to those distributed in plastic bottles.9

What is LF? Lymphatic filariasis is a poverty-related disease that impairs or permanently disables millions of people every year, often resulting in life-long physical pain and social stigmatization. Helminths (parasitic worms), carried by mosquitoes, cause the disease primarily by attacking the lymphatic system. The infection usually begins in childhood, with approximately one-third of children in endemic areas infected before age five.10 In children the disease presents with adenitis and adenopathy. Starting after puberty, adult clinical symptoms include permanent lymphatic system, liver, and kidney damage, sometimes leading to death. In later stages, the disease causes recurrent secondary bacterial infections hastening a hardening and thickening of the skin, known as elephantiasis.

An advanced case of lymphatic filariasis elephantiasis in India

MDA is a key strategy in fighting against LF, approved globally to prevent lymphatic filariasis in endemic areas and requiring administration to all the susceptible population in the community once or twice a year. MDA decreases transmission rates and prevents progression from subclinical to clinical disease and worse morbidity.11 In the past, the primary drug DEC, or else drugs ALB and DEC combined were used for this purpose. In 2017, new recommendations11 for eliminating the disease were published by the World Health Organization (WHO) and funded by the US Agency for International Development (USAID). Depending on special criteria and on co-endemic loiasis or onchocerciasis, there are four recommended treatments: annual triple therapy of ALB, DEC, and IVM (a combination used in most of India); annual dual therapy of ALB and IVM; annual dual therapy of DEC and IVM; or biannual ALB alone.

Bend Biomedical is working on an acceptance and effectiveness study to evaluate single-drug blister packs vs loose pills for LF PC in an urban subdistrict with slum areas. The new formulation will be used in selected areas, and using a control arm, the coverage of MDA with the new formulation will be compared to the same for the conventional formulation. Further it will also be interesting to examine the number of people who have never been treated who agree to be treated precisely because of the blister packs. The models tell us that if the proportion of non-compliant (never treated) declines, treatment will be more effective. The existing drug formulation for LF MDA consists of pills in bottles: IVM 3 mg at 200 mcg/kg (or height), DEC 100 mg at 6 mg/kg (or age), and ALB 400 mg. The trial formula is the same, but the tablets are in single-drug blister packs. All bottled drugs during routine MDA rounds in the control arm will come from the name-brand free-drug manufacturers: MSD, Eisai, and GSK. Households will be selected for each arm, and eligible participants will receive one or the other formula. The number of compliant patients in each arm and mean microfilariae Mf% using night blood survey and filarial test strips after treatment will be compared.

Use of IVM for LF is contraindicated in areas co-endemic for loiasis and is used restrictively for onchocerciasis based on potential serious adverse events in loiasis patients.11 DEC is also contraindicated in areas co-endemic for onchocerciasis and loiasis.11

Onchocerciasis and loiasis are not endemic in India.12,13 However the slum areas selected for blister packs must be eligible for ALB, DEC, and IVM triple therapy for lymphatic filariasis. The Government of India will issue locations for implementation. Healthcare workers will screen for neurocysticercosis and seizures during MDA.

DEC is a harsh drug especially in children. Care needs to be taken with allergy, itching, and swelling (especially of the eyes). In some, this may be life-threatening. This is more common in people with allergic challenges. Having plans for steroids and antihistamines available will always be recommended by us to GOI.

Note that the most pills any patient should receive in India is 8 pills for a tall adult: 1 ALB, 3 DEC, and 4 IVM.


A supply chain has already been established.14

Lucknow, Uttar Pradesh, India

ABBREVIATIONS
ALB: Albendazole; DEC: Diethylcarbamazine citrate; ELF: Elimination of Lymphatic Filariasis; GOI: Government of India; IDA: Ivermectin with diethylcarbamazine and albendazole; IVM: Ivermectin; MDA: Mass drug administration; Mf%: Proportion microfilaremic; NLEP: National Leprosy Eradication Programme; NTEP: National Tuberculosis Elimination Programme; NVBDCP: National Vector Borne Disease Control Programme; USAID: United States Agency for International Development; WHO: World Health Organization.

1Rahi M, Chaturvedi R, Das P, Sharma A (2021) India can consider integration of three eliminable disease control programmes on malaria, lymphatic filariasis, and visceral leishmaniasis. PLoS Pathog 17(5): e1009492. 2021 May 20.

2Filaria endemic districts. National Vector Borne Disease Control Programme. Available from: https:// nvbdcp.gov.in/index4.php?lang=1&level=0&linkid=453&lid=3733. [cited 2021 Feb 6].

3Modi A, Vaishnav KG, Kothiya K, Alexander N. Lymphatic filariasis elimination endgame in an urban Indian setting: the roles of surveillance and residual microfilaremia after mass drug administration. Infect Dis Poverty. 2021 May 18;10(1):73.

4Banerjee S, Bandyopadhyay K, Khan MF, Akkilagunta S, Selvaraj K, Tripathy JP, Solanki R, Kushwaha AS, Deshmukh P. Coverage of mass drug administration for elimination of lymphatic filariasis in urban Nagpur, Central India: A mixed method study. J Family Med Prim Care. 2019 Sep 30;8(9):3009-3014.

5Whitehead N. Ready, Set … Think! Hackathon Aims to Kill Off Fake Health Rumors. NPR. 2021 June 10.

6Kapa DR, Mohamed AJ. Progress and impact of 20 years of a lymphatic filariasis elimination programme in South-East Asia. Int Health. 2020;13(Suppl 1):S17-S21. doi:10.1093/inthealth/ihaa056

7Chandna H. Poor campaign, aversion to medicines — why India is unlikely to eliminate filariasis by 2021. MARIJUANAPY THE WORLD NEWS. 2020 November 13.

8PJ Hotez, Fenwick A, Molyneux DH. Collateral Benefits of Preventive Chemotherapy—Expanding the War on Neglected Tropical Diseases. N Engl J Med. 2019 June; 380(25):2389–91.

9aSuman KJ, Karna B, Mahajan K. Tropical Pulmonary Eosinophilia. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan.

9Smith W. Blister Packaging vs. Bottles for Pharmaceutical Products: Factors to consider for packaging over-the-counter and prescription medications include safety, adherence and product quality. Packaging Strategies. 2018 May.

10Witt C, Ottesen EA. Lymphatic filariasis: an infection of childhood. Trop Med Int Health. 2001 Aug;6(8):582-606.
 
11Guideline: Alternative mass drug administration regimens to eliminate lymphatic filariasis. Geneva: World Health Organization; 2017. License: CC BY-NC-SA 3.0 IGO.

12Kumari V, Ahmad S, Singh A, Banerjee T. Presence of adult Loa loa in the anterior chamber of the eye along with microfilaremia from nonendemic region: A rare presentation from India. Ci Ji Yi Xue Za Zhi. 2019;31(4):283-285. Published 2019 Sep 16. doi:10.4103/tcmj.tcmj_227_18    

13Shivalingaiah PR, Veerabhadraiah P, et al. Onchocerciasis in the Orbital Region: An Unexpected Guest From Tropics. Int J Head Neck Surg 2018;9(4):137–139.

14Souza AA, Holloway C, Williams T. The NTD Supply Chain Forum—Strengthening the backbone of NTD programs. PLoS Negl Trop Dis. 2020 Nov 5;14(11).


Right now we are also assessing lymphatic filariasis in Tanzania, Haiti, Brazil, Nigeria, and American Samoa.