Date Published: January 5, 2017
Publisher: Public Library of Science
Author(s): Peter U. Fischer, Christopher L. King, Julie A. Jacobson, Gary J. Weil, Timothy G. Geary. http://doi.org/10.1371/journal.pntd.0005163
Partial Text: Recent studies have shown that single-dose combination therapy with three currently approved antifilarial drugs (ivermectin, diethylcarbamazine (DEC), and albendazole, or IDA) is superior to current regimens used in lymphatic filariasis (LF) elimination programs. IDA may help to accelerate LF elimination in Africa, which has lagged behind other regions. Although it has not yet been tested, IDA may also be useful for treating onchocerciasis. There is a serious concern about using DEC in sub-Saharan Africa because of ocular adverse events after DEC treatment of onchocerciasis in the past. This paper discusses published experience with DEC in onchocerciasis patients and describes strategies for studying the effects of IDA in patients with onchocerciasis and LF in Africa.
The Global Program to Eliminate Lymphatic Filariasis (GPELF) has made significant progress in many countries. GPELF has delivered 5,600 million treatments to more than 763 million people living in 61 countries between the years 2000 and 2014, and it was estimated to have prevented 36 million clinical cases and saved 175 million disability adjusted life years (DALYs) . Although elimination of LF is a major goal of the London Declaration on Neglected Tropical Diseases (NTDs), it is unlikely that LF will be eliminated by the target year of 2020 . The key strategy of the elimination program comprises repeated annual rounds of mass drug administration (MDA) to populations at risk of acquiring the infection with diethylcarbamazine (DEC) plus albendazole outside of Africa and with ivermectin plus albendazole in Africa . MDA reduces microfilariae (Mf) in human blood that are necessary for transmission by mosquito vectors, and one aim of the program is to interrupt transmission. Repeated rounds of MDA are required because current regimens fail to kill all adult worms and completely clear Mf following single-dose treatments. Successful programs have sustained annual MDA with high compliance for several years. Seventy-three countries were considered to be endemic for LF in 2015, and 55 of them still required MDA . The GPELF has lagged in sub-Saharan Africa, where only 2 of 35 LF-endemic countries have stopped MDA and started post-MDA surveillance. Many countries in this region have either not started MDA or have less than 65% geographical coverage. Hence, a more effective treatment strategy could have a major impact on LF elimination in Africa.
Thomsen et al. have recently reported that a single dose of coadministered IDA was superior to the standard two-drug regimen of DEC with albendazole for clearing Wuchereria bancrofti Mf in infected subjects in Papua New Guinea . All 12 of the heavily infected subjects treated with IDA had complete clearance of Mf one year after treatment, whereas only 1 of 12 subjects treated with DEC plus albendazole had complete clearance of Mf at 12 months. In addition, all 6 IDA-treated subjects retested at 24 months were still Mf negative at that time. This suggests that a single dose of IDA either kills or permanently sterilizes adult W. bancrofti worms and prevents their hosts from contributing parasites for transmission by mosquitoes. The Thomsen et al. study also showed that IDA was safe and that there were no significant interactions between the drugs in the IDA regimen. Early results from larger clinical trials of IDA in Papua New Guinea and Cote d’Ivoire are consistent with the results reported by Thomsen et al. These results suggest that IDA has the potential to dramatically accelerate LF elimination programs. Several large community trials are underway to confirm the safety and efficacy of IDA in different epidemiological settings. Because DEC has the potential to cause ocular adverse events in individuals infected with O. volvulus, all of these studies are being conducted in areas without coendemic onchocerciasis.
Although most sub-Saharan countries endemic for LF use ivermectin combined with albendazole in their elimination programs, the region includes also countries or areas that are nonendemic for onchocerciasis or loiasis (e.g., Kenya, Zanzibar, Comoros, Sao Tome and Principe, Eritrea, Madagascar, Zambia, and Zimbabwe), and these countries currently use or plan to use DEC combined with albendazole in their LF elimination programs . These countries stand to immediately benefit from the more effective IDA regimen if results from ongoing safety trials are favorable. For other countries, we need to consider how IDA might be used for LF elimination in areas without coendemic onchocerciasis. In some countries (e.g., Tanzania) onchocerciasis foci are limited and geographically separated from LF-endemic areas, and IDA might be used to eliminate LF in these areas at the district level. However, this strategy requires accurate disease maps, careful assessment of human migration patterns, an ability to safely screen out individuals that may be at risk of onchocerciasis, and an understanding of the effects and adverse events associated with DEC treatment of onchocerciasis.
Diethylcarbamazine (N, N-diethyl-4-methyl-1-piperazine carboxamide) was shown to be effective against filarial parasites in the late 1940s [12–15]. Although it was recognized early that DEC can cause adverse reactions in individuals infected with O. volvulus, it was the recommended first line treatment for onchocerciasis for about 40 years because better alternatives were not available until ivermectin was introduced [16–18]. A treatment course of oral DEC was used for both individual and community treatment . In addition, topical DEC or eye drops containing DEC were sometimes used to specifically target skin or ocular disease, respectively [20–22]. Since eye lesions were among the most severe clinical signs of O. volvulus infection, people with ocular involvement were often preferentially treated . DEC was administered in multiple doses, and many different dosing regimens were evaluated (Table 1). One common regimen recommended for a 50 kg adult was a total dose of 1,350 mg over eight days (average total dose per course of 27 mg/kg body weight), with a low dose of 1 mg/kg on day one and higher doses thereafter. Patients were often treated with a second course of DEC four months later . The efficacy and safety of single-dose treatment with DEC (6 mg/kg) combined with albendazole (400 mg) used for elimination of LF outside Africa was never evaluated in patients with onchocerciasis because of the risk of inducing Mazzotti reactions and ocular adverse events in Mf-positive individuals and because ivermectin was much better tolerated. DEC-fortified cooking salt that is sometimes used for LF intervention was reported to be safe but not effective in subjects with onchocerciasis .
Ivermectin is currently widely used for control and elimination of onchocerciasis. A single 150 μg/kg dose usually clears skin Mf and causes temporary sterility for about three to four months, after which Mf newly released from female worms repopulate the skin. The related drug moxidectin (8 μg/kg) clears skin Mf for about twice as long, but the drug is not yet approved for human use . If IDA is as effective against O. volvulus adult worms as it appears to be against W. bancrofti, it might permanently sterilize the adult worms and permanently clear Mf from the skin. If it is effective, IDA treatment could also be useful in areas that have had suboptimal responses to ivermectin alone .
The epidemiological situation of onchocerciasis has dramatically changed since the era of widespread DEC use in the 1960s and 70s. Onchocerciasis is believed to be eliminated from most savanna areas in West Africa where blinding onchocerciasis was highly prevalent in the past [43, 44]. Persisting foci of onchocerciasis mainly occur in forested regions of West and Central Africa, where blinding onchocerciasis is not common . Community-directed treatment using ivermectin in hyper- and mesoendemic foci has reduced Mf prevalence and density considerably in the countries of the former African Program for Onchocerciasis Control . However, many of these areas still require ivermectin because of the continuing presence of viable adult female worms that cause low-level microfiladermia (usually less than 5 Mf/mg skin) with little or no eye involvement. These would be suitable areas for community studies of IDA if RCTs have shown that the regimen is safe and effective for treatment of onchocerciasis. The new push for onchocerciasis elimination will also extend mass treatment into hypoendemic areas where Mf rates are less than 20%. The danger of DEC in such areas is likely to be relatively low but not zero because some untreated individuals in hypoendemic areas may have high skin Mf counts with ocular Mf or because they have recently moved from hyperendemic areas. Therefore, documented ivermectin pretreatment at the level of individuals would still be required prior to IDA use in such areas.
The proposed IDA RCTs in persons infected with O. volvulus may serve a dual purpose: First, they may demonstrate that IDA can be safely used for LF elimination in areas that are coendemic for onchocerciasis (Fig 1). Second, they may show that IDA is more effective than ivermectin alone for treatment of onchocerciasis. If preliminary studies show that IDA can be safely used in persons with onchocerciasis following pretreatment with ivermectin, then it potentially could be used in large parts of Africa that are currently using or plan to use ivermectin combined with albendazole for LF elimination. Although we hope that IDA will be superior to ivermectin alone for onchocerciasis, this need not be the case for IDA to be useful for LF elimination programs in areas of Africa with coendemic onchocerciasis.
Carefully designed IDA RCTs in individuals with onchocerciasis will have a low but manageable risk. On the other hand, IDA’s potential benefit is huge because it could significantly accelerate elimination of both LF and onchocerciasis in Africa. It is also possible that IDA will not be safe enough for use as MDA in most regions of Africa. But this possibility should not prevent performance of RCTs for onchocerciasis because a therapy that cannot be used for MDA may still be useful for individual case management. We believe it is likely that a single dose of IDA (administered several months following an Mf-clearing dose of ivermectin) will be much more effective for long-term clearance of O. volvulus Mf than ivermectin alone. We call this strategy “pretreat and treat.” It is also possible that IDA will kill or permanently sterilize adult female O. volvulus worms. These hypotheses must be tested because IDA has the potential to completely change the game for onchocerciasis as it is likely to do for LF.
Of course, W. bancrofti and O. volvulus are not the only human filarial parasites that occur in Africa that could be affected by IDA. At present, there is no effective single-dose treatment for Mansonella perstans, which may be the most abundant and widespread filarial parasite in Africa . Therefore, it would be important to perform trials to assess the safety of IDA in persons infected with M. perstans, and these studies would also assess whether IDA is an effective single-dose treatment for this infection. This would be important so that any rollout of IDA for use in LF or onchocerciasis elimination programs would not be limited by the presence of M. perstans. Because Mansonella streptocerca has a limited geographical distribution, usually produces low Mf densities, and is highly susceptible to both DEC and ivermectin, IDA is likely to be safe for use in persons with that infection.
IDA has the potential to be a game changer for LF elimination in Africa, especially in countries and regions without coendemic onchocerciasis or loiasis. More research is required to determine if there is a safe and effective way to use IDA in coendemic settings. Additional research will be needed to test whether IDA is safe and effective for treating onchocerciasis, first in individuals and later in endemic populations with or without coendemic LF. We are very enthusiastic about this possibility because IDA is likely to be more effective for clearance and suppression of Mf than ivermectin alone. Compared to drugs that have not yet been tested in humans, IDA provides a potential fast-track and low-cost option that could accelerate elimination of LF and onchocerciasis in Africa.