There is considerable geographic overlap between areas with high prevalence of NTDs and HIV, raising the possibility of complex polypharmacy and drug–drug interactions. Antiretroviral drugs pose a particularly high risk for potential drug–drug interactions. These may be pharmacokinetic or pharmacodynamic in nature and can result in raising or lowering the plasma or tissue concentrations of co-prescribed drugs. Depending on the magnitude of the interaction, elevated drug concentrations may be associated with drug toxicity and lower drug concentrations may be associated with therapeutic failure. Sub-therapeutic concentrations are of particular concern in the discipline of infectious diseases due to the possible emergence of drug-resistant strains, which can compromise the utility of anti-infective agents on an individual patient or a population basis. The bi-directional nature of drug–drug interactions raises the possibility of alteration of drug levels of either the prescribed antiretroviral drugs or the drugs used to treat the NTD. Sub-therapeutic levels may go unnoticed, as there is often a delay between the use of treatment and the emergence of clinical failure or resistance. Furthermore, when available, therapeutic drug monitoring for either antiretrovirals or NTD medicines is complex and expensive.
Consensus international and national guidelines for the treatment of HIV-infected patients recommend initiating therapy with either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor-based regimen. These two commonly prescribed classes of antiretroviral drugs are both substrates for and modulators of the cytochrome P450 isoenzyme system. Additionally drug interactions with antiretroviral drugs can occur through mechanisms including drug influx and efflux transporters, glucuronidation, nuclear receptor activation and pH-dependent absorption. Also, overlapping toxicities of antiretrovirals and co-administered drugs must be taken into consideration, as severe toxicities may be exacerbated with some drug combinations.
The aim of this paper is to review the currently available data on interactions between antiretroviral drugs and drugs used in the management of NTDs. It is intended to serve as a resource for policy makers and clinicians caring for these patients to support the WHO 2020 Roadmap and the 2012 London Declaration on NTDs. Additionally it is envisaged that it can inform the research agenda in this area. The Liverpool HIV drug interactions website (http://www.hiv-druginteractions.org) has recently been updated to include drugs from the WHO Model List of Essential Medicines, including those used in the treatment of NTDs as discussed in this review. As such, this will serve as an ongoing resource in this neglected and important area of clinical care.
Table 1 summarizes current WHO Treatment Guidelines and the prevalence and distribution of NTDs. The metabolism and elimination profiles of the drugs are summarized, and the potential for pharmacokinetic interaction with antiretrovirals. Since there is overlap in the drugs used in the management of NTDs we have discussed the available data by drug rather than disease. Table 2 summarizes potential drug–drug interactions between drugs for NTDs and antiretrovirals. Rifampicin, azithromycin, streptomycin and steroids were not included in the discussion as these are well described in the literature due to their therapeutic importance outside of the scope of NTDs.
Potential interactions with antiretrovirals
Albendazole and mebendazole
Albendazole and mebendazole are structurally related and may both be used to treat infection with soil-transmitted helminths, including Ascaris and Tricuris species, and hookworm. Albendazole may also be used in lymphatic filariasis (Table 2). Additionally, albendazole is effective in cestode infections such as cysticercosis and echinococcosis (hydatid disease) and tissue nematode infections. Albendazole rapidly undergoes extensive first-pass metabolism in the liver and is generally not detected in the plasma. Albendazole sulfoxide is the primary metabolite which is thought to be the active moiety in effectiveness against systemic infections. Formation of albendazole sulfoxide is stereoselective with CYP3A4 involved in the formation of (-)- albendazole sulfoxide, whereas formation of (+)-albendazole sulfoxide is mediated by the flavine-containing monooxygenase system. CYP2C9 and CYP1A2 are also involved in albendazole and albendazole sulfoxide metabolism [13,14]. Albendazole sulfoxide appears to be principally eliminated in the bile with only a small proportion appearing in the urine.
Mebendazole also undergoes extensive first pass metabolism in the liver and both the parent drug and its amino and hydroxlated amino metabolites undergo enterohepatic circulation. This extensive liver metabolism and the poor solubility mean that bioavailablity is only 1–2% .
The interaction potential of both mebendazole and albendazole with emtricitabine, lamivudine, tenofovir, abacavir, didanosine, stavudine, maraviroc, raltegravir and rilpivirine is thought to be low although no formal pharmacokinetic studies exist.
Albendazole, and less frequently mebendazole have been shown to cause bone marrow suppression and may increase the risk of haematological toxicity associated with zidovudine. This is of particular concern in patients with liver disease including echinococcosis who are already at higher risk of pancytopaenia, agranulocytosis and leukopenia. There is a single case report of an HIV-infected patient with alveolar echinococcosis who developed pancytopaenia with haemoglobin of 5.8 mg/dl, thrombocytopenia and neutropenia when albendazole at a dose of 400 mg twice daily was added to his regimen of zidovudine, lamivudine and nelfinavir. The patient's regimen was changed to stavudine, abacavir and lopinavir boosted with ritonavir for HIV, and mebendazole for echinococcosis. Therapeutic drug monitoring of mebendazole then showed that therapeutic concentrations of mebendazole were achieved with one-tenth of the normal dose of mebendazole . Hence caution is advised when administering mebendazole and by inference albendazole to patients receiving CYP3A4-inhibiting drugs such as the HIV protease inhibitors.
Ritonavir has the potential to reduce plasma concentrations of the active metabolite of albendazole . In two sequential studies, healthy male volunteers were administered either a single oral dose of 400 mg of albendazole or 1000 mg of mebendazole. After short-term (2 weeks) and long-term (8 days) treatment with ritonavir 200 mg twice daily, pharmacokinetic parameters of albendazole and its metabolite were not changed by short-term administration of ritonavir. Long-term administration resulted in significant decrease in albendazole and albendazole sulfoxide area under curve (AUC) (73 and 59%, respectively) and C max (74 and 48%, respectively). A trend towards an increase in mebendazole exposure after short-term intake of ritonavir was seen but long-term administration resulted in a significant decrease in mebendazole AUC (57%) and C max (59%). These reductions for both albendazole and mebenazole are most likely due to ritonavir mediated induction of metabolizing enzymes (CYP2C9, CYP1A2, UGT) or transporters although changes in absorption are possible . The clinical significance of this is unknown but may result in decreased efficacy especially in the treatment of systemic helminthiasis. Further studies are needed especially with commonly prescribed protease inhibitor regimens such as ritonavir boosted lopinavir.
Phenytoin, carbamazepine and phenobarbitone appear to induce the oxidative metabolism of albendazole . Whereas there are no data on the interaction between albendazole or mebendazole and efavirenz, etravirine, nevirapine, an interaction cannot be excluded in view of their CYP3A-inducing properties and should be formally evaluated.
Triclabendazole is used to treat fluke infections such as fascioliasis, where praziquantel is ineffective, and paragonimiasis. There are no data on interactions between antiretroviral drugs and triclabendazole. In vivo, triclabendazole is rapidly oxidized to its sole oxide metabolite  and there is low potential for interactions with nucleoside reverse transcriptase inhibitors or raltegravir. Coadministration of triclabendazole and protease inhibitors, NNRTIs and maraviroc may result in increased levels of the antiretroviral drugs, as triclabendazole has been found to inhibit metabolism mediated by CYP3A4. There is potential for protease inhibitors to increase levels of triclabendazole via enzyme inhibition, but due to the short-term dosing of triclabendazole, this is unlikely to be clinically relevant. NNRTIs may reduce exposure to triclabendazole and therefore potentially reduce its efficacy.
Benznidazole and nifurtimox
Benznidazole and nifurtimox are used in the treatment of Trypanosoma cruzi infection (Chagas’ disease). Oral benznidazole and nifurtimox are well absorbed and are rapidly and extensively metabolized, with minimal renal elimination of unchanged drug [20,21]. Both benznidazole and nifurtimox are thought to undergo NADPH-dependent nitroreductive metabolic biotransformation; however, the mechanisms are not well understood [22–25]. Data are lacking to predict whether pharmacokinetic interactions will occur between benznidazole or nifurtimox and antiretrovirals. Clinicians should therefore use such combinations with caution.
The most severe adverse effects of benznidazole are bone marrow depression, thrombocytopenic purpura and agranulocytosis . Caution should therefore be exercised when administering benznidazole with zidovudine.
Clofazimine is used in multidrug regimens for the treatment of multibacillary leprosy. Information on the metabolism of this drug is limited. Three metabolites have been identified in urine and unchanged clofazimine is excreted via the bile . Available data suggest limited potential for interactions between clofazimine and any of the antiretroviral drugs with the exception of the buffered formulation of didanosine. A healthy volunteer cross-over study demonstrated that an aluminium magnesium antacid decreased clofazimine bioavailability by 22% . No interaction is expected with the more commonly used enteric-coated capsule didanosine formulation.
Dapsone is used as part of multidrug regimens in the treatment of all forms of leprosy, and also for prophylaxis of pneumocystis pneumonia in patients with HIV. Due to minimal excretion of unchanged drug via the kidneys, there is negligible potential for interactions between dapsone and renally excreted nucleoside reverse transcriptase inhibitors (NRTIs) via competition for renal elimination pathways. Dapsone is metabolized mainly by N-acetylation with a component of N-hydroxylation, and via multiple CYP P450 enzymes including CYP3A4, CYP2C9, CYP2D6, 2C8 and 2C19 . Clinically significant interactions via modulation of CYP450 enzymes by antiretrovirals are therefore unlikely, but cannot be excluded. Although specific studies have not been performed, the manufacturer of saquinavir advises that co-administration of saquinavir/ritonavir with dapsone may result in elevated dapsone plasma concentrations, and that this combination should be given with caution. It is recommended that regular blood counts are performed during treatment with dapsone, and that it is used with caution in anaemia. Care should therefore be taken when co-administering with zidovudine, due to its myelosuppressive potential.
Diethylcarbamazine is used to treat lymphatic filariasis, and can also be used in loiasis and toxocariasis. It is readily absorbed through the gastrointestinal tract, skin and conjunctiva and is excreted unchanged and as the N-oxide in the urine . There is limited potential for drug interactions based on available data on the metabolism of this drug, although no formal trials with antiretroviral drugs have been conducted.
Eflornithine is used intravenously to treat African trypanosomiasis due to Trypanosoma brucei gambiense (sleeping sickness). Approximately 80% of an oral or intravenous dose of eflornithine is excreted unchanged via the kidneys . As there are no data available to determine whether excretion is via active tubular secretion or glomerular filtration, there is potential for competition with tenofovir, lamivudine, emtricitabine or stavudine for active renal transport mechanisms, which may lead to increased levels of either drug. Rilpivirine can inhibit the active renal tubular secretion of creatinine, and may increase exposure to drugs eliminated via this pathway, vigilance is therefore warranted if administering with eflornithine.
Intravenous or oral eflornithine treatment commonly causes myelosuppression that may lead to anaemia, leucopenia and thrombocytopenia. Anaemia, neutropenia and leucopenia can be expected to occur in patients receiving zidovudine, so if concomitant treatment is necessary, then monitoring of haematological parameters is advised.
Ivermectin is used to treat lymphatic filariasis and also onchocerciasis (‘river blindness’). It is metabolized in the liver and the parent drug and metabolites are excreted almost exclusively in the faeces. In-vitro data show that ivermectin is primarily metabolized by CYP3A  suggesting the theoretical possibility of interactions with protease inhibitors, which may increase ivermectin levels, and NNRTIs, which may potentially decrease ivermectin levels, although the clinical significance of this is unknown.
Melarsoprol is effective in the treatment of all stages of African trypanosomiasis due to T.b. gambiense or T. brucei rhodesiense, but is usually reserved for stages of disease with central nervous system (CNS) involvement, due to its toxicity. The pharmacokinetics of melarsoprol have not been fully evaluated, and administration of melarsoprol with antiretrovirals has not been investigated. Melarsoprol is a prodrug and is rapidly metabolized to the active form, melarsen oxide . Melarsoprol has a plasma half-life of 30 min and is excreted in the faeces and urine. In-vitro studies suggest that melarsen oxide may be formed by hydrolysis, and not only in liver microsomal reactions . A clinical study investigating urinary arsenic clearance and toxicity found that urinary pharmacokinetic parameters are not predictive of toxicity or therapeutic efficacy . Based on limited data concerning metabolism, elimination and toxicity, there is little potential for interaction with antiretrovirals.
The pentavalent antimonials meglumine antimoniate and sodium stibogluconate are used in the treatment of leishmaniasis including cutaneous, visceral and mucocutaneous forms. The pentavalent antimony compounds are poorly absorbed orally but are rapidly distributed by the parenteral route. Elimination occurs in two phases: a rapid elimination phase in which the majority is excreted via the kidneys and a slower phase possibly reflecting reduction to the trivalent antimony. There is little potential for competition for renal clearance of meglumine when coadministered with emtricitabine, lamivudine or tenofovir, as elimination occurs via glomerular filtration with no significant active transport [33,34]. However, renal impairment and sometimes fatal renal failure have been described with meglumine antimoniate treatment, and monitoring of renal function is warranted [35–37]. Cardiotoxicity including QTc interval prolongation and torsades de pointes have been observed during meglumine administration [38–42]. Coadministration with other drugs known to increase the risk of cardiotoxicity should be performed under caution. The manufacturer of saquinavir states that co-administration of ritonavir-boosted saquinavir and other medication which may prolong the QT interval is contraindicated.
Ritonavir is also associated with PR interval prolongation in healthy volunteers and heart block has occurred in patients with underlying structural heart disease who were receiving medicinal agents known to prolong the PR interval [43,44]. For patients taking protease inhibitors, it may be advisable to switch to another third agent for the duration of meglumine treatment, for example raltegravir. Rilpivirine has been associated with QTc prolongation at supra-therapeutic doses of 75 to 300 mg daily. Cardiotoxicity has not been observed at the recommended doses of rilpivirine of 25 mg daily and hence can be used with caution with medicinal products known to cause torsades de pointes.
Pancreatitis is a relatively common serious adverse effect of pentavalent antimonials [35,36] and since it is also described with didanosine, ritonavir-boosted lopinavir and stavudine; meglumine should only be used with extreme caution in these patients.
Parenteral pentamidine is used in the treatment of early African trypanosomiasis due to T.b. gambiense, but is not effective in cases with CNS involvement. It may also be used in visceral leishmaniasis, and mucocutaneous leishmaniasis due to Leishmania braziliensis or L. aethiopica that has not responded to antimonials. Pentamidine is predominantly metabolized via CYP1A1 , with minimal renal elimination of unchanged drug. Pentamidine is well known for its allergic reactions but also has toxic effects. It is both hepatotoxic and nephrotoxic and anecdotal evidence suggests that it should be used with extreme caution in combination with other nephrotoxic drugs such as aminoglycoside antibiotics. This caution extends to many antiretrovirals such as tenofovir, which can also affect renal function, and the renally excreted NRTIs. It has frequently been used as an inhaled formulation in HIV patients in the developed world for treatment of pneumocystic carinii pneumonia associated with HIV, however adverse effects are frequent and sometimes severe when it is given parenterally and toxicity is more common in patients with AIDS . Pentamidine can also cause thrombocytopenia and leucopenia and as such should be used cautiously in combination with zidovudine. Fatalities due to pancreatitis have been reported with pentamidine use; therefore caution must be exercised if co-administering stavudine or didanosine, as risk of pancreatitis may be increased. Likewise, hepatotoxicity has been reported, and the manufacturers advise liver function monitoring every 3–5 days in patients taking other potentially hepatotoxic drugs; this may be warranted in patients taking stavudine, didanosine or nevirapine.
In addition, pentamidine may cause arrhythmias and as such should be used cautiously with ritonavir, some protease inhibitors such as lopinavir/ritonavir and rilpivirine.
Paromomycin is used parenterally in visceral leishmaniasis, and can also be used for intestinal protozoal infections such as giardiasis. Paromomycin is not metabolized in vivo and is excreted unchanged in the urine . There is little potential for interaction via competition for active renal elimination pathways; however, aminoglycosides as a class have an inherent potential for causing nephrotoxicity . Concurrent or sequential use of other potentially nephrotoxic drugs should be avoided because of the possibility of additive toxicity. Since paromomycin may also result in pancreatitis ; extreme care is advised when coadministering paromomycin with drugs associated with pancreatitis such as stavudine or didanosine-containing regimens. Paromomycin is also used in the treatment of intestinal protozoal infections, including amoebiasis, cryptosporidiosis and giardiasis. It should be noted that in patients with chronic gastrointestinal infection, absorption of antiretroviral drugs may be significantly impaired.
Praziquantel is used to treat schistosomiasis, and is also effective in treatment of fluke infections and tapeworm infection, including neurocysticercosis. Praziquantel is metabolized by CYP3A4, CYP1A2 and CYP2C19  and as such there is limited potential for interaction with the nucleoside reverse transcriptase inhibitors, maraviroc, raltegravir or rilpivirine. Available data show that known enzyme inducers carbamazepine, phenytoin and rifampicin reduce plasma praziquantel levels [47,48]. In the absence of interaction data with NNRTIs, metabolism and elimination data suggest the possibility of an interaction between praziquantel and NNRTIs, which may reduce concentrations of praziquantel. Single doses of praziquantel in patients on NNRTIs may have reduced efficacy, and clinical vigilance for treatment failure is advised. Data from a crossover healthy volunteer study with ketoconazole showed that praziquantel exposure doubled in the presence of ketoconazole . Therefore interactions are possible between praziquantel and the boosted protease inhibitors via enzyme inhibition, which may increase levels of praziquantel; however, no clinical data are available.
Pyrantel may be used to treat soil-transmitted helminth infection, including mixed or single infections with intestinal nematodes including roundworms (Ascaris lumbricoides), threadworms or pinworms (Enterobius vermicularis), and Trichostrongylus spp., the tissue nematode Trichinella spiralis, and hookworms. Pyrantel is metabolized by CYP2D6 in vitro , however only a very small proportion of pyrantel embonate is absorbed from the gastrointestinal tract  and therefore there is limited potential for interactions.
Sodium stibogluconate is excreted rapidly via the kidneys. Renal elimination of this drug is similar to the rate of glomerular filtration [50,51], therefore there is limited potential for interaction with emtricitabine, lamivudine or tenofovir via competition for active renal transport. Pancreatitis has been described as a relatively common serious adverse effect of sodium stibogluconate [52–54] and it should therefore be used with extreme caution in patients taking stavudine, didanosine and ritonavir-containing regimens. Similar to meglumine antimonate, sodium stibogluconate is associated with QTc prolongation and torsades de pointes [55–57]. Hence ritonavir-boosted saquinavir is contraindicated and caution is advised in patients on other ritonavir-boosted regimens or rilpivirine. Sodium stibogluconate has been reported to cause haematological suppression in 44% of patients [52,53]: hence caution is advised in patients taking zidovudine.
Suramin is used in the treatment of African trypanosomiasis and also may be used as an anthelmintic in the treatment of onchocerciasis. Suramin is predominantly eliminated unchanged by the kidneys  which limits its potential interaction with the protease inhibitors and NNRTIs. However, there is a possibility of competition for renal elimination with emtricitabine, lamivudine or tenofovir. Suramin is associated with myelosuppresssion and may increase the risks of adverse reactions with zidovudine.
Neglected tropical diseases are neglected by virtue of their geographic distribution in the poorest communities rather than any lack of importance in terms of burden of disease and human suffering. As such they are an uncomfortable testament to contemporary inequity in global health which has prompted the WHO 2020 Roadmap and 2012 London Declaration on NTDs. From this review it is clear that these diseases are additionally neglected from the perspective of clinical pharmacology as only two studies were identified evaluating drug interactions between antiretroviral drugs and drugs for the treatment of NTDs, and these were conducted in healthy volunteers rather than in the relevant patient population. In the absence of formal drug interaction studies, we utilized what knowledge was available on the clinical and preclinical pharmacology of these drugs to make recommendations in this article and we acknowledge the limitation of this approach. Pharmacokinetics may differ considerably between healthy volunteers, HIV-positive patients and people suffering from NTDs who may have different diet, absorption and nutritional status. Protein levels and alpha1 acid glycoprotein levels may differ, in addition to differences in key drug disposition genes from their healthy volunteer counterparts. Additionally these patients may be suffering from more than one NTD in addition to HIV. Due to the extensive geographic overlap and co-endemicity of these diseases, efforts to expand global access to drugs will likely aim to integrate treatment programs via harmonization and coordination of the partnerships involved in control or elimination of the most prevalent NTDs and linking them with national health ministries and the WHO . Therefore, there is potential for complex interactions between multiple drugs which are difficult to predict in the absence of data from specific pharmacokinetic studies.
Clinical pharmacology research in the area of NTDs is clearly needed and should ideally address treatment regimens for both mass treatment programmes and management of acute infections which may differ in terms of dosing or duration of drugs. In the interim strengthening pharmacovigilance may yield helpful data and is extremely important in view of the possibility of serious adverse events with pancreatitis and cardiac toxicity. Case reports are also valuable and formed a significant part of the evidence base for this review.
Unfortunately it is more difficult to capture therapeutic failure due to drug–drug interactions as this treatment failure does not fall under the purview of traditional pharmacovigilance and sadly is often accepted in the communities affected by these diseases as the inevitable consequences of the infections themselves.
We recognize the clear humanitarian imperative to make drugs widely available to those populations who need them most, yet can afford these agents least. However, alongside this must also run an ethical imperative, to ensure that treatment is both safe, effective and management of drug–drug interaction with antiretrovirals is evidence-based. A series of well designed relatively inexpensive pharmacokinetic studies in the affected populations could bring excellence in prescribing and quality assurance to the populations who most need it, and thereby ensure that the good intentions of the donors and policy makers translate into ‘healthier and more productive lives’.
K.S. undertook the literature search, C.M. and K.S. wrote the manuscript, S.K., D.B., M.L., P.B.-K., N.P. and J.M. made significant contribution to the content and writing of the manuscript.
Conflicts of interest
We acknowledge support from a Wellcome Trust Programme Grant award: PK-PD modelling to optimize treatment for HIV, TB and malaria. (ref 083851/Z/07/Z).
M.L. and P.B. are supported by European and Developing Countries Clinical Trials Partnership grants (TA.09.40200.020 and TA.11.40200.047).
Transparency Declaration: D.J.B. and S.H.K. have received research funding for development of the web site http://www.hiv-druginteractions.org from Viiv, BMS, Gilead, Janssen, Merck, Boehringer-Ingelheim. DJB has received honoria for lectures or Advisory Boards from Viiv, BMS, Gilead, Janssen, Merck.
M.L. has received grants from Janssen and is supported by the Sewankambo scholarship at IDI which is funded by Gilead Foundation.
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Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
drug interactions; HIV/AIDS; neglected tropical diseases; pharmacokinetics