Drug–Drug Interactions Between Antiretrovirals and Drugs Used in the Management of Neglected Tropical Diseases

Important Considerations in the WHO 2020 Roadmap and London Declaration on Neglected Tropical Diseases

Kay Seden; Saye Khoo; David Back; Natalie Prevatt; Mohammed Lamorde; Pauline Byakika-Kibwika; Jonathan Mayito; Mairin Ryan; Concepta Merry

Disclosures

AIDS. 2013;27(5):675-686. 

In This Article

Abstract and Introduction

Abstract

The group of infections known as the neglected tropical diseases (NTDs) collectively affect one billion people worldwide, equivalent to one-sixth of the world's population. The NTDs cause severe physical and emotional morbidity, and have a profound effect on cycles of poverty; it is estimated that NTDs account for 534 000 deaths per year. NTDs such as soil-transmitted helminth infections and the vector-borne protozoal infections leishmaniasis and trypanosomiasis occur predominantly in the most economically disadvantaged and marginalized communities. It is estimated that all low-income countries harbour at least five of the NTDs simultaneously. NTDs are neglected because they do not individually rank highly in terms of mortality data, and because they affect populations with little political voice. There is considerable geographic overlap between areas with high prevalence of NTDs and HIV, raising the possibility of complex polypharmacy and drug–drug interactions. Antiretrovirals pose a particularly high risk for potential drug–drug interactions, which may be pharmacokinetic or pharmacodynamic in nature and can result in raising or lowering plasma or tissue concentrations of co-prescribed drugs. Elevated drug concentrations may be associated with drug toxicity and lower drug concentrations may be associated with therapeutic failure. The aim of this paper is to review the currently available data on interactions between antiretrovirals 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, and to support the recent WHO 2020 Roadmap and the 2012 London Declaration on NTDs.

Introduction

The WHO 2020 Roadmap on neglected tropical diseases (NTDs) and the 2012 London Declaration on NTDs aim to 'enable more than a billion people suffering from neglected tropical diseases to lead healthier and more productive lives' and 'chart a new course towards health and sustainability'. Two out of the five strategies for the prevention, control, elimination and eradication of NTDs set out in the WHO 2020 Roadmap involve sustaining and expanding existing drug donation programs to meet demand through to 2020. To this end, the governments of the US, UK and United Arab Emirates, the World Bank and the Bill and Melinda Gates Foundation along with 13 pharmaceutical companies, have announced the largest collaborative effort to date to combat NTDs.

The NTDs (Table 1) cause severe physical, emotional and mental morbidity and have a profound effect on cycles of poverty. They are neglected because they do not individually rank highly in terms of mortality data, and because they affect populations with little political voice and do not travel well to the western world. The NTDs collectively affect one billion people; equivalent to one-sixth of the world's population. Though often described as causing morbidity rather than mortality, it is estimated that NTDs account for 534 000 deaths per year.[1] NTDs occur predominantly in the most economically disadvantaged, marginalized and vulnerable communities and it is estimated that all the low-income countries harbour at least five of the NTDs simultaneously.[2]

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.

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