The potential for interactions between antimalarial and antiretroviral drugs

Introduction The rapid increase in access to antiretroviral therapy in developing countries has brought with it new challenges. These include the unprecedented need for lifelong treatment for an infectious disease, and the pressure this will place on health services. The use of fixed dose combinations from generic manufacturers does not easily allow for individualization of dosage (e.g. with coadministered drugs for tuberculosis). Gaps in current knowledge that urgently need to be addressed are the effect of ethnicity, gender and body weight upon antiretroviral drug disposition, and defining interactions with other drugs, including antimalarial and antituberculosis drugs and traditional medicines. Malaria is widespread across areas of the world where resources are limited, and most of these areas also bear the brunt of the HIV pandemic. There are potentially many different ways in which both diseases interact, at political, social and public health levels, as well as emerging evidence for how one disease may affect the pathogenesis and outcome of the other. At a time when access to antiretroviral drugs is increasing, and new combinations of antimalarial drugs are being evaluated, it is important that potential interactions between therapies for these two infections are also reviewed. Pharmacology of antiretroviral drugs That antiretroviral drugs have the ability to prolong survival and improve well-being of HIV-positive individuals is beyond question; yet their therapeutic effects may be limited by toxicity, pill burden, the need for strict adherence to treatment, emerging prevalence of resistance and the risk of developing adverse drug interactions. At least 19 drugs from three classes – nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI), are available for the oral treatment of HIV infection. Fusion inhibitors (enfuvirtide) are an additional class of parenterally administered drug. For most countries in Africa, preferred combinations are represented by the four ‘3 by 5’ regimens, which are made up of 2NRTI [zidovudine (ZDV) or stavudine (d4T) plus lamivudine (3TC)] plus an NNRTI [nevirapine (NVP) or efavirenz (EFV)]. Problems of cost, shelf life, storage and toxicity of PI drugs currently limits their availability and use, even with generic manufacture or discounting through United Nations drug-access initiatives. However, the emergence of NNRTI resistance will limit the useful therapeutic lifespan of NNRTI, and the use of PI in developing countries (currently available in many private clinics) is likely to grow. The pharmacology of antiretroviral drugs will be familiar to most readers and has been detailed in previous issues of this journal [1]. A summary is provided for those unfamiliar with this topic (Table 1).Table 1: Pharmacokinetics of antimalarial and anti-HIV drugs.Table 1: (Continued)Absorption NRTI [with the exception of didanosine (ddI)] and NNRTI are well absorbed. The absorption of PI drugs is improved with food, and this is especially important for nelfinavir where drug exposure is almost twice that when taken fasting. The absorption of PI is limited by metabolic degradation by cytochrome P450 enzymes (mainly the CYP 3A4 isoform) within the gut as well as the presence of drug efflux transporters (e.g. P-glycoprotein). Ritinavir (RTV) may be used to ‘boost’ the bioavailability of other PI such as saquinavir (SQV) or lopinavir (LPV), mainly through inhibition of gut CYP 3A4. Distribution Since HIV replicates within cells, drugs that target its replication must penetrate into infected cells and anatomical compartments such as the CNS and genital tract at sufficiently high concentrations to exert their effect; failure to do so results in the establishment of a sanctuary site. The tissue and intracellular accumulation of HIV drugs is determined primarily by their physicochemical characteristics (e.g., lipophilicity, charge), by the extent of protein binding and probably by the influence of active transport (mediated by transporters such as P-glycoprotein, multidrug resistance proteins 1 and 2) [2]. Metabolism and elimination PI drugs are extensively metabolized by cytochrome P450 enzymes, most notably the isoform CYP 3A4. In the case of nelfinavir, CYP 2C19 is also involved in the formation of the active M8 metabolite. PI have short plasma elimination half-lives (generally ≤8 h), even with RTV boosting. Excretion is mainly via the liver for all PI, with the exception of indinavir (IDV), which is also excreted by the kidney. RTV boosting reduces the hepatic clearance of IDV, amprenavir, fosamprenavir and atazanavir by inhibiting hepatic metabolism, and thereby increasing plasma concentrations of these drugs. NNRTI drugs are metabolized by CYP 3A4 and CYP 2B6. The latter may be important when considering ethnic variability in pharmacokinetics (see below). EFV and NVP have long elimination half-lives (30–35 h) than delavirdine (6 h), which is seldom used. NNRTI are excreted via the liver. The NRTI must also undergo phosphorylation once inside cells to produce the active metabolites. There is a disparity between the plasma elimination half-lives of NRTI, which lie in the range 2–6 h, and those of the active intracellular phosphorylated metabolites, which are far longer [ZDV, 7 h; 3TC, 17 h; abacavir (ABC), 22 h; ddI, 30 h; emtricitabine, 40 h; and tenofovir, ∼60 h] and which correlate moderately or poorly with plasma concentrations of parent drug. Tenofovir, ddI, d4T and 3TC are excreted largely unchanged by the kidney; ZDV is excreted via the liver, mainly through glucoronidation. Drug transporters in the kidney and biliary tract almost certainly play an important role in the elimination of antiretroviral drugs but these have not yet been fully characterized. Toxicity The major toxicities of NRTI include rash, lactic acidosis and mitochondrial dysfunction (through inhibition of DNA polymerase γ), neuropathy (ddI, d4T, 3TC, zalcitabine), pancreatitis (ddI), anaemia/neutropenia (ZDV) and myositis (ZDV). ABC is associated with a systemic hypersensitivity reaction, which may be severe (affecting 4–8% of patients). NVP and EFV may cause hepatotoxicity [3]. NVP may also be associated with a systemic hypersensitivity syndrome comprising fever, rash, myalgia and hepatotoxicity. NVP hypersensitivity/hepatotoxicity is associated with female gender and immune status, and women with CD4 cell count >250 × 106 cells/l appear to be at highest risk. Preexisting liver dysfunction (such as that in chronic viral hepatitis) is also an important risk factor for drug-induced hepatotoxicity. There is some crossover in hypersensitivity between NVP and EFV. EFV is associated with CNS symptoms such as dizziness, poor sleep and bad dreams; animal reproductive toxicology studies have suggested the potential for teratogenesis. PI drugs are associated with diarrhoea and gastrointestinal disturbance, hepatotoxicity, nephrolithiasis (IDV), elevated lipids, glucose intolerance and body fat changes. Other recognized toxicities include osteopenia, osteoporosis and avascular necrosis. Interindividual variability and effect of gender, weight and ethnicity Huge (over 50-fold) variability has been observed for PI and NNRTI [4], and large variability has also been reported for intracellular active NRTI metabolites [5]. The causes of this variability are probably multifactorial and include adherence, drug interactions, body weight, gender and drug absorption. In both the Dutch [6] and UK (unpublished data) therapeutic drug monitoring schemes, women tend to have higher plasma concentrations (and are more likely to have ‘toxic’ drug concentrations) of EFV and NVP than men. In addition, we have observed differences in LPV exposure according to gender and body weight [7], and one study has recently reported higher peak concentrations of IDV in Thai subjects, suggesting that individuals with very low body weight may be predisposed to IDV nephrotoxicity [8]. Ethnic differences owing to genetic variability may also play a role. Black Africans have been found to have lower EFV clearance (and consequently higher plasma concentrations), possibly as a result of polymorphisms in drug-metabolizing enzymes such as CYP 2B6 [9,10]. One study measuring intracellular concentrations of ZDV trisphosphate observed no difference between Thai and Caucasian subjects [11]. Gender differences have been reported in formation of the intracellular drug trisphosphates of ZDV and 3TC [5]. Ethnic and gender differences have also been observed for drug toxicity. Lipodystrophy and ABC hypersensitivity appear to be less common in African-Americans than in Caucasians, and certain MHC haplotypes and HSP70 have been associated with ABC reactions [12]). Women have a higher risk of developing lipodystrophy and NVP hypersensitivity. Potential for drug interactions with antiretroviral drugs Detailed discussion of individual drug interactions involving HIV drugs is not within the scope of this article but may be found elsewhere (e.g., www.hiv-druginteractions.org). Most clinically significant drug interactions involve PI (inhibition of P450 enzymes) and to a lesser degree NNRTI (induction and/or inhibition of P450 enzymes). Since P450 enzymes (in particular CYP 3A4) are central to the metabolism of a broad array of drugs including antituberculosis drugs, anticonvulsants, antihistamines, macrolides, azole antifungal drugs, antiarrhythmic drugs, opiates and statins, the capacity for important (and potentially dangerous) drug interactions needs to considered when prescribing these drugs. Other important interactions not involving P450 enzymes include acid-modifying drugs (such as the histamine H2 receptor antagonists, proton pump inhibitors), which impair the absorption of IDV, atazanavir and fosamprenavir. In contrast, NRTI have fewer interactions. Most of these are intracellular drug activations between drugs of this class or with other nucleoside analogues such as ribavirin, hydroxyurea and mycophenolic acid. One important finding is that tenofovir significantly reduces plasma concentrations of atazanavir. Pharmacology of antimalarial drugs Drug discovery in malaria has, by and large, been serendipitous. Mechanisms of action are still incompletely understood and have only been properly studied subsequent to long-term use [13]. A number of mechanisms are known to be involved. Haemoglobin digestion in the food vacuole. Chloroquine [14], amodiaquine, quinine and mefloquine all interfere with this essential process. The folate pathway. Sulfadoxine–pyrimethamine and the newer combination chlorproguanil–dapsone are competitive inhibitors of key enzymes in the folate pathway. High folate concentrations probably oppose the effects of this drug group in vivo[15], whereas some additivity with trimethoprim–sulfamethoxazole may be expected. Alkylating agents: the artemisinin derivatives. It is thought that breakdown of a labile peroxide bridge within the sesquiterpene lactone artemisinin molecule generates free radicals that rapidly alkylate key parasite molecules [16]. Haemazoin probably catalyses the decomposition of these drugs, which may explain the large therapeutic index of the drug group. Sensitivity to the artemisinins may be declining in parts of China, but resistance Plasmodium falciparum is not yet a major problem. In contrast to other antimalarial drug groups, the artemisinins have marked effects on the circulating forms of the parasite, the viability of which decline soon after the start of treatment. The artemisinins have gametocytocidal effects on P. falciparum, and this may help to reduce transmission. Mitochondrial function. Atovaquone works by inhibition of cytochrome c reductase, which may be the basis of its synergy with the prodrug proguanil. Unfortunately, the parasite readily develops resistance to atovaquone. The apicoplast. The antibiotics (including tetracyclines) interfere with protein translation at this site [17]. The 4-aminoquinolines Chloroquine is probably still the most widely used antimalarial drug in Africa. The extensive spread of resistance has severely limited its usefulness for falciparum malaria, although it remains effective for Plasmodium ovale, Plasmodium malariae and most cases of Plasmodium vivax infection. Chloroquine is rapidly absorbed from the gut and from intramuscular or subcutaneous injections [18]. Approximately half of the absorbed chloroquine is cleared unchanged by the kidney, the being in the liver to and clearance is in it is not to reduce the The elimination is very long Chloroquine is well but adverse are including dizziness, and in of the and effects include of of the and Chloroquine when it may cause In contrast to is extensively to its which is for most of the antimalarial higher concentrations than its parent drug has an important role in reactions is no longer for of and but it may be used for treatment where the risk is considered to be is used in parts of at a of The The are used in fixed Sulfadoxine–pyrimethamine is currently the drug for falciparum malaria in many parts of Africa. resistance to this combination is is well absorbed after oral or intramuscular which only be peak plasma concentrations in and has a short elimination most of the antimalarial results from its The extent of metabolism metabolism is by the cytochrome P450 group (mainly CYP which is to genetic of low or concentrations of but have to in such and are well and less to reactions than or the and only and have been widely used in malaria The elimination of is limited metabolism the and The degree of between as a result of a genetic reactions to are well in the case of drugs such reactions be has a of and is associated with a range of and adverse However, a large of chlorproguanil–dapsone reported the combination to be and well The and are in common may be used parenterally for severe malaria For malaria, are in combination with other drugs this the of treatment. public health are upon this drug with as the only combination widely and its (such as and are rapidly in to a active parent drugs and are rapidly The role of other metabolites in The of is so rapid that it may be considered a prodrug for is also in use as a drug and is being in combination with are and well The current on reproductive with effects reported from and of long in some animal It that the extensive use of artemisinins in large of individuals from and has been and on from the have no evidence of adverse are being The has that the artemisinins be for treatment of malaria in the not be are for the and only be used in when other are considered It be that malaria in be and that no antimalarial drug is free from reproductive The is less than chloroquine and has a therapeutic range but resistance is in Africa. quinine is the drug of for severe malaria, and oral quinine is an for malaria where multidrug resistance is a problem. is extensively to plasma to the In subjects, of the plasma quinine is but in with malaria, concentrations and is this may explain the lower toxicity of high quinine concentrations in with malaria with that in have taken a extensive hepatic and less than of the drug is excreted unchanged in The elimination of quinine is in health h), longer in with malaria h) and still in with malaria and is common at therapeutic of quinine and does not dose but potentially adverse are hypersensitivity reactions and which has with is widely used in with an limits its use in Africa. drug is very the from to and (in the of is after adverse reactions are and most gastrointestinal CNS including are to in 1 in which is the reported as The of CNS (including dizziness, and between and (and is higher in than these are to those for but higher than reported by no use the risk of and be and is seldom used of toxicity, but is only in combination with for the treatment of falciparum is incompletely from the gut and this may is by with It is with a of is well does not to prolong the There are that may affect but the of this to remains to be Other antimalarial drugs is used for treatment and of falciparum its it has to public health in most is an primarily used for of malaria by of P. vivax and P. in the liver. effects are and (in with of glucose and the have useful antimalarial are used but are most to quinine for oral this is most in areas of drug resistance (such as where clearance of with quinine may be interactions between antiretroviral and antimalarial drugs In interactions involve HIV PI and NNRTI PI are the most inhibitors of cytochrome P450 enzymes CYP CYP and for use in and their role in interactions is made more some PI also their metabolism (e.g. and other enzymes for drug PI may also the multidrug efflux These are when RTV is to other PI to bioavailability or to reduce hepatic clearance amprenavir, through inhibition of CYP 3A4 in the gut or liver, The NNRTI drugs NVP and EFV are of CYP delavirdine is an of CYP 3A4 (and has also been used to However, these to the high risk of drug interactions of which are potentially through the inhibition or of metabolism of a broad array of drugs which undergo hepatic or from studies interactions between antiretroviral and antimalarial drugs are and of the risk for drug interactions from knowledge of the pharmacokinetics of these drugs, or more from in In the of a risk of potential drug interactions involving antiretroviral and antimalarial drugs is in drug interactions between antimalarial and antiretroviral are and are to by number in is extensively metabolized by CYP 3A4. be by RTV or PI regimens, and by of CYP 3A4 by NVP and EFV reduce plasma quinine Since is a prodrug and is to is that inhibition of metabolism by RTV or PI will reduce However, synergy with is to not the drugs are CYP 2C19 inhibition potentially this which may Metabolism of is mainly by with a of via CYP P450 significant interactions are but be effect on RTV no after a dose but plasma the by and plasma concentrations by after Pharmacokinetics of mefloquine not significantly by RTV A case has observed no drug between IDV or nelfinavir and mefloquine is metabolized via CYP 3A4 to both have antimalarial has of CYP 3A4 reduce but increase and potentially increase the short of The effects of PI and NNRTI are and are extensively metabolized by CYP 3A4. of metabolism potentially prolong the therapeutic index of this combination with PI is and NVP and EFV be used with does not to prolong the and is than interactions with PI and NNRTI drugs are and the of that of CYP 3A4 inhibitors such as PI are the increasing use of for malaria, we when The need for is and studies be to this in Atovaquone IDV plasma concentrations by A study observed an of for IDV but an increase in of and of when the drugs coadministered dosage are for when with The of IDV concentrations is these studies RTV boosting is no longer the preferred of studies have higher plasma IDV in Thai have lower body the toxicity of IDV at higher dosage are not for IDV with when with or LPV may plasma concentrations of atovaquone. The of this is not in dosage may be Atovaquone the oral clearance of to a increase in its plasma The of this is not and no dose is of in some cases to failure of for has been observed with newer interactions between antiretroviral and antimalarial drugs interactions between malaria and HIV interactions between malaria and HIV have been in from have reported an increase in the prevalence of P. falciparum in with HIV women with falciparum malaria have parasite in and and are at risk of fever, severe and adverse than risk is highest in HIV is subsequent in HIV-positive women HIV also associated with malaria and from falciparum malaria in an of malaria in malaria to increase HIV viral although the of this are of antimalarial drugs Chloroquine and replication in does its possibly by inhibition of HIV In studies chloroquine in cells has some additivity with ZDV and synergy with some PI drugs in cell However, only anti-HIV has been observed for chloroquine and mefloquine and no for and significant synergy observed between mefloquine and the PI and between chloroquine and The of these is remains is that the antiretroviral effects of chloroquine are when with that of combination antiretroviral one study from no effect of chloroquine on HIV in of HIV-positive of the Plasmodium the presence of and that have key such as digestion of within the food vacuole. antimalarial PI drugs are being as new therapy for this disease, but knowledge of their site of action potential with 4-aminoquinolines such as or not HIV PI drugs antimalarial in or in is effects with and RTV at concentrations have been observed in although the high protein binding of these drugs in and of on their into cells that is to the of these The HIV PI drugs RTV and have been in to of a key receptor the of to the that HIV PI may disease of or not this finding is of in is not and malaria in have a effect of or trimethoprim–sulfamethoxazole in and in with and HIV disease by and study in in recently when significantly lower in the trimethoprim–sulfamethoxazole The widespread use of this combination may have for malaria as it has and malaria (and in areas of the world where resistance to is trimethoprim–sulfamethoxazole for in the for and reductase, up of resistance to and However, the of these resistance is with trimethoprim–sulfamethoxazole with that with will on of resistance and the of trimethoprim–sulfamethoxazole used. For lower or three all used or poor adherence to trimethoprim–sulfamethoxazole for falciparum and the for of resistance may be where a degree of parasite resistance still for resistance to drugs. However, such as have to a to in across It is important for to be in place to allow for drug resistance and in where trimethoprim–sulfamethoxazole treatment are and toxicity or toxicity may the in malaria and HIV and it to the malaria, HIV drug hypersensitivity such as that with ABC or NVP common finding in in may be HIV or by drugs (e.g. in with of glucose or malaria or be by ZDV or by including with HIV most antimalarial and anti-HIV drugs cause ABC lactic NRTI, malaria NNRTI, PI, NRTI, chronic malaria HIV dosage used for P. IDV, the prevalence of malaria and HIV in many parts of the knowledge of how these two important diseases is still by of knowledge in many key interactions between for these two diseases may but these are to be for and with PI or The between quinine and needs to be However, drug interactions only a very of the potentially number of ways in which HIV and malaria to the of of a to a on between HIV and