Drug Drug Interactions Review (WHO)

8/11/2019 Drug Drug Interactions Review (WHO)

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SYSTEMATIC REVIEW:

Drug-drug Interactions between Antiretrovirals and medications used to treatTB, Malaria, Hepatitis B&C and opioid dependence

SH Khoo1, S Gibbons1, K Seden2, DJ Back1

1 Department of Pharmacology, University of Liverpool, 70 Pembroke Place, Liverpool L693GF, UK

2 NIHR Biomedical Research Centre in Microbial Diseases, Royal Liverpool UniversityHospital, Prescott St, Liverpool L7 8XP, UK

+44 151 794 5560+44 151 794 5656 (fax)

Correspondence to [email protected]


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Table of Contents:

Page

1 Introduction 3

2 Methods 5

2.1 Search Strategy2.2 Study Selection2.3 Study Quality Assessment2.3.1 Strength of recommendation2.3.2 Grading of evidence2.4 Data Synthesis

3 Results 8

3.1 Antimalarials3.2 TB Drugs

3.3 Hepatitis B & C Treatment3.4 Opioid dependence

4 Discussion

5 Acknowledgements and Declarations

6 References

7 Appendix A Antimalarial Drugs

Appendix B Antituberculous Drugs

Appendix 3 Hepatitis B and C Treatment

Appendix 4 Drugs used in Opioid Dependence


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1 INTRODUCTIONDrug-drug interactions (DDIs) are an important and widely under-recognised source of medicationerrors, which represent significant risk of harm to patients and opportunity cost for healthcaresystems. The co-administration of contraindicated drugs has been found to account for 5.2% of

209 hospital admissions in the USA in patients receiving antiretrovirals (ARVs) [Rastegar et al,2006]. Although studies are limited, clinically significant DDIs involving ARVs are common,affecting at least 14-41% of patients in the US, the Netherlands and UK [Shah et al, 2007; de Maatet al, 2004; Cottle et al, 2009]. A substantial proportion of these have the potential for an adverseimpact on ARV exposure. Conversely, DDIs may result in increased exposure to ARVs or co-administered drugs, precipitating drug toxicity or greater severity and incidence of adversereactions. Data from developing countries are sparse, though it is likely that clinically significantDDIs are prevalent [Kigen et al, 2008].

DDIs may be pharmacokinetic or pharmacodynamic in nature. ARVs are among the mosttherapeutically risky drugs for DDIs, due to potent inhibition or induction of liver enzymes such asthe cytochrome P450 isoenzymes (CYP450), which metabolise a broad array of other medications.DDIs involving protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI)are more likely to be attributable to hepatic metabolic pathways than DDIs involving nucleoside or

nucleotide reverse transcriptase inhibitors (NRTI), which in some cases can be due to competitionfor renal tubular secretion. DDIs are more prevalent in regimens containing PIs than NNRTIs [Milleret al,2007; Cottle et al, 2009].

Although all patients receiving ARVs are potentially at risk of DDIs, this risk is increased in certainpatient groups and clinical scenarios:

1.1 Use of New HIV DrugsAssessment of the potential for DDIs during the clinical phase of drug development, althoughcomprehensively undertaken, is at best incomplete. Screening of a new molecular entity forpotential as a substrate, inducer or inhibitor of phase I and II metabolic enzymes and influx/effluxdrug transporters is limited by a lack of validated expression systems and standardised protocols,particularly for drug transporters.

It cannot be assumed that drugs from the same class have broadly similar potential for interaction.For example, the integrase inhibitors raltegravir and elvitegravir differ in metabolic pathways andinteraction potential with regard to cytochrome P450 enzymes. Further, raltegravir has significantinteractions with proton pump inhibitors as a result of physiochemical characteristics which lead topH-dependent solubility. In addition, there will always be surprises in the form of unanticipatedDDIs which emerge after licensing, and may lead to diminished therapeutic effect of ARVs, such aslopinavir and rosuvastatin. This highlights the need for standard protocols for interaction screeningof new drugs, as well as clinical vigilance as experience in their use develops.

1.2 Co-infections, particularly in the developing worldThroughout the world, HIV overlaps with other epidemics such as tuberculosis (TB), malaria andchronic viral hepatitis. TB is the leading cause of death among people living with HIV in Africa, andglobally 456,000 people died of HIV-associated TB in 2007. Difficulties in treating TB in HIVpatients may arise due to interactions with rifampicin which is a potent inducer of liver enzymes.

Several ARVs contraindicate the use of rifampicin and others may require dose modification. HIValso has a considerable impact on malaria, affecting parasitaemia, disease severity (in areas ofunstable transmission) and mortality during pregnancy. Drug interactions are understudied, butimportant interactions have already been identified between antiretrovirals and quinine,amodiaquine and lumefantrine.

Worldwide, an estimated two billion people have been infected with the hepatitis B virus (HBV),and more than 350 million have chronic (long-term) liver infections. An estimated 170 millionpersons are chronically infected with Hepatitis C (HCV) with 3 to 4 million persons are newly


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infected each year. Therapy for chronic HCV infection is set to dramatically change with theproliferation of new drugs directed against HCV polymerase, protease and other targets, andalthough data are sparse, interactions between HIV nucleoside reverse transcriptase inhibitors andPIs, and new or existing HCV drugs have been identified.

The inflexibility of dosing when using fixed-dose combinations of ARVs makes many DDIs harderto manage. ARV coverage in middle and low income countries has increased 45% between 2006

and December 2007 [UNAIDS, 2008], and with increasing coverage, it is likely that access to othermedication will also improve, for example various integrated programmes for neglected tropicaldiseases, which aim to combine mass drug administration for conditions such as helminthinfection. This inevitably increases the scope for DDIs.

1.3 Polypharmacy in an ageing populationThere are an increasing number of patients over 50 years living with HIV [Nguyen et al, 2008], inwhom chronic conditions associated with ageing may co-exist. These include cardiovascular drugs,lipid lowering agents, antihypertensives and analgesics. The use of non-prescribed medications inpatients taking ARV in Canada and the UK is widespread [Dhalla et al, 2006, Ladenheim et al,2008]. These include recreational or illicit drug use.

1.4 Decentralised models of careIn many healthcare settings, the provision of antiretroviral therapy is progressively devolving fromtertiary carein developing countries, this means the decentralisation of care to district level. Evenwith an intensive programme of training and education, practitioners with less expertise inprescribing of ARVs may be less likely to identify DDIs or recognise their adverse consequences.

1.5 Lack of monitoring in resource-poor settingsLack of pharmacovigilance structures, and laboratory monitoring coupled with the high backgroundof febrile and other illness may mask clinically significant DDIs in resource-poor settings. Moreoverthe syndromic management of illness, the high rates of self-treatment (especially for malaria) andwidespread use of traditional medicines (which may contain ingredients such as St Johns Wortand steroids) make a complete list of patient medications difficult to compile.

Minimising Harm From DDIsWhile DDIs involving HIV drugs are often unavoidable, many can be better managed. Lack ofawareness and recognition of clinically significant DDIs is a major obstacle to safe ARVprescribing. This review undertakes a systematic evaluation of potential DDIs between ARVs anddrugs used to treat TB, malaria, chronic Hepatitis B&C infections and opioid dependence.


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2 METHODS

2.1 Search StrategyThe following searches were used on PubMed (1987-July 31

st2009). If the standard searched

returned numerous results which were not relevant, then the refined search was used.

Standard SearchDrugName AND CoMed AND english[Language] NOT review[Publication Type] NOT child[MeSHTerms]

Refined SearchDrugName AND CoMed AND english[Language] NOT review[Publication Type] NOT child[MeSHTerms] AND (drug interactions[MeSH Terms] OR anti-hiv agents/pharmacokinetics[MeSH Terms]OR reverse transcriptase inhibitors/pharmacokinetics[MeSH Terms])

For all antiretrovirals, we searchedthe manufacturers Summary of Product Characteristics(Europe) (http://emc.medicines.org.uk/) and Product Information (USA) (from each anti-retroviralmanufacturers website). Websites were accessed (to August 21st2009) .

We searched the following conference reports for (peer-reviewed) DDI abstracts:

Conference on Retroviruses and Opportunistic Infections (2004 - February 2009)

International AIDS Society Conference (2005 July 2009)

World AIDS Conference (2004- July 2008) Interscience Conference on Antimicrobial Agents and Chemotherapy (2004 - Sept

2008)

International Workshop on Clinical Pharmacology of HIV Therapy (2004 - April 2009)

International Congress on Drug Therapy in HIV Infection (2004 - December 2008)

European AIDS Clinical Society (2005, 2007)

2.2 Study SelectionWe included all studies that evaluated pharmacokinetic data when antiretrovirals were combinedwith: TB drugs, antimalarials, hepatitis B treatment, hepatitis C treatment, and drug used to treatopioid dependence. Studies which reported clinical interactions only, or overlapping toxicity werenot included. Drugs in development which were not yet licensed were excluded. Studies involvingchildren were excluded.

2.3 Study Quality AssessmentIn order to develop a system which is robust, easy to applyin a consistent manner and allows theuser to assess the applicability of existing data to clinical practice, we will apply the GRADEsystem of classification to the strength of recommendation (Table 1), and the quality of evidence(Table 2) [Atkins et al, 2004]. The strength of evidence is framed in the following question: Is it safeto administer both drugs? We will utilise our existing traffic lights system, which maps onto

GRADE equivalents outlined in Table 1.


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2.3.1 Strength of Recommendation

Table 1 Traffic lights summary of Drug-drug interactions

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2.3.2 Grading of EvidenceGrading of quality of evidence will be achieved using a methodology based upon the GRADEsystem of classification [Atkins et al, 2005,] (Table 2). Four categories are proposed, which reflecta hierarchy of methodological design and execution of a study. Ability to up- or down-grade theassessment of quality is also set out in Table 2 and closely mirrors GRADE.

Table 2 Assessment of Quality of DDI Evidence

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3 RESULTS

3.1 AntimalarialsIn general there are potential interactions between HIV protease inhibitors and NNRTIs andlumefantrine, quinine and amodiaquine. However, only few drug interaction studies havebeen performed. These studies have varied in design and quality, utilising both healthy

volunteers and HIV-positive subjects. They may not reflect what happens in real life,particularly as the pharmacokinetics of many antimalarials alter with disease. For example,the protein binding and plasma half-life of quinine increases with severity of malaria,lumefantrine absorption is decreased during acute malaria and the pharmacokinetics ofmefloquine also alters with disease. Concentrations of quinine and lumefantrine alsoaccumulate with multiple dosing, and single dose studies only yield limited data. Inaddition, pharmacogenetic effects are not usually explored in small drug interaction studies,for example pyrimethamine is predominantly metabolised by CYP2C19, and the frequencyof poor metabolisers differs between Africans (3%), South East Asians (20%) andCaucasians. Specific points to note are:

3.1.1 Quinine Quinine is extensively metabolised by CYP3A4, and its AUC is increasedover fourfold by ritonavir (200mg) in healthy volunteers. However, the impact of the moreusual dose of ritonavir (100mg) is uncertain, and this study needs repeating. It seems

likely, given the limited data, that HIV positive patients on boosted PIs may be at increasedrisk of cinchonism. An important issue is whether or not a loading dose of quinine isrequired in patients with severe malaria who are receiving a boosted protease inhibitor.The AUC of quinine is reduced by approximately a third with nevirapine, although theclinical significance of this is uncertain.

3.1.2 Amodiaquine Excessive risk of hepatotoxicity has been reported in healthyvolunteers who were also given efavirenz. There are no data for nevirapine and otherboosted protease inhibitors although such studies should be undertaken very cautiously(using very low doses initially) in healthy volunteers. Prolonged neutropenia has beenreported in Ugandan children treated with amodiaquine, who were also receivingantiretrovirals.

3.1.3 Lumefantrine Lumefantrine is extensively metabolised by cytochrome P450 CYP

3A4. Lumefantrine does not seem to prolong the QT interval, but its pharmacokinetics arecomplex and variable and a marked food effect is observed. Interactions with PIs andNNRTIs are likely, and the manufacturers SPC advises that co-administration of CYP3A4inhibitors such as PIs are contraindicated. An approximately twofold rise in AUC wasreported in healthy volunteers who were given lumefantrine with lopinavir/ritonavir. Thisinteraction may be beneficial if it could be shown to reduce the marked pharmacokineticvariability of lumefantrine, or to abolish the food restrictions required with this antimalarial.

3.1.4 Artemether is metabolised via CYP3A4 to dihydro artemesinin (although bothcompounds have anti-malarial activity, dihydro artemesinin has greater potency). Inhibitionof 3A4 would reduce dihydro artemesinin, but increase artemether and potentially increasethe short half life of artemether (1-2 h). The effects of PIs and NNRTIs are unclear.

3.1.5 Mefloquine had variable effect on ritonavir metabolism - no interaction was noted

after a single dose but ritonavir plasma AUC was reduced by 31% and Cmax by 36% aftermultiple dosing. PK of mefloquine was not significantly influenced by RTV.

3.1.6 Since proguanil is a pro-drug and is partially activated (CYP2C19) to cycloguanilthere is concern that inhibition of metabolism by ritonavir or ritonavir-containing boosted PIregimens will reduce pharmacological effect. However, synergy with atovaquone is relatedto proguanil, not cycloguanil. When both drugs are co-administered, CYP2C19 inhibitioncould potentially enhance this synergistic effect, which may off-set decreased cycloguanilformation.


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3.1.7 Atovaquone decreases zidovudine oral clearance leading to a 35 % 23 %increase in plasma zidovudine AUC. The clinical significance of this is unknown, and nodose modification is recommended.

Lopinavir may decrease plasma concentrations of atovaquone, the clinical significance of

which is unknown, however, increases in atovaquone doses may be needed. Atovaquonelowers indinavir exposure, reducing Cmin by ~23%. Another healthy volunteer studyobserved indinavir AUC decrease of 5%, but increase in atovaquone AUC (13%) and Cmax(16%) when both drugs were co-administered. No dosage adjustments are necessary foratovaquone when given with indinavir. The clinical significance of lowered indinavirconcentrations is uncertain since these were healthy volunteer studies carried out withoutritonavir boosting (which is no longer the preferred means of giving indinavir ). Moreover,clinical studies have shown higher plasma indinavir in Thai patients (who have lower bodyweight), and given the toxicity of indinavir at higher doses, dosage adjustments are notindicated for indinavir (boosted with ritonavir) when dosed with atovaquone or malarone.

3.1.8 Previous formulations of ddI (buffered tablets) decrease dapsone concentrations, insome cases leading to failure of Pneumocystis prophylaxis. No interaction was observedwith newer formulations.

Interactions between co-trimoxazole use and malaria, or antiprotozoal effects of protease inhibitorsare not within the scope of this review.

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3.2 TB DrugsDrug-drug interactions should be viewed as only one part of a complex and multi-facetedclinical problem when treating both diseases. Factors such as timing the introduction ofantiretroviral therapy, its effect in preventing early mortality, use of alternative rifamycins,overlapping toxicity and immune reconstitution are important issues which are currentlybeing assessed within clinical trials. Suffice to say, despite recent advances in drug

development, there remains no real alternative to rifampicin use in developing countries inthe foreseeable future.

3.2.1 In general, interactions between rifampicin and protease inhibitors(boosted/unboosted) result in substantially lowered PI exposure, which renders theseinteractions difficult or impossible to manage in clinical practice. Strategies to overcomethis interaction have yielded only limited success. Ritonavir (at full dose) is poorly tolerated.Doubling the dose of lopinavir/ritonavir, or super-boosting with higher ritonavir dosesincreased lopinavir exposure in one PK study, but double dose lopinavir/ritonavir failed toprevent low drug exposure in a significant number of children in South Africa with HIV/TBco-infection [McIlleron et al 2009]. Moreover, healthy volunteers given rifamycin withboosted protease inhibitors (saquinavir, lopinavir, atazanavir) appeared to be at excessiverisk of hepatotoxicity, making this pharmacokinetic interaction difficult to study safely.

3.2.2 NNRTIs Pharmacokinetic studies suggest that rifampicin has a greater impact inlowering drug exposure of nevirapine (AUC 40-58%) compared with efavirenz (AUC 26%). One large cohort study reported that when antiretroviral therapy is commenced inpatients receiving rifampicin-containing TB treatment, treatment outcomes with standarddose efavirenz are superior to nevirapine, and comparable with patients on efavirenz whowere not receiving TB therapy. No difference in efficacy was observed in patients receivingeither efavirenz or nevirapine who subsequently required TB therapy. These differencescould have resulted from the lead-in phase of dosing of nevirapine undertaken duringrifampicin therapy.

3.2.3 Current international treatment guidelines prefer efavirenz to nevirapine in patientsrequiring rifampicin. However, there is no universal consensus about how to manage theefavirenz-rifampicin interaction. Lopez-Cortes et al [2006] conducted a two periodsequential study which supported weight-based dose increment of efavirenz during

rifampicin therapy. However, other studies in Africans and South-East Asians have shownthat while pharmacokinetic variability of efavirenz is markedly increased in the presence ofrifampicin, median exposures are adequate, and outcome is good. Numerous factors mayaccount for these differences, not least sampling strategy (trough versus random versusAUC sampling), body weight and pharmacogenetic influences (cytochrome P450 CYP2B6poor metabolisers are more common in black Africans and South East Asians comparedwith Caucasians).

3.2.4 NRTIs Although use of triple NRTI regimens as first line agents has resulted ininferior outcomes, combination treatment with three (zidovudine, lamivudine, abacavir) orfour (zidovudine, lamivudine, abacavir plus tenofovir) drugs during TB therapy has yet to beproperly assessed.

3.2.5 Newer drugs Of the newer agents, raltegravir has shown promise as an effective

antiretroviral in patients receiving rifampicin, since plasma exposure is only modestlyreduced. Furthermore, dose ranging studies have shown that the marked antiviral effect ofraltegravir is not blunted even when doses as low as 100mg twelve hourly (a quarter of theadult daily dose) are administered. This lack of a clear pharmacokinetic-pharmacodynamicrelationship has caused regulatory authorities to differ in recommendations when raltegraviris co-prescribed with rifampicin. The FDA recommends no dose increment, while theEMEA suggests that a dose increment of raltegravir could be considered. Clinical trial dataare awaited. Enfuvirtide is also an option, but the high cost and need for twice dailyinjections makes this a second line option.


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3.3 Hepatitis B and C treatment

3.3.1 Hepatitis BHepatitis B infection is widely prevalent in Asia and Africa. Infection with HIV is common.Management of both diseases is complex since in addition to increased risk of liverdysfunction with antiretrovirals, HIV drugs such as lamivudine, emtricitabine and tenofovir

have activity against hepatitis B virus. Entecavir (a hepatitis B drug) may also exhibit anti-HIV activity. There is concern that lack of routine hepatitis B testing within nationalantiretroviral programmes in developing countries, coupled with the use of first lineregimens based on stavudine/lamivudine or zidovudine/lamivudine plus an NNRTI willeffectively deliver 3TC monotherapy, and may result in widespread drug resistance tohepatitis B in resource-limited settings.

Clinically significant drug interactions mainly involve tenofovir and are listed below.

3.3.1.1 Tenofovir has known interactions with HIV protease inhibitors, increasing theexposure of darunavir and saquinavir modestly. In contrast, plasma exposure to atazanavir

is decreased (AUC 25%) by tenofovir. This interaction may to some degree be offset bythe use of boosted atazanavir (at doses of either 300mg or 400mg combined with 100mg ofritonavir).

3.3.1.2 Tenofovir exposure is also modestly increased by certain boosted protease inhibitorcombinations such as lopinavir/ritonavir, saquinavir/ritonavir and darunavir/ritonavir.

3.3.1.3 Tenofovir significantly increases didanosine exposure (through inhibition of purinenucleoside phosphorylation) and the combination is contraindicated.

3.3.2 Hepatitis CRecent advances in the development of agents that act specifically to inhibit hepatitis Cvirus (HCV) look set to fundamentally change the way that patients will be treated. Newdirectly acting anti-HCV agents such as protease and polymerase inhibitors will initially beadded to standard care with pegylated interferon alfa and ribavirin. However, future therapy

is likely to constitute combinations of agents which act at distinct stages of viral replicationand have differing resistance profiles. While directly acting anti-HCV agents willundoubtedly improve treatment outcomes, the introduction of combination therapy may notbe without complication in some patient groups. HIV positive patients who are receivingantiretrovirals are relatively highly represented among those with HCV infection, and are athigh risk of drug-drug interactions.

3.3.2.1 Concomitant administration of abacavir with PEG-IFN and ribavirin has beenassociated with an increased risk of non-response to anti-HCV therapy [Bani-Sadr et al,2007]and an interaction between abacavir and ribavirin has been suggested. As both drugsare guanosine analogues and have some metabolic pathways in common, an inhibitorycompetition for phosphorylation may be possible between ribavirin and abacavir [Mira et al,2008].

3.3.2.2 Combinations of zidovudine with ribavirin and PEG-IFN can lead to increased risk ofsevere haematological toxicity, including anaemia. The use of zidovudine has beenidentified as an independent factor contributing to haematological adverse events inpatients undergoing ribavirin and PEG-IFN treatment; the combination is not recommended[Mira et al, 2007].

3.3.2.3 The use of didanosine alongside ribavirin is associated with increased risk ofmitochondrial toxicity, which may be attributed to increased exposure to the activemetabolite of didanosine, dideoxyadenosine 5-triphosphate when didanosine is


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coadministered with ribavirin [Bani-Sadr et al, 2005; Montes Ramirez et al, 2002; Videx USPrescribing Information]. Toxicity may be severe and coadministration is notrecommended.

3.3.2.4 Mitochondrial toxicity has also been observed with combinations of stavudine andribavirin.In vitrodata has shown that ribavirin can inhibit phosphorylation of zidovudine and

stavudine. The clinical significance is not clear, however manufacturers of ribavirin adviseclose monitoring of HIV RNA with this combination.

3.3.2.5 Although clinical significance is not thought to be high, the use of atazanavir withribavirin and IFN has been associated with hyperbilirubinaemia [Rodriguez-Novoa et al,2008].

3.3.2.6 In the case of patients receiving efavirenz alongside PEG-IFN, monitoring of centralnervous system effects is important, as incidence of depressive symptoms in patients withHIV/HCV co-infection treated with IFN is reportedly high [Laguno et al, 2004].

Currently, ARV treatment may be adjusted, as far as is practicable, to enable optimaladministration of anti-HCV therapy, without compromising ARV efficacy. This will becomeincreasingly complex to manage with the addition of new Hepatitis C agents.

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8

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8

-1

8

-1

$ IG

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8

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8

-1

8

-1

8

-1

8

-1

8

-1

8

-1=/ 8

-1

8

-1

4

-1

@ 8

-1

8

-1

8

-1

4/ 0

-1

4

-1

8

-1

8

-1

0

-1

8

-1

4

-19

%/ 8

-1

8

-1

8

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-19

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19/23

F

3.4 Opioid DependenceMethadone and buprenorphine are the two most commonly used drugs as replacementtherapy for opioid dependency. Methadone is usually prescribed as a racemic mixture,containing equal proportions of R-methadone (the active form) and S-methadone (with lessactivity, but may be responsible for some toxicity). Buprenorphine undergoes extensivefirst pass metabolism, and is consequently administered sublingually. It is metabolised

principally by hepatic cytochrome P450 CYP3A4 (to norbuprenorphine), and byglucuronidation. As a result there are potential significant interactions with proteaseinhibitors.

3.4.1 Methadone Boosted protease inhibitors and NNRTIs increase the clearance ofR-methadone by enzyme induction. Clinical symptoms of opioid withdrawal are welldocumented. If co-administered, consider increasing the dose of methadone.

3.4.2 Buprenorphine Some studies have reported that exposure of buprenorphine andits metabolites may be increased by concomitant protease inhibitor use, while others havefailed to observe this. The clinical significance is uncertain. It seems prudent to commencereplacement with a low dose of buprenorphine in a patient receiving boosted proteaseinhibitors.

Table 6 Opioid Replacement Therapy

Opioid Replacement Therapy & PIs

Protease Inhibitors

ATV DRV FPV IDV LPV NFV RTV SQV TPV

Buprenorphine Amber

(3)

Amber

(4)

Amber

(4)

Amber

(4)

Green

(3)

Amber

(3)

Amber

(3)

Amber

(4)

Amber

(4)

Methadone Green

(2)

Amber

(4)

Amber

(2)

Amber

(2)

Amber

(2)

Amber

(2)

Amber

(2)

Amber

(2)

Amber

(4)

Opioid Replacement Therapy & NNRTIs, Others

NNRTIs Others

EFV ETV NVP MVC RAL

Buprenorphine Amber(2)

Amber(4)

Amber(4)

Green(4)

Green(4)

Methadone Amber

(2)

Amber

(3)

Amber

(2)

Green

(4)

Green

(4)

Opioid Replacement Therapy & NRTIs

NRTIs

ABC ddI FTC 3TC d4T TDF ZDV

Buprenorphine Amber

(4)

Green

(4)

Green

(4)

Green

(4)

Green

(4)

Green

(4)

Green

(3)

Methadone Amber

(4)

Amber

(3)

Green

(4)

Green

(3)

Amber

(3)

Green

(2)

Amber

(2)


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H

4 DISCUSSION

Drug-drug interactions are one of the commonest causes of medication error in developedcountries, and antiretrovirals among the most therapeutically risky drugs for clinically significantdrug interactions. Studies in the Netherlands and New York involving 115 and 550 patientssuggest a prevalence of 20-25% CSDIs [de Maat at al, 2004; Shah et al, 2007]. A second study in

New York involving 153 patients reported a prevalence of 41.2% [Miller et al, 2007]. Two recentstudies conducted in Liverpool (159 patients) and Switzerland (771 patients) reported prevalenceof 26.3% and 61% respectively [Cottle at al, 2009; Marzolini at al, 2008]. Although definitionsdiffered, four out of five of these studies utilised the Liverpool Drug Interactions website to screenfor interactions. There have been no such studies in resource-limited settings where risk isarguably increased as a result of less laboratory monitoring, high rates of background illness(which may result in adverse effects being missed), lack of affordable alternative treatments, use offixed dose combinations (that offer less flexibility for managing interactions) and lack ofpharmacovigilance data. In addition, there is a higher cost of treatment failure in these settings,since options are limited compared with developed countries.

Use of therapeutic drug monitoring is not feasible as a strategy for managing CSDIs in resource-poor settings. Practical steps that can be instituted to reduce the risk of adverse outcomes fromCSDIs include integrating national treatment programmes for HIV and other diseases (with

protocols that minimise drug interactions), establishing regional networks for pharmacovigilance,and improving the quality of prescribing through training and education of health care workers.Knowledge of common interactions involving antiretrovirals on a country-specific basis will allowtargeted training, monitoring and protocol development. Finally, we believe that large antiretroviralprogrammes should consider undertaking an audit of clinically significant drug interactions as aproxy for the quality of prescribing within that scheme.


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5 Acknowledgements & Declarations

We thank Holger Schunemann and Paul Garner for advice on applying GRADE criteria to theassessment and classification of drug interactions. Our classification system was developed inLiverpool and its use does not imply endorsement from the GRADE Working Group.

The Liverpool HIV Drug interactions Website (www.hiv-drug-interactions.org) receives educationalgrants from Abbott, Gilead, Merck, Bristol-Myers-Squibb, Pfizer, Tibotec, GlaxoSmithKline andBoehringer Ingelheim. Support has also been received from research grant funding from the UKNational Institute for Health Research, and the EU. Editorial content remains entirely independent.SK and DJB have received research grant support, PhD studentships, travel bursaries andconsultancy fees from Boehringer, GlaxoSmithKline, Tibotec, Merck, Bristol-Myers-Squibb andPfizer.


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6 REFERENCES

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Drug Drug Interactions Review (WHO)