Study inclusion criteria & search strategy

The following search was used on PubMed (1987-August 2016).

DrugName AND CoMed AND english[Language] NOT review[Publication Type]

We searched the following conference reports for (peer-reviewed) abstracts relating to DDIs:

• Conference on Retroviruses and Opportunistic Infections (2004 –March 2016)
• International AIDS Society Conference (2005 –July 2015)
• International AIDS Conference (2004- July 2016)
• Interscience Conference on Antimicrobial Agents and Chemotherapy (2004—Sept 2015)
• International Workshop on Clinical Pharmacology of HIV Therapy/HIV & Hepatitis Therapy (2004—June 2016)
• International Congress on Drug Therapy in HIV Infection (2004—November 2014)
• European AIDS Clinical Society (2005-October 2015)
• British HIV Association Annual Conference (2002-April 2016)

For all co-prescribed drugs, we searched the manufacturer’s SPC (UK) (http://emc.medicines.org.uk/) and Prescribing Information (USA) (from each ARV manufacturer’s website). Websites were accessed to June 2016). We utilised a standard data extraction template to systematically assess and summarise the evidence, and extracted relevant data into evidence summary templates (see S1 Table). To generate recommendations, manufacturer prescribing information was considered alongside published data, particularly where no data were available.

Study quality assessment

Grading quality of evidence.

Grading of quality of evidence was achieved using a methodology adapted from the GRADE system of classification[9] (Table 1).The study design considered to yield the highest quality of evidence for assessing DDIs was an appropriately powered randomised, controlled interaction trial, with full pharmacokinetic sampling and clinical or validated surrogate endpoints.[13] However trials of this nature are rarely pragmatic or feasible; costly, difficult to recruit to and may not be ethically justifiable. Our evidence base was therefore gathered from smaller pharmacokinetic-based studies, retrospective cohort surveys or case reports. Evidence based on population pharmacokinetic modelling was graded according to the quality of the primary data upon which that model was based. Specific examples of issues leading to downgrading were: lack of clinical endpoints (as adverse clinical events are considered a critical outcome), trough, or ‘random’ pharmacokinetic sampling or sparse sampling not supported by a validated population pharmacokinetic approach, use of single dose studies (more acceptable for known enzyme inhibitors, less acceptable for known enzyme inducers), healthy volunteer data where existing literature suggests different plasma drug exposure in disease.

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Table 1. Stages and criteria for quality of evidence assessment.

https://doi.org/10.1371/journal.pone.0173509.t001

Perhaps the most controversial issue is developing criteria for downgrading studies due to insufficient power to exclude clinically significant pharmacokinetic changes. The meaningfulness of any change in pharmacokinetics relates to the magnitude of that change in relation to both the therapeutic index of the drug and its pharmacokinetic-pharmacodynamic relationship. Superimposed on this are differences in pharmacokinetics and susceptibility to toxicity between HIV positive patients and patients with other conditions. Regulatory authorities accept data from relatively small studies (typically n = 12–24) for new drug applications, although these numbers frequently yield <80% power to demonstrate non-bioequivalence. Certainly pharmacokinetic changes just outside bioequivalence are unlikely to be clinically meaningful for most drugs, particularly those with a large background variability in pharmacokinetics (CV>25%). We therefore based our criteria on 2012 draft FDA guidance[14] as follows: For drugs with defined ‘no effect’ boundaries, we interpreted the significance of pharmacokinetic changes with reference to these thresholds (Table 1). For the majority of drugs, where ‘no effect’ boundaries have not been characterised, we took an arbitrary but pragmatic view that any sample size should at least be able to rule out a large change such as a halving or doubling in AUC (assuming a typical CV of 50%), with at least 80% power, recognising that this is an area which still requires further debate. Where AUC was not reported, a similar magnitude of change in Cmax, Cmin or Ctrough was used. For reference, FDA recommendations for drug-interaction studies classify strong inhibitors of CYP450 enzymes as those causing a ≥5 fold increase in AUC or a >80% decrease in CL; moderate inhibitors a ≥2 to < 5-fold increase in AUC or 50–80% decrease in CL; and weak inhibitors cause a ≥1.25 but < 2-fold increase in AUC or 20–50% decrease in CL. Likewise, strong inducers are considered those which cause ≥80% decrease in AUC, moderate inducers cause 50–80% decrease in AUC, and weak inducers cause 20–50% decrease in AUC.[14]

Table 1 gives examples of initial quality levels assigned to study designs, with up- or down-grading specifically applied to drug interaction data. Studies available as abstracts only, or evidence from in-house studies of drug interactions which were not published in peer-reviewed journals were graded as ‘very low’, where insufficient details concerning study design were available. Studies demonstrating a large magnitude of effect, such as a major clinical or laboratory abnormality, as judged by grader consensus, or a large change in pharmacokinetic parameters were upgraded providing there was demonstrable lack of bias. Down-grading was applied for inconsistency, reporting bias and limitations in pharmacokinetic sampling. All gradings were carried out independently by two assessors (KS and SG), and then discussed among a team of four (KS, SG, SK, DJB) in order to reach consensus. All gradings and recommendations were verified by a fifth assessor (CM), in order to obtain expert advice which was independent to the development of the process. Further adjustments were by discussion and consensus. Quality of evidence gradings were assigned to each study, which differs from the GRADE approach, which assesses quality of a body of evidence as a whole, for each recommendation. Assessing each study individually for a large number of interaction pairs facilitated development of the initial confidence levels and upgrade/downgrade criteria. Final quality gradings were then allocated to the body of evidence as a whole for each interaction studied. It should be noted that this classification system was not developed with or sanctioned by the GRADE Working Group, and no GRADE-based classification system currently exists for evaluating DDIs.

Strength of recommendation.

The strength of recommendation was formed around the question: ‘is it safe to co-administer both drugs?’ The existing University of Liverpool HIV drug interaction key was used to give the strength of recommendation (Table 2). A RED recommendation was assigned where combinations were contraindicated or to be avoided, AMBER for caution (i.e. potentially manageable interaction with increased vigilance, or monitoring, or dose modification), YELLOW for possible or theoretical interactions, where clinical significance is unclear or unlikely; and GREEN where co-administration of both drugs was considered to be safe. We recognised that in patients with multiple co-morbidities, potential interactions could not be altogether avoided, so a distinction between AMBER or YELLOW was made on the basis of likely potential adverse impact of this interaction, and the therapeutic index of affected drug(s). We ensured that recommendations were consistent with the current licensing guidance wherever possible. Where differences exist between FDA and EMA opinions around a DDI, our recommendations reflect the more conservative approach.

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Table 2. Strength of recommendation key for co-administration of antiretrovirals with anti-malarial drugs.

https://doi.org/10.1371/journal.pone.0173509.t002

Quinine

In one study single dose quinine AUC was increased over fourfold by ritonavir (200mg BD)[15] whereas in others it was halved with lopinavir plus ritonavir (LPV/r 400/100mg BD) with significantly decreased exposure (AUC↓69–99%) to the active metabolite 3-hydroxyquinine. [16, 17] All studies were in healthy volunteers, and since the unbound fraction of quinine is known to be altered with malaria, and both quinine and some HIV protease inhibitors are known to cause ECG changes such as QT prolongation, no change to quinine dosing is recommended, but close monitoring is warranted. Monitoring for ECG changes is also warranted when quinine is administered with rilpivirine and EFV, due to QT prolongation risk.

Quinine exposure (after single dose) is reduced by approximately a third with nevirapine, although the clinical significance is uncertain.[18] A case report in a single patient observed increased P. falciparum parasitaemia in the presence of quinine in a patient taking nevirapine (attributed to CYP3A4 induction), and switching to atovaquone/proguanil was effective in treating the patient’s malaria.[19] Quinine concentrations were lower, and 3-hydroxyquinine higher, in 6 pregnant women with detectable nevirapine, compared to one patient without. Quinine concentrations were below the therapeutic range in 50% of the patients, however all were successfully treated for malaria.[20] As quinine is an inhibitor of P-gp,[21] an interaction with maraviroc, a P-gp substrate, cannot be excluded. Cobicistat would be expected to increase exposure to quinine via CYP3A4 inhibition.

Amodiaquine

Significant elevations in hepatic transaminases were reported in the first two healthy volunteers given efavirenz with amodiaquine leading to the premature discontinuation of the study; amodiaquine exposures were significantly increased.[22] A parallel-group comparison in HIV positive patients found that exposure to amodiaquine and its active metabolite were significantly reduced when taken with nevirapine. The mechanism for the interaction is not fully elucidated.[23]

There are no available data for boosted PIs, although caution is advised as protease inhibitors (saquinavir, lopinavir, tipranavir) and some NNRTIs (efavirenz but not nevirapine) are potent CYP2C8 inhibitors[24] in vitro, with potential for increased amodiaquine toxicity. In addition, PIs and amodiaquine have each been associated with QT prolongation.[25]

Prolonged neutropenia has been reported in Ugandan children treated with amodiaquine, who were also receiving ARVs, although it is unclear to what extent co-administration with zidovudine may have driven this observation.[26, 27]

Lumefantrine

Lumefantrine does not seem to prolong the QT interval, but its pharmacokinetics are variable and a marked food effect is observed. The manufacturers advise caution if administering with other drugs which may cause QT interval prolongation, or increase exposure to lumefantrine. Interactions with PIs, NNRTIs and elvitegravir/cobicistat are likely as lumefantrine is a CYP3A substrate, and the manufacturer’s SPC advises that co-administration of CYP3A4 inhibitors such as PIs and cobicistat should be undertaken with caution. An approximately twofold rise in AUC was reported in healthy volunteers who were given lumefantrine with lopinavir/ritonavir,[25] or darunavir/ritonavir[28] and this was confirmed in HIV positive (but malaria negative) patients (lumefantrine AUC increased between 3-fold and 5-fold, 7 day lumefantrine concentration increased up to 10-fold, when compared to ARV naive patients, or those with an EFV-containing regimen).[29, 30] Paediatric patients, but not adults, were found to experience increased adverse events when taking lumefantrine with LPV/r.[31] No change in ECG parameters were observed despite the significantly increased exposure, during single dosing, or a standard six dose regimen.[30, 32] This interaction may be beneficial if it could be shown to reduce the marked pharmacokinetic variability of lumefantrine, or to abolish the food restrictions required. LPV/r increased the exposure to lumefantrine by 439%, but decreased the exposure to dihydroartemisinin by 59.7%. Because of the fixed dose artemether-lumefantrine formulation, no dose adjustment is proposed.[33] In paediatric patients, lumefantrine exposure increased 108%, and 7 day lumefantrine levels were increased 3.4 fold.[34] Lumefantrine exposure increased between 6-fold-10-fold with LPV/r compared to EFV containing ARVs, in HIV positive, malaria positive paediatric patients.[34, 35]

Two well-designed studies demonstrated a decrease in lumefantine exposure (AUC↓56%),[36] and 7day exposure (↓46%)[37] when co-administered with efavirenz at steady state. Etravirine decreased lumefantrine AUC by 13%.[28] Unexpectedly, nevirapine was found to significantly increase exposure to lumefantrine in some studies, [31, 35, 38, 39]

And decrease exposure to lumefantrine in others.[33, 40, 41] Two studies reported no change in lumefantrine exposure (although 7 day lumefantrine concentrations increased in paediatrics) in the presence of nevirapine,[36, 37] and one reports a decrease in nevirapine exposure by 46%.[36] Studies varied in design (healthy subjects, HIV positive vs negative, paediatrics, pharmacokinetic sampling and modelling), although no distinct factor explains the variation in results.

Pharmacokinetic studies in HIV-malaria co-infected children found exposure of artemether and lumefantrine to increase significantly in children taking lopinavir/r as a third agent, compared to efavirenz or nevirapine. HIV positive children taking PI-based regimens have been found to be at reduced risk for malaria compared to NNRTI-based ARVs. Higher rates of malaria treatment failure were observed in children taking efavirenz.[31, 42] 85% of paediatric patients who were taking EFV based ARV regimens had day 7 lumefantrine levels below the treatment threshold. The authors conclude there is a need for alternative dosing of artemether-lumefantrine for children taking EFV-based ARVs.[34]

An observational pharmacokinetic study in adults found that cumulative risk of recurrent parasitaemia was 20-fold higher in patients taking EFV with artemether-lumefantrine, than HIV positive patients taking no ARVs.[40] Dosing adjustments of artemether-lumefantrine were assessed via pharmacokinetic modelling of these data, and an extension of the duration of treatment to five days using the standard dose is suggested.[43] High EFV plasma concentration and CYP2B6*6/*6 genotype have been associated with low lumefantrine plasma concentration and poor malaria treatment response in HIV-malaria- coinfected patients receiving concomitant EFV-based ART. In the absence of concomitant EFV, CYP2B6*6 genotype had no significant influence on lumefantrine plasma exposure.[44] Patients with CYP2B6*6 genotype are at increased risk of QT interval prolongation[45], so monitoring is warranted when co-administering EFV with lumefantrine.

Artemether

Artemether is metabolised via CYP3A4 to dihydroartemesinin (DHA) (although both compounds have anti-malarial activity, DHA has greater potency). Inhibition of 3A4 would reduce DHA, but increase artemether and potentially increase the short half life of artemether.

In 2 parallel studies, lopinavir/ritonavir reduced exposure to DHA, with artemether increasing in one study, and remaining unchanged in another. A predicted interaction may have been increased arthemeter exposure resulting from lopinavir/ritonavir inhibition of CYP3A4.[29, 30] A crossover study in healthy volunteers observed small decreases in artemether exposure which did not reach statistical significance, and moderate decrease in DHA AUC (↓45%).[25] The observed increased clearance and decreased artemether exposure is likely due to induction of CYP enzymes by lopinavir/ritonavir whereas a decrease in DHA could result from the induction of glucuronidation by ritonavir. No significant changes in QT interval were observed in a single dose study of artemether/lumefantrine and steady state lopinavir/ritonavir.[32] Darunavir/ritonavir was found to decrease steady state artemether and DHA AUC by 16% and 18% in a crossover study in healthy subjects.[28]

Nevirapine was found to decrease exposure to artemether, with little effect, or small decrease in DHA exposure.[36, 39, 41] One crossover study observed a significant decrease in NVP exposure (AUC↓46%),[36] possibly due to artemether induction of CYP3A4, or the effects of nevirapine CYP3A4 autoinduction. In paediatric patients, NVP reduced artemether AUC by 64%, and DHA AUC by 30%.[34]

Efavirenz significantly reduced exposure to artemether and DHA (AUC ↓79%, ↓75% respectively) in HIV positive patients.[36] A smaller healthy volunteer study found no significant reduction in artemether AUC, and a moderate decrease in DHA exposure, although large variability in artemether pharmacokinetics were observed.[37]

Population pharmacokinetic modelling using pooled data[29, 36] proposes the following dose modifications for artemether-lumefantrine: efavirenz decreased exposure to lumefantrine and dihydroartemisinin by 69.9% and 71.7%, respectively. A 250% increase in dose would achieve exposures similar to those without concomitant HIV treatment. Etravirine co-administration reduced artemether AUC by 38% and DHA AUC by 15% at steady state.[28] NVP decreased the exposures to lumefantrine and dihydroartemisinin (25.2% and 41.3%, respectively). A 75% artemether-lumefantrine dose increase would result in adequate exposures. Cobicistat could potentially increase plasma levels of artemether via enzyme inhibition.

Artesunate

Artesunate is metabolised via hydrolysis and CYP2A6, whereas DHA is predominantly glucuronidated via UGT1A9 and 2B7. Nevirapine has been found to increase overall exposure to artesunate, with DHA pharmacokinetics remaining largely unchanged, with the exception of a decreased DHA:artesunate AUC ratio.[46] No treatment-limiting adverse events were observed in this trial of HIV positive patients stable on nevirapine-based ARVs. However, DHA total exposure was shown to be approximately 2-fold higher in patients with active malaria than healthy volunteers.[47]

Ritonavir moderately increased artesunate AUC (27%), with little effect on Cmax. The effect is thought to be minimal, particularly in the context of variable inter-subject artesunate pharmacokinetics. Decreased exposure to DHA in the presence of ritonavir was observed (AUC↓38%, Cmax↓27%), which may be explained by induction of UGT enzymes by ritonavir.[42] Lopinavir/ritonavir increased artesunate AUC by 80%, and decreased DHA AUC24h by 58.2%.[48]

Co-administration of pyronaridine/artesunate substantially increased exposure to ritonavir. In vitro data demonstrate that pyronaridine may inhibit CYP2D6 metabolism and P-gp efflux transport of ritonavir. Coadministration of ritonavir and pyronaridine/artesunate appear to have increased the likelihood of liver enzyme elevations which could not be accounted for by the observed pharmacokinetic parameters associated with co-administration.[42]

Dihydroartemisinin

Ritonavir and other PIs including atazanavir are unlikely to affect conversion of DHA to the inactive α-DHA-β-glucuronide, as in vitro studies have demonstrated that they do not significantly inhibit UGT1A9 or 2B7.[49] Induction of glucuronidation by ritonavir or cobicistat however, cannot be ruled out.

Mefloquine

Mefloquine had variable effect on ritonavir metabolism: no interaction was noted after a single dose but ritonavir AUC was reduced by 31% and Cmax by 36% after multiple dosing. A decrease in bioavailability appears responsible for the reduced levels of ritonavir.[50]

Pharmacokinetics of mefloquine were not significantly influenced by ritonavir.[50] However, months of concurrent therapy would be necessary for the full extent of an interaction to be reported due to the long half-life of mefloquine. Lopinavir/ritonavir decreased mefloquine AUC 48h by 28.7%. Lopinavir exposure was unchanged, while Cmax was decreased by 22%. Ritonavir AUC24h decreased 44.6%, when administered with artesunate-mefloquine.[48]

A case study including pharmacokinetics in a single patient reported an absence of toxic or sub-therapeutic levels when mefloquine was taken with a regimen containing indinavir and nelfinavir.[51] Cobicistat may potentially increase exposure of mefloquine via CYP3A4 inhibition, whereas EFV, NVP and ETV, may decrease mefloquine exposure via induction of CYP3A4. Mefloquine should be administered with caution with other agents which prolong the QT interval.

Proguanil

Proguanil is a pro-drug and is partially activated (CYP2C19) to cycloguanil. Interactions may be complex, since synergy with atovaquone is related to proguanil, not cycloguanil.

A parallel group study found that in HIV positive patients taking ATV/r-containing regimens, proguanil AUC decreased by 41% compared to healthy volunteers. Similarly with efavirenz-containing regimens, proguanil AUC decreased 43%, and a decrease of 38% was observed with lopinavir/r.[52] A crossover study in healthy volunteers demonstrated a significant increase in proguanil exposure (AUC↑113%), and a decrease in cycloguanil exposure (↓38%) when administered with efavirenz at steady state.[53] A study in healthy subjects found that lopinavir/r potently induced CYP2C19 activity.[54] The clinical relevance of altering exposure of proguanil in relation to cycloguanil is not known.

Atovaquone

Atovaquone decreases zidovudine oral clearance leading to a 35% increase in plasma zidovudine AUC, possibly due to inhibition of zidovudine-glucuronide formation. The clinical significance is unknown, and no dose modification is recommended.[55, 56]

Lopinavir/r, atazanavir/r and efavirenz have been found to decrease plasma concentrations of atovaquone. The clinical significance is unknown, however, increases in atovaquone doses may be needed.[52] In a crossover study of HIV positive subjects, Subjects on efavirenz-based ARVs had 47% and 44% lower atovaquone exposure than subjects with no ARVs, at atovaquone doses of 750mg twice daily and 1500mg twice daily, respectively. These doses of atovaquone related to treatment of pneumocystis pneumonia and toxoplasmosis, and differed from regimens used in the treatment or prophylaxis of malaria. In this study, atazanavir/r did not significantly affect exposure to atovaquone.[57]

Atovaquone lowers indinavir exposure, reducing Cmin by~23%. Another healthy volunteer study observed 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 for atovaquone when given with indinavir. The clinical significance of lowered indinavir concentrations is uncertain since these were healthy volunteer studies carried out without ritonavir boosting. Moreover, clinical studies have shown higher plasma indinavir in Thai patients (who have lower body weight), and given the toxicity of indinavir at higher doses, dosage adjustments are not indicated for indinavir/r when dosed with atovaquone or malarone.[30]

A case study in a single patient demonstrated a significant increase in etravirine and unboosted saquinavir exposure (AUC↑55% and 274% respectively) when prophylaxis with atovaquone and proguanil was initiated in a stable patient. No adverse events were reported. Slight, and clinically significant decrease in maraviroc and raltegravir exposure were observed, however no dose alteration is required.[58]

Piperaquine

Piperaquine is an inhibitor of CYP3A4. It is metabolised by CYP3A4 in vitro, however the contribution of CYP3A4 to in vivo elimination is unknown. Piperaquine undergoes a low level of metabolism by CYP2C19, and is also an inhibitor of this enzyme. Piperaquine may therefore increase exposure to NNRTIs, PIs, rilpivirine and maraviroc. Exposure to piperaquine may be increased by PIs and cobicistat via CYP3A4 inhibition; or decreased by nevirapine or efavirenz via CYP3A4 induction. A PK study nested in a clinical trial of malaria prevention in pregnant women found that piperaquine exposure and day 7–21 levels were significantly decreased in patients taking EFV-containing ARVs. The efficacy data is yet to be reported.[59] Piperaquine may lead to prolongation of the QT interval and should be used with caution in patients taking agents which also have potential to prolong QT interval, such as PIs EFV and rilpivirine.[37] A study in a cohort of Ugandan paediatric patients has concluded that treatment with dihydroartemisinin and piperaquine alongside LPV/r or NNRTIs is safe and effective.[60] Piperaquine may potentially increase exposure to dolutegravir and elvitegravir via CYP3A4 inhibition, although the clinical significance is unknown.

Pyronaridine

A parallel group study of healthy volunteers found that artesunate/pyronaridine increased exposure to ritonavir 3-fold, with no change in pyronaridine exposure. This was associated with discontinuations due to increased liver enzymes.[42] Cobicistat as a boosting agent, may be less susceptible to significant interaction with pyronaridine, as CYP2D6 is a minor route of cobicistat metabolism, however an interaction cannot be ruled out.[8] As liver toxicity including significant rises in ALT and AST have been observed with pyronaridine treatment, monitoring of liver function may be advised if using alongside nevirapine or efavirenz. Falls in haemoglobin have also been observed, which may be exacerbated by concurrent treatment with zidovudine[35] As pyronaridine is an inhibitor of P-gp,[61] interaction with maraviroc, or dolutegravir, which are P-gp substrates, cannot be excluded.

Doxycycline

In an observational pharmacokinetic study, doxycycline did not affect trough concentrations of atazanavir (boosted or unboosted) efavirenz, lopinavir/r or nevirapine.[62] Although no data are available with NNRTIs and doxycycline pharmacokinetics, manufacturers of doxycycline caution that hepatic enzyme inducers may accelerate the decomposition of doxycycline, decreasing its half-life.[39]

Chloroquine

Although no pharmacokinetic studies concerning concomitant administration with ARVs are available, clinically significant pharmacokinetic drug interactions are unlikely with chloroquine, due to multiple mechanisms of metabolism and elimination. However, caution is warranted if chloroquine is administered with other agents that may prolong the QT interval, such as ATV/r, LPV/r, rilpivirine and efavirenz. [47]

Clindamycin

In vitro studies have demonstrated that clindamycin is predominantly metabolised via CYP3A4. In this analysis, ketoconazole, a CYP3A4 inhibitor, markedly inhibited clindamycin S-oxidase formation.[63] However, there are no available clinical data investigating the effect of ARVs, or other CYP3A4 inhibitors or substrates on clindamycin exposure, therefore the clinical relevance is unknown. Clindamycin inhibited CYP3A4 by approximately 26% in vitro.

Primaquine

The metabolism and elimination of primaquine has not been fully elucidated, and in vitro studies have differed in their findings. It has been reported that metabolites formed by CYP2E1, CYP2B6, CYP1A2, CYP2D6 and CYP3A4 variably contributed to the haemotoxicity of primaquine. Significant inhibition of primaquine haemotoxicity by inhibitors of CYP2B6, CYP2D6 and CYP3A4 was observed.[64] Another study reported that CYP2D6 and monoamine oxidase-A are the key enzymes associated with primaquine metabolism, with CYP2D6 mediated pathways playing a main role in efficacy and haemolytic toxicity.[65] The effect of ARVs which may inhibit or induce these enzymes is unknown, however efficacy and toxicity of primaquine should be monitored when co-administed with PIs or NNRTIs.

Pyrimethamine/Sulfadoxine

Pyrimethamine may depress folate metabolism in patients taking agents associated with myelosuppression, such as zidovudine.[46] Pyrimethamine did not affect zidovudine exposure at doses used to treat cerebral toxoplasmosis.[66] Potentially, pyrimethamine may reduce the renal clearance of emtricitabine and lamivudine, as in vitro data suggest that pyrimethamine inhibits renal transport via the multidrug and toxin extrusion transporter MATE1.[67, 68]