CIN2013

Slide 2: The effects of ART on the kidney have previously been reported: in general, the eGFR in patients with i paired renal function increases, and the GFR in patients with nor al!high eGFR declines in the first " weeks, with subse#uent stable easure ents over $%&'"" weeks( Slide ): ART appears to slow the rate of eGFR decline, nonetheless, on&going eGFR loss has been reported in patients treated with cART Slide ": *ore recently, patients participating in the Gilead clinical trials were noted to have early reductions in creatinine clearance when rando ised to T+F!FT, with cobicistat!elvitegravir or ritonavir!ata-anavir( Again, these reductions were fully established by " weeks with no subse#uent change up to $% weeks( Slide .: /ndeed, any AR01s have now been associated with this pattern of early 23&" weeks4 reductions in creatinine clearance 5 the agnitude of eGFR change varies fro appro6i ately &. 7! in for rilpivirine and raltegravir to appro6i ately &'. 7! in for cobicistat and dolutegravir( /n ost cases, no other features of renal in8ury 2proteinuria, hae aturia, glycosuria4 were observed( Slide %: The e6planation for these early, non&progressive changes in creatinine clearance are effects of AR01s on creatinine secretion by the renal tubules( ,reatinine is freely filtered at the glo erulus9 renal tubules contribute appro6i ately '.: to creatinine clearance( Studies have found no changes in GFR 2 easured by iohe6ol or iothala ate4 in patients with these reductions in creatinine clearance( Slide ;: <f note, the transporters involved in creatinine secretion differ fro those involved in tenofovir transport9 the use of a different set of transporters suggests that there should be no drug&drug interaction of rilpivirine, dolutegravir, cobicistat and ritonavir with tenofovir at the level of the renal tubule( Slide =: >owever, in the A,TG .232 study, co&ad inistration of ata-anavir!ritonavir with T+F!FT, 2but not with A?,!)T,4 resulted in reductions in creatinine clearance( Slide $: /n addition, a nu ber of patients who received T+F!FT, together with ritonavir!ata-anavir, cobicistat!elvitegravir or cobicistat!ata-anavir developed pro6i al tubulopathy, with no cases observed in the T+F!FT,!efaviren- ar ( Altogether, these results suggest that there ay be a clinically significant drug&drug interaction between T+F and ritonavir or cobicistat in a s all nu ber of patients( Slide '3: /n case series, tenofovir&induced renal tubular disease is ainly observed in patients who were si ultaneously treated with a boosted protease inhibitor( ?one pain in fre#uent, and one third of patients develop osteo alacia 5 which ay result in fractures( Slide '': @ro6i al tubulopathy results fro itochondrial dysfunction( /n severe cases, arked orphological changes of the itochondria have been observed(

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/t is possible that a drug&drug reaction at the level of the tubular cells results in increased intra&cellular tenofovir levels, leading to to6ic alterations to the respiratory chain( Slide '2: Ahile severe for s of pro6i al tubulopathy are al ost e6clusively encountered with tenofovir, ilder for s of pro6i al tubular dysfunction are also uch ore co on in patients whose cART contains T+F( Slide '): Sub&clinical tubular dysfunction has been associated with the presence of genetic poly orphis s in the tubular transporters A?,,2 2encoding ulti&drug resistance protein B*R@C&24, A?,," 2*R@&"4 and A?,,'3 2*R@&;4( Slide '": /n cohort studies, several drugs have been associated with chronic kidney disease B,D+C and!or ,D+ progression( Tenofovir, indinavir, ata-anavir and lopinavir increased the risk of developing eGFR E%3 or F2.: eGFR decline in those with eGFR E%3 at baseline( <ther factors included a lower eGFR at baseline, older age, hypertension, diabetes and hepatitis , co&infection( Slide '.: The results for T+F in the GuroS/+A study were confir ed in the 0A cohort9 indeed T+F was associated with proteinuria, eGFR decline F) 7! in!'(;) 2!year, and incident ,D+ in various statistical odels( Slide '%: As far as the associations with other AR01s, indinavir was associated with ,D+, ata-anavir with rapid eGFR decline and ritonavir with proteinuria( Slide ';: ,hanges in eGFR with T+F!FT, plus ata-anavir!ritonavir have been co pared to those observed with T+F!FT, plus lopinavir!ritonavir( Aith AT0!r, a so ewhat greater initial eGFR decline was observed 2first % onths4, while si ilar, stable eGFR was observed thereafter( Slide '=: G6posure to ata-anavir has been well recognised as a risk factor for developing kidney stones( These stones on che ical analysis consist of 2al ost4 pure ata-anavir( /n other patients, drug precipitation and crystal for ation ay lead to an interstitial nephritis with loss of kidney function( Slide '$: The propensity to for kidney stones appears uni#ue to ata-anvir( /n this study, no risk factors were identified( Slide 23: ?y contrast, this study fro 7ondon noted eGFR E%3 at the ti e of AT0 initiation in nearly half of all patients who developed kidney stones, suggesting that low eGFR ay be a potent risk factor for subse#uent stone for ation( Slide 2': This Table su arises the effects of current AR01s on the kidney 5 these effects ay be relatively benign and non&progressive 2and thus not treat ent&li iting4 or severe and typically re#uiring treat ent discontinuation( Treat ent li iting events are generally rare with an overall prevalence of '&2: or less( Slide 22: /n the HD, these data have been incorporated in the 23'2 version of the >/0 treat ent guidelines: tenofovir and ata-anavir are best avoided in patients with eGFR E%3 if suitable alternatives are available( This advice ay be

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e6tended to those with an eGFR 8ust above %3 2i(e( E;.4 who are eGFR decline and progression to ,D+(

ost at risk of

Slide 2): And this is what ore or less happens in clinical practice: an eGFR E;3 was associated with an increased likelihood that tenofovir was discontinued, and an eGFR E.3 with an increased likelihood that ata-anavir was discontinued(