Case report Transmitted raltegravir resistance in an HIV-1 CRF_AG-infected patient

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1 Antivirl Therpy 2011; 16: in press (doi: /IMP1749) Cse report Trnsmitted rltegrvir resistnce in n HIV-1 CRF_AG-infected ptient Srit D Boyd 1,2,3 *, Frnk Mldrelli 4, Irini Sereti 2, G Liss Ouedrogo 1,2,5, Ctherine A Rehm 2, Vlerie Boltz 6, Din Shoemker 2, Alice K Pu 2 1 SAIC-Frederick, Inc., Frederick, MD, USA 2 Ntionl Institute of Allergy nd Infectious Diseses, Ntionl Institutes of Helth, Bethesd, MD, USA 3 Present: Center for Drug Evlution nd Reserch, US Food nd Drug Administrtion, Silver Spring, MD, USA 4 HIV Drug Resistnce Progrm, Ntionl Cncer Institute, Ntionl Institutes of Helth, Bethesd, MD, USA 5 Present: Henry Jckson Foundtion, Division of AIDS, Bethesd, MD, USA 6 HIV Drug Resistnce Progrm, Ntionl Cncer Institute, Ntionl Institutes of Helth, Frederick, MD, USA *Corresponding uthor e-mil: srit.boyd@fd.hhs.gov Here, we describe n HIV-infected ptient with pretretment resistnce to rltegrvir, nucleoside reverse trnscriptse inhibitors, non-nucleoside reverse trnscriptse inhibitors nd protese inhibitors, nd the ultimte bility to chieve virl suppression. Pretretment integrse resistnce testing is not routinely performed becuse trnsmitted integrse muttions conferring resistnce to rltegrvir re currently thought to be negligible. We suggest obtining pretretment integrse genotype in ptients with trnsmitted multiclss drug resistnce in order to crete n optiml first regimen nd increse the chnce for virologicl suppression. Introduction Trnsmitted drug resistnce occurs t reported percentge of 8 15% of HIV-infected ptients in the United Sttes nd commonly involves muttions ffecting nucleoside reverse trnscriptse inhibitors (NRTIs), non-nucleoside reverse trnscriptse inhibitors (NNRTIs) nd, to lesser extent, protese inhibitors (PIs) [1 3]. As result, tretment guidelines recommend obtining stndrd genotype prior to strting ntiretrovirl therpy (ART) [4]. Rltegrvir, the first FDA-pproved HIV integrse strnd trnsfer inhibitor (INSTI), commonly used in slvge regimens, is now n option for use s prt of first-line ART in tretment-nive ptients. Given the lck of evidence of trnsmitted rltegrvir resistnce to dte, tretment guidelines currently do not recommend obtining n integrse genotype prior to strting rltegrvir-bsed regimen [4]. Here, we report cse of trnsmitted multiclss drug resistnce, including rltegrvir, PIs, NNRTIs nd NRTIs, nd the difficulty in chieving virl suppression. Cse The ptient is 47-yer-old femle who immigrted to the United Sttes from Cmeroon in 2001 nd ws well until September 2009 when she ws hospitlized with cerebrl toxoplsmosis nd found to be infected with HIV-1 CRF_AG. The ptient hd n HIV RNA of 179,826 copies/ml nd CD4 + T-cell count of 4 cells/mm 3. She ws treted with sulfdizine, pyrimethmine nd leucovorin for 3 weeks during hospitliztion nd for 4 weeks fter dischrge, with rdiogrphic improvement of the toxoplsmosis lesions. Her course ws complicted by new onset seizure, which ws treted with phenytoin nd subsequently chnged to levetircetm 5 dys prior to ART initition to void potentil cytochrome P450 (CYP)- medited drug interctions. Becuse of the desire to void efvirenz nd PIs until wshout of CYP induction effects of phenytoin nd bsed on the pretretment genotype test (TRUGENE TM HIV-1; Siemens Helthcre Dignostics, Deerfield, IL, USA), which noted the presence of mjor nd minor PI resistnce muttions nd one thymidine nlogue muttion, the ptient ws strted on rltegrvir nd tenofovir disoproxil fumrte/emtricitbine tretment. Figure 1 shows the ptient s ntiretrovirl regimens, HIV RNA, CD4 + T-cell count nd resistnce testing results up to week 48 of therpy Interntionl Medicl Press (print) (online) Pge numbers not for cittion purposes 1

2 SD Boyd et l. Figure 1. Antiretrovirl regimens, HIV RNA, CD4 + T-cell count nd resistnce testing results through to week 48 of tretment 7 RAL + TDF/ FTC EFV/TDF/FTC DRV/r + RAL + TDF/FTC DRV/r + ETR + TDF/FTC DOT: 3 doses f DOT: 22 doses Plsm HIV RNA, log 10 copies/ml b c e d Virl lod CD4 + T-cell count CD4 + T-cell count, cells/mm 3 2 HIV RNA =50 copies/ml Weeks on ntiretrovirl therpy Stndrd genotype testing: the nucleoside reverse trnscriptse inhibitor (NRTI) muttions detected were T215N/T/Y/S; nd the protese inhibitors (PI) muttions detected were L10I/V, V11I/V, I13V, G16E, K20I, L33F, M36I, M46M/L, Q58Q/E, H69K, T74P nd L89M. b Allele-specific PCR: the non-nucleoside reverse trnscriptse inhibitor (NNRTI) muttion detected bove bckground levels ws K103N. c Integrse genotype testing: the INSTI muttions detected were N155H/N, E138E/D, E157E/Q nd G163G/R. d Integrse genotype testing: the INSTI muttions detected were N155H, E157Q, G163R nd N232D. Stndrd genotype testing: the NRTI muttions detected were T215N/T/Y/S; nd PI muttions detected were L10I/V, V11I, K20I, L33F, M36I, M46L, Q58E nd T74P. e Integrse phenotype testing: 25-fold chnge in rltegrvir 50% inhibitory concentrtion. f Stndrd genotype testing: the NNRTI muttions detected were K103N nd V108I; the NRTI muttion detected ws M184V; nd the PI muttions were I13V, G16E, K20I, M36I, H69K nd L89M. DOT, directly observed therpy; DRV/r, drunvir plus low-dose ritonvir; EFV, efvirenz; ETR, etrvirine; FTC, emtricitbine; RAL, rltegrvir; TDF, tenofovir disoproxil fumrte. At week 2 fter inititing ART, the ptient s HIV RNA declined 100-fold from bseline to 1,915 copies/ ml. At week 4, however, her HIV RNA remined reltively unchnged t 5,228 copies/ml. In order to better ssess dherence, stored smple from week 2 ws sent to determine rltegrvir concentrtion (HPLC ssy; University of Florid, College of Phrmcy, Infectious Disese Phrmcokinetics Lbortory, Ginesville, FL, USA), which ws 300 ng/ml. The therpeutic trough of rltegrvir, lthough not definitively estblished, hs widely vried, rnging from <20 to 2,470 ng/ml with medin of 90 ng/ml [5]. Bsed on therpeutic rltegrvir concentrtion, pill count, refill history nd self-report, the ptient ppered to be dherent to her medictions. At week 4, rltegrvir ws chnged to efvirenz for ptient convenience. By week 8, however, the ptient s HIV RNA returned to pretretment level (268,036 copies/ml) nd stndrd genotype reveled K103N nd M184V muttions. Although resistnce to NNRTIs ws not seen on the pretretment stndrd genotype, n llele-specific PCR (NCI Drug Resistnce Progrm Core Lbortory, Frederick, MD, USA) performed on pretretment stored smple suggested tht low-level K103N ws present bove bckground levels. Pretretment NNRTI resistnce muttions Y181C nd G190A nd the NRTI muttion M184V were not detected by llele-specific PCR. At week 12, the ptient s regimen ws switched to drunvir/ritonvir (600 mg/100 mg twice dily) with re-initition of rltegrvir nd continution of tenofovir disoproxil fumrte/emtricitbine. Her HIV RNA declined but filed to remin <50 copies/ml. Adherence ws gin confirmed by pill count, refill history, pillbox check, self-report nd fmily report. Drunvir trough 2 Pge numbers not for cittion purposes 2011 Interntionl Medicl Press

3 Trnsmitted rltegrvir, PI, NNRTI nd NRTI drug resistnce Tble 1. Designtion of the ptient s pretretment genotypic muttions s drug resistnce muttions by three sources, nd the prevlence of ech muttion in tretment-nive CRF_AG HIV-1-infected ptients Ptient pretretment IAS USA drug resistnce Stnford University Surveillnce drug Prevlence in tretment-nive muttions muttion HIVdb muttion b resistnce muttion c CRF_AG ptients, % c NRTI T215N 0 T215T 0 T215Y X X X 0 T215S X X 0.1 NNRTI K103N X X X 0.2 PI L10I X X 4.9 L10V X X 10 V11I X X 2 I13V X 92 G16E X X 21 K20I X X 93 L33F X X Mjor 0.4 M36I X X 97 M46L X Mjor X Mjor X 0.3 Q58E X Mjor X 0 H69K X 97 T74P X Mjor X 0.1 L89M X 96 From [11]. b From [12]. c From [7]. IAS USA, Interntionl AIDS Society USA; HIVdb, HIV Drug Resistnce Dtbse; NRTI, nucleoside reverse trnscriptse inhibitor; NNRTI, non-nucleoside reverse trnscriptse inhibitor; PI, protese inhibitor. levels (1,320 ng/ml nd 1,740 ng/ml; HPLC ssy) mesured 10 weeks prt were t the lower end of the therpeutic trough rnge seen in tretment-experienced clinicl trils (1,255 7,368 ng/ml) [6], prompting n increse in drunvir dose to 800 mg twice dily. At the sme time, rltegrvir ws switched to etrvirine, nd her HIV RNA consequently declined to <50 copies/ml. An integrse genotype (HIV GenoSURE; LbCorp, Reserch Tringle Prk, NC, USA) performed on stored smple from week 2 reveled mjor rltegrvir muttion, N155H, nd minor muttions E157Q nd G163R. A rltegrvir phenotype (PhenoSense Integrse; Monogrm Biosciences, Inc., Sn Frncisco, CA, USA) from week 4 stored smple showed 25-fold increse in resistnce, indicting substntil reduction in susceptibility to rltegrvir, nd 36% repliction cpcity, suggesting virus with reduced repliction compred with the pnl43 lbortory strin. These results prompted us to obtin n integrse genotype (HIV-1 Integrse Genotype; Quest Dignostics, Nichols Institute, Sn Jun Cpistrno, CA, USA) on pre-art stored smple, which reveled tht the rltegrvir resistnce muttions were present before rltegrvir exposure. The ptient repetedly denied receiving ny ntiretrovirl medictions prior to entering into cre t our clinic nd dmitted to potentil HIV exposure in the United Sttes s lte s December 2008 with mle prtner from Cmeroon. Her history nd pretretment genotypes, including number of muttions in the surveillnce drug resistnce muttion list [7] (Tble 1), strongly suggest she cquired resistnce to four ntiretrovirl drug clsses, including INSTI, vi trnsmission. Discussion To our knowledge, this cse is the first report of trnsmitted rltegrvir resistnce muttions in tretmentnive ptient infected with HIV-1 CRF_AG. Rltegrvir trnsmitted resistnce hs been reported in the United Sttes [8]; s rltegrvir use nd subsequent filure increses, the number of ptients with integrse muttions is likely to increse. The frequency of rltegrvir resistnce nd risk of trnsmitting rltegrvir-resistnt HIV is uncler, nd whether the prevlence of trnsmitted integrse resistnce will be similr to NRTIs nd NNRTIs or reltively low s with PIs remins to be seen. Our cse dds to the evidence tht rltegrvir resistnce cn be cquired during primry infection nd, furthermore, trnsmission of four-clss drug resistnce is possible. Trnsmitted resistnce muttions ffecting NRTIs, NNRTIs nd, to lesser extent, PIs hve been reported in ptients with CRF_AG [9,10], similr to ptients with other HIV subtypes nd recombinnt forms. Antivirl Therpy Pge numbers not for cittion purposes 3

4 SD Boyd et l. Although mny of our ptient s pretretment protese muttions re highly prevlent in tretment-nive CRF_AG ptients, 2 3 re mjor protese muttions [11,12] prevlent in <0.5% of tretment-nive CRF_ AG ptients [7] (Tble 1). Mny of her pretretment muttions re considered drug resistnce muttions by the Interntionl AIDS Society USA nd the Stnford University dtbse [11,12], but the observtion tht she hrboured surveillnce drug resistnce muttions T215Y/S, K103N nd M46L (Tble 1) supports the notion tht she hd trnsmitted drug resistnce [7]. Trnsmitted integrse resistnce regrdless of subtype or recombinnt form hs not yet been widely reported given tht rltegrvir is reltively new drug with novel mechnism of ction. Integrse genotypic nd phenotypic studies in INSTI-nive ptients hve shown tht E157Q nd G163R cn occur nturlly, prticulrly in CRF_AG viruses, but cuse little-to-no rltegrvir resistnce [13 15]. By contrst, the mjor muttion N155H hs not been routinely detected in INSTI-nive ptients, even by llele-specific PCR [16], nd primrily occurs s result of rltegrvir tretment filure [17]. Therefore, it is highly likely tht our ptient cquired N155H through infection but possible tht the minor muttions occurred nturlly. Current stndrd commercil genotyping/phenotyping ssys do not detect resistnce muttions below threshold of 10 20% nd do not routinely include nlysis of integrse resistnce. Bsed on the pretretment stndrd genotype test result, our ptient s first regimen of rltegrvir plus tenofovir disoproxil fumrte/emtricitbine presumbly contined three fully ctive drugs nd ws currently preferred regimen for tretment-nive ptients bsed on the Deprtment of Helth nd Humn Services guidelines [4]. Preexisting rltegrvir resistnce ws not found until stored smple ws sent for integrse genotype testing. Furthermore, the bseline stndrd genotype did not detect the NNRTI resistnce muttion K103N, which ws lter found t very low levels. A lck of these test results prior to tretment initition, neither of which re current stndrd of cre, contributed to filure of the ptient s first two regimens. Our determintion of her lck of prior therpy is bsed on her denil of hving received ny medicl cre from 2001 until lte She hs been resident of the United Sttes for mny yers, nd she reports sexul contct with mn from Cmeroon since rriving in the United Sttes from whom she my hve been infected. Specificlly, she resides in Mrylnd, where the rte of non-subtype B infection hs been reported to be pproximtely 13%, of which CRF_AG is most common [18]. The peripherl CD4 + T-cell count mesured in this ptient ws profoundly suppressed, suggesting tht she ws infected for prolonged period or hd rpid loss of CD4 + T-cells s consequence of infection. The ptient s humn leukocyte ntigen type ws B*07, which hs not been ssocited with rpid progression to AIDS [19]. If she ws initilly infected prior to rltegrvir vilbility, she my hve been re-infected with resistnt virus more recently. Despite lck of informtion of HIV trnsmission in this ptient, these dt highlight the potentil for multidrug resistnce even in non-b subtypes circulting in the United Sttes. HIV RNA decline t weeks 2 nd 4 in the presence of n dequte rltegrvir concentrtion nd rltegrvir muttions my represent residul ctivity of rltegrvir despite the mjor muttion N155H. Upon restrting rltegrvir t week 12 in slvge-like regimen, HIV RNA reched <50 copies/ml, which ws likely becuse of the high potency of drunvir/ritonvir nd ctivity of tenofovir disoproxil fumrte rther thn residul ctivity of rltegrvir. Subsequent increse of HIV RNA by >10-fold by week 26 confirmed insufficient rltegrvir ctivity in the presence of N155H nd incresed risk of virologicl filure. Rltegrvir ws discontinued fter virologicl rebound s continution of rltegrvir- bsed regimen in the fce of rltegrvir resistnce with ongoing virl repliction my select for dditionl integrse muttions [20], which my or my not ffect the use of future, second-genertion integrse inhibitors [21,22]. First- genertion integrse inhibitors, rltegrvir nd elvitegrvir, pper to shre mjor resistnce pthwys, but second- genertion integrse inhibitors my hve ctivity in the presence of some integrse muttions [21,22]. Despite multiclss resistnce, it ws still possible to construct suppressive regimen with PI, NNRTI nd NRTI components for this ptient. Integrse inhibitors represent new clss of ntiretrovirl drugs with incresing usge in both tretmentnive nd tretment-experienced ptients. This cse provides evidence tht rltegrvir resistnce muttions cn be cquired t the time of HIV trnsmission. Although pretretment integrse genotypes re not current stndrd of cre, prctitioners my consider obtining one before strting rltegrvir-bsed regimen in tretment-nive ptient if significnt resistnce muttions re present on the stndrd genotype. Acknowledgements This work ws supported in prt by the Intrmurl Reserch Progrm of the Ntionl Institute of Allergy nd Infectious Diseses, Ntionl Institutes of Helth. It is lso funded, in prt, with federl funds from the Ntionl Cncer Institute, Ntionl Institutes of Helth, under contrct number HHSN E. The content of this publiction does not necessrily reflect the views or policies of the Deprtment of Helth nd Humn Services, nor does mention of trde nmes, 4 Pge numbers not for cittion purposes 2011 Interntionl Medicl Press

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