qanastek/EMEA-V3 huggingface dataset:
Caution should be exercised when prescribing adefovir dipivoxil to the elderly, keeping in mind the greater frequency of decreased renal or cardiac function in these patients, and the increase in concomitant diseases or concomitant use of other medicinal products in the elderly.
Għandha tingħata attenzjoni meta adefovir dipivoxil jingħata b’ riċetta lill- anzjani billi wieħed iżomm f’ moħħu l- frekwenza akbar ta ’ tnaqqis fil- funzjoni renali u tal- qalb f’ dawn il- pazjenti u ż- żieda ta ’ mard konkomitanti jew użu konkomitanti ta ’ prodotti mediċinali fl- anzjani.
Resistance to adefovir dipivoxil (see section 5.1) can result in viral load rebound which may result in exacerbation of hepatitis B and, in the setting of diminished hepatic function, lead to liver decompensation and possible fatal outcome.
Ir- reżistenza għal adefovir dipivoxil (ara sezzjoni 5. 1) tista ’ tirriżulta f’ viral load rebound li tista ’ tirriżulta fl- aggravament ta ’ epatite B u, fl- isfond ta ’ funzjoni epatika mnaqqsa, twassal għal dikumpensazzjoni epatika u għall- possibbiltà ta ’ riżultat fatali.
Virological response should be closely monitored in patients treated with adefovir dipivoxil, with HBV DNA measured every 3 months.
Ir- rispons viroloġiku għandu jkun immonitorjat mill- qrib f’ pazjenti kkurati b’ adefovir dipivoxil, bid- DNA tal- HBV li għandha titkejjel 5 kull 3 xhur.
If viral rebound occurs, resistance testing should be performed.
Jekk isseħħ il- viral rebound, għandu jsir ittestjar għar- reżistenza.
In case of emergence of resistance, treatment should be modified.
F’ każ ta ’ żvilupp ta ’ reżistenza, il- kura għandha tkun mibdula.
Patients should be advised that therapy with adefovir dipivoxil has not been proven to reduce the risk of transmission of hepatitis B virus to others and therefore appropriate precautions should still be taken.
Il- pazjenti għandhom jiġu avżati li ma kienx ippruvat li t- terapija b’ adefovir dipivoxil tnaqqas ir- riskju ta ’ trasmissjoni tal- virus ta ’ l- epatite B lil ħaddieħor u għalhekk xorta jridu jittieħdu prekawzjonijiet adegwati.
Hepsera contains lactose monohydrate.
Hepsera fiha lactose monohydrate.
Consequently, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
Konsegwentement, pazjenti li għandhom problemi ereditarji rari ta ’ intolleranza għall- galactose, nuqqas ta ’ Lapp lactase jew għandhom problemi biex jassorbu l- glucose - galactose m’ għandhomx jieħdu dan il- prodott mediċinali.
5 4.5 Interaction with other medicinal products and other forms of interaction
4. 5 Prodotti mediċinali oħra li ma jaqblux ma ’ dan il- prodott u affarijiet oħra li jistgħu jibdlu l- effett farmaċewtiku tal- prodott
Interaction studies have only been performed in adults.
Ma sarux studji dwar l- effett ta ’ mediċini jew ta ’ affarijiet oħra fuq l- effett farmaċewtiku tal- prodott fl - adulti.
The potential for CYP450 mediated interactions involving adefovir with other medicinal products is low, based on the results of in vitro experiments in which adefovir did not influence any of the common CYP isoforms known to be involved in human drug metabolism and based on the known elimination pathway of adefovir.
Il- potenzjal ta ’ interazzjonijiet medjati minn CYP450 li jinvolvu adefovir ma ’ prodotti mediċinali oħra hu baxx, ibbażat fuq ir- riżultati ta ’ esperimenti in vitro li fihom adefovir ma influwenzax l- ebda waħda mill- iżoformi komuni CYP magħrufa li huma involuti fil- metaboliżmu tal- mediċini fil- bnedmin u li huma bbażati fuq ir- rotta ta ’ eliminazzjoni magħrufa ta ’ adefovir.
A clinical study in liver-transplant patients has shown that no pharmacokinetic interaction occurs when adefovir dipivoxil 10 mg once daily is administered concomitantly with tacrolimus, an immunosuppressant which is predominantly metabolised via the CYP450 system.
Studju kliniku f’ pazjenti li kellhom trapjant tal- fwied wera li ma sseħħ l- ebda interazzjoni farmakokinetika meta 10 mg ta ’ adefovir dipivoxil jingħataw darba kuljum flimkien ma ’ tacrolimus, immunosuppressant li hu fil- biċċa l- kbira tiegħu metabolat permezz tas- sistema CYP450.
A pharmacokinetic interaction between adefovir and the immunosuppressant, cyclosporin, is also considered unlikely as cyclosporin shares the same metabolic pathway as tacrolimus.
Interazzjoni farmakokinetika bejn adefovir u l- immunosuppressant cyclosporin, hi wkoll ikkunsidrata li x’ aktarx li mhux ser isseħħ, għax cyclosporin jaqsam l- istess rotta metabolika ta ’ tacrolimus.
Nevertheless, given that tacrolimus and cyclosporin can affect renal function, close monitoring is recommended when either of these agents is coadministered with adefovir dipivoxil (see section 4.4).
Madankollu, minħabba li tacrolimus u cyclosporin jistgħu jaffettwaw il- funzjoni renali, monitoraġġ mill- qrib hu rakkomandat meta xi wieħed minn dawn is- sustanzi jingħata flimkien ma ’ adefovir dipivoxil (ara sezzjoni 4. 4).
Concomitant administration of 10 mg adefovir dipivoxil and 100 mg lamivudine did not alter the pharmacokinetic profile of either medicinal product.
L- għoti flimkien ta ’ 10 mg ta ’ adefovir dipivoxil u ta ’ 100 mg lamivudine ma bidilx il- profil farmakokinetiku ta ’ l- ebda wieħed minn dawn il- prodotti mediċinali.
Co-administration of 10 mg adefovir dipivoxil with other medicinal products that are eliminated by tubular secretion or alter tubular function may increase serum concentrations of either adefovir or the co-administered medicinal product (see section 4.4).
L- għoti flimkien ta ’ 10 mg ta ’ adefovir dipivoxil ma ’ prodotti mediċinali oħra li huma eliminati permezz ta ’ sekrezzjoni tubulari jew li jibdlu l- funzjoni tubulari tista ’ żżid il - konċentrazzjonijiet fis- serum jew ta ’ adefovir jew tal- prodott mediċinali mogħti flimkien (ara sezzjoni 4. 4).
No data on the concomitant use with other medicinal products (including interferon) are available.
M’ hemmx informazzjoni disponibbli dwar l- użu flimkien ma ’ prodotti mediċinali oħra (fosthom interferon).
There are no adequate data on the use of adefovir dipivoxil in pregnant women.
M’ hemmx tagħrif biżżejjed dwar l- użu ta ’ adefovir dipivoxil waqt it- tqala.
Studies in animals administered adefovir intravenously have shown reproductive toxicity (see section 5.3).
Studji fuq annimali li ngħataw adefovir ġol- vini wrew ħsara fuq is- sistema riproduttiva (ara sezzjoni 5. 3).
Studies in orally dosed animals do not indicate teratogenic or foetotoxic effects.
Studji fuq annimali li ngħataw doża mill- ħalq ma jurux effetti teratoġeniċi jew fetotossiċi.
Adefovir dipivoxil should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Adefovir dipivoxil għandu jintuża biss waqt it- tqala jekk il- benefiċċju potenzjali jiġġustifika r- riskju possibbli għall- fetu uman.
There are no data on the effect of adefovir dipivoxil on transmission of HBV from mother to infant.
M’ hemmx informazzjoni dwar l- effett ta ’ adefovir dipivoxil fit- trasmissjoni ta ’ HBV mill- omm għat - tarbija.
Therefore, the standard recommended procedures for immunisation of infants should be followed to prevent neonatal acquisition of HBV.
Għalhekk il- proċeduri standard irrakkomandati għat- tilqim tat- trabi għandhom jiġu segwiti biex jiġu evitat it- teħid ta ’ l- HBV mit- tarbija.
Given that the potential risks to developing human foetuses are unknown, it is recommended that women of child-bearing potential treated with adefovir dipivoxil use effective contraception.
6 Madankollu, peress li r- riskji potenzjali għal- feti umani li qegħdin jiżviluppaw m’ humiex magħrufa, hu rakkomandat li n- nisa li jistgħu joħorġu tqal għandhom jużaw kontraċettiv effettiv waqt it - trattament b’ adefovir dipivoxil.
It is not known whether adefovir is excreted in human milk.
Mhux magħruf jekk adefovir joħroġx fil- ħalib tas- sider.
Mothers should be instructed not to breast-feed if they are taking adefovir dipivoxil tablets.
L- ommijiet għandhom jingħataw struzzjonijiet biex ma jreddgħux jekk ikunu qegħdin jieħdu l- pilloli ta ’ adefovir dipivoxil.
However, based on the safety profile and mechanism of action, adefovir dipivoxil is expected to have no or negligible influence on these abilities.
Madankollu, ibbażat fuq il - profil tas- sigurtà u l- mekkaniżmu ta ’ l- azzjoni, adefovir dipivoxil hu mistenni li ma jkollu l- ebda jew ftit li xejn effett fuq dawn il- ħiliet.
In patients with compensated liver disease, the most frequently reported adverse reactions during 48 weeks of adefovir dipivoxil therapy were asthenia (13%), headache (9%), abdominal pain (9%) and nausea (5%).
F’ pazjenti b’ mard tal- fwied kumpensat, l- aktar reazzjonijiet avversi li kienu rrappurtati b’ mod frekwenti matul 48 ġimgħa ta ’ terapija b’ adefovir dipivoxil kienu astenja (13%), uġigħ ta ’ ras (9%), uġigħ addominali (9%) u tqalligħ (5%).
6 Assessment of adverse reactions is based on experience from post-marketing surveillance and from three pivotal clinical studies in patients with chronic hepatitis B:
L- istima ta ’ reazzjonijiet avversi hija bbażata fuq esperjenza minn sorveljanza ta ’ wara t- tqegħid fis - suq u minn tliet studji kliniċi ta ’ importanza kbira f’ pazjenti b’ epatite B kronika:
• two placebo-controlled studies in which 522 patients with chronic hepatitis B and compensated liver disease received double-blind treatment with 10 mg adefovir dipivoxil (n=294) or placebo (n=228) for 48 weeks. • an open-label study in which pre- (n=226) and post-liver transplantation patients (n=241) with lamivudine-resistant HBV were treated with 10 mg adefovir dipivoxil once daily, for up to 203 weeks (median 51 and 99 weeks, respectively).
• żewġ studji kkontrollati bi plaċebo, li fihom 522 pazjent b’ epatite B kronika u mard tal- fwied kumpensat li ngħataw trattament double- blind b’ 10 mg ta ’ adefovir dipivoxil (n=294) jew plaċebo (n=228) għal 48 ġimgħa. • fi studju open- label li fih pazjenti ta ’ qabel (n=226) u wara t- trapjant tal- fwied (n=241) b’ HBV reżistenti għal lamivudine kienu kkurati b’ 10 mg ta ’ adefovir dipivoxil darba kuljum, għal sa 203 ġimgħa (medjan 51 u 99 ġimgħa, rispettivament).
The adverse reactions considered at least possibly related to treatment are listed below, by body system organ class, and frequency.
Ir- reazzjonijiet avversi kkunsidrati li kienu possibbilment assoċjati mat- trattament huma elenkati hawn taħt, skond il- klassi ta ’ sistema ta ’ l- organi fil- ġisem u skond il- frekwenza.
Frequencies are defined as very common (≥ 1/ 10), common (≥ 1/ 100, < 1/ 10) or not known (identified through post-marketing safety surveillance and the frequency cannot be estimated from the available data).
Il- frekwenzi huma deskritti bħala komuni ħafna (≥ 1/ 10), komuni (≥ 1/ 100, < 1/ 10) jew mhux magħrufa (identifikati permezz ta ’ sorveljanza tas- sigurtà wara t- tqegħid fis- suq u għall- frekwenza ma tistax tittieħed stima mid- data disponibbli).
Common (≥ 1/ 100, < 1/ 10): headache.
Komuni (≥ 1/ 100, < 1/ 10): uġigħ ta ’ ras.
Common (≥ 1/ 100, < 1/ 10): diarrhoea, vomiting, abdominal pain, dyspepsia, nausea, flatulence.
Komuni (≥ 1/ 100, < 1/ 10): dijarrea, rimettar, uġigħ addominali, dispepsja, tqalligħ, gass fl- istonku.
Frequency not known: pancreatitis.
Frekwenza mhux magħrufa: pankreatite.
Common (≥ 1/ 100, < 1/ 10): rash, pruritus.
Komuni (≥ 1/ 100, < 1/ 10): raxx, ħakk.
Musculoskeletal and connective tissue disorders:
Disturbi muskolu- skeletrali u tal- connective tissue:
Frequency not known: myopathy, osteomalacia (both associated with proximal renal tubulopathy).
Frekwenza mhux magħrufa: mijopatija, osteomalaċja (it- tnejn assoċjati ma ’ tubulopatija prossimali renali).
Very common (≥ 1/ 10): increases in creatinine.
Komuni ħafna (≥ 1/ 10): żidiet fil- krejatinina.
Common (≥ 1/ 100, < 1/ 10): renal failure, abnormal renal function, hypophosphatemia.
Komuni (≥ 1/ 100, < 1/ 10): kollass tal- kliewi, funzjoni renali anormali, ipofosfatimja.
Fanconi syndrome, proximal renal tubulopathy.
Frekwenza mhux magħrufa: is- sindromu ta ’ Fanconi, tubulopatija prossimali renali.
General disorders and administration site conditions:
7 Disturbi ġenerali u kundizzjonijiet ta ’ mnejn jingħata:
Very common (≥ 1/ 10): asthenia.
Komuni ħafna (≥ 1/ 10): astenja.
Exacerbation of hepatitis:
Epatite li tmur għall- agħar:
Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of treatment with 10 mg adefovir dipivoxil (see section 4.4).
Evidenza klinika u tal- laboratorju ta ’ epatite li tmur għall- agħar seħħet wara l- waqfien tat- trattament b’ 10 mg ta ’ adefovir dipivoxil (ara sezzjoni 4. 4).
Long-term safety data in patients with compensated disease:
Dejta dwar is- sigurtà fit- tul f’ pazjenti f’ mard kumpensat:
In a long-term safety study of 125 HBeAg negative patients with compensated liver disease, the adverse event profile was overall unchanged after a median exposure of 226 weeks.
Fi studju fit- tul dwar is- sigurtà ta ’ 125 pazjent negattivi għal HBeAg b’ mard tal- fwied kumpensat, ġeneralment ma kienx hemm bidla fil- profil ta ’ l- effetti avversi wara espożizzjoni medjana ta ’ 226 ġimgħa.
No clinically significant changes in renal function were observed.
L- ebda tibdil klinikament sinifikanti fil- funzjoni renali ma kienu osservati.
However, mild to moderate increases in serum creatinine concentrations, hypophosphatemia and a decrease in carnitine concentrations were reported in 3%, 4% and 6% of patients, respectively, on extended treatment.
Madankollu, żidiet minn ħfief sa moderati fil- konċentrazzjonijiet tal- krejatinina fis- serum, ipofosfatimja u nuqqas fil- konċentrazzjonijiet tal- carnitine kienu rrappurtati fi 3%, 4% u 6% tal- pazjenti rispettivament, li kienu fuq trattament imtawwal.
In a long-term safety study of 65 HBeAg positive patients with compensated liver disease (after a median exposure of 234 weeks), 6 patients (9%) had confirmed increases in serum creatinine of at least 0.5 mg/ dl from baseline with 2 patients discontinuing from the study due to the elevated serum creatinine concentration.
Fi studju fit- tul dwar is- sigurtà ta ’ 65 pazjent pożittivi għal HBeAg b’ mard tal- fwied kumpensat (wara medjan ta ’ esponiment ta ’ 234 ġimgħa), 6 pazjenti (9%) kellhom żidiet ikkonfermati fil- krejatinina fis - serum ta ’ mill- inqas 0. 5 mg/ dl mil- linja bażi, b’ 2 pazjenti li ma komplewx l- istudju minħabba l- konċentrazzjoni għolja tal- krejatinina fis- serum.
Patients with a confirmed increase in creatinine of ≥ 0.3 mg/ dl by week 48 were at a statistically significant higher risk of a subsequent confirmed increase in creatinine of ≥ 0.5 mg/ dl.
Pazjenti b’ żieda kkonfermata fil- krejatinina ta ’ ≥ 0. 3 mg/ dl sa ġimgħa 48 kienu f’ riskju ogħla li kien statistikament sinifikanti, ta ’ żieda kkonfermata sussegwenti fil- krejatinina ta ’ ≥ 0. 5 mg/ dl.
Hypophosphatemia and a decrease in carnitine concentrations were reported each in 3% of patients on extended treatment.
Ipofosfatemja u tnaqqis fil- konċentrazzjonijiet tal- carnitine kienu t- tnejn irrappurtati fi 3% tal- pazjenti li kienu fuq trattament imtawwal.
7 Safety in patients with decompensated disease:
Is- sigurtà f’ pazjenti b’ mard dikumpensat:
In patients with decompensated liver disease, the most frequently reported adverse reactions during up to 203 weeks of adefovir dipivoxil therapy were increased creatinine (7%) and asthenia (5%).
F' pazjenti b’ mard tal- fwied dikumpensat, l- aktar reazzjonijiet avversi rrappurtati b’ mod frekwenti matul sa 203 ġimgħa ta ’ terapija b’ adefovir dipivoxil kienu żieda fil- krejatinina (7%) u astenja (5%).
Renal toxicity is an important feature of the safety profile of adefovir dipivoxil in patients with decompensated liver disease.
It- tossiċità renali hi karatteristika importanti tal- profil tas- sigurtà ta ’ adefovir dipivoxil f’ pazjenti b’ mard tal- fwied dikumpensat.
In clinical studies of wait-listed and post-liver transplantation patients, four percent (19/ 467) of patients discontinued treatment with adefovir dipivoxil due to renal adverse events.
Fi studji kliniċi fuq pazjenti li kienu qed jistennew it- trapjant u ta ’ pazjenti ta ’ wara t- trapjant tal- fwied, erba ’ fil- mija (19/ 467) tal- pazjenti waqfu t- trattament b’ adefovir dipivoxil minħabba effetti avversi renali.
Administration of 500 mg adefovir dipivoxil daily for 2 weeks and 250 mg daily for 12 weeks has been associated with the gastrointestinal disorders listed above and anorexia.
L- għoti ta ’ 500 mg ta ’ adefovir dipivoxil għal ħmistax, u 250 mg kuljum għal 12- il ġimgħa kien assoċjat mal- disturbi gastrointestinali elenkat hawn fuq u l- anoressija.
If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
Jekk iseħħ każ ta ’ doża eċċessiva, il- pazjent għandu jiġi mmonitorjat għal sinjali ta ’ tossiċità, u t- trattament ta ’ appoġġ regolari għandu jingħata kif meħtieġ.
Adefovir can be removed by haemodialysis; the median haemodialysis clearance of adefovir is 104 ml/ min.
Adefovir jista ’ jitneħħa permezz ta ’ dijaliżi tad- demm; it- tneħħija b’ dijaliżi tad- demm medjana ta ’ adefovir hi ta ’ 104 ml/ min.
The elimination of adefovir by peritoneal dialysis has not been studied.
It- tneħħija ta ’ adefovir bid- dijaliżi peritoneali ma ġietx studjata.
Adefovir dipivoxil is an oral prodrug of adefovir, an acyclic nucleotide phosphonate analogue of adenosine monophosphate, which is actively transported into mammalian cells where it is converted by host enzymes to adefovir diphosphate.
Adefovir dipivoxil hu prodrug ta ’ adefovir li jittieħed mill- ħalq, acyclic nucleotide phosphonate analogue ta ’ adenosine monophosphate li jinġarr attivament fiċ- ċelluli tal- mammiferi fejn il- host enzymes jibdluh f’ adefovir diphosphate.
Adefovir diphosphate inhibits viral polymerases by competing for direct binding with the natural substrate (deoxyadenosine triphosphate) and, after incorporation into viral DNA, causes DNA chain termination.
Adefovir diphosphate jimpedixxi l- polimerases virali billi jikkompeti għat- twaħħil dirett mas- sottostrat naturali (deoxyadenosine triphosphate) u wara li jiġi inkorporat fid- DNA virali jikkawza t- terminazzjoni tal- katina tad- DNA.
Adefovir diphosphate selectively inhibits HBV DNA polymerases at concentrations 12-, 700-, and 10-fold lower than those needed to inhibit human DNA polymerases α, β, and γ, respectively.
Adefovir diphosphate jimpedixxi selettivament il- polimerases tad- DNA tal- HBV f’ konċentrazzjonijiet ta ’ 12 -, 700 -, u 10 darbiet anqas minn dawk meħtieġa biex jimpedixxu l- polimerases tad- DNA uman α, β, u γ 8 rispettivament.
Adefovir diphosphate has an intracellular half-life of 12 to 36 hours in activated and resting lymphocytes.
Adefovir diphosphate għandu half- life ta ’ bejn 12 u 36 siegħa f’ limfoċiti attivati u dawk li jkunu jistrieħu.
Adefovir is active against hepadnaviruses in vitro, including all common forms of lamivudine-resistant HBV (rtL180M, rtM204I, rtM204V, rtL180M/ rtM204V), famciclovir-associated mutations (rtV173L, rtP177L, rtL180M, rtT184S or rtV207I) and hepatitis B immunoglobulin escape mutations (rtT128N and rtW153Q), and in in vivo animal models of hepadnavirus replication.
Adefovir hu attiv in vitro kontra l- ħepadnaviri fosthom il- forom komuni kollha ta ’ HBV reżistenti għal lamivudine (rtL180M, rtM204I, rtM204V, rtL180M/ rtM204V), mutazzjonijiet assoċjati ma ’ famciclovir (rtV173L, rtP177L, rtL180M, rtT184S jew rtV207I) u l- mutazzjonijiet ta ’ l- immunoglobulina ta ’ l- epatite B li jaħarbu (rtT128N u rtW153Q), u in vivo f’ mudelli ta ’ l- annimali tar- replikazzjoni tal- ħepadnavirus.
The demonstration of the benefit of adefovir dipivoxil is based on histological, virological, biochemical, and serological responses in adults with:
Id- dimostrazzjoni tal- benefiċċji ta ’ adefovir dipivoxil hi bbażata fuq riżultati istoloġiċi, viroloġiċi, bijokimiċi u seroloġiċi f’ adulti b ’:
• HBeAg positive and HBeAg negative chronic hepatitis B with compensated liver disease.
• epatite B kronika HBeAg pożittiva u HBeAg negattiva b’ mard tal- fwied kumpensat.
• lamivudine-resistant HBV with either compensated or decompensated liver disease, including patients pre- and post-liver transplantation or co-infected with HIV.
• HBV reżistenti għal lamivudine jew b’ mard tal- fwied kumpensat jew mhux kumpensat fosthom pazjenti qabel ma kellhom, jew wara li kellhom, trapjant tal- fwied, jew li huma infettati ukoll bl- HIV.
In the majority of these studies adefovir dipivoxil 10 mg was added to ongoing lamivudine treatment in patients failing lamivudine therapy.
Fil- biċċa l- kbira ta ’ dawn l- istudji, 10 mg ta ’ adefovir dipivoxil ġie miżjud ma ’ trattament kurrenti b’ lamivudine f’ pazjenti li ma kienux qed jirnexxu bit- terapija b’ lamivudine.
In these clinical studies patients had active viral replication (HBV DNA ≥ 100,000 copies/ ml) and elevated ALT levels (≥ 1.2 x Upper Limit of Normal (ULN)).
F’ dawn l- istudji kliniċi l- pazjenti kellhom replikazzjoni virali attiva (DNA tal - HBV ≥ 100, 000 kopja/ ml) u livelli ta ’ l- ALT għolja (≥ 1. 2 x il- Limitu ta ’ Fuq tan- Normal (Upper Limit of Normal, ULN)).
Experience in patients with compensated liver disease:
Esperjenza f’ pazjenti b’ mard tal- fwied kumpensat:
In two placebo-controlled studies (total n=522) in HBeAg positive or in HBeAg negative chronic hepatitis B patients with compensated liver disease, significantly more patients (p < 0.001) in the 10 mg adefovir dipivoxil groups (53 and 64%, 8 respectively) had histological improvement from baseline at week 48 than in the placebo groups (25 and 33%).
F’ żewġ studji kkontrollati bil- plaċebo (total n=522) f’ pazjenti b’ epatite B kronika ta ’ HBeAg pożittiva jew HBeAg negattiva b’ mard tal- fwied kumpensat, numru sinifikanti akbar ta ’ pazjenti (p < 0. 001) fil- gruppi ta ’ 10 mg ta ’ adefovir dipivoxil (53 u 64%, rispettivament) kellhom titjib istoloġiku mil- linja bażi fil- Ġimgħa 48 minn dawk fil- gruppi plaċebo (25 u 33%).
Improvement was defined as a reduction from baseline of two points or more in the Knodell necro-inflammatory score with no concurrent worsening in the Knodell fibrosis score.
It- titjib ġie deskritt bħala tnaqqis mil- linja bażi ta ’ żewġ punti jew aktar fil- punteġġ nekro - infjammatorju ta ’ Knodell, bla ebda telf fil- punteġġ tal- fibrożi ta ’ Knodell.
Histological improvement was seen regardless of baseline demographic and hepatitis B characteristics, including prior interferon-alpha therapy.
Kien hemm titjib istoloġiku, kienu x’ kienu l- karatteristiċi tal- linja bażi demografika u epatite B, fosthom terapija preċedenti bl- interferon- alpha.
High baseline ALT levels (≥ 2 x ULN) and Knodell Histology Activity Index (HAI) scores (≥ 10) and low HBV DNA (< 7.6 log10 copies/ ml) were associated with greater histological improvement.
Livelli għolja tal- linja bażi fl- ALT (≥ 2 x ULN) u ta ’ l- Indiċi ta ’ l- Attività tal- Istoloġija (Histology Activity Index, HAI) ta ’ Knodell (≥ 10) u DNA tal- HBV baxxa (< 7. 6 log10 kopja/ ml) kienu assoċjati ma ’ titjib istoloġiku ikbar.
Blinded, ranked assessments of both necro- inflammatory activity and fibrosis at baseline and week 48, demonstrated that patients treated with 10 mg adefovir dipivoxil had improved necro-inflammatory and fibrosis scores relative to placebo- treated patients.
Stimi blinded u rrankjati, kemm ta ’ l- attività nekro- infjammatorja u kemm tal- fibrożi fil- linja bażi u fil- Ġimgħa 48, urew li l- pazjenti ttrattati b’ 10 mg ta ’ adefovir dipivoxil kellhom punteġġi ta ’ nekro- infjammazzjoni u ta ’ fibrożi aħjar meta mqabbla ma ’ dawk ta ’ pazjenti ttrattati bil- plaċebo.
Assessment of the change in fibrosis after 48 weeks treatment using the Knodell scores confirms that patients treated with adefovir dipivoxil 10 mg had more regression and less progression of fibrosis than patients treated with placebo.
L- istima tal- bidla fil- fibrożi bil- punteġġ ta ’ Knodell wara 48 ġimgħa ta ’ trattament jikkonferma li l- pazjenti ttrattati b’ 10 mg ta ’ adefovir dipivoxil kellhom aktar rigressjoni u anqas progressjoni tal - fibrożi minn pazjenti ttrattati bil- plaċebo.
In the two studies mentioned above, treatment with 10 mg adefovir dipivoxil was associated with significant reductions in serum HBV DNA (3.52 and 3.91 log10 copies/ ml, respectively, versus 0.55 and 1.35 log10 copies/ ml), increased proportion of patients with normalisation of ALT (48 and 72% versus 16 and 29%) or increased proportion of patients with serum HBV DNA below the limits of quantification (< 400 copies/ ml Roche Amplicor Monitor PCR assay) (21 and 51% versus 0%) when compared with placebo.
Fiż- żewġ studji msemmija hawn fuq, it- trattament b’ 10 mg ta ’ adefovir dipivoxil kien assoċjat ma ’ tnaqqis sinifikanti fis- serum tad- DNA tal- HBV (3. 52 u 3. 91 log10 kopja/ ml, rispettivament, kontra 0. 55 u 1. 35 log10 kopja/ ml), ma ’ numru akbar ta ’ pazjenti b’ normalizzazzjoni ta ’ l- ALT (48 u 72% kontra 16 u 29%) jew ma ’ numru akbar ta ’ pazjenti bis- serum tad- DNA tal- HBV taħt il- limiti tal - kwantifikazzjoni (< 400 kopja/ ml assay ta ’ Roche Amplicor Monitor PCR) (21 u 51% kontra 0%) meta mqabbla bl- plaċebo.
In the study in HBeAg positive patients, HBeAg seroconversion (12%) and HBeAg loss (24%) was observed significantly more frequently in patients receiving 10 mg adefovir dipivoxil than in patients receiving placebo (6% and 11%, respectively) after 48 weeks of treatment.
Fl- istudju f’ pazjenti HBeAg pożittivi, serokonverżjoni ta ’ HBeAg (12%) u tnaqqis ta ’ HBeAg (24%) kienu osservati b’ mod iżjed frekwenti sinifikanti f’ pazjenti li kienu jieħdu 10 mg ta ’ adefovir dipivoxil milli f’ pazjenti li kienu jieħdu l- plaċebo (6% u 11%, rispettivament) wara 48 ġimgħa ta ’ trattament.
In the HBeAg positive study, treatment beyond 48 weeks resulted in further reductions in serum HBV DNA levels and increases in the proportion of patients with ALT normalisation, HBeAg loss and seroconversion.
Fl- istudju dwar HBeAg pożittiv, trattament wara 48 ġimgħa rriżulta fi tnaqqis addizzjonali fil- livelli fis- serum tad- DNA tal- HBV u f’ żidiet fil- proporzjon ta ’ pazjenti b’ normalizzazzjoni ta ’ l- ALT, telfien ta ’ HBeAg, u serokonverżjoni.
In the HBeAg negative study patients on adefovir dipivoxil (0-48 weeks) were re-randomised in a blinded-manner to continue on adefovir dipivoxil or receive placebo for an additional 48 weeks.
Fl- istudju ta ’ pazjenti b’ HBeAg negattiv li kienu fuq adefovir dipivoxil (0- 48 ġimgħat) kienu randomised mill- ġdid b’ mod blinded biex ikomplu fuq adefovir dipivoxil jew jirċievu plaċebo għal 9 48 ġimgħa addizzjonali.
At week 96, patients continuing on adefovir dipivoxil 10 mg had sustained suppression of serum HBV with maintenance of the reduction seen at week 48.
Fil- Ġimgħa 96, il- pazjenti li komplew fuq 10 mg ta ’ adefovir dipivoxil kienu ġarrbu tnaqqis fis- serum ta ’ HBV, biż- żamma ta ’ dan it- tnaqqis li kienet innutata fil- Ġimgħa 48.
In over two thirds of patients suppression of serum HBV DNA was associated with normalisation of ALT levels.
F’ iżjed minn żewġ terzi tal- pazjenti, it- tnaqqis fis- serum ta ’ DNA tal- HBV kien assoċjat man - normalizzazzjoni tal- livelli ta ’ l- ALT.
In most patients who stopped treatment with adefovir dipivoxil, serum HBV DNA and ALT levels returned towards baseline.
Fil- biċċa l- kbira tal- pazjenti li waqqfu t- trattament b’ adefovir dipivoxil, il- livelli fis- serum ta ’ DNA tal- HBV irritornaw lejn il- linja bażi.
Treatment with adefovir dipivoxil resulted in improvement in the liver fibrosis from baseline to 96 weeks therapy when analysed using the Ishak score (median change:
It- trattament b’ adefovir dipivoxil irriżulta f’ titjib fil- fibrożi tal- fwied mil- linja bażi sa 96 ġimgħa ta ’ terapija meta analizzat bl- użu tal- punteġġ ta ’ Ishak (tibdil medjan:
No differences in the median fibrosis score were seen between groups using the Knodell fibrosis score.
L- ebda differenza fil - punteġġ medjan tal- fibrożi ma kienet innutata bejn il- gruppi bl- użu tal- punteġġ tal- fibrożi ta ’ Knodell.
Patients who completed the first 96 weeks of the HBeAg negative study and received adefovir dipivoxil treatment during weeks 49 to 96, were offered the opportunity to receive open-label treatment with adefovir dipivoxil from study week 97 through to week 240.
Pazjenti li temmew l- ewwel 96 ġimgħa ta ’ l- istudju dwar HBeAg negattiv u rċivew trattament ta ’ adefovir dipivoxil matul ġimgħat 49 sa 96, ingħataw l- opportunità li jirċievu trattament open- label b’ adefovir dipivoxil mill- ġimgħa ta ’ l- istudju 97 sa ġimgħa 240.
Serum HBV DNA levels remained undetectable and ALT levels normalised in approximately two thirds of patients following treatment with adefovir dipivoxil for up to 240 weeks.
Il- livelli tad- DNA tal- HBV fis- serum baqgħu ma jistgħux jiġu osservati u l- livelli ta ’ l- ALT innormalizzaw f’ madwar żewġ terzi tal- pazjenti wara t- trattament b’ adefovir dipivoxil sa 240 ġimgħa.
Clinically and statistically significant improvement in fibrosis was seen in the changes in Ishak scores from the start of adefovir dipivoxil treatment to the end of the study (week 240) (median change:
Titjib klinikament u statistikament sinifikanti fil- fibrożi ntwera fit- tibdil fil- punteġġi ta ’ Ishak mill- bidu tat- trattament b’ adefovir dipivoxil sat - tmiem ta ’ l- istudju (Ġimgħa 240) (tibdil medjan:
By the end of the study, 7 of 12 patients (58%) with bridging fibrosis or cirrhosis at baseline, had an improved Ishak fibrosis score of ≥ 2 points.
Sat- tmiem ta ’ l- istudju, 7 minn 12- il pazjent (58%) b’ fibrożi bridging jew ċirrożi fil- linja bażi, kellhom titjib fil- punteġġ tal- fibrożi ta ’ Ishak ta ’ ≥ 2 punti.
Five patients achieved and maintained HBsAg seroconversion (HBsAg negative/ HBsAb positive).
Ħamsa pazjenti laħqu u żammew serokonverżjoni ta ’ l- HBsAg (HBsAg negattiv/ HBsAb pożittiv).
Experience in patients pre- and post-liver transplantation with lamivudine-resistant HBV:
Esperjenza f’ pazjenti qabel u wara li kellhom it- trapjant tal- fwied, b’ HBV reżistenti għal lamivudine:
In a clinical study in 394 chronic hepatitis B patients with lamivudine-resistant HBV (pre-liver transplantation (n=186) and post-liver transplantation (n=208)), treatment with 10 mg adefovir dipivoxil resulted in a median reduction in serum HBV DNA of 4.1 and 4.2 log10 copies/ ml, respectively, at week 48.
Fi studju kliniku fi 394 pazjent b’ epatite B kronika u b’ HBV lamivudine reżistenti (ta ’ qabel it- trapjant tal- fwied (n=186) u ta ’ wara t- trapjant tal- fwied (n=208)), it- trattament b’ 10 mg ta ’ adefovir dipivoxil irriżulta fi tnaqqis medjan tad- DNA ta ’ HBV ta ’ 4. 1 u ta ’ 4. 2 log10 kopja/ ml, rispettivament, fil - Ġimgħa 48.
In the pre-liver transplantation and post-liver transplantation cohorts 77 of 109 (71%) patients and 64 of 159 (40%) patients, respectively, achieved undetectable HBV DNA levels at week 48 (< 1,000 copies/ ml Roche Amplicor Monitor PCR assay).
Fil- gruppi ta ’ qabel it- trapjant u ta ’ wara t- trapjant tal- fwied, 77 minn 109 (71%) tal - pazjenti u 64 minn 159 (40%) tal- pazjenti rispettivament, laħqu livelli tad- DNA tal- HBV li ma setgħux jiġu osservati fil- Ġimgħa 48 (< 1, 000 kopja/ ml assay ta ’ Roche Amplicor Monitor PCR).
Treatment with 10 mg adefovir dipivoxil showed similar
It - trattament b’ 10 mg ta ’ adefovir dipivoxil wera effikaċja simili minkejja l- proċessi ta ’ mutazzjoniet ta ’ polimerase tad- DNA tal- HBV reżistenti għal lamivudine fil- linja bażi.
9 efficacy regardless of the patterns of lamivudine-resistant HBV DNA polymerase mutations at baseline.
Titjib jew stabilizzazzjoni ġew innutati fir- riżultati tal- punteġġ ta ’ Child- Pugh- Turcotte.
Normalisation of ALT, albumin, bilirubin and prothrombin time was seen at week 48 in 51-85% of the patients.
Kien hemm normalizzazzjoni ta ’ l- ALT, ta ’ l- albumina, bilirubina u tal- ħin tal- prothrombin raw fil- Ġimgħa 48 51- 85% mill- pazjenti.
In the pre-liver transplantation cohort, 25 of 33 (76%) patients achieved undetectable HBV DNA levels and 84% of patients had ALT normalisation at 96 weeks.
Fil- grupp ta ’ qabel it- trapjant tal- fwied, 25 minn 33 (76%) tal- pazjenti laħqu livelli tad- DNA tal- HBV li ma setgħux jiġu osservati u 84% tal- pazjenti kellhom normalizzazzjoni ta ’ l- ALT fil- Ġimgħa 96.
In the post-liver transplantation cohort, 61 of 94 (65%) and 35 of 45 (78%) of patients achieved undetectable HBV DNA levels at 96 and 144 weeks, respectively, and 70% and 58% of patients had ALT normalisation at these study visits.
Fil- grupp ta ’ wara t- trapjant tal- fwied, 61 minn 94 (65%) u 35 minn 45 (78%) tal- pazjenti laħqu livelli tad- DNA tal- HBV li ma setgħux jiġu osservati fil- Ġimgħat 96 u 144 rispettivament, u 70% u 58% tal - pazjenti kellhom normalizzazzjoni ta ’ l- ALT f’ dawn l- eżamijiet mediċi li saru matul dan l- istudju.
The clinical significance of these findings as they relate to histological improvement is not known.
Is - sinifikat kliniku ta ’ dawn ir- riżultati f’ rabta mat- titjib istoloġiku mhux magħruf.
Experience in patients with compensated liver disease and lamivudine-resistant HBV:
Esperjenza f’ pazjenti b’ mard tal- fwied kumpensat u HBV reżistenti għal lamivudine:
In a double-blind comparative study in chronic hepatitis B patients with lamivudine-resistant HBV (n=58), there was no median reduction in HBV DNA from baseline after 48 weeks of treatment with lamivudine.
Fi studju komparat double- blind f’ pazjenti b’ epatite B kronika b’ HBV reżistenti għal lamivudine (n=58), ma kienx hemm tnaqqis medjan fid- DNA tal- HBV mil- linja bażi wara 48 ġimgħa ta ’ trattament b’ lamivudine.
Forty-eight weeks of treatment with adefovir dipivoxil 10 mg alone or in combination with lamivudine resulted in a similar significant decrease in median serum HBV DNA levels from baseline (4.04 log10 copies/ ml and 3.59 log10 copies/ ml, respectively).
Tmienja u erbgħin ġimgħa ta ’ trattament b’ 10 mg ta ’ adefovir dipivoxil waħdu jew flimkien ma ’ lamivudine wassal għal tnaqqis sinifikanti simili tal- livelli medjani fis- serum tad- DNA tal- HBV meta mqabbel mal- linja bażi (4. 04 log10 kopja/ ml u 3. 59 log10 kopja/ ml, rispettivament).
The clinical significance of these observed changes in HBV DNA has not been established.
Is - sinifikat kliniku ta ’ dan it- tibdil osservat fid- DNA tal- HBV ma ġiex stabbilit.
Experience in patients with decompensated liver disease and lamivudine-resistant HBV:
Esperjenza f’ pazjenti b’ mard tal- fwied mhux kumpensat u b’ HBV reżistenti għal lamivudine:
In 40 HBeAg positive or HBeAg negative patients with lamivudine-resistant HBV and decompensated liver disease receiving treatment with 100 mg lamivudine, addition of 10 mg adefovir dipivoxil treatment for 52 weeks resulted in a median reduction in HBV DNA of 4.6 log10 copies/ ml.
F’ 40 pazjent b’ HBeAg pożittiv jew HBeAg negattiv b’ HBV reżistenti għal lamivudine u b’ mard tal - fwied mhux kumpensat li kienu jirċievu trattament b’ 100 mg ta ’ lamivudine, iż- żieda ta ’ trattament b’ 10 mg ta ’ adefovir dipivoxil għal 52 ġimgħa wassal għal tnaqqis medjan fid- DNA tal- HBV ta ’ 4. 6 log10 kopja/ ml.
Improvement in liver function was also seen after one year of therapy.
Titjib fil- funzjoni tal- fwied ġie innutat wara sena ta ’ terapija.
Experience in patients with HIV co-infection and lamivudine-resistant HBV:
Esperjenza f’ pazjenti li huma infettati ukoll bl- HIV u HBV reżistenti għal lamivudine:
In an open-label investigator study in 35 chronic hepatitis B patients with lamivudine-resistant HBV and co-infected with HIV, continued treatment with 10 mg adefovir dipivoxil resulted in progressive reductions in serum HBV DNA levels and ALT levels throughout the course of treatment up to 144 weeks.
Fi studju open - label investigattiv f’ 35 pazjent b’ epatite B kronika b’ HBV reżistenti għal lamivudine u li huma infettati ukoll bl- HIV, trattament kontinwu b’ 10 mg ta ’ adefovir dipivoxil irriżulta fi tnaqqis 10 progressiv fil- livelli ta ’ serum tad- DNA tal- HBV u fil- livelli ta ’ l- ALT matul il- kors tat- trattament sa 144 ġimgħa.
In a second open-label, one-arm study, 10 mg adefovir dipivoxil and pegylated interferon alpha-2a were added to ongoing lamivudine therapy in 18 HIV/ HBV co-infected patients with lamivudine-resistant HBV.
Fit- tieni studju open- label, one- arm, 10 mg ta ’ adefovir dipivoxil u pegylated interferon alpha- 2a kienu miżjuda ma ’ terapija kurrenti b’ lamivudine fi 18- il pazjent infettati ukoll bl- HIV/ HBV b’ HBV reżistenti għal lamivudine.
Patients were all HBeAg positive and had median CD4 cell count of 441 cells/ mm3 (no patient had CD4 count < 200 cells/ mm3).
Il- pazjenti kienu kollha HBeAg pożittivi u kellhom medjan ta ’ għadd taċ - ċelluli CD4 ta ’ 441 ċelluli/ mm3 (l- ebda pazjent ma kellu għadd ta ’ CD4 < 200 ċelluli/ mm3).
During therapy, serum HBV DNA levels were significantly lower compared to baseline for up to 48 weeks of treatment while ALT levels declined progressively from week 12.
Matul it - terapija, il- livelli ta ’ serum tad- DNA tal- HBV kienu iktar baxxi b’ mod sinifikanti meta mqabbla mal - linja bażi sa 48 ġimgħa ta ’ trattament, filwaqt li l- livelli ta ’ l- ALT naqsu b’ mod progressiv minn ġimgħa 12.
However, on-treatment HBV DNA response was not maintained off-therapy since all the patients had a rebound in HBV DNA after adefovir dipivoxil and pegylated interferon alpha-2a discontinuation.
Madankollu, ir- rispons tad- DNA tal- HBV għall- kura ma nżammx meta l- kura twaqqfet, għax il- pazjenti kollha kellhom rebound fid- DNA tal- HBV wara li adefovir dipivoxil u pegylated interferon alpha- 2a twaqqfu.
No patients became HBsAg- or HBeAg-negative during the study.
Ħadd mill- pazjenti ma sar HBsAg jew HBeAg negattiv matul l- istudju.
Due to the small sample size and the study design, in particular the lack of treatment arms with pegylated interferon alpha-2a monotherapy and with adefovir monotherapy, it is not possible to draw formal conclusions on the best therapeutic management of HIV co-infected patients with lamivudine-resistant HBV.
Minħabba d- daqs żgħir tal- kampjun u d- disinn ta ’ l- istudju, b’ mod partikulari n- nuqqas ta ’ gruppi tat - trattament bil- monoterapija b’ pegylated interferon alpha- 2a u bil- monoterapija b’ adefovir, mhuwiex possibbli li tasal għal konklużjonijiet formali dwar l- aħjar immaniġġjar terapewtiku ta ’ pazjenti b’ HBV reżistenti għal lamivudine li huma infettati ukoll bl- HIV.
The efficacy and safety of a daily dose of 0.25 mg/ kg to 10 mg adefovir dipivoxil in children (aged from 2 to < 18 years) was examined in a double-blind, randomised, placebo-controlled study in 173 paediatric patients (115 on adefovir dipivoxil, 58 on placebo) who had HBeAg positive chronic hepatitis B, serum ALT levels ≥ 1.5 x upper limit of normal (ULN) and compensated liver disease.
L- effikaċja u s- sigurtà ta ’ doża ta ’ kuljum ta ’ 0. 25 mg/ kg sa 10 mg ta ’ adefovir dipivoxil fit- tfal (ta ’ bejn 2 sa < 18- il sena) kienu eżaminati fi studju double- blind, randomised, ikkontrollat bil- plaċebo li sar fuq 173 pazjenti pedjatriċi (115 fuq adefovir dipivoxil, 58 fuq il- plaċebo) li kellhom HBeAg pożittiva għal epatite B kronika, livelli ta ’ ALT fis- serum ≥ 1. 5 x il - Limitu ta ’ Fuq tan- Normal (ULN) u mard tal- fwied kumpensat.
At week 48, in children aged 2 to 11 years old, no statistically significant difference was observed in the proportions of patients that achieved the primary endpoint of serum HBV DNA < 1,000 copies/ ml and normal ALT levels between the placebo arm and the adefovir dipivoxil arm.
Fil- ġimgħa 48, fit- tfal ta ’ bejn 2 u 11 - il sena, l- ebda differenza statistikament sinifikanti ma kienet osservata fil- porzjonijiet ta ’ pazjenti li laħqu r- riżultat aħħari primarju ta ’ serum tad- DNA tal- HBV ta ’ < 1, 000 kopja/ ml u livelli normali ta ’ ALT bejn il- parti ta ’ l- istudju dwar il- plaċebo u l- parti dwar adefovir dipivoxil.
In the adolescent population (n=83) (aged from 12 to < 18 years), significantly more patients treated with adefovir dipivoxil achieved the primary efficacy endpoint and obtained significant reductions in serum HBV DNA (23%) compared to placebo-treated patients (0%).
Fil- popolazzjoni adolexxenti (n=83) (ta ’ bejn 12 u < 18- il sena), kien hemm iktar pazjenti trattati b’ adefovir dipivoxil li b’ mod sinifikanti laħqu r- riżultat aħħari ta ’ l- effikaċja primarja u li kisbu tnaqqis sinifikanti fis- serum tad- DNA ta ’ l- HBV (23%) meta mqabbla mal- pazjenti trattati bil- plaċebo (0%).
However, the proportions of subjects who achieved HBeAg seroconversion at week 48 were similar (11%) between the placebo arm and the adefovir dipivoxil 10 mg arm in adolescent patients.
Madankollu, il - porzjonijiet ta ’ pazjenti li laħqu serokonverżjoni ta ’ HBeAg fil- ġimgħa 48 kienu l- istess (11%) bejn il - parti ta ’ l- istudju dwar il- plaċebo u l- parti dwar 10 mg ta ’ adefovir dipivoxil f’ pazjenti adolexxenti.
10 Overall, the safety profile of adefovir dipivoxil in children was consistent with the known safety profile in adult patients.
Kollox ma ’ kollox, il- profil tas- sigurtà ta ’ adefovir dipivoxil fit- tfal kien konsistenti mal- profil tas - sigurtà magħruf f’ pazjenti adulti.
However, a signal towards a higher rate of decreased appetite and/ or food intake was observed in the adefovir arm as compared to the placebo arm.
Madankollu, ġie osservat ħjiel li jindika rata aktar għolja ta ’ nuqqas ta ’ ġuħ u/ jew konsum ta ’ ikel fil- parti ta ’ l- adefovir meta mqabbel mal- parti tal- placebo.
At week 48 and 96, mean changes from baseline in weight and BMI Z scores tended to decrease in adefovir dipivoxil-treated patients.
F’ ġimgħa 48 u 96, il- medja tat- tibdil mil- linja bażi fil- piż u fil- BMI fil- punteġġi Z kellhom tendenza li jonqsu f’ pazjenti kkurati b’ adefovir dipivoxil.
No long-term safety data or long-term resistance data are available with adefovir dipivoxil in children.
M’ hemm l- ebda informazzjoni disponibbli dwar is- sigurtà jew ir- reżistenza fit- tul dwar adefovir dipivoxil fit- tfal.
The clinical data available are insufficient to draw definitive conclusions on the benefit/ risk ratio of the adefovir treatment in children with chronic hepatitis B (see section 4.2).
(ara sezzjoni 4. 2).
Clinical resistance in patients receiving adefovir dipivoxil as monotherapy and in combination with lamivudine:
Reżistenza klinika f’ pazjenti li qed jirċievu adefovir dipivoxil bħala monoterapija u flimkien ma ’ lamivudine:
In several clinical studies (HBeAg positive, HBeAg negative, pre- and post-liver transplantation with lamivudine-resistant HBV and lamivudine-resistant HBV co-infected with HIV patients), genotypic analyses were conducted on HBV isolates from 379 of a total of 629 patients, treated with adefovir dipivoxil for 48 weeks.
F’ diversi studji kliniċi, (pazjenti pożittivi għal HBeAg, pazjenti negattivi għal HBeAg, pazjenti ta ’ qabel u ta ’ wara t- trapjant tal- fwied b’ HBV reżistenti għal lamivudine u pazjenti b’ HBV reżistenti għal lamivudine li huma infettati ukoll bl- HIV), saru analiżi ġenotipiċi fuq iżolati ta ’ HBV fuq 379 minn total ta ’ 629 pazjenti, ittrattati b’ adefovir dipivoxil għal 48 ġimgħa.
No HBV DNA polymerase mutations associated with resistance to adefovir were identified when patients were genotyped at baseline and at week 48.
L- ebda mutazzjonijiet fil- polimerase tad- DNA tal- HBV assoċjati ma ’ reżistenza għal adefovir ma ġew identifikati meta l- pazjenti ġew ġenotipati fil- linja bażi u fil- Ġimgħa 48.
After 96, 144, 192 and 240 weeks of treatment with adefovir dipivoxil, resistance surveillance was performed for 293, 221, 116 and 64 patients, respectively.
Wara 96, 144, 192 u 240 ġimgħa ta ’ trattament b’ adefovir dipivoxil, sorveljanza tar- reżistenza twettqet fuq 293, 221, 116 u 64 pazjenti rispettivament.
Two novel conserved site mutations were identified in the HBV polymerase gene (rtN236T and rtA181V), which conferred clinical resistance to adefovir dipivoxil.
Żewġ mutazzjonijiet ġodda (rtN236T u rtA181V) tal- lok konservat kienu identifikati fil- ġene tal- polimerase ta ’ HBV, li offrewiet reżistenza klinika għal adefovir dipivoxil.
The cumulative probabilities of developing these adefovir-associated resistance mutations in all patients treated with adefovir dipivoxil were 0% at 48 weeks and approximately 2%, 7%, 14% and 25% after 96, 144, 192 and 240 weeks, respectively.
Il- probabbiltajiet kumulattivi li dawn il- mutazzjonijiet assoċjati mar- reżistenza għal adefovir jiżviluppaw fil- pazjenti kollha ttrattati b’ adefovir dipivoxil kienu ta ’ 0% wara 48 ġimgħa, u madwar 2%, 7%, 14% u 25% wara 96, 144, 192 u 240 ġimgħa, rispettivament.
Clinical resistance in monotherapy studies in nucleoside naïve patients:
11 Reżistenza klinika fl- istudji dwar il- monoterapija f’ pazjenti li qatt ma kellhom nukleoside:
In patients receiving adefovir dipivoxil monotherapy (HBeAg negative study) the cumulative probability of developing adefovir-associated resistance mutations was 0%, 3%, 11%, 18% and 29% at 48, 96, 144, 192 and 240 weeks respectively.
F’ pazjenti li qed jirċievu monoterapija b’ adefovir dipivoxil (studju dwar HBeAg negattiv) il- probabbiltà kumulattiva li jiżviluppaw mutazzjonijiet assoċjati mar- reżistenza għal adefovir kienet ta ’ 0%, 3%, 11%, 18% u 29% fil- Ġimgħa 48, 96, 144, 192 u 240 rispettivament.
In addition, the long-term (4 to 5 years) development of resistance to adefovir dipivoxil was significantly lower in patients who had serum HBV DNA below the limit of quantification (< 1,000 copies/ ml) at week 48 as compared to patients with serum HBV DNA above 1,000 copies/ ml at week 48.
Flimkien ma ’ dan, l- iżvilupp fuq tul ta ’ żmien (4 sa 5 snin) tar- reżistenza għal adefovir dipivoxil kien iktar baxx b’ mod sinifikanti f’ pazjenti li kellhom serum tad- DNA tal- HBV taħt il- limiti tal- kwantifikazzjoni (< 1, 000 kopja/ ml) fil- Ġimgħa 48 meta mqabbla ma ’ pazjenti bis- serum ta ’ DNA tal- HBV ta ’ iktar minn 1, 000 kopja/ ml fil- Ġimgħa 48.
In HBeAg positive patients, the incidence of adefovir-associated resistance mutations was 3% (2/ 65), 17% (11/ 65) and 20% (13/ 65) after a median duration exposure of 135, 189 and 235 weeks respectively.
F’ pazjenti pożittivi għal HBeAg, l- inċidenza ta ’ mutazzjonijiet assoċjati mar - reżistenza għal adefovir kienet ta ’ 3% (2/ 65), 17% (11/ 65) u 20% (13/ 65) wara tul medjan ta ’ esponiment ta ’ 135, 189 u 235 ġimgħa rispettivament.
Clinical resistance in studies where adefovir dipivoxil was added to ongoing lamivudine in patients with lamivudine-resistance:
Reżistenza klinika fi studji fejn adefovir dipivoxil kien miżjud ma ’ trattament kurrenti b’ lamivudine f’ pazjenti li kellhom reżistenza għal lamivudine:
In an open-label study of pre- and post-liver transplantation patients with clinical evidence of lamivudine-resistant HBV, no adefovir-associated resistance mutations were observed at week 48.
Fi studju open- label ta ’ pazjenti qabel u wara li kellhom it- trapjant tal- fwied, b’ evidenza klinika ta ’ HBV reżistenti għal lamivudine, l- ebda mutazzjonijiet assoċjati mar- reżistenza għal adefovir ma kienu osservati fil- Ġimgħa 48.
With up to 3 years of exposure, no patients receiving both adefovir dipivoxil and lamivudine developed resistance to adefovir dipivoxil.
Sa 3 snin ta ’ esponiment, ħadd mill- pazjenti li kienu qed jirċievu kemm adefovir dipivoxil kif ukoll lamivudine ma żviluppaw reżistenza għal adefovir dipivoxil.
However, 4 patients who discontinued lamivudine treatment developed the rtN236T mutation while receiving adefovir dipivoxil monotherapy and all experienced serum HBV rebound.
Madankollu, 4 pazjenti li waqqfu l- monoterapija b’ lamivudine żviluppaw il- mutazzjoni rtN236T waqt li kienu qed jieħdu monoterapija b’ adefovir dipivoxil, u kollha esperjenzaw HBV fis- serum lura.
The currently available data both in vitro and in patients suggest that HBV expressing the adefovir- associated resistance mutation rtN236T is susceptible to lamivudine.
L- informazzjoni disponibbli bħalissa, kemm in vitro u kemm fil- pazjenti, tissuġġerixxi li HBV li jesprimi l- mutazzjoni rtN236T assoċjata mar- reżistenza għal adefovir, huwa suxxettibbli għal lamivudine.