Cytomegalowirus – Leczenie

Cytomegalowirus
Leczenie

Cytomegalowirus (CMV) jest wirusem z rodziny Herpesviridae, który pozostaje latentny w organizmie po zakażeniu. U osób immunokompetentnych zakażenie przebiega zwykle bezobjawowo lub jako łagodny zespół mononukleozopodobny, nie wymagający leczenia przeciwwirusowego. W grupach immunosupresyjnych, takich jak pacjenci z HIV/AIDS (zwłaszcza przy liczbie CD4+ <50 komórek/mm3), biorcy przeszczepów narządów lub komórek macierzystych, zakażenie CMV może prowadzić do poważnych powikłań (np. zapalenie płuc, wątroby, jelita grubego, siatkówki). Leczenie pierwszego rzutu opiera się na gancyklowirze (5 mg/kg i.v. 2x/d przez 2-3 tygodnie) oraz jego doustnym proleku walgancyklowirze (900 mg 2x/d p.o.), z zastosowaniem foskarnetu (90 mg/kg i.v. 2x/d) lub cidofowiru w przypadku oporności lub nietolerancji. Nowe leki, takie jak letermowir (480 mg/d p.o., dawka zmniejszona do 240 mg/d przy jednoczesnym stosowaniu cyklosporyny) i maribawir (400-800 mg 2x/d p.o.), oferują dodatkowe opcje profilaktyki i terapii, zwłaszcza u biorców przeszczepów z wysokim ryzykiem CMV. Profilaktyka przeciwwirusowa i terapia wyprzedzająca (preemptive therapy) są kluczowe w zapobieganiu rozwojowi choroby CMV u pacjentów z grup ryzyka, a monitorowanie wiremii CMV (PCR, antygenemia pp65) umożliwia szybkie wdrożenie leczenia.

Leczenie cytomegalowirusa

Cytomegalowirus (CMV) to powszechnie występujący wirus z rodziny Herpesviridae, który po zakażeniu pozostaje w organizmie na całe życie. Leczenie zakażenia CMV zależy od stanu immunologicznego pacjenta, nasilenia objawów oraz postaci klinicznej choroby. U osób immunokompetentnych zakażenie CMV zwykle przebiega bezobjawowo lub objawia się łagodnym zespołem mononukleozopodobnym, który zazwyczaj nie wymaga specyficznego leczenia¹²³.

Leczenie u osób immunokompetentnych

U osób z prawidłowo funkcjonującym układem odpornościowym zakażenie CMV jest zwykle samolimitujące. Leczenie objawowe obejmuje odpoczynek w łóżku, nawodnienie i leczenie objawowe (przeciwgorączkowe, przeciwbólowe). Nie zaleca się stosowania leków przeciwwirusowych u immunokompetentnych osób z CMV⁴⁵⁶.

Leczenie u pacjentów z upośledzonym układem odpornościowym

Pacjenci z osłabionym układem odpornościowym, w tym osoby z AIDS, biorcy przeszczepów oraz osoby poddawane chemioterapii, wymagają specyficznego leczenia przeciwwirusowego. Zakażenie CMV w tej grupie pacjentów może powodować poważne powikłania, takie jak zapalenie płuc, zapalenie wątroby, zapalenie jelita grubego, zapalenie nerek i zapalenie siatkówki¹⁷.

Leki przeciwwirusowe w leczeniu CMV

Gancyklowir i walgancyklowir

Gancyklowir (GCV) jest lekiem pierwszego wyboru w leczeniu zakażeń CMV. Dostępny jest w formie dożylnej i stosowany jest w dawce 5 mg/kg dwa razy dziennie przez 2-3 tygodnie jako terapia indukcyjna, a następnie jako terapia podtrzymująca⁸⁹. Gancyklowir wykazuje aktywność przeciwko CMV, HSV, VZV i HHV-6, HHV-7 oraz HHV-8, jednak w przypadku zakażeń VZV i HSV preferowane są inne analogi nukleozydowe⁸.

Walgancyklowir (VGC) jest doustną postacią (estrem L-walylowym) gancyklowiru, zatwierdzoną do leczenia zapalenia siatkówki wywołanego przez CMV u pacjentów HIV-pozytywnych. Badania wykazały, że doustny walgancyklowir jest równie skuteczny jak dożylny gancyklowir w leczeniu początkowym zapalenia siatkówki wywołanego przez CMV⁹¹⁰.

Główne działania niepożądane terapii gancyklowirem obejmują gorączkę, wysypkę, biegunkę oraz efekty hematologiczne (neutropenię, anemię, trombocytopenię). Neutropenię leczy się poprzez zmniejszenie dawki i/lub dodanie czynników wzrostu (G-CSF, GM-CSF)⁸.

Foskarnet

Foskarnet jest inhibitorem fosforylacji łańcucha DNA i jest uważany za lek z wyboru w przypadku zakażeń CMV opornych na gancyklowir. Stosowany jest w dawce 90 mg/kg dwa razy dziennie przez dwa tygodnie, a następnie jako terapia podtrzymująca w dawce 90-120 mg/kg dziennie¹¹¹². Foskarnet jest często stosowany jako alternatywa, gdy występuje toksyczność lub oporność na gancyklowir¹².

Cidofowir

Cidofowir jest alternatywnym lekiem przeciwwirusowym stosowanym głównie w przypadkach oporności na gancyklowir i foskarnet. Ma dłuższy okres półtrwania i może być podawany raz w tygodniu podczas terapii indukcyjnej, a następnie co dwa tygodnie jako terapia podtrzymująca¹³. Jego stosowanie jest ograniczone ze względu na toksyczność nerek¹⁴.

Letermowir

Letermowir jest nowym inhibitorem terminazy wirusowej, stosowanym w profilaktyce CMV u dorosłych seropozytywnych biorców allogenicznego przeszczepu komórek macierzystych (HSCT) oraz u biorców przeszczepu nerki z wysokim ryzykiem (dawca CMV seropozytywny/biorca CMV seronegatywny [D+/R-])¹¹¹⁵. Standardowa dawka profilaktyczna wynosi 480 mg dziennie (dożylnie lub doustnie), jednak ze względu na interakcję z cyklosporyną zaleca się zmniejszenie dawki do 240 mg dziennie¹⁵.

Maribawir

Maribawir jest doustnym przeciwwirusowym lekiem benzimidazolowym, który wykazuje znaczącą aktywność przeciwko CMV i wirusowi Epsteina-Barr. Jest wskazany do leczenia opornych/nawrotowych zakażeń CMV u biorców przeszczepów¹¹¹⁶. Wieloośrodkowe badanie kliniczne fazy 3 wykazało większą skuteczność maribawairu w porównaniu z terapią przypisaną przez badacza u biorców przeszczepów SOT i HSCT z opornym/nawrotowym CMV¹⁷.

Leflunomid

Leflunomid jest antymetabolitem stosowanym jako lek modyfikujący przebieg choroby w reumatoidalnym zapaleniu stawów. Był również z powodzeniem stosowany off-label zarówno w leczeniu, jak i profilaktyce choroby CMV¹⁸.

Strategie leczenia CMV

Profilaktyka CMV

Profilaktyka jest stosowana u pacjentów w celu zapobiegania pierwotnym, reaktywacji lub nawrotowym zakażeniom. Obejmuje ona podawanie leków przeciwwirusowych wszystkim pacjentom z wysokim ryzykiem rozwoju choroby CMV¹⁹. W przypadku biorców przeszczepów narządów miąższowych stosowanie profilaktyki przeciwwirusowej zmniejsza występowanie choroby CMV i śmiertelności związanej z CMV²⁰.

Niektóre badania wykazały, że wysokie dawki acyklowiru lub walacyklowiru w profilaktyce znacznie zmniejszają zakażenie CMV u biorców allo-HSCT. Dożylny gancyklowir również był testowany, co doprowadziło do pewnego zmniejszenia zakażenia CMV, jednak nie zapewniło to ogólnej korzyści w przeżyciu i wiązało się z supresją szpiku kostnego (neutropenia wywołana gancyklowirem)¹⁹.

Terapia wyprzedzająca

Terapia wyprzedzająca (preemptive therapy) polega na podawaniu leków przeciwwirusowych bezobjawowym pacjentom z wykrytym CMV w testach przesiewowych¹⁹²¹. Dodatnie wyniki badań kultur krwi, antygenemii pp65 i CMV PCR były wykorzystywane jako markery do rozpoczęcia terapii¹¹.

U biorców przeszczepów regularne monitorowanie i szybkie wdrożenie terapii przeciwwirusowej w przypadku wykrycia replikacji wirusa może skutecznie zapobiegać rozwojowi choroby CMV²¹²².

Leczenie ustalonej choroby CMV

Leczenie ustalonej choroby CMV zależy od manifestacji klinicznej i stanu immunologicznego pacjenta. Ogólnie, łagodna choroba u pacjentów z immunosupresją może być leczona doustnym walgancyklowirem. W przypadku innych zespołów inwazyjnych tkankowo, preferowane jest rozpoczęcie od dożylnego gancyklowiru lub fozkarnetu w pełnych dawkach (dostosowanych do funkcji nerek)⁷.

Leczenie w pełnych dawkach powinno być kontynuowane do ustąpienia objawów i do czasu usunięcia antygenemii (lub DNAemii) z krwi²³. Pacjenci otrzymujący leczenie muszą być ściśle monitorowani pod kątem działań niepożądanych leków, a także odpowiedzi na leczenie⁷.

Leczenie CMV w specyficznych populacjach

CMV u pacjentów z HIV/AIDS

U pacjentów z HIV/AIDS, choroba końcowych narządów spowodowana przez CMV występuje u osób z zaawansowaną immunosupresją, zazwyczaj u tych z liczbą komórek CD4+ T limfocytów <50 komórek/mm3, którzy nie otrzymują, nie przestrzegają lub nie reagują na terapię antyretrowirusową (ART)²⁴.

Podejście terapeutyczne do zapalenia siatkówki wywołanego przez CMV powinno być zindywidualizowane w oparciu o tolerancję leków systemowych, wcześniejszą ekspozycję na leki anty-CMV i potencjalnie lokalizację zmian. Doustny walgancyklowir, dożylny gancyklowir lub dożylna terapia indukcyjna gancyklowirem, a następnie doustna terapia podtrzymująca walgancyklowirem są terapiami pierwszego wyboru w leczeniu zapalenia siatkówki wywołanego przez CMV²⁵.

W przypadku pacjentów z zapaleniem jelita grubego lub przełyku, wielu specjalistów ds. HIV zaleca terapię anty-CMV przez 21-42 dni lub do ustąpienia objawów. Dożylny gancyklowir jest generalnie terapią z wyboru i można go zamienić na doustny walgancyklowir, gdy pacjent może tolerować i wchłaniać leki doustne²⁵.

Terapia dobrze udokumentowanej choroby neurologicznej również nie została szeroko zbadana. Biorąc pod uwagę złe wyniki u wielu pacjentów z chorobą neurologiczną związaną z CMV, niektórzy eksperci rozpoczęliby terapię zarówno dożylnym gancyklowirem, jak i dożylnym foskarnetem, pomimo znacznej toksyczności związanej z takim podejściem²⁶²⁷.

CMV u biorców przeszczepów

Cytomegalowirus (CMV) pozostaje jednym z najczęstszych powikłań infekcyjnych po przeszczepieniu narządów miąższowych (SOT) i przeszczepieniu komórek macierzystych układu krwiotwórczego (HSCT)²⁸.

Bez zapobiegawczej terapii CMV, 30-75% biorców przeszczepów rozwija zakażenie CMV, a 8-30% rozwija chorobę CMV⁹. Profilaktyczne lub wyprzedzające leczenie gancyklowirem okazało się skuteczne w zapobieganiu chorobie CMV u biorców przeszczepów⁹.

W leczeniu zapalenia płuc wywołanego przez CMV, gancyklowir jest podawany wraz z immunoglobuliną specyficzną dla CMV. Chociaż gancyklowir zmniejszał wiremię CMV o 99% w płucach pacjentów z zapaleniem płuc wywołanym przez CMV, dziewięciu na dziesięciu pacjentów, którym podano dożylny gancyklowir, nadal zmarło. Jednak dodanie immunoglobulin zmniejszyło śmiertelność²⁹³⁰.

W przypadku pacjentów z nawracającym CMV po okresie bez choroby i bez leków, można rozważyć dodatkową immunoglobulinę CMV u pacjentów z hipogammaglobulinemią³¹.

Strategia	Populacja	Zalecane leki	Dawkowanie
Profilaktyka	Biorcy przeszczepu CMV-seropozytywni lub D+/R-	Walgancyklowir lub Letermowir	Walgancyklowir: 900 mg 1x dziennie p.o. Letermowir: 480 mg 1x dziennie p.o. (240 mg z cyklosporyną)
Terapia wyprzedzająca	Wykrycie wiremii CMV bez objawów	Walgancyklowir lub Gancyklowir	Walgancyklowir: 900 mg 2x dziennie p.o. Gancyklowir: 5 mg/kg 2x dziennie i.v.
Leczenie choroby CMV	Objawowa choroba CMV	Gancyklowir, Walgancyklowir lub Foskarnet	Gancyklowir: 5 mg/kg 2x dziennie i.v. przez 2-3 tygodnie Walgancyklowir: 900 mg 2x dziennie p.o. Foskarnet: 90 mg/kg 2x dziennie i.v.
Oporny/nawrotowy CMV	Niepowodzenie standardowej terapii	Maribawir, kombinacja Gancyklowir + Foskarnet, Leflunomid	Maribawir: 400-800 mg 2x dziennie p.o. Leflunomid: dawkowanie indywidualne

Wrodzone zakażenie CMV

Wrodzone zakażenie CMV jest najczęstszą przyczyną wrodzonej infekcji wirusowej na świecie, najczęstszą niegenenetyczną przyczyną niedosłuchu czuciowo-nerwowego u dzieci oraz przyczyną zaburzeń neurorozwojowych mózgu³².

Niemowlęta z objawowym wrodzonym zakażeniem CMV mogą odnieść korzyści w zakresie słuchu i rozwoju neurologicznego, szczególnie jeśli leczenie przeciwwirusowe zostanie rozpoczęte w ciągu pierwszego miesiąca życia³².

Obecnie zalecany schemat lekowy dla objawowych niemowląt z wrodzonym zakażeniem CMV jest następujący: niemowlęta z zagrażającymi życiu objawami są początkowo leczone dożylnym gancyklowirem przez 2-6 tygodni, a następnie przechodzą na doustny walgancyklowir, podczas gdy te bez zagrażających życiu objawów są leczone doustnym walgancyklowirem przez cały 6-miesięczny okres³²³³.

Podczas leczenia przeciwwirusowego wymagane jest monitorowanie bezwzględnej liczby neutrofili, liczby płytek krwi, azotu mocznikowego we krwi, kreatyniny i testów czynności wątroby w celu identyfikacji neutropenii, trombocytopenii, niewydolności nerek i niewydolności wątroby³³.

Oporność na leki i leczenie opornego CMV

Oporność na CMV powinna być podejrzewana u każdego pacjenta po przeszczepieniu, który nie reaguje na terapeutyczne dawki gancyklowiru lub którego stan zdrowia szybko się pogarsza³⁴. Obecnie dostępne są testy na oporność na CMV w ośrodkach transplantacyjnych³⁴.

Zakażenia CMV, które stają się oporne/nawrotowe (R/R) na dostępne leki przeciwwirusowe, stanowią wyzwanie kliniczne i są związane ze zwiększoną zachorowalnością i śmiertelnością³⁵. Ważnym krokiem w leczeniu zakażenia R/R jest identyfikacja specyficznych mutacji nadających oporność poprzez sekwencjonowanie genotypowe w celu podejmowania decyzji terapeutycznych³⁶.

Opcje terapeutyczne w przypadku oporności na gancyklowir obejmują:

Foskarnet – jest często stosowany u pacjentów z CMV opornym na gancyklowir, ale wyniki są mieszane²⁹²³
Maribawir – został zatwierdzony przez FDA i inne agencje medyczne do leczenia zakażeń R/R CMV zarówno u biorców HCT, jak i SOT³⁶
Kombinacja gancyklowiru i fozkarnetu – może być stosowana w skrajnych przypadkach⁷
Leflunomid, artesunate – inne środki, które były badane w literaturze³⁷²³
Terapia komórkami T specyficznymi dla CMV – może być obiecującą opcją dla R/R CMV u biorców SOT, ale bezpieczeństwo i skuteczność muszą zostać potwierdzone w badaniach kontrolowanych³⁸

Nowe kierunki w leczeniu CMV

Pomimo znacznych postępów, poszukiwane są nowe leki przeciwwirusowe i cząsteczki zdolne do hamowania replikacji CMV z najniższą toksycznością³⁹. Odkrycie nowych celów antywirusowych i opracowanie nowych terapii jest niezbędne, aby skuteczniej leczyć zakażenia CMV przy jednoczesnym zmniejszeniu działań niepożądanych⁴⁰.

Cząsteczki o bezpośrednim działaniu przeciwko HCMV obejmują brincidofovir, cyclopropavir i analogi benzimidazolowe anty-terminazy³⁹⁴¹. Skuteczność immunoglobulin anty-CMV jest dyskutowana w zakażeniu wrodzonym CMV i w połączeniu z bezpośrednią terapią przeciwwirusową u pacjentów z przeszczepem serca⁴².

Naukowcy badali również eksperymentalny preparat CMX001 (heksadecyloksypropylo-CDV), który jest doustnie dostępnym lipidowym acyklicznym fosfonianem nukleotydowym, dostarczającym wysokie wewnątrzkomórkowe poziomy CDV-difosforanu. Wczesne badania na ludziach nie wykazały znaczącego wpływu na chemię krwi ani hematologię³⁷²³.

Obecnie trwają badania nad szczepionkami dla kobiet w wieku rozrodczym. Szczepionki te mogą być przydatne w zapobieganiu zakażeniom CMV u matek i niemowląt oraz zmniejszaniu prawdopodobieństwa, że u dzieci urodzonych przez kobiety, które zostały zakażone podczas ciąży, rozwiną się niepełnosprawności⁴³.

Podsumowanie praktycznego podejścia do leczenia CMV

Leczenie cytomegalowirusa jest zindywidualizowane i zależy od stanu immunologicznego pacjenta, manifestacji klinicznej zakażenia oraz wcześniejszej ekspozycji na leki anty-CMV. Osoby zdrowe z zakażeniem CMV zwykle nie wymagają specyficznego leczenia, podczas gdy pacjenci z osłabionym układem odpornościowym oraz noworodki z objawowym wrodzonym zakażeniem CMV powinni otrzymać leczenie przeciwwirusowe¹².

Gancyklowir i walgancyklowir pozostają podstawą leczenia zakażeń CMV, z foskarnetem jako opcją drugiego rzutu w przypadku oporności na gancyklowir⁷. Nowe leki, takie jak letermowir i maribawir, oferują nowe możliwości w zapobieganiu i leczeniu zakażeń CMV, szczególnie u pacjentów po przeszczepieniu³⁶.

Profilaktyka anty-CMV jest zalecana dla biorców przeszczepów narządów miąższowych z wysokim ryzykiem zakażenia CMV²⁰. Terapia wyprzedzająca, polegająca na regularnym monitorowaniu i szybkim wdrożeniu leczenia przeciwwirusowego w przypadku wykrycia wiremii CMV, jest skuteczną strategią u wybranych pacjentów²¹.

Leczenie wrodzonego zakażenia CMV u noworodków z objawami powinno być rozpoczęte w ciągu pierwszego miesiąca życia, aby poprawić słuch i wyniki neurorozwojowe³². Trwają badania nad nowymi lekami przeciwwirusowymi i szczepionkami, które mogą w przyszłości poprawić wyniki leczenia zakażeń CMV⁴⁰.

Kolejne rozdziały

Zapraszamy do dalszego czytania naszego leksykonu.

Wybierz kolejny rozdział z menu poniżej, aby otworzyć nową podstronę kompedium wiedzy i uzyskać szczegółowe informację o leku, substancji lub chorobie.

Materiały źródłowe

#1 Cytomegalovirus (CMV) infection – Diagnosis & treatment – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/cmv/diagnosis-treatment/drc-20355364
Treatment generally isn’t necessary for healthy children and adults. Healthy adults who develop CMV mononucleosis generally recover without medication. […] Newborns and people who have weakened immunity need treatment when they’re experiencing symptoms of CMV infection. The type of treatment depends on the signs and symptoms and their severity. […] Antiviral medications are the most common type of treatment. They can slow reproduction of the virus, but can’t eliminate it. Researchers are studying new medications and vaccines to treat and prevent CMV.
#2 Cytomegalovirus (CMV) Infection: Causes & Symptoms
https://my.clevelandclinic.org/health/diseases/21166-cytomegalovirus
A provider can treat CMV with the antiviral medications ganciclovir (GCV) or valganciclovir (VGC). These drugs are given directly into your vein (IV infusion) or swallowed in a pill. Providers usually only treat CMV in people who have a compromised immune system or babies who are born with symptoms of CMV. In people with healthy immune systems, CMV usually goes away without treatment. […] Antiviral medications cant reverse any damage thats already been done. They can lessen the risk of health problems in babies born with CMV but may not completely prevent them. Children with congenital CMV can also be treated with speech and occupational therapy to manage the effects of hearing loss and developmental issues.
#3 Cytomegalovirus (CMV): Symptoms, Causes, Treatment
https://www.webmd.com/hiv-aids/aids-hiv-opportunistic-infections-cytomegalovirus
If you’re healthy, usually you won’t need treatment for CMV. Most people get better without any medicine. If you have a weakened immune system or your newborn has CMV, a doctor may suggest treatment depending on how severe the symptoms are. Antiviral medicines are the most common way to treat it. They can’t make the virus go away, but they can slow it down. […] Your doctor might prescribe drugs including: Acyclovir (Sitavig, Zovirax), Cidofovir (Vistide), CMV immune globulin (CytoGam), Foscarnet (Foscavir), Ganciclovir (Cytovene), Leflunomide (Arava), Letermovir (Prevymis), Maribavir (Livtencity), Valganciclovir (Valcyte). […] These drugs generally can’t cure the disease, but they can help if you have a weak immune system and symptoms from a CMV infection. If you have advanced HIV, they can control the infection while you get antiretroviral therapy (ART) for your HIV infection. […] If you have retinitis because of CMV, your doctor may give you strong medications intravenously (through a vein) for a couple of weeks, a process called induction therapy. After a while, they may switch you to pills.
#4 Cytomegalovirus (CMV) | Signs, Symptoms & Treatment
https://www.cincinnatichildrens.org/health/c/cytomegalovirus
An antiviral medication may be used to treat a cytomegalovirus infection in people whose immune systems are weakened or for transplant patients. These people usually need to be in the hospital. […] Additionally, cellular therapy may be used to treat CMV in patients with a weakened immune system. Viral specific T cells (VSTs) have been successfully used to treat CMV (and other viruses) without the need for potentially toxic anti-viral medications. […] Healthy people infected with CMV usually do not need medication. In healthy people, the body should be able to control the infection on its own and the signs of infection are treated as they happen. […] Most children should get better in a couple of weeks after an infection. If your child is not getting better, call your child’s doctor.
#5 Cytomegalovirus – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK459185/
Cytomegalovirus (CMV) is a wide-spread virus, with manifestations ranging from asymptomatic to severe end-organ dysfunction in immunocompromised patients with congenital CMV disease. […] This activity reviews the role of health professionals working together to manage cytomegalovirus. […] Summarize the treatment of cytomegalovirus. […] Antiviral therapy should be considered in severe cases of CMV mononucleosis, CMV infection, and CMV disease in immunocompromised patients. […] Several antiviral agents have been approved for the treatment of CMV (cidofovir, foscarnet, ganciclovir, valganciclovir). […] The use of antiviral therapy is not without risk. Toxicity is common with the use of these agents and must be weighed against the benefits of initiating treatment. […] Patients without CMV infection who receive organ transplants from CMV-infected donors should receive prophylactic treatment with valganciclovir or ganciclovir, and regular serological monitoring; if treated, the early establishment of a potentially life-threatening infection can be avoided.
#6 Cytomegalovirus (CMV)
https://www.nhs.uk/conditions/cytomegalovirus-cmv/
If cytomegalovirus (CMV) is not causing symptoms, you or your baby may not need any treatment. […] There’s currently no treatment for CMV in pregnancy, but in most cases the virus does not cause any problems. […] Antiviral medicine may be used to treat: babies diagnosed with congenital CMV after they’re born, people with a weakened immune system, people who have had a stem cell transplant or organ transplant. […] Treatment weakens the virus and lowers the chance of serious problems, but it does not cure the CMV infection.
#7 Cytomegalovirus Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC4431713/
In treating cytomegalovirus (CMV) infection, it is crucial to decide whether one is treating pre-emptively or if one is treating established disease. Disease may be further divided into viral syndrome and tissue-invasive disease. Generally, mild disease in immunosuppressed patients may be treated with oral valganciclovir. Treatment may also be started with valganciclovir for CMV retinitis in AIDS patients. In other tissue-invasive syndromes, starting with intravenous ganciclovir or foscarnet at full doses (adjusted for renal function) is preferred. Treatment at full doses should be continued until symptom resolution and until blood antigenemia (or DNAemia) is cleared. Patients receiving treatment must be closely monitored for side effects to the drugs, as well as for response. Drug-resistant CMV is a therapeutic challenge; combination therapy with both ganciclovir and foscarnet may be tried. In extreme cases, resorting to unconventional agents like leflunomide or maribavir may be necessary. Immune reconstitution, through reduction in immunosuppression, or the introduction of anti-retroviral therapy, should be attempted. CMX001 is a novel agent active against double-stranded viruses; thus far, resistance to CMX001 does not confer resistance to ganciclovir or foscarnet. Hence, prophylaxis or pre-emptive treatment with CMX001 may allow the use of ganciclovir or foscarnet for treatment.
#8 Cytomegalovirus (CMV) Treatment & Management: Medical Care, Consultations, Activity
https://emedicine.medscape.com/article/215702-treatment
The drug of choice for the treatment of CMV disease is intravenous ganciclovir, although valganciclovir may be used for nonsevere CMV treatment in selected cases. […] Ganciclovir has activity against CMV, HSV, VZV, and HHV-6, HHV-7, and HHV-8. However, one of the other nucleoside analogues (eg, famciclovir, penciclovir, acyclovir) is preferred to treat VZV and herpes simplex infections. […] The major adverse effects of ganciclovir therapy include fever, rash, diarrhea, and hematologic effects (ie, neutropenia, anemia, thrombocytopenia). Neutropenia is managed by dose reduction and/or the addition of growth factors (ie, granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF]). […] Oral ganciclovir results in serum levels that are 5-10 times less than intravenous ganciclovir, making oral ganciclovir a less-than-optimal agent for the management of active disease. Valganciclovir hydrochloride, an oral version (L-valyl ester) of ganciclovir, has been approved for the treatment of CMV retinitis in HIV-positive patients.
#9 Cytomegalovirus (CMV) Treatment & Management: Medical Care, Consultations, Activity
https://emedicine.medscape.com/article/215702-treatment
A randomized trial of patients with CMV retinitis showed that oral valganciclovir was as effective as intravenous ganciclovir when used as an initial treatment. […] In the treatment of CMV pneumonia, ganciclovir is administered with CMV-specific immune globulin (dosing in Medication section). […] The length of treatment varies. Some clinicians have administered ganciclovir for as long as 2-4 weeks from the end of the induction period, depending on the clinical status of the patient. […] Other uses of ganciclovir include treatment of GI disease in transplant recipients and in patients who are HIV positive. Ganciclovir has been used to treat CMV esophagitis in both of these patient populations. […] A major successful use of ganciclovir has been prophylactic or preemptive treatment of CMV disease in transplant recipients. Without preventive CMV therapy, 30-75% of transplant recipients develop CMV infection, and 8-30% develop CMV disease.
#10 Cytomegalovirus (CMV) Infection – Infectious Diseases – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/infectious-diseases/herpesviruses/cytomegalovirus-cmv-infection
Ganciclovir and other antiviral medications are used to treat severe disease, particularly retinitis. […] For serious disease, antivirals (eg, ganciclovir, valganciclovir, foscarnet, cidofovir, maribavir) are used. […] CMV retinitis, which occurs mostly in AIDS patients, is treated with systemic antivirals. […] Anti-CMV medications are used to treat severe disease other than retinitis but are less consistently effective than in retinitis. […] Most patients receive induction therapy with IV ganciclovir or oral valganciclovir. […] Maintenance (suppressive) therapy with ganciclovir or valganciclovir is given after induction. […] Alternatively, IV foscarnet can be given with or without ganciclovir. […] Cidofovir therapy is another alternative. […] Maribavir is an oral medication for treatment of refractory CMV disease.
#11 Cytomegalovirus (CMV) Treatment & Management: Medical Care, Consultations, Activity
https://emedicine.medscape.com/article/215702-treatment
Prophylaxis is provided to all patients who have positive CMV serology results. Positive findings on blood cultures, pp65 antigenemia, and CMV PCR have been used as markers for the initiation of therapy. […] Letermovir is indicated for prophylaxis of CMV infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). […] Additionally, letermovir is indicated for prophylaxis of CMV disease in adult kidney transplant recipients at high risk (donor CMV seropositive/recipient CMV seronegative [D+/R-]). […] Foscarnet is a DNA chain inhibitor of phosphorylation and it is considered the drug of choice for ganciclovir-resistant CMV infections. […] Maribavir has significant activity against both human cytomegalovirus (CMV) and Epstein-Barr virus, but not other herpesviruses.
#12 CMV Retinitis – EyeWiki
https://eyewiki.org/CMV_Retinitis
Cytomegalovirus (CMV) Retinitis is an acquired immunodeficiency syndrome (AIDS)-related opportunistic infection that can lead to blindness. […] With the advent of antiretroviral therapies, the incidence of CMV retinitis has decreased by 90% in AIDS population. […] Management is largely medically based with intravenous (IV), oral, and intravitreal anti-viral medications. […] There are at least 8 options for therapy of CMV retinitis. […] First line therapy is generally oral valganciclovir, which is a pro-drug of ganciclovir. […] IV ganciclovir is given at 5 mg/kg twice daily for two to three weeks as induction therapy then followed by daily 5 mg/kg infusions. […] Foscarnet is given at 90 mg/kg twice daily for two weeks followed by maintenance therapy of 90-120 mg/kg daily through IV infusion.
#13 CMV Retinitis – EyeWiki
https://eyewiki.org/CMV_Retinitis
Cidofovir has a longer half life and can be administered weekly during induction followed by bi-weekly maintenance therapy. […] Other options for therapy are oral leflunomide and oral letermovir. […] In patients with immediately sight-threatening lesions (lesions close to the macula or optic nerve head), intravitreal injection of ganciclovir (2mg in 0.1 mL injection) or foscarnet (2.4 mg in 0.1 mL injection) or fomvirsen 330 micrograms, or cidofovir 20micrograms with concurrent systemic therapy can be done. […] CMV retinitis can be become drug resistant the longer the duration of treatment lasts. […] Discontinuing antiretroviral therapy is not recommended because it reduces the CD4+ T lymphocyte count and increases the risk of opportunistic infections. […] The prognosis was almost uniformly fatal prior to the advent of HAART. Now it carries a much better prognosis, but even with HAART and anti-CMV therapy, mortality is still increased after diagnosis of CMV retinitis.
#14 Cytomegalovirus (CMV) Infection: Symptoms, Treatment, Pregnancy
https://www.medicinenet.com/cytomegalovirus_cmv/article.htm
Foscarnet (Foscavir) is active against CMV by a different mechanism than ganciclovir and is used to treat infections with CMV that are resistant to ganciclovir. It is a second-line therapy for patients who do not tolerate ganciclovir treatment. Foscarnet is toxic to the kidneys and can cause seizures due to an imbalance of minerals and electrolytes. […] Cidofovir (Vistide) is an alternative therapy for patients who have failed ganciclovir and foscarnet treatment. Its use is limited due to toxicity to the kidneys. It is used mainly for the treatment of CMV infection of the eye (retinitis) in patients with acquired immune deficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV). […] CMV immune globulin contains antibodies (proteins) that are specific to CMV. It may be prescribed to prevent CMV infection in high-risk lung transplant patients when given in addition to ganciclovir. It is also used with ganciclovir to treat CMV pneumonia.
#15 Frontiers Publishing Partnerships | New Treatment Options for Refractory/Resistant CMV Infection
https://www.frontierspartnerships.org/journals/transplant-international/articles/10.3389/ti.2023.11785/full
Letermovir is a 3,4-dihydroquinazoline derivative and is an inhibitor of the viral terminase complex, mainly at the pUL56 subunit. Terminase inhibition leads to compromised viral replication by inhibiting the cleavage of genome particles to units of proper length and accumulation of immature viral DNA. Based on the mechanism of action, letermovir is selectively active only against CMV, and mechanism-derived adverse effects are unlikely. Letermovir was approved in 2017 for prophylactic use in adult CMV-seropositive allogeneic hematopoietic stem cell transplant (HCT) recipients, where it has shown good efficacy in the placebo-controlled phase III trial and as of 6 June 2023, the US FDA approved letermovir for the new indication of CMV prophylaxis in D+/Râ kidney transplant recipients, based on the results of the Phase 3 trial. No statistically significant differences were seen in the frequency or severity of any adverse events between letermovir and placebo, although gastrointestinal adverse events (such as nausea) were slightly more common in the letermovir group. It is available in both peroral (PO) and intravenous (IV) formulations. The standard dose is 480 mg daily (IV/PO) when used as prophylaxis. However, due to interaction via the hepatic drug transporter organic-anion-transporting polypeptide (OATP), cyclosporine increases bioavailability of letermovir, and dose reduction to 240 mg daily is recommended.
#16 Frontiers Publishing Partnerships | New Treatment Options for Refractory/Resistant CMV Infection
https://www.frontierspartnerships.org/journals/transplant-international/articles/10.3389/ti.2023.11785/full
In summary, R/R CMV remains a major challenge and new effective and safe treatment options are needed. […] In this review, we summarize and discuss the latest findings on maribavir, letermovir, and CMV-specific adoptive T cell therapies as treatment options for R/R CMV after SOT. […] Maribavir is an oral benzimidazole riboside antiviral which has been in development for many years, but only recently became available as therapy for R/R CMV. It inhibits viral UL97 kinase and thus interferes with multiple pathways including nuclear egress of CMV viral capsids. It has no significant renal, hematologic, or hepatic toxicity; its most common adverse effect is dysgeusia. Early trials for prophylaxis in stem cell transplant and liver transplant recipients failed to show efficacy, likely because the dose selected, 100 mg twice daily, was too low. However, a case series of six patients with R/R CMV treated with compassionate use maribavir at doses of 400â800 mg twice daily showed striking responses in several patients. This, and the toxicity of other agents available for R/R CMV, spurred the performance of a Phase 2 trial of 3 dosing regimens for maribavir (400, 800, and 1,200 mg twice daily) among SOT and HSCT recipients. This study demonstrated clearance of CMV DNAemia at 6 weeks of therapy in 70%, 63%, and 68%, respectively, in this highly treatment-experienced population.
#17 Frontiers Publishing Partnerships | New Treatment Options for Refractory/Resistant CMV Infection
https://www.frontierspartnerships.org/journals/transplant-international/articles/10.3389/ti.2023.11785/full
Subsequently, a multicenter Phase 3 trial of maribavir versus investigator-assigned therapy (IAT) was performed involving 352 SOT and HSCT recipients in a 2:1 randomization. IAT, which could be ganciclovir, valganciclovir, foscarnet, cidofovir, or a combination of these, was chosen as the comparator because of patientsâ varied treatment histories. The primary endpoint, confirmed CMV-DNA clearance at the end of week 8, was achieved by 55.7% in the maribavir arm vs. 23.9% in the IAT arm (p > 0.001). The key secondary endpoint, a composite of CMV-DNA clearance and symptom control at the end of week 8 maintained through week 16, was achieved by 18.7% vs. 10.3% (p = 0.01). Dysgeusia was the most frequent adverse effect in the maribavir group (37.2%); the maribavir group also had significantly less neutropenia than the val/ganciclovir group and less acute kidney injury than the foscarnet group. These results led to the approval of maribavir by the US FDA in 2021 for treatment of post-transplant CMV infection/disease in patients age 12 and older, that is refractory (with or without genotypic resistance) to treatment with ganciclovir, valganciclovir, cidofovir or foscarnet, with a similar authorization by the EMA in 2022.
#18 Cytomegalovirus (CMV) Treatment & Management: Medical Care, Consultations, Activity
https://emedicine.medscape.com/article/215702-treatment
Leflunomide is an antimetabolite used as a disease-modifying agent in rheumatoid arthritis. It has also been successfully used off-label in both CMV disease treatment and prophylaxis. […] CMV immune globulin has been approved by the US Food and Drug Administration for the prophylaxis of CMV disease in high-risk lung transplant recipients when given in conjunction with ganciclovir.
#19 Cytomegalovirus (CMV) Treatment & Management: Medical Care, Consultations, Activity
https://emedicine.medscape.com/article/215702-treatment
There are various CMV-treatment approaches based on the patients CMV status and co-morbidities. Some patients receive prophylaxis whereas some receive preemptive therapy. Prophylaxis is given to a patient to prevent primary, reactivation, or recurrent infection. Preemptive therapy is given to asymptomatic CMV-infected patients with CMV detected by screening tests. Some studies have shown that high-dose acyclovir or valacyclovir prophylaxis markedly reduces CMV infection in allo-HSCT recipients. Intravenous ganciclovir also has been tested, with some reduction in CMV infection; however, this did not provide overall survival benefit and was associated with bone marrow suppression (ganciclovir-induced neutropenia). […] Letermovir, a novel viral terminase inhibitor, has been used for primary prevention of CMV in sero-positive allo-HSCT recipients, however, has not been approved for solid organ transplant recipients.
#20 Cytomegalovirus (CMV) | Causes, Symptoms, and Treatment
https://patient.info/doctor/cytomegalovirus
There are several drugs available for treatment of CMV disease: […] Ganciclovir is related to aciclovir but it is more active against CMV. It is also much more toxic than aciclovir. […] Oral ganciclovir provides much lower serum levels than intravenous, and so oral ganciclovir is mainly restricted to use as prophylaxis for CMV disease. […] Intravenous ganciclovir is used for the initial treatment of CMV retinitis. […] For the treatment of CMV pneumonia, ganciclovir is administered with immunoglobulin. […] Other uses of ganciclovir include treatment of gastrointestinal disease in patients who have received transplants and in patients who are HIV-positive. […] Valganciclovir may be used to treat neonates with symptoms at birth. […] Congenitally infected infants, both symptomatic and asymptomatic at birth, require follow-up evaluation to detect sequelae. […] Prophylaxis with antiviral medications reduces CMV disease and CMV-associated mortality in solid organ transplant recipients. They should be used routinely in CMV-positive recipients and in CMV-negative recipients of CMV-positive organ transplants.
#21 Cytomegalovirus (CMV): symptoms, treatments and diagnosis
https://www.kidneyresearchuk.org/conditions-symptoms/cytomegalovirus/
Transplant units will generally use preventative and/or pre-emptive therapies to minimise the impact of CMV. […] To prevent CMV infection, Doctors will prescribe antiviral medicines, taken orally, for around three to six months after a transplant. The amount of time a person will receive this preventative medicine for depends on their risk of getting a CMV infection and the intensity of their immunosuppression treatment. However, sometimes people can get a CMV infection after stopping these medicines. […] With pre-emptive therapy, transplant recipients are regularly monitored and are given antiviral medicines as soon as they are judged to be at risk of developing a CMV infection. […] If a person does go on to develop a CMV infection their antiviral medication will be given at a treatment dose, or may need to be delivered directly into the bloodstream through an IV line if oral tablets are not possible. […] These medicines, combined with the lowering of immunosuppression, can effectively treat CMV and reduce the chance of serious problems.
#22 Comprehensive CMV Testing: Assessing, Treating, and Managing Cytomegalovirus
https://www.eurofins-viracor.com/news-and-events/posts/2023/july/comprehensive-cmv-testing-assessing-treating-and-managing-cytomegalovirus/
Regular monitoring of CMV through comprehensive testing allows healthcare providers to detect viral reactivation or new infections early on. […] Comprehensive CMV testing provides critical information for tailoring treatment strategies to individual patients. […] The management of CMV in pregnant women depends on various factors, including the timing of infection during pregnancy and the presence of symptoms. […] In cases of primary CMV infection during pregnancy, antiviral therapy may be considered to reduce the risk of transmission to the fetus. […] CMV prophylaxis involves the administration of antiviral medications to prevent CMV infection in high-risk transplant recipients. […] In preemptive therapy, regular monitoring of CMV viral load is performed, and antiviral treatment is initiated promptly upon detection of viral replication.
#23
https://link.springer.com/article/10.1007/s40506-014-0021-5
The first-line options for therapy of CMV disease, as mentioned above, are almost always i.v. GCV or p.o. VGC. However, in the early post-HSCT period, or in the severely neutropenic patient, one may have to start with FOS. […] Therapy of CMV disease should be started at full doses (adjusted for renal function) and continued until symptoms are clearly improved, and until antigenemia (or even DNAemia) has resolved. […] Reports of drug-resistant CMV in transplant patients are increasing. The risk factors have been covered in detail elsewhere. […] Although it is intuitive to use FOS for GCV-resistant CMV, published results are mixed. […] The other agents that have been tried in the literature are artesunate, maribavir (MBV), and leflunomide. […] CMX001 (hexadecyloxypropyl CDV) is an orally available lipid acyclic nucleotide phosphonate that delivers high intracellular levels of CDV-diphosphate. Early human studies showed no significant effects on blood chemistries or hematology.
#24 Cytomegalovirus Disease: Adult and Adolescent OIs | NIH
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cytomegalovirus
Cytomegalovirus (CMV) is a double-stranded DNA virus in the herpesvirus family that can cause disseminated or localized end-organ disease in people with HIV with advanced immunosuppression. Most clinical disease occurs in individuals previously infected with CMV experiencing reactivation of latent infection. Infection with a novel strain also may occur. […] End-organ disease caused by CMV occurs in patients with HIV and advanced immunosuppression, typically those with CD4+ T lymphocyte cell (CD4) counts 50 cells/mm3 who are not receiving, adherent to, or responding to antiretroviral therapy (ART). Among those treated with ART who have achieved virologic control, a new diagnosis of CMV end-organ disease is exceedingly rare. […] CMV end-organ disease is best prevented using ART to maintain the CD4 count 100 cells/mm3. A randomized, placebo-controlled trial addressed whether valganciclovir (the current standard oral agent for treatment of CMV disease) in addition to ART might reduce CMV end-organ disease in AIDS patients at high risk (CD4 count 100 cells/mm3 and CMV viremia detected by plasma CMV DNA PCR assay). This study failed to show a benefit for such preventive therapy; therefore, valganciclovir primary prophylaxis is not recommended to prevent CMV end-organ disease in people with HIV, even among patients who have CMV viremia.
#25 Cytomegalovirus Disease: Adult and Adolescent OIs | NIH
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cytomegalovirus
The therapeutic approach to CMV retinitis should be individualized based on tolerance of systemic medications, prior exposure to anti-CMV drugs, and possibly the location of lesions. CMV retinitis should ideally be treated with the active participation of an ophthalmologist who is familiar with the diagnosis and management of this retinal disease. […] Oral valganciclovir, intravenous (IV) ganciclovir, or IV ganciclovir induction followed by oral valganciclovir maintenance are first-line therapies for treating CMV retinitis. […] Treatment with systemic anti-CMV therapy, such as oral valganciclovir for the first 3 to 6 months until ART has induced immune recovery, is beneficial. […] For patients who have colitis or esophagitis, many HIV specialists recommend anti-CMV therapy for 21 to 42 days or until signs and symptoms have resolved. IV ganciclovir generally is the therapy of choice and can be switched to oral valganciclovir once the patient can tolerate and absorb oral medications.
#26 Cytomegalovirus Disease: Adult and Adolescent OIs | NIH
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cytomegalovirus
Therapy for well-documented neurologic disease also has not been extensively studied. Given the poor outcomes in many patients with CMV-related neurologic disease, some experts would initiate therapy with both IV ganciclovir and IV foscarnet, despite the substantial toxicities associated with such an approach.
#27 CMV, neurologic | Johns Hopkins HIV Guide
https://www.hopkinsguides.com/hopkins/view/Johns_Hopkins_HIV_Guide/545043/all/CMV__neurologic
CMV encephalitis/polyradiculomyelitis: primary induction […] Preferred: given poor outcomes, many prefer to use combination CMV therapy, although weak data support its use and toxicities are significant. […] Ganciclovir 5 mg/kg IV q12h PLUS foscarnet 90 mg/kg IV q12h […] An open-label trial showed 94 d median survival vs. 42 d historical control using monotherapy with a combination regimen poorly tolerated. […] Monitor at least twice weekly CBC, chemistries including phosphorous during induction, once weekly during maintenance. […] Alternatives: Monotherapy with either ganciclovir or foscarnet. […] The decision to use ganciclovir and/or foscarnet often in part decided upon hematologic and renal aspects. […] Duration, induction therapy: 2 wks or until resolution of neurologic symptoms (not well-established)
#28 Frontiers Publishing Partnerships | New Treatment Options for Refractory/Resistant CMV Infection
https://www.frontierspartnerships.org/journals/transplant-international/articles/10.3389/ti.2023.11785/full
New Treatment Options for Refractory/Resistant CMV Infection […] Despite advances in monitoring and treatment, cytomegalovirus (CMV) infections remain one of the most common complications after solid organ transplantation (SOT). CMV infection may fail to respond to standard first- and second-line antiviral therapies with or without the presence of antiviral resistance to these therapies. This failure to respond after 14 days of appropriate treatment is referred to as âresistant/refractory CMV.â Limited data on refractory CMV without antiviral resistance are available. Reported rates of resistant CMV are up to 18% in SOT recipients treated for CMV. Therapeutic options for treating these infections are limited due to the toxicity of the agent used or transplant-related complications. This is often the challenge with conventional agents such as ganciclovir, foscarnet and cidofovir. Recent introduction of new CMV agents including maribavir and letermovir as well as the use of adoptive T cell therapy may improve the outcome of these difficult-to-treat infections in SOT recipients. In this expert review, we focus on new treatment options for resistant/refractory CMV infection and disease in SOT recipients, with an emphasis on maribavir, letermovir, and adoptive T cell therapy.
#29 Cytomegalovirus Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC4431713/
The recommended treatment of CMV-p in the HSCT recipient is i.v. GCV with immunoglobulins. Although GCV reduced viral load by 99 % in the lungs of patients with CMV pneumonitis, nine of ten patients given i.v. GCV still died. However, the addition of immunoglobulins has reduced the mortality of CMV-p. […] The optimal treatment of CMV encephalitis/myelitis is undefined. Expert reviews favor a combination of i.v. GCV and FOS. This is based on an observational study from the pre-ART era. […] The first-line options for therapy of CMV disease, as mentioned above, are almost always i.v. GCV or p.o. VGC. However, in the early post-HSCT period, or in the severely neutropenic patient, one may have to start with FOS. FOS is likely as good as i.v. GCV, and possibly better. […] Reports of drug-resistant CMV in transplant patients are increasing. The risk factors have been covered in detail elsewhere. Generally, one suspects resistance when the CMV viral load rises, or fails to fall, during therapy.
#30
https://link.springer.com/article/10.1007/s40506-014-0021-5
The treatment of CMV retinitis is guided by studies in patients with AIDS. The use of i.v. GCV, i.v. FOS, p.o. VGC, and the GCV implant are all supported by randomized controlled trial (RCT) data. […] The recommended treatment of CMV-p in the HSCT recipient is i.v. GCV with immunoglobulins. Although GCV reduced viral load by 99 % in the lungs of patients with CMV pneumonitis, nine of ten patients given i.v. GCV still died. However, the addition of immunoglobulins has reduced the mortality of CMV-p. […] The optimal treatment of CMV encephalitis/myelitis is undefined. Expert reviews favor a combination of i.v. GCV and FOS. […] The treatment of CMV disease in immunocompetent hosts is not established. However, anterior uveitis and corneal endotheliitis in immunocompetent individuals likely require treatment.
#31
https://journals.lww.com/transplantjournal/fulltext/2016/03001/cmv_immunoglobulins_for_the_treatment_of_cmv.2.aspx
Despite high rates of response when CMV disease is treated with IV ganciclovir or valganciclovir, recurrence remains a problem. […] The 2013 CMV Consensus Conference of The Transplantation Society recommends that in cases of recurrent CMV in thoracic transplant patients after a disease- and drug-free period, adjunctive CMVIG can be considered in patients with hypogammaglobulinemia. […] There are few therapeutic options for ganciclovir-resistant CMV infections. […] Foscarnet is the most frequent choice, but is used off-label in this setting and is limited by severe bone marrow and renal toxicity. […] In cases of suspected ganciclovir-resistant CMV infection where the patient is asymptomatic or not severely ill, increased ganciclovir exposure with CMVIG and reduced immunosuppressive therapy have been proposed.
#32 Treatment of congenital cytomegalovirus infection
https://www.e-cep.org/journal/view.php?number=20125555586
Congenital cytomegalovirus (CMV) is the most common cause of congenital infection worldwide, the most common nongenetic cause of sensorineural hearing loss in children, and a cause of neurodevelopmental disorders in the brain. Infants with symptomatic congenital CMV infection may benefit from hearing and neurodevelopmental outcomes, particularly if antiviral treatment is initiated within the first month of life. […] Infants with life-threatening symptoms are recommended to receive 26 weeks of intravenous ganciclovir and then switch to oral valganciclovir, and those without life-threatening symptoms are recommended to use oral valganciclovir during the entire 6-month period. […] This review investigated the evidence to date of treating congenital CMV infection. […] Congenital CMV is initially treated with intravenous ganciclovir for 26 weeks and switched to oral valganciclovir, or with oral valganciclovir for the entire 6-month period.
#33 Treatment of congenital cytomegalovirus infection
https://www.e-cep.org/journal/view.php?number=20125555586
Antiviral treatment is recommended in infants with congenital CMV infection and end-organ symptoms in one or more organs or evidence of CNS involvement. […] Treatment with intravenous ganciclovir and oral valganciclovir in infants with these symptoms improves long-term hearing and neurodevelopmental outcomes. […] In a series of 23 infants treated with oral valganciclovir for 12 months, Amir et al. found that long-term treatment was safe and associated with improved auditory outcomes compared with previous controls who received 6 weeks of treatment. […] The currently recommended drug regimen for symptomatic infants with congenital CMV infection is as follows: infants with life-threatening symptoms are initially treated with intravenous ganciclovir for 26 weeks and then switched to oral valganciclovir, while those without life-threatening symptoms are treated with oral valganciclovir for the entire 6-month period. […] Monitoring of ANC, platelet count, blood urea nitrogen, creatinine, and liver function tests is required to identify neutropenia, thrombocytopenia, renal failure, and liver failure during antiviral treatment.
#34 Cytomegalovirus – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK459185/
Testing for CMV resistance is now common in transplant centers. Resistance to ganciclovir has been noted in many transplant patients and makes treatment difficult. Resistance to CMV should be suspected in any transplant patient who fails to respond to therapeutic doses of ganciclovir or is rapidly declining in health. […] If the patient is about to undergo a transplant, one should discuss prophylaxis with ganciclovir. […] Anti-CMV drugs target the viral DNA polymerase, pUL54. […] The involvement of an interprofessional team can improve outcomes.
#35 Refractory/Resistant Cytomegalovirus Infection in Transplant Recipients: An Update
https://www.mdpi.com/1999-4915/16/7/1085
Despite the significant progress made, CMV infection is one of the most frequent infectious complications in transplant recipients. CMV infections that become refractory or resistant (R/R) to the available antiviral drugs constitute a clinical challenge and are associated with increased morbidity and mortality. Novel anti-CMV therapies have been recently developed and introduced in clinical practice, which may improve the treatment of these infections. […] In this review, we aim to summarize the treatment options for R/R CMV infections in adult HCT and SOT recipients, with a special focus on newly available antiviral agents with anti-CMV activity, including maribavir and letermovir. […] Until recently, only CMV DNA polymerase (UL54) inhibitors were available, and those drugs still constitute the first line for CMV treatment. Ganciclovir and its oral prodrug valganciclovir are guanine analogs that first need to be phosphorylated by a viral kinase, UL97, to further inhibit CMV DNA replication by acting as chain terminators.
#36 Refractory/Resistant Cytomegalovirus Infection in Transplant Recipients: An Update
https://www.mdpi.com/1999-4915/16/7/1085
An important step in the management of R/R infection is the identification of specific resistance-conferring mutations by genotypic sequencing to inform treatment decisions. […] Recent data suggest that CMV-specific T cell immunity could potentially inform decisions about duration of make it possible to stratify patient risk for discontinuation of CMV prophylaxis or preemptive treatment and need for secondary prophylaxis. […] With a multimodal antiviral effect, maribavir, a benzimidazole riboside, was initially developed more than 20 years ago, but was only recently approved for the treatment of R/R CMV infections. […] This trial led to the approval of maribavir by the FDA and other relevant medical agencies for R/R CMV infections in both HCT and SOT recipients. […] Letermovir is available in both oral and IV formulations. Its oral bioavailability is excellent, even in patients with severe GIT GvHD. […] However, in the absence of large clinical studies, more data on the potential utility of letermovir in combination with other modalities in the management of R/R CMV infection or as secondary prophylaxis in high-risk transplant patients are urgently needed.
#37 Cytomegalovirus Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC4431713/
Although it is intuitive to use FOS for GCV-resistant CMV, published results are mixed. Reddy et al. used FOS (with/without GCV) for lung transplant recipients with UL97 mutations and noted that the viral load declined in all. […] The other agents that have been tried in the literature are artesunate, maribavir (MBV), and leflunomide. […] CMX001 (hexadecyloxypropyl CDV) is an orally available lipid acyclic nucleotide phosphonate that delivers high intracellular levels of CDV-diphosphate. Early human studies showed no significant effects on blood chemistries or hematology. HSCT recipients randomized to CMX001 prophylaxis had significantly fewer CMV events than those randomized to placebo.
#38 Frontiers Publishing Partnerships | New Treatment Options for Refractory/Resistant CMV Infection
https://www.frontierspartnerships.org/journals/transplant-international/articles/10.3389/ti.2023.11785/full
CMV-specific adoptive T cell therapy is an appealing option for R/R CMV in SOT. However, safety and efficacy need to be confirmed in controlled trials. Additional data is needed to identify the best protocols in terms of T cell generation and optimal time point of application and the influence of different immunosuppressive therapies on treatment efficacy should be investigated. At this point, we recommend that CMV-specific T cell therapies should be preferentially offered within clinical trials in order to close the knowledge gaps.
#39 Frontiers | Anti-CMV therapy, what next? A systematic review
https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2023.1321116/full
Human cytomegalovirus (HCMV) is one of the main causes of serious complications in immunocompromised patients and after congenital infection. There are currently drugs available to treat HCMV infection, targeting viral polymerase, whose use is complicated by toxicity and the emergence of resistance. Maribavir and letermovir are the latest antivirals to have been developed with other targets. The approval of letermovir represents an important innovation for CMV prevention in hematopoietic stem cell transplant recipients, whereas maribavir allowed improving the management of refractory or resistant infections in transplant recipients. However, in case of multidrug resistance or for the prevention and treatment of congenital CMV infection, finding new antivirals or molecules able to inhibit CMV replication with the lowest toxicity remains a critical need. This review presents a range of molecules known to be effective against HCMV. Molecules with a direct action against HCMV include brincidofovir, cyclopropavir and anti-terminase benzimidazole analogs.
#40 Frontiers | Anti-CMV therapy, what next? A systematic review
https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2023.1321116/full
The burden of long-term therapies for immunocompromised patients, and the emergence of new resistance mechanisms, the unmet need for low toxic treatments to prevent or cure cCMV, make it essential to find new antiviral targets and to develop new therapies, in order to treat CMV infections more efficiently while reducing side effects.
#41 Frontiers | Anti-CMV therapy, what next? A systematic review
https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2023.1321116/full
Recently, two antiviral drugs with new targets, high specificity and low toxicity, reached clinical development: letermovir targets the highly virus-specific terminase complex (UL56, UL98 and UL51) and maribavir inhibits the UL97 viral kinase. Letermovir (LMV) was approved in 2017 by the Food and Drug Administration (FDA) for the prophylaxis of CMV infection in hematopoietic stem cell transplant patients with high risk of CMV infections. This new antiviral inhibits the terminase complex, a viral component not found in human cells, thereby reducing its toxicity. Similarly, maribavir (MBV) was approved in 2021 for the treatment of adults and children presenting post-transplant CMV infections refractory or resistant to antivirals. […] This is why it is necessary to find new molecules with an anti-CMV spectrum. In this context, this review summarizes the panel of molecules with antiviral activity, including direct inhibitors (brincidofovir, cyclopropavir, anti-terminase benzimidazole analogs), molecules acting through cellular pathways inhibition (artemisinin derivatives, flavonoids, leflunomide, everolimus, or anti Cox) and immunoglobulins.
#42 Frontiers | Anti-CMV therapy, what next? A systematic review
https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2023.1321116/full
The efficacy of anti-CMV immunoglobulins are discussed in CMV congenital infection and in association with direct antiviral therapy in heart transplanted patients. All molecules are described, with their mode of action against HCMV, preclinical tests, clinical studies and possible resistance. All these molecules have shown anti-HCMV potential as monotherapy or in combination with others. These new approaches could be interesting to validate in clinical trials. […] Currently, available antivirals are limited to virostatic polymerase inhibitors (ganciclovir, its oral prodrug valganciclovir, cidofovir and foscarnet). Neutropenia limits efficacy of ganciclovir or valganciclovir and this hematological toxicity prevents its use as a prophylaxis in the stem cell recipients. Cidofovir and foscarnet are highly nephrotoxic and restricted to second line treatment. The second limitation of these molecules is the emergence of resistance, favored by prolonged treatments in highly immunocompromised hosts, and use of lower doses due to renal impairment.
#43 Cytomegalovirus (CMV) infection – Symptoms & causes – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/cmv/symptoms-causes/syc-20355358
Cytomegalovirus (CMV) is a common virus. Once infected, your body retains the virus for life. Most people don’t know they have cytomegalovirus (CMV) because it rarely causes problems in healthy people. […] There is no cure, but there are medications that can help treat the symptoms. […] If you have weakened immunity, you may benefit from taking antiviral medication to prevent CMV disease. […] Experimental vaccines are being tested for women of childbearing age. These vaccines may be useful in preventing CMV infection in mothers and infants, and reducing the chance that babies born to women who are infected while pregnant will develop disabilities.