RU2740943C1 - Method of treating cytomegaloviral retinitis after haemopoetic stem cell transplantation - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: present invention relates to ophthalmology and is intended for treating cytomegaloviral retinitis (CMVR) in patients after transplantation of haemopoetic stem cells. Method of treating cytomegaloviral retinitis (CMVR) after transplantation of haemopoietic stem cells involves an intravitreal introduction (IVI) of the antiviral preparation once a week under the control of the number of copies of the virus in the anterior chamber moisture. Introducing a preparation showing antiviral activity in systemic administration, according to this, Ganciclovir is introduced intravitreally in amount of 2–6 mg, wherein the dose is increased in proportion to the number of copies of CMV DNA in aqueous humor, or Foscavir in amount of 2.4 mg. At the first IVI, the number of copies of the virus in the moisture of the anterior chamber of both eyes is determined, including, when CMVR is detected only on one eye, if there is no decrease in the number of copies in the moisture of the anterior chamber, one preparation is substituted for the other one. Intravitreal injections are performed until the virus completely eliminates the moisture of anterior chamber 1 week after the last IVI, the intraocular fluid control sampling is performed from both eyes even in cases when CMVR is detected only on one eye.

EFFECT: using the given method provides healing of retinal necrosis centres and minimizes probability of recurrent CMVR.

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Description

The present invention relates to ophthalmology and is intended for the treatment of cytomegalovirus retinitis (CMVR) in patients after hematopoietic stem cell transplantation.

Cytomegalovirus infection is lifelong due to the fact that the virus persists in the body in a latent state, and clinical manifestations are associated with a weakening of cellular immunity. With the spread of cytomegalovirus infection through the hematoretinal barrier, cytomegalovirus retinitis (CMVR) develops, which requires intensive local treatment.

, Thomas Mertens, Wolfram Ebell, and Helga Meisel. Fatal Reactivation of Postnatal Cytomegalovirus Infection with Rapid Emergence of Ga nciclovir Resistance in an Infant after Allogeneic Stem Cell Transplantation. J Clin Microbiol. 2005 Jul; 43(7): 3551-3554.], а также с тракционной отслойкой сетчатки [Eid AJ, Bakri SJ, Kijpittayarit S, Razonable RR. Clinical features and outcomes of cytomegalovirus retinitis after transplantation. Transpl Infect Dis. 2008 Feb;10(1): 13-8. Epub 2007 May 19], которая развивается после завершения острого периода воспаления. Залогом благоприятного исхода цитомегаловирусного ретинита является его ранняя диагностика и своевременное начало лечения [Tun N, London N, Kyaw MK, Smithuis F, Ford N, Margolis T, Drew W L, Lewallen S, Heiden D. CMV retinitis screening and treatment in a resource-poor setting: threeyear experience from a primary care HIV/AIDS programme in Myanmar. J Int AIDS Soc. 2011 Aug 15; 14:41.].Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for many malignant diseases of the blood system, primary immunodeficiencies, and severe forms of anemia. This method of treatment is associated with severe immunosuppression and a high risk of infectious complications, which include virus-associated retinonecrosis. CMRR can cause irreversible blindness, which is associated with the vastness of the area of retinonecrosis [Sebastian Voigt, Detlef Michel, Olivia K ershaw,

, Thomas Mertens, Wolfram Ebell, and Helga Meisel. Fatal Reactivation of Postnatal Cytomegalovirus Infection with Rapid Emergence of Ga nciclovir Resistance in an Infant after Allogeneic Stem Cell Transplantation. J Clin Microbiol. 2005 Jul; 43 (7): 3551-3554.], As well as with traction retinal detachment [Eid AJ, Bakri SJ, Kijpittayarit S, Razonable RR. Clinical features and outcomes of cytomegalovirus retinitis after transplantation. Transpl Infect Dis. 2008 Feb; 10 (1): 13-8. Epub 2007 May 19], which develops after the end of the acute period of inflammation. The key to a favorable outcome of cytomegalovirus retinitis is its early diagnosis and timely initiation of treatment [Tun N, London N, Kyaw MK, Smithuis F, Ford N, Margolis T, Drew WL, Lewallen S, Heiden D. CMV retinitis screening and treatment in a resource- poor setting: threeyear experience from a primary care HIV / AIDS program in Myanmar. J Int AIDS Soc. 2011 Aug 15; 14:41.].

A known method of treating CMRR in patients with AIDS, which involves multiple intravitreal administration of the drug Ganciclovir at a dose of 5.0 mg / 0.1 ml once a week until ophthalmoscopically significant regression is achieved [Arevalo JF, Garcia RA, Mendoza AJ. High-dose (5000-microg) intravitreal ganciclovir combined with highly active antiretroviral therapy for cytomegalovirus retinitis in HIV-infected patients in Venezuela. Eur J Ophthalmol. 2005 Sep-Oct; 15 (5): 610-8.].

There is a known method for the treatment of CMRR in hematopoietic stem cell recipients, which consists in systemic antiviral therapy, which is supplemented with intravitreal injections only in those patients in whom CMRR foci are located in the macular region or near the optic nerve head [Vishnevskia-Dai V, Shapira Y, Rahav G, Shimoni A, Somech R, Moisseiev J. Cytomegalovirus retinitis in HIV-negative patients: a practical management approach. Ophthalmology. 2015 Apr; 122 (4): 866-868.e3.].

Both of these methods have a significant disadvantage because they are uncontrollable. First, CMRR is a recurrent disease [Lawrence P. Iu, Michelle C. Fan, Jordy K. Lau, Thomas S. Chan, Yok-LamKwong, Ian Y. Wong. Long-term Follow-up of Cytomegalovirus Retinitis in Non-HIV Immunocompromised Patients: Clinical Features and Visual Prognosis. American Journal of Ophthalmology Volume 165, May 2016, Pages 145-153], and repeated intravitral administration of antiviral drugs under the control of ophthalmoscopy cannot provide confidence in achieving remission of CMR. Secondly, these methods of treatment leave possible excessive manipulations on the eyeball itself, or excessive systemic antiviral therapy, which in hematopoietic stem cell recipients can cause transplant rejection due to the myeolotoxicity of ganciclovir. Third, CMR-induced blindness is associated with the development of retinal detachments [Ei d AJ, Bakri SJ, Kijpittayarit S, Razonable RR. Clinical features and outcomes of cytomegalovirus retinitis after transplantation. Transpl Infect Dis. 2008 Feb; 10 (1): 13-8. Epub 2007 May 19], the likelihood of which depends on the area of retinonecrosis [Eid AJ, Bakri SJ, Kijpittayarit S, Razonable RR. Clinical features and outcomes of cytomegalovirus retinitis after transplantation. Transpl Infect Dis. 2008 Feb; 10 (1): 13-8. Epub 2007 May 19].

The closest analogue of the present invention is a method for the same purpose, including intravitreal administration of the antiviral drug ganciclovir 1 mg once a week, only 4 injections under the control of the virus copy number in the moisture of the anterior chamber using the quantitative polymerase chain reaction MiaoH in 2013 [Miao H, Tao Y , Jiang YR, Li XX. Multiple intravitreal injections of ganciclovir f or cytomegalovirus retinitis after stem-cell transplantation. Graefes Arch Clin Exp Ophthalmol. 2013 Jul; 251 (7): 1829-33.]. In this method, it was not possible to achieve complete elimination of the virus from the moisture of the anterior chamber in most patients, which was reflected in clinical indicators - in 11 eyes of patients, a decrease in the number of copies was noted, and in 18 eyes - an increase, which indicates insufficient efficiency when using this mode of administration. ganciclovir.

The objective of the invention was the further development of the CMRR treatment regimen.

The technical result of the proposed invention is to minimize the recurrence of the disease and prevent retinal detachment after CMRR.

The technical result is achieved due to intravitreal administration of the drug, which has shown efficiency when administered systemically, changing the drug in the absence of positive dynamics in the number of virus copies in the moisture of the anterior chamber, and administering the drug until the virus is completely eliminated from the eyeball.

CMRR is a progressive disease and the blindness associated with it has two pathogenetic mechanisms. The first is the retinonecrosis itself - the decrease in vision in this case depends on the area of the retinal lesion and localization. The second mechanism for the development of blindness is traction retinal detachment, which is associated with post-inflammatory compaction of the vitreous body, and its likelihood also depends on the area of the retinal membrane lesion. Taking into account the above, a favorable outcome of CMRR is inversely proportional to the area of necrosis, and depends on the timing of diagnosis, initiation and treatment regimen. The main goal is to reduce the number of relapses.

We have conducted studies comparing the effectiveness of the proposed method of treating CMRR using intravitreal injections (IVI) of antiviral drugs under the control of the number of virus copies in the moisture of the anterior chamber by the method of treating this disease - IVI of antiviral drugs under ophthalmoscopic control in patients after HSCT. In our study, we evaluated the effectiveness of treatment according to the following parameters: the number of relapses of retinonecrosis and the number of retinal detachments that developed after the completion of active inflammation. Data analysis for each of these parameters was carried out separately.

Analysis of the statistics of relapses of CMR

Relapse of CMRR was considered the appearance of new foci of retinonecrosis after the patient was recognized as cured of this disease.

The study included 47 patients. Steel inclusion criteria - CMWR transferred by TGSK.

All patients were divided into 2 groups. The first group (7 people, 11 eyes) included those children in whom CMRR was treated with IVI antiviral drugs under ophthalmoscopic control. Cured was a patient whose CMRR foci: a) completely resorbed, b) transformed into retinal cicatricial changes, c) transformed into chorioretinal cicatricial changes with pigmentation. The second group (40 people, 72 eyes) included those patients in whom CMRR were treated with IVI antiviral drugs with monitoring of HRV PCR. A patient was considered cured if the CMV copies were completely eleminated from aqueous humor and a control study of the IHF, which was carried out 1 week after the last IVI, gave a negative result.

In the first group, relapses of retinonecrosis were detected in 4 of 11 eyes, which amounted to 36.36%. In the second group, CMRR relapses were diagnosed in 15 eyes, which amounted to 20.83%.

Analysis of the statistics of retinal detachments after CMR:

The study included 49 patients. Steel inclusion criteria - CMWR transferred by TGSK.

All patients were divided into 2 groups. The first group (9 people, 15 eyes) included those children in whom CMRR was treated with IVI antiviral drugs under ophthalmoscopic control. Cured was a patient whose CMRR foci: a) completely resorbed, b) transformed into retinal cicatricial changes, c) transformed into chorioretinal cicatricial changes with pigmentation. The second group (40 people, 72 eyes) included those patients in whom CMRR were treated with IVI antiviral drugs with monitoring of HRV PCR. A patient was considered cured if the CMV copies were completely eleminated from aqueous humor and a control study of the IHF, which was carried out 1 week after the last IVI, gave a negative result.

In the first group, retinal detachments were detected in 3 of 15 eyes, accounting for 20%. In the second group, retinal detachment was diagnosed in 2 eyes out of 72, which was 2.78%.

The above difference in the number of relapses of retinonecrosis and retinal detachments associated with CMRR demonstrates the effectiveness of evaluating CMRR treatment with antiviral drugs by determining the copies of the virus in the moisture of the anterior chamber.

The method is carried out as follows.

In a patient after hematopoietic stem cell transplantation, intravitreal administration (IVI) of an antiviral drug is performed once a week under the control of the number of virus copies in the moisture of the anterior chamber. A drug is introduced that has shown antiviral activity when administered systemically. In accordance with this, ganciclovir in the amount of 2-6 mg or foscavir in the amount of 2.4 mg is administered intravitreally. In the absence of a decrease in the number of copies in the moisture of the anterior chamber, substitute one drug for another. Intravitreal injections are carried out until the complete elimination of the virus from the moisture of the anterior chamber 1 week after the last IVS.

All patients who have undergone HSCT are given weekly plasma PCR. All patients who have CMV viremia or who have a proven CMV-related infectious lesion receive systemic antiviral therapy with Ganciclovir (180 mg / kg / day intravenously). With negative dynamics of CMV viremia, detected by PCR of blood plasma, antiviral therapy is escalated on Foskavir at a dose of 120 mg / kg / day intravenously.

For patients diagnosed with CMRR after HSCT, in addition to systemic therapy, IVI of antiviral drugs is performed once a week.

All intraocular manipulations are carried out in an aseptic operating unit with visualization using a microscope for ophthalmic surgery. The introduction of the drug into the vitreous cavity is carried out according to the generally accepted method with the volume of the injected drug 0.1 ml.

During the first IVI, IHV collection is performed from both eyes, even in cases where CMRR is detected in only one eye. Further IVS are planned based on the results of PCR of the IHV.

Each time after the introduction of the drug into the vitreous cavity, 0.2-0.3 ml of liquid is taken from the anterior chamber according to the generally accepted method. Material analysis is carried out using real-time PCR.

The choice of drug and dose for subsequent IVS is chosen as follows: in the absence of data on resistance to ganciclovir or foskavir, choose a drug that has shown antiviral activity when administered systemically. If, during IVI of one of the selected drugs, PCR of the HCV indicates the absence of positive dynamics in relation to the number of copies of the virus, the drug is replaced with another one (ganciclovir to foscavir and vice versa) and the IVI is continued until the virus is completely eliminated from the HCV. After reaching a negative result of PCR of the IHF, one week after the last IVI, two weeks later, re-sampling of the IHF is made for real-time PCR. A control sampling of HVH is performed from both eyes, even in cases where CMR is detected in only one eye. If a repeated negative result is obtained, the patient is considered cured of CMR.

Clinical examples

Example 1:

Patient F. In the post-transplant period, CMV viremia was detected up to 64,500 CMV copies per 1.0 ml of blood plasma, which was completely negativized under the influence of systemic antiviral therapy with Ganciclovir at a dose of 180 mg / kg / day. During a routine examination of the fundus with mydriasis, the patient was diagnosed with CMRR in the right and left eyes. Treatment was started: intravitreal administration of the drug Ganciclovir 2.0 mg was carried out on each eye with the intake of high-frequency fluid. Polymerase chain reaction of aqueous humor revealed 75,423 copies of CMV in the right eye and 98,582 copies of CMV in the left. After analyzing the results, it was decided to increase the amount of ganciclovir and, weekly, 4.0 mg of this drug was injected into each eye. After each IVI, IHF was taken from the anterior chamber of the eye for real-time PCR; a consistent decrease in the number of CMV copies in aqueous humor was observed.

A negative result of HRV PCR was achieved after 5 IVIs on the right eye and after 6 IVIs on the left eye. Two weeks after the last IVI, the patient underwent control IVF sampling. PCR for CMV was negative on both sides.

Further, the patient underwent monthly fundus ophthalmoscopy with mydriasis up to 365x post-transplant days. No new foci of CMVR were found.

In this clinical case, the lowest dose Ganciclovir was chosen for the first administration, because it has demonstrated its effectiveness in the systemic therapy of CMV infection in this patient. After analyzing the results of HPV PCR, the dose was increased in proportion to the number of copies of CMV DNA in aqueous humor. The treatment was discontinued after complete elimination of CMV from the IHF.

Example 2:

Patient D. In the post-transplant period, CMV viremia was detected up to 15890 CMV copies per 1.0 ml of blood plasma. Systemic antiviral therapy with Ganciclovir at a dose of 180 mg / kg / day was prescribed, however, the CMV viremia values reached 25342 CMV copies per 1.0 ml of blood plasma. Exalation of systemic therapy to Foskavir at a dose of 120 mg / kg / day was performed. CMV viremia was completely negative. During a routine examination of the fundus with mydriasis, the patient was diagnosed with CMRR in the right eye. Treatment was started: an intravitreal injection of the drug Foskavir 2.4 mg was performed on the right eye with the intake of high-blood fluid from both eyes. The polymerase chain reaction of aqueous humor revealed 7542 copies of CMV in the right eye and a negative result in the left eye. Weekly, 2.4 mg of this drug was injected into the right eye. After each IVI, IHF was taken from the anterior chamber of the eye for real-time PCR; a consistent decrease in the number of CMV copies in aqueous humor was observed.

A negative PCR result of HIV was achieved after 5 IVIs. Two weeks after the last IVI, the patient underwent control IHF sampling from both eyes. PCR for CMV was negative on both sides.

Further, the patient underwent monthly fundus ophthalmoscopy with mydriasis up to 365x post-transplant days. No new foci of CMVR were found.

In this clinical case, for the first administration, Foscavir was chosen at a standard concentration, because it demonstrated its effectiveness in the systemic therapy of CMV infection in this patient in the absence of the effect of systemic therapy with Ganciclovir. The treatment was discontinued after complete elimination of CMV from the IHF.

Example 3:

Patient L. In the post-transplant period, CMV viremia was detected up to 85382 CMV copies per 1.0 ml of blood plasma, which was completely negatively affected by systemic antiviral therapy with Ganciclovir at a dose of 180 mg / kg / day. During a routine examination of the fundus with mydriasis, the patient was diagnosed with CMRR in the right eye. Treatment was started: an intravitreal injection of the drug Ganciclovir 2.0 mg was performed on the right eye, with the intake of IHF from both eyes. The polymerase chain reaction of aqueous humor revealed 27,522 copies of CMV in the right eye and 1,334 copies of CMV in the left. After analyzing the results, the dose of ganciclovir was maintained and 2.0 mg of the drug was injected into each eye weekly. After each IVI, IHF was taken from the anterior chamber of the eye for real-time PCR; a consistent decrease in the number of CMV copies in aqueous humor was observed.

A negative result of HRV PCR was achieved after 6 IVIs on the right eye and after 3 IVIs on the left eye. Two weeks after the last IVI, the patient underwent control IVF sampling. PCR for CMV was negative on both sides.

Further, the patient underwent monthly fundus ophthalmoscopy with mydriasis up to 365x post-transplant days. No new foci of CMVR were found.

In this clinical case, the lowest dose Ganciclovir was chosen for the first administration, because it has demonstrated its effectiveness in the systemic therapy of CMV infection in this patient. After analyzing the results of PCR of the high blood flow, the dose was retained, the treatment was stopped after the complete elimination of CMV from the high blood flow.

Example 4:

Patient K. In the post-transplant period, CMV viremia was detected up to 73810 CMV copies per 1.0 ml of blood plasma, which was completely negatively affected by systemic antiviral therapy with Ganciclovir at a dose of 180 mg / kg / day. During a routine examination of the fundus with mydriasis, the patient was diagnosed with CMRR in the right and left eyes. Treatment was started: intravitreal administration of the drug Ganciclovir 2.0 mg was carried out on each eye with the intake of high-frequency fluid. Polymerase chain reaction of aqueous humor revealed 147820 copies of CMV in the right eye and 124118 copies of CMV in the left. After analyzing the results, the dose of ganciclovir was recalculated and, weekly, 6.0 mg of this drug was injected into each eye. After each IVI, IHF was taken from the anterior chamber of the eye for real-time PCR; a consistent decrease in the number of CMV copies in aqueous humor was observed.

A negative result of HRV PCR was achieved after 14 IVIs on the right eye and after 12 IVIs on the left eye. Two weeks after the last IVI, the patient underwent control IVF sampling. PCR for CMV gave a negative result on the left and allowed to identify 324 copies of CMV on the right. The right treatment was continued. The patient underwent 2 IVIs of the drug Ganciclovir at a dose of 6.0 / 0.1 ml with the sampling of HF for PCR and after each manipulation, an increase in the number of copies of the virus in the aqueous humor was determined. Local antiviral therapy was escalated on Foskavir at a dose of 2.4 mg / 0.1 ml. The patient underwent 4 IVIs of the drug Foskavir at a dose of 2.4 / 0.1 ml with the intake of HF for PCR. A complete negativization of the PCR results of HIV was achieved.

Two weeks after the last IVI, the patient underwent control IHF sampling from both eyes. PCR for CMV was negative on both sides.

Further, the patient underwent monthly fundus ophthalmoscopy with mydriasis up to 365x post-transplant days. No new foci of CMVR were found.

In this clinical case, the lowest dose Ganciclovir was chosen for the first administration, because it has demonstrated its effectiveness in the systemic therapy of CMV infection in this patient. After analyzing the results of HPV PCR, the dose was increased in proportion to the number of copies of CMV DNA in aqueous humor. The treatment was discontinued after the complete elimination of CMV from the VHF in the left eye, and in the right eye due to the presence of an increase in virus copies in the VHF even after treatment with ganciclovir at the maximum dose, the treatment was continued with the replacement of the drug with foscavir 2.4 mg until the virus was completely eliminated.

Thus, the proposed method for the treatment of CMRR after hematopoietic stem cell transplantation provides high efficiency with the prevention of relapses and complications, which allows preserving visual functions in this category of patients.

Claims (1)

A method of treating cytomegalovirus retinitis (CMVR) after transplantation of hematopoietic stem cells, including intravitreal administration (IVV) of an antiviral drug once a week under the control of the number of virus copies in the moisture of the anterior chamber, characterized in that the drug that has shown antiviral activity when administered systemically is administered to in accordance with this, ganciclovir is administered intravitreally in an amount of 2-6 mg, while the dose is increased in proportion to the number of copies of CMV DNA in aqueous humor, or foscavir in an amount of 2.4 mg, and at the first IVI, the number of virus copies in the moisture of the anterior chamber of both eyes is determined, including, when CMVR is detected in only one eye, in the absence of a decrease in the number of copies in the moisture of the anterior chamber, one drug is replaced with another, intravitreal injections are carried out until the virus is completely eliminated from the moisture of the anterior chamber 1 week after the last IVI, the control both eyes, even when CMRR was detected in only one eye.