Sandbox jyostna

• 1. Retinitis

• Preferred regimen (1) for immediate sight-threatening lesions: Ganciclovir intraocular implant AND Valganciclovir 900 mg PO q24h.
• Preferred regimen (2) for peripheral lesions: Valganciclovir 900 mg PO q12h for 14–21 days, then 900 mg PO q24h for maintenance therapy
• Alternative regimen for retinitis: Ganciclovir 5 mg/kg IV q12h for 14–21 days, then Valganciclovir 900 mg PO q24h OR Foscarnet 60 mg/kg IV q8h or 90 mg/kg IV q12h for 14–21d, then 90–120 mg/kg IV q24h OR Cidofovir 5 mg/kg IV for 2wks, then 5 mg/kg every other wk; each dose should be administered with IV saline hydration AND oral probenecid OR repeated intravitreal injections with Fomivirsen (for relapses only, not as initial therapy)

Note (1): Most common cause of blindness in AIDS patients with <50/mm3 CD4 counts is Cytomegalovirus.

Note (2): 19/30 pts (63%) with inactive CMV retinitis who responded to HAART (increase of ≥60 CD4 cells/mL) developed immune recovery vitreitis (vision decreases and floaters with posterior segment inflammation vitreitis, papillitis & macular changes) an average of 43 wks after teatment started.

Note (3): Corticosteroid treatment decreases inflammatory reaction of immune recovery vitreitis without reactivation of CMV retinitis, either periocular Corticosteroids or short course of systemic Steroid.

Note (4): Differential diagnosis is HIV retinopathy, herpes simplex retinitis, varicella-zoster retinitis (rare, hard to diagnose).

Note (5): Valganciclovir PO equal to Ganciclovir IV in induction of remission: Cannot use Ganciclovir ocular implant alone as approx. 50% risk of CMV retinitis other eye at 6 months and 31% risk visceral disease. Risk decreases with systemic treatment but when contralateral retinitis does occur, Ganciclovir-resistant mutation often present. Concurrent systemic treatment recommended.

Note (6): Because of unique mode of action, Fomivirsen may have a role if isolates become resistant to other therapies.

Note (7): Retinal detachments 50–60% within 1 year of diagnosis of retinitis.

Note (8): Equal efficacy of IV Ganciclovir and Foscarnet. Ganciclovir avoids nephrotoxicity of Foscarnet; Foscarnet avoids bone marrow suppression of Ganciclovir. Although bone marrow toxicity may be similar to Ganciclovir. Oral Valganciclovir should replace both.

• Post treatment suppression (prophylactic) if CD4 count <100/mm3

• Preferred regimen: Valganciclovir 900 mg PO q24h.

Note (1): Discontinue if CD4 >100/mm3 for 6 months on ART.

Note (2): Patients who discontinue suppression therapy should undergo regular eye examination for early detection of relapses.

• 2. In Transplant patients

• Preferred regimen: Valganciclovir

Note (1): Use of Valganciclovir to prevent infections in CMV seronegative recipients who receive organs from a seropositive donor and in seropositive receivers has been highly effective.

Note (2): Others suggest preemptive treatment when pt develops CMV antigenemia or positive PCR post-transplant.

• 3. Colitis, Esophagitis

Dx by biopsy of ulcer base/edge  with demonstration of CMV inclusions & other pathogen.

Ganciclovir as with retinitis except induction period extended for 3–6 wks. No agreement on use of maintenance; may not be necessary except after relapse. Responses less predictable than for retinitis.

Valganciclovir also likely effective.

Switch to oral valganciclovir when PO tolerated & when symptoms not severe enough to interfere with absorption.

Antiretroviral therapy is essential in long term suppression.

• 4. Encephalitis, Ventriculitis

Treatment not defined, but should be considered the same as retinitis. Disease may develop while taking ganciclovir as suppressive therapy.

 Lumbosacral polyradiculopathy: diagnosis by CMV DNA in CSF Ganciclovir, as with retinitis. Foscarnet 40 mg/kg IV q12h another option.Switch to valganciclovirwhen possible. Suppression continued until CD4 remains >100/mm3 for 6 mos. About 50% will respond; survival Ĺ (5.4wks to 14.6wks) (CID 27:345, 1998). Resistance can be demonstrated genotypically. 

Mononeuritis multiplex Not defined Due to vasculitis & may not be responsive to antiviral therapy 

Pneumonia— Seen predominantly in transplants (esp. bone marrow), rare in HIV. Treat only when histological evidence resent in IDS pts & other pathogens not identified. High rate of CMV reactivation in immunocompetent ICU patients; prolonged hospitalizations and increased mortality. Ganciclovir/valganciclovir, as with retinitis. In bone marrow transplant pts, combination therapy with CMV immune globulin. In bone marrow transplant pts, serial measure of pp65 antigen was useful in establishing early diagnosis of CMV interstitial pneumonia with good results if ganciclovir was initiated within 6 days of antigen positivity (Bone Marrow Transplant 26:413, 2000). For preventive therapy, see Table 15E. 

Cidofovir (Vistide) 5 mg per kg IV once weekly for 2 weeks, then once every other week. Properly timed IV prehydration with normal saline &Probenecidmust be used with each cidofovir infusion: 2 gm po 3 hrs before each dose and further 1 gm doses 2 & 8 hrs after completion of the cidofovir infusion. Renal function (serum creatinine and urine protein) must be monitored prior to each dose (see pkg insert for details). Contraindicated if creatinine >1.5 mg/dL, CrCl ”55 mL/min or urine protein •100 mg/dL.

Adverse effects: Nephrotoxicity; dose-dependent proximal tubular injury (Fanconi-like syndrome): proteinuria, glycosuria, bicarbonaturia, phosphaturia, polyuria (nephrogenic diabetic insipidus, Ln 350:413, 1997), acidosis, Ĺ creatinine. Concomitant saline prehydration, probenecid, extended dosing intervals allowed use but still highly nephrotoxic. Other toxicities: nausea 69%, fever 58%, alopecia 27%, myalgia 16%, probenecid hypersensitivity 16%, neutropenia 29%. Iritis and uveitis reported; also Ļ intraocular pressure. Black Box warning. Renal impairment can occur after ”2 doses. Contraindicated in pts receiving concomitant nephrotoxic agents. Monitor for Ļ WBC. In animals, carcinogenic, teratogenic, causes Ļ sperm and Ļ fertility. FDA indication only CMV retinitis in HIV pts. Comment: Recommended dosage, frequency or infusion rate must not be exceeded. Dose must be reduced or discontinued if changes in renal function occur during rx. For Ĺ of 0.3–0.4 mg per dL in serum creatinine, cidofovir dose must be Ļ from 5 to 3 mg per kg; discontinue cidofovir if Ĺ of 0.5 mg per dL above baseline or 3+ proteinuria develops (for 2+ proteinuria, observe pts carefully and consider discontinuation).

Foscarnet (Foscavir) Indction: 90 mg per kg IV, over 1.5-2 hours, q12h OR 60 mg per kg, over 1 hour, q8h

Maintenance: 90 –120 mg per kg IV, over 2 hours, q24h Dosage adjustment with renal dysfunction (see Table 17).Use infusion pump to control rate of administration. Adverse effects: Major toxicity is renal impairment (1/3 of patients) --Ĺ creatinine, proteinuria, nephrogenic diabetes insipidus, ↓K+, ↓Ca++, ↓ Mg++. Toxicity Ĺ with other nephrotoxic drugs [ampho B, aminoglycosides or pentamidine (especially severe ↓ Ca++)]. Adequate hydration may ↓ toxicity. Other: headache, mild (100%); fatigue (100%), nausea (80%), fever (25%). CNS: seizures. Hematol: ↓ WBC, ↓ Hgb. Hepatic: liver function tests Ĺ. Neuropathy. Penile and oral ulcers

Ganciclovir (Cytovene) IV: 5 mg per kg q12h times 14 days (induction)5 mg per kg IV q24h or 6 mg per kg 5 times per wk (maintenance)Dosage adjust. with renal dysfunction (see Table 17)

Adverse effects: Black Box warnings: cytopenias, carcinogenicity/teratogenicity & aspermia in animals.Absolute neutrophil count dropped below 500 per mm3 in 15%, thrombocytopenia 21%, anemia 6%. Fever 48%. GI 50%: nausea, vomiting, diarrhea, abdominal pain 19%, rash 10%. Retinal detachment 11% (likely due to underlying diseases). Confusion, headache, psychiatric disturbances and seizures. Neutropenia may respond to granulocyte colony stimulating factor (G-CSF or GM-CSF). Severe myelosuppression may be Ĺ with coadministration of zidovudine or azathioprine. 32% dc/interrupted rx, principally for neutropenia. Avoid extravasation.

Oral: 1.0 gm tid with food (fatty meal) (250 mg & 500 mg cap) Hematologic less frequent than with IV. Granulocytopenia 18%, anemia 12%, thrombocytopenia 6%. GI, skin same as with IV. Retinal detachment 8%.

Ganciclovir (Vitrasert)Intraocular implant Adverse effects: Late retinal detachment (7/30 eyes). Does not prevent CMV retinitis in good eye or visceral dissemination. Comment: Replacement every 6 months recommended

 Valganciclovir (Valcyte)900 mg (two 450 mg tabs) po bid times 21 days for induction, followed by 900 mg po q24h. Take with food. Dosage adjustment for renal dysfunction (See Table 17A).A prodrug of ganciclovir with better bioavailability than oral ganciclovir: 60% with food. Adverse effects: Similar to ganciclovir. 

Herpesvirus Infections Cytomegalovirus (CMV)

Marked decrease in HIV associated CMV infections & death with Highly Active Antiretroviral Therapy. Initial treatment should optimize HAART.

Primary prophylaxis not generally recommended. Preemptive therapy in patients with increased in  CMV DNA titers in plasma & CD4 <100/mm3. Recommended by some: valganciclovir 900 mg po q24h. Authors rec. primary prophylaxis be dc if response to HAART with incerase in CD4 >100 for 6 months. 

Risk for developing CMV disease correlates with quantity of CMV DNA in plasma: each log10Ĺ associated with 3.1-fold increase in disease.

CMV(Recipient + OR Donor +/Recipient –)

HSCT

Preemptive therapy

Monitor

≥

1

×

/wk (days 10-100) CMV viremia by PCR or CMV-antigenemia and star

t rx if positive. Traditional a

pproach was to use ganciclovir

5 mg/kg iv Q12H for 7-14 days, then 5 mg/kg iv Q24H 5 days/wk to the longer of: d 100 or

≥

3 wks (

MMWR 49(RR-10):1, 2000

).

More recently, valganciclovir used more often in those who can ta

ke oral medications. Continue therapy until viral load negativ

e (preferably

×

2).

•

One study found valganciclovir 900 mg po bid comparable

to ganciclovir 5 mg/kg iv bid in preemptive regimen (

BMTr 37:693, 2006

).

•

Valganciclovir 900 mg po bid for 2 wks, then 900 mg po Q24H for

≥

7 days after negative viral assay, was effective (

BMTx 37:851, 2006

).

•

Preemptive regimen of valganciclovir 900 mg po bid

×

2 wks, then 450 mg po bid, was effective (

TransInfectDis 9:102, 2007

).

OR, alternatively

Prophylaxis approach

(for high-risk pts (

see CID 35:999, 2002

) or when CMV detection tests not rapidly availa

ble): From engraftment to day 100, ganciclovir

5 mg/kg iv Q12H for 7 days, then 5 mg/kg iv Q24H 5 to 6 days per wk.

Comments

For reviews, see

CMR 16:647, 2003

and

Herpes 15:4, 2008

.SOT

Kidney, Kidney/Pancreas, Heart:Valganciclovir 900 mg po Q24H; start by day 10 and continue to at least day 100. Liver: Ganciclovir 5 mg/kg iv once daily or ganciclovir 1 gm po tid; start by day 10 and continue to at least day 100. Or, with caution, valganciclovir†. Lung: Ganciclovir 5 mg/kg iv Q12H for 5-7 days, then valganciclovir 900 mg po Q24H for 6 mos (or at least 3 mo)†. Comments: •For recommendations of US and Canadian societies, see AmJTranspl 4(Suppl 10):51, 2004 & 5:218, 2004. Optimal approach—preemption versus universal prophylaxis—still debated (CID 47:702, 2008; CID 46:732, 2008; CID 47:296, 2008), but prophylaxis approach favored by most. •With antiviral prophylaxis, onset of CMV is appearing later; optimal duration of prophylaxis under study (CID 46: 732, 2008). •† Valganciclovir does not have FDA indication for CMV prevention in liver or lung transplantation, but commonly used (AmJTranspl 8:158, 2008). •In selected cases, some institutions add CMV immune globulin to antiviral drug in high risk cases (CID 47:702, 2008). Regimen for lung, heart, liver, pancreas: 150 mg/kg within 72 h of transplant and at 2, 4, 6 & 8 wks post-transplant; then 100 mg/kg at wks 12 & 16.