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 Guide Editors
 Editor In Chief
    Joel E. Gallant, MD, MPH

Pharmacology Editor
    Paul Pham, PharmD, BCPS

Zambia Guideline Team
   Peter Mwaba MMed PhD FRCP
   Alywn Mwinga MMed
   Isaac Zulu MMed MPH
   Velepie Mtonga MMed
   Albert Mwango MBChB
   Jabbin Mulwanda MMed FCS



Diagnosis>Opportunistic Infections>
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CMV retinitis

James P. Dunn, M.D

  • CMV is ubiquitous virus and considered endemic in Zambia, but limited data on epidemiology of CMV retinitis in Zambia.
  • Most studies demonstrate higher prevalence of CMV antibody in Africans vs. persons in developed world.
  • In contrast, limited reports suggest that prevalence of CMV retinitis in Africa is lower than in developed world. This may be because of higher mortality at earlier stage of HIV infection, before development of CMV disease.
  • Dx of CMV retinitis can be made by fundoscopic examination by experienced observers.
  • CMV PCR not available in Zambia.
  • None of typical treatments for CMV retinitis, besides ART, are readily available in Zambia.
Zambia Information Author: Larry William Chang, MD, MPH


  • Cytomegalovirus (CMV): ubiquitous beta-herpesvirus that reactivates with advanced HIV (CD4 <50). Most HIV+ pts have latent infection (+ anti-CMV IgG).


  • CMV retinitis (CMV-R) occurred in ~30% AIDS pts pre-HAART, now ~5% or less in HAART era.
  • Most common cause of visual loss in AIDS and most common ocular disease; major cause of impaired quality of life. Retinitis comprises 80-90% of end-organ CMV disease.
  • Med. survival after Dx w/ CMV-R 8.5-12 mos in pre-HAART era.
  • Sx: (1) often none (15-50% asymptomatic) (2) floaters, photopsias, blind spots, distortion; (blind spots % distortion especially if macula involved) (3) no pain, redness, photophobia.
  • Bilateral involvement at time of Dx in 35%. 50% w/ unilateral retinitis develop contralateral involvement within 6 mos if untreated.
  • Causes of visual loss: central macular (foveal) necrosis (irreversible); optic neuritis (occasionally reversible); macular edema (occasionally reversible); retinal detachment (surgically treatable). Greater risk in eyes with larger lesions and with lesions involving vitreous base anteriorly. 50% will have detachment in >1 eye at 1 yr after Dx of CMV-R without immune recovery; 33% of eyes will suffer detachment. In HAART era, detachment rate has decreased, but remains similar among those with CD4 <50.  Cataract and macular edema are most common causes of visual loss in patients with immune recovery uveitis.
  • Clinical course: relentless progression of retinitis in untreated pts: 24 microns/day (range 0-164).


  • Location of retinitis: Zone 1 (posterior, often visible with direct ophthalmoscopy) within 1500 mu (~1 disc diameter) of optic disc or 3000 mu of fovea; considered immediately vision-threatening. Zone 2 (peripheral to zone 1 but posterior to zone 3) not considered immediately vision-threatening; direct ophthalmoscopy in well-dilated pupil can image retina into mid-periphery of zone 2. Zone 3 (anterior to imaginary circle connecting ampulla of vortex veins).
  • Spectrum of clinical findings: (1) Fulminant/granular retinitis: hemorrhagic retinal necrosis, often with perivascular sheathing (may be present in retina away from area of necrosis); rarely mis-Dx'd (2) Indolent/granular retinitis: minimal or no hemorrhage and no perivascular sheathing; more commonly misdiagnosed (3) Mixed features can be present (4) dry, granular-appearing border characteristic (5) Lesions may be single or multiple, unilateral or bilateral (6) Full-thickness retinal necrosis with irreversible loss of function in affected tissue (7) Mild anterior chamber & vitreous inflammatory reaction usually present; fine keratic precipitates typical; no posterior synechiae.
  • DDx: acute retinal necrosis (HSV or VZV), progressive outer retinal necrosis (VZV), toxoplasmosis, syphilis, cotton-wool spots, metastatic Candida or other fungal endophthalmitis, intraocular lymphoma, tuberculosis
  • Dx: Dx made clinically, confirmatory tests rarely necessary. CMV PCR from vitreous, blood, other sources not in widespread clinical use, but vitreous PCR occasionally helpful in distinguishing CMV-R from necrotizing herpetic retinitis or toxoplasmosis. CMV viral load: not used, uncertain significance.
  • Sensitivity testing: not yet in widespread use; resistant CMV uncommon at time of Dx but reported to occur at rate of 0.25/person-year in pre-HAART era, similar for ganciclovir and foscarnet; rate is lower in era of HAART, perhaps due to more potent anti-CMV therapy.


General principles

  • Induction-maintenance: induction: higher or more frequent doses of drug given initially with systemic therapy for 2-3 wks; maintenance (2o prophylaxis): lower or less frequent chronic suppressive doses continued indefinitely to prevent relapse
  • Choice of treatment based on location of retinitis, pt preference, overall general health.
  • IV Ganciclovir (GCV) and foscarnet (FOS) now rarely used because of need for permanent indwelling catheter and availability of safer options (e.g., valganciclovir).
  • Systemic GCV shown in randomized clinical trial to reduce risk of KS in patients with CMV-R. Systemic anti-CMV therapy in persistently immunocompromised patients increases survival.
  • Zone 1 lesions in eyes of pts without immune recovery are best candidates for GCV implant. Small Zone 2 or Zone 3 lesions may respond to HAART alone (see below), but concurrent valganciclovir therapy for up to 6 mos recommended.
  • Additional anti-CMV Rx may decrease risk of immune recovery uveitis (see below) and may have systemic benefits. Relapse after cessation of therapy is certain in pts not on HAART: average within 4 wks.
  • Clinical features of treated retinitis: sharp demarcation between necrotic and uninvolved retina; variable pigmentation of necrotic retina; lipid or calcification may be present and should not be confused with active retinitis.
Systemic therapy

  • IV GCV (FDA-approved): induction: 5 mg/kg twice-daily x 2 wks; maintenance: 5 mg/kg once-daily. Side effects: reversible bone marrow suppression (especially leukopenia & anemia), GI (nausea, diarrhea), requires indwelling central venous catheter for daily infusions.
  • Oral ganciclovir (GCV) (FDA-approved for maintenance therapy only after 3-wk IV induction therapy completed): 1 gm PO three times a day. Side effects: similar to IV GCV but no catheter-related complications. Due to large pill burden, use has been replaced by valganciclovir.
  • Valganciclovir (FDA-approved): valine ester (pro-drug) of GCV gives comparable serum levels to IV GCV. Induction: 900 mg PO twice-daily x 3 wks; maintenance: 900 mg orally PO once-daily. Side effects: similar to IV GCV but no catheter-related complications.
  • Foscarnet (FOS) (FDA-approved): induction 90 mg/kg IV q12h x 2 wks then maintenance 90-120 mg/kg IV once-daily. Efficacy similar to IV GCV. Side effects: reversible nephrotoxicity (dose adjustment required), nausea, hypocalcemia, genital ulcerations, catheter-related infections (including sepsis). Use of FOS now generally limited to pts with bone marrow suppression, unable to tolerate GCV implant surgery, and/or evidence of resistance to GCV. In pre-HAART era, survival in pts treated with FOS longer than with IV GCV (12.6 v. 8.5 mos), possibly due to weak antiretroviral effect of FOS. Probably no enhanced survival benefit of FOS vs. GCV in pts concurrently treated with HAART.
  • Cidofovir (CDV) (FDA-approved): induction: 5 mg/kg IV q wk x 2 wks then maintenance: 5 mg/kg IV q2wks. Avoids need for permanent IV catheter. Side effects: nephrotoxicity (drug given with probenecid and saline hydration before and after CDV infusion), which is usually but not always reversible, cessation of CDV usually required; probenecid toxicity (rash, malaise); uveitis - may be severe, with loss of vision due to ocular hypotony (more common with repeated infusions, usually responds to topical corticosteroids and cessation of cidofovir therapy). Efficacy: comparable to GCV implant in randomized clinical trial.
Local therapy

  • GCV ocular implant (FDA-approved): 4.5 mg sustained-release pellet of GCV surgically placed into vitreous cavity through pars plana incision. Provides constant drug levels x ~8 mos. Intravitreous GCV levels 4-fold higher than IV GCV: faster, more sustained response. Rapid loss of anti-CMV effect when implant exhausted of drug. Planned exchange of implant sometimes recommended in pts with advanced zone 1 disease not on HAART. Side effects: requires surgery, cataract, endophthalmitis (approximately 0.5%/surgery), vitreous hemorrhage, retinal detachment, no systemic anti-CMV effect. Implant usually given with systemic anti-CMV therapy (e.g., valganciclovir) to reduce risk of contralateral CMV-R (2o prophylaxis) or extraocular CMV and perhaps to improve survival.
  • Intravitreous injections (non-FDA-approved): sometimes used to obtain rapid intraocular drug levels in eyes with Zone 1 disease prior to more definitive therapy. Usually not sole therapy as inconvenient, provides no protection against contralateral or extraocular CMV infection. May allow control of retinitis during times when pt unable to tolerate systemic therapy because of illness or toxicity. Dosages: GCV 2 mg/0.1 ml 1-2 x/wk; FOS 2.4 mg/0.1 ml 1-2 x/wk. Side effects: infection, retinal detachment, vitreous hemorrhage, cataract. Note: intravitreous CDV is toxic to the eye (inflammation and hypotony) and should not be used.

Drug Comments

Valganciclovir Preferred for most cases of CMV-R; efficacy comparable to IV forms of therapy with fewer side effects. Particularly effective when combined with ART. Should also be used as 2o prophylaxis when GCV implant used to reduce risk of visceral CMV disease and decrease mortality.
Ganciclovir Difficult to obtain in oral formulation with no benefit over valganciclovir. IV GCV can be substituted for valganciclovir in patients unable to tolerate oral anti-CMV therapy. GCV implant often the preferred therapy in pts with CMV-R threatening optic nerve or fovea, particularly in pts not taking or poorly responsive to HAART.
Foscarnet IV FOS not used as primary therapy for CMV-R but may be useful in patients with GCV resistance or severe bone marrow suppression. Short half-life, nephrotoxicity, and limitation to IV form are major drawbacks. Intravitreal FOX can be useful as short-term therapy for lesions threatening optic nerve and macula.
Cidofovir IV CDV has efficacy comparable to GCV implant plus oral therapy but usually less well tolerated because of nephrotoxicity, long duration of infusion, and side effects of probenecid that must be given with cidofovir to reduce risk of renal disease. May be useful in pts with GCV resistance. Intravitreous CDV should not be used.



  • Clinical features of relapse or progression: increased border opacification ("smoldering retinitis"); expansion of previously inactive border of retinitis; appearance of new lesions in same or fellow eye; progression may occur without visible border opacification.
  • Careful monitoring of retinitis with serial retinal photographs is most effective means of determining active vs. inactive disease.
  • Effect of progression on vision is function of location: small progression in zone 1 disease may cause severe visual loss; occurs within 48-121 days in pts not treated with HAART (depending on criteria used to define relapse).
  • Hemorrhage alone not an indication of relapse.
  • Causes: non-adherence to therapy; poor intraocular drug availability; antiviral resistance (occurred at a rate of ~0.25/person-year with systemic therapy in pre-HAART era, but much lower now).
  • Resistance: (1) UL97 mutations: low-grade GCV resistance. Results in decreased phosphorylation of GCV (required for cellular antiviral effect uptake) May respond to GCV implant; usually responds to cidofovir or FOS (neither requires phosphorylation by viral enzymes) (2)UL54 mutations: high-grade GCV resistance. Results in failure to impair CMV DNA polymerase Often causes resistance to GCV implant and cidofovir. (3) mutations causing FOS resistance less well studied and more difficult to identify
Treatment of relapse (or progression)

  • Options: Reinduction with same drug.
  • Higher dose of maintenance therapy (e.g., FOS 120 vs. 90 mg/kg/day) after reinduction.
  • Change to different drug (e.g., CDV instead of GCV; use of GCV implant)
  • Combination therapy (e.g., GCV+ FOS); may be more effective but also more toxic.
  • Most effective means of treating or preventing relapse is immune recovery with ART.
  • Response to treatment: relapse-free intervals become progressively shorter.
Impact of HAART

  • Reduced incidence of CMV-R and other ocular infection: 75-85% reduction in incidence of CMV-R in several studies.
  • ART alone may control CMV-R: occasional finding of inactive or regressing CMV-R in pts treated with HAART but no specific anti-CMV therapy.
  • Not recommended as sole therapy due to: (1) risk of spread of retinitis to fovea or optic nerve before immune recovery occurs in pts with zone 1 disease; (2) increased risk of immune recovery uveitis among pts with inadequate treatment of CMV-R then started on ART; (3) benefit of systemic anti-CMV therapy on survival among immunocompromised patients.
  • Use of HART associated with fewer ocular complications in patients with CMV-R and lower risks of retinal detachment and vision loss.
  • Immune recovery uveitis (IRU): syndrome of vitritis and other sequelae of increased intraocular inflammation (+/- cystoid macular edema [CME], epiretinal membranes) in pts with CMV-R who have been treated with ART. More common in eyes with larger area of retinal involvement, in less aggressively treated eyes, and in eyes of pts treated with IV cidofovir. Dx: clinical examination, fluorescein angiography, optical coherence tomography. Rx: 50% of pts with CME respond to oral or periocular corticosteroids . Relapse of retinitis in pts treated with corticosteroids rare. May respond to valganciclovir.
  • Cessation of anti-CMV therapy: chronic maintenance can be safely discontinued in pts with immune recovery (CD4 >100x >3-6 mos. Resume maintenance if CD4 declines to <75. Best candidates are those who are ART-nave at time of Dx, show good immune recovery, and are adherent to ART regimen. Pts with immune recovery have relapse rate of 0.03/person-yr and require regular ophthalmic follow-up (recommended q 3 mos).


  • Most newly Dx'd CMV-R now found in ART-experienced pts.
  • ART reduces ocular morbidity associated with CMV-R, especially in pts with immune recovery but to a lesser extent even in non-responders.
  • Progression of CMV-R can occur even in pts with excellent response to ART (0.03/person-yr), so regular ophthalmic monitoring is indicated.

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