Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents Disease Specific Recommendations Cytomegalovirus Disease Epidemiology Cytomegalovirus (CMV) is a double-stranded DNA virus in the Herpesvirus family that might reactivate to cause disseminated or localized end-organ disease among patients with advanced immunosuppression who have been previously infected with CMV. The majority of infections derive from reactivation of latent infection.       Before potent ART, an estimated 30% of patients with AIDS experienced CMV retinitis some time between the diagnosis of AIDS and death Incidence for new cases of CMV end-organ disease have reached <2--3 cases per 100 person-years; for those with established CMV retinitis, recurrences continue at a rate estimated at <25% of the peak during the mid-1990s.       Endorgan disease caused by CMV occurs among persons with advanced immunosuppression, typically those with CD4+ T lymphocyte counts <50 cells/µL, who are either not receiving or have failed to respond to ART). Other risk factors include previous OIs, particularly MAC disease, and high plasma HIV-1 RNA levels (>100,000 copies/mL). Clinical Manifestations       Retinitis is the most common clinical manifestation of CMV end-organ disease. CMV retinitis usually occurs as unilateral disease, but in the absence of therapy, viremic dissemination results in bilateral disease in the majority of patients.       Peripheral retinitis might be asymptomatic or present with floaters, scotomata, or peripheral visual field defects. Central retinal lesions or lesions impinging on the macula are associated with decreased visual acuity or central field defects. The characteristic ophthalmologic appearance of CMV lesions includes perivascular fluffy yellow-white retinal infiltrates, typically described as a focal necrotizing retinitis, with or without intraretinal hemorrhage, and with little inflammation of the vitreous unless immune recovery with potent ART intervenes . Blood vessels near the lesions might appear to be sheathed. Occasionally, the lesions might have a more granular appearance.       In the absence of ART or specific anti-CMV therapy, retinitis invariably progresses, usually within 10--21 days after presentation. Progression of retinitis occurs in "fits and starts" and causes a characteristic brushfire pattern, with a granular, white leading edge advancing before an atrophic, gliotic scar.       Colitis is the second most common manifestation, occurring in 5%--10% of persons with AIDS and CMV end-organ disease . The most frequent clinical manifestations are fever, weight loss, anorexia, abdominal pain, debilitating diarrhea, and malaise. Extensive mucosal hemorrhage and perforation can be life-threatening complications.       Esophagitis caused by CMV, which occurs in <5%--10% of persons with AIDS who develop CMV end-organ disease, causes fever, odynophagia, nausea, and occasionally mid-epigastric or retrosternal discomfort.       CMV pneumonitis is uncommon, but when it occurs, it presents with shortness of breath, dyspnea on exertion, a nonproductive cough, and hypoxemia, associated with interstitial infiltrates on chest radiograph.       CMV neurologic disease causes dementia, ventriculoencephalitis, or ascending polyradiculomyelopathy . Patients with dementia typically have lethargy, confusion, and fever, but the clinical presentation might mimic that of HIV-1 dementia. CSF generally demonstrates lymphocytic pleocytosis (although a mixture of neutrophils and lymphocytes might be seen), low-to-normal glucose levels, and normal-to-elevated protein levels.       Patients with ventriculoencephalitis have a more acute course, with focal neurologic signs, often including cranial nerve palsies or nystagmus, and rapid progression to death.       Periventricular enhancement of CT or MRI images is indicative of CMV ventriculoencephalitis rather than HIV-1--related neurologic disease. CMV polyradiculomyelopathy causes a Guillian-Barre--like syndrome characterized by urinary retention and progressive bilateral leg weakness. The clinical symptoms generally progress over several weeks to include loss of bowel and bladder control and to flaccid paraplegia. A spastic myelopathy has been reported and sacral paresthesia might occur. The CSF generally indicates a neutrophilic pleocytosis (usually 100--200 neutrophils/mL and some erythrocytes) accompanied by hypoglycorrhachia and elevated protein levels. Diagnosis CMV viremia can be detected by PCR, antigen assays, or blood culture and is generally detected in end-organ disease, but viremia also might be present in the absence of end-organ disease .The presence of serum antibodies to CMV is not diagnostically useful. A negative IgG antibody level indicates that CMV is unlikely to be the cause of the disease process being investigated (although rarely, primary CMV infection occurs and is associated with end-organ disease), but certain patients with advanced immunosuppression might serorevert from antibody positive to antibody negative; as a result, a negative CMV IgG antibody test does not definitively eliminate the possibility of CMV disease. The diagnosis of CMV retinitis is generally made on the basis of recognition of characteristic retinal changes observed on funduscopic examination by an experienced ophthalmologist.   The demonstration of mucosal ulcerations on endoscopic examination combined with colonoscopic or rectal biopsy with histopathological demonstration of characteristic intranuclear and intracytoplasmic inclusions are required for the diagnosis of CMV colitis   The diagnosis of CMV esophagitis is established by the presence of extensive large, shallow ulcers of the distal esophagus and biopsy evidence of intranuclear inclusion bodies in the endothelial cells with an inflammatory reaction at the edge of the ulcer   Culturing CMV from a biopsy or cells brushed from the colon or the esophagus is not sufficient to establish the diagnosis of CMV colitis or esophagitis because certain persons with low CD4+ T lymphocyte counts might be viremic and have positive cultures for CMV in the absence of clinical disease . Diagnosis of CMV pneumonitis should be made in the setting of pulmonary interstitial infiltrates and identification of multiple CMV inclusion bodies in lung tissue, and the absence of other pathogens that are more commonly associated with pneumonitis in this population  CMV neurologic disease is diagnosed on the basis of a compatible clinical syndrome and the presence of CMV in cerebrospinal fluid or brain tissue  Detection of CMV is greatly enhanced by PCR in this setting   Treatment Recommendations The choice of initial therapy for CMV retinitis should be individualized based on the location and severity of the lesion(s), the level of underlying immune suppression, and other factors such as concomitant medications and ability to adhere to treatment . Oral valganciclovir, intravenous ganciclovir, intravenous ganciclovir followed by oral valganciclovir, intravenous foscarnet, intravenous cidofovir, and the ganciclovir intraocular implant coupled with valganciclovir are all effective treatments for CMV retinitis . The ganciclovir intraocular implant plus oral valganciclovir is superior to once daily intravenous ganciclovir (and presumably to once-daily oral valganciclovir) for preventing relapse of retinitis . For this reason, certain HIV specialists recommend the intraocular implant plus valganciclovir as the preferred initial therapy, particularly for patients with immediately sight-threatening lesions (adjacent to the optic nerve or fovea); others prefer oral valganciclovir alone . Among patients with peripheral lesions that are not immediately sight-threatening, oral valganciclovir is preferable to the ganciclovir intraocular implant, intravenous ganciclovir, or intravenous foscarnet  because of its greater ease of administration and lack of surgical or catheter-associated complications. However, any of the treatment regimens can be chosen because epidemiologic studies and clinical trials have not demonstrated substantially reduced rates of loss of visual acuity among patients treated with the ganciclovir implant compared with those treated with systemic therapies  .   Certain clinicians would not treat small peripheral CMV retinitis lesions if ART is to be initiated soon because immune recovery might ultimately control the retinitis. However, immune recovery uveitis might be more common among patients given less aggressive anti-CMV therapy . Therefore, treatment of CMV retinitis until sufficient immune recovery occurs (i.e., CD4+ T lymphocyte count >100 cells/µL for 3--6 months) is still preferred . For therapy of colitis or esophagitis, the majority of specialists would treat with intravenous ganciclovir or foscarnet (or with oral valganciclovir if symptoms are not severe enough to interfere with oral absorption) for 21--28 days or until signs and symptoms have resolved. Certain HIV specialists would withhold therapy unless moderate to severe symptoms justify the use of systemic treatment  if ART is soon to be initiated or can be optimized. Treatment should be considered for persons with histologic evidence of CMV pneumonitis who do not respond to treatment of other pathogens . For neurological disease, initiating therapy promptly is critical for an optimal clinical response. Although combination treatment with ganciclovir and foscarnet might be preferred as initial therapy to stabilize disease and maximize response , this approach is associated with substantial rates of adverse effects, and optimal treatment for neurologic disease if ART can be optimized is unknown. Studies are underway to evaluate the utility of pre-emptive therapy with systemic treatment among patients with CMV viremia and no evidence of organ system disease. Until such studies are completed, treatment of CMV viremia in the absence of organ system involvement is not recommended (DIII). No data are available to demonstrate that starting ART among treatment-naïve patients with CMV retinitis would have an adverse effect on retinitis, gastrointestinal disease, or pneumonitis, or worsen immune recovery uveitis if this occurs. Therefore, no reason exists to delay initiation of appropriate ART, which should be administered to those with acute CMV retinitis, gastrointestinal disease, or pneumonitis  Although, no data indicate that immune recovery inflammatory reactions worsen CMV neurologic disease syndromes, because of the localized morbidity that might occur with such an inflammatory reaction, a brief delay in initiation of ART in this setting until clinical improvement occurs might be prudent . Monitoring and Adverse Events Management of CMV retinitis requires close monitoring by an experienced ophthalmologist and the primary clinician. Dilated indirect ophthalmoscopy should be performed at the time of diagnosis of CMV retinitis, after completion of induction therapy, 1 month after the initiation of therapy, and monthly thereafter while the patient is on anti-CMV treatment (AIII). Monthly fundus photographs, using a standardized photographic technique that documents the appearance of the retina, provide the optimum method for following patients and detecting early relapse (AIII). Adverse effects of ganciclovir include neutropenia, thrombocytopenia, nausea, diarrhea, and renal dysfunction. Adverse effects of foscarnet include anemia, nephrotoxicity, electrolyte abnormalities, and neurologic dysfunction. Seizures have been reported with both ganciclovir and foscarnet. For patients receiving ganciclovir or foscarnet, monitoring of complete blood counts and serum electrolytes and renal function should be performed twice weekly during induction therapy and once weekly thereafter (AIII). Cidofovir is associated with dose-related nephrotoxicity and hypotony. For patients receiving intravenous cidofovir, blood urea nitrogen, creatinine, and urinalysis should be performed before each infusion; administration of the drug is contraindicated if renal dysfunction or proteinuria is detected. Immune recovery uveitis is an immunologic reaction to CMV characterized by inflammation in the anterior chamber or vitreous in the setting of immune recovery after initiation of ART and is generally observed among those with a substantial rise in CD4+ T lymphocyte counts in the 4--12 weeks after initiation of ART.   Ocular complications of uveitis include macular edema and the development of epiretinal membranes, which can cause loss of vision. Treatment usually requires periocular corticosteroids or short courses of systemic corticosteroids. Estimated response rates are approximately 50%.   Management of Treatment Failure For patients without immune recovery after initiation of ART and who are receiving chronic maintenance therapy with systemic anti-CMV drugs, relapse of retinitis is likely to occur over time. Although drug resistance might be responsible for some episodes of relapse, early relapse is most often caused by the limited intraocular penetration of systemically administered drugs . Because it results in greater drug levels in the eye, the placement of a ganciclovir implant in a patient who has relapsed while receiving systemic treatment (IV ganciclovir or oral valganciclovir) is generally recommended and often will control the retinitis for 6--8 months until the implant requires replacement . Reinduction with the same drug followed by reinstitution of maintenance therapy can control the retinitis, although for progressively shorter periods of time , and the majority of specialists recommend this approach for initial treatment of relapsed disease (AII). Changing to an alternative drug at the time of first relapse typically does not result in superior control of the retinitis but should be considered if drug resistance is suspected or if side effects or toxicities interfere with optimal courses of the initial agent  (AIII).   Combination ganciclovir and foscarnet are generally superior to systemic therapy with either agent alone for patients with relapsed retinitis  but is accompanied by greater toxicity; this approach might be considered for patients who are not candidates for other alternatives   Drug resistance occurs among patients receiving long-term therapy .Reported rates typically are <10% during the first 3 months of therapy but increase to 25%--30% by 9 months of therapy. Reported rates are similar for ganciclovir, foscarnet, and cidofovir . Low-level resistance to ganciclovir occurs through mutations in the CMV UL97 (phosphotransferase) gene, and high-level resistance to ganciclovir typically occurs because of mutations in both the CMV UL97 and UL54 (DNA polymerase) genes. Resistance to foscarnet and resistance to cidofovir each occur because of mutations in the CMV UL54 gene. High-level resistance to ganciclovir is frequently associated with cross-resistance to cidofovir and occasionally to foscarnet. Although early relapse is generally not a result of resistance, later relapse often is. Because patients with resistant CMV nearly always have mutations in the CMV UL97 gene, and because a limited number of mutations produce the majority of cases of resistance, resistance testing in peripheral blood using a CMV DNA PCR assay and sequencing for CMV UL97 mutations or using a point mutation assay  might be reasonable for patients who relapse on therapy. Although this approach also has not been validated, certain specialists would recommend performance of resistance testing using this technique, if available, to guide therapy in those with repeated relapses of CMV disease (CIII). Patients with low-level ganciclovir-resistant isolates in the eye might respond to a ganciclovir implant because of the higher local levels of ganciclovir resulting from this form of therapy. However, patients with high-level ganciclovir resistant isolates typically will not respond and will require a switch to alternative therapy. Repetitive intravitreous injections of fomivirsen can be used for relapsed retinitis (BI) but should be combined with systemic therapy . Prevention of Recurrence After induction therapy, secondary prophylaxis (i.e., chronic maintenance therapy) is recommended for life , unless immune reconstitution occurs as a result of ART. Regimens demonstrated to be effective for chronic suppression in randomized, controlled clinical trials include parenteral or oral ganciclovir, parenteral foscarnet, combined parenteral ganciclovir and foscarnet, parenteral cidofovir, and (for retinitis only) ganciclovir administration through intraocular implant or repetitive intravitreous injections of fomivirsen (AI). Oral valganciclovir has been approved by FDA for both acute induction therapy and for maintenance therapy, although published data are limited. Repetitive intravitreous injections of ganciclovir, foscarnet, and cidofovir have been effective for secondary prophylaxis of CMV retinitis in uncontrolled case series. Intraocular therapy alone does not provide protection to the contralateral eye or to other organ systems and typically is combined with oral valganciclovir. The choice of a chronic maintenance regimen for patients treated for CMV disease should be made in consultation with a specialist.   For patients with retinitis, this decision should be made in consultation with an ophthalmologist and should take into consideration the anatomic location of the retinal lesion, vision in the contralateral eye, the immunologic and virologic status of the patient, and the patient's response to ART. Patients with immediately vision-threatening lesions need prompt anti-CMV therapy because progression of the retinitis can occur during the time in which immune recovery is occurring. Daily oral ganciclovir is less effective than daily intravenous ganciclovir for maintenance therapy  and with the availability of oral valganciclovir should no longer be used (DIII) . Patients with immediately sight-threatening retinitis still might benefit most from the use of the ganciclovir implant and its superior ability to control retinitis progression (BIII). However, replacement of the ganciclovir implant at 6--8 months might not be necessary for those with sustained immune recovery. If the ganciclovir implant is used, it should be combined with oral valganciclovir until immune recovery occurs (BIII). Chronic maintenance therapy is not routinely recommended for gastrointestinal disease but should be considered if relapses occur . A role for maintenance therapy for CMV pneumonitis has not been established . Discontinuing secondary prophylaxis (chronic maintenance therapy) should be considered for patients with a sustained (> 6 months) increase in CD4+ T lymphocyte counts >100--150 cells/µL in response to ART  Such decisions should be made in consultation with an ophthalmologist and should take into account such factors as magnitude and duration of CD4+ T lymphocyte increase, anatomic location of the retinal lesions, vision in the contralateral eye, and the feasibility of regular ophthalmologic monitoring . All patients who have had anti-CMV maintenance therapy discontinued should continue to undergo regular ophthalmologic monitoring for early detection of CMV relapse and for immune recovery vitritis/uveitis . Relapse of CMV retinitis occurs among patients whose anti-CMV maintenance therapies have been discontinued and whose CD4+ T lymphocyte counts have decreased to <50 cells/µL. Therefore, reinstitution of secondary prophylaxis should occur when the CD4+ T lymphocyte count has decreased to <100--150 cells/µL . Relapse has been reported among patients whose CD4+ T lymphocyte counts are >100 cells/µL, but such reports are rare. Because of the potential for rapid relapse of retinitis when CD4+ T lymphocyte counts decline and the potential for rapid decline of CD4+ T lymphocyte counts with interruption of ART, patients with immune reconstitution not receiving CMV maintenance therapy should still undergo ophthalmologic monitoring .   Special Considerations During Pregnancy The diagnostic considerations among pregnant women are the same as for the nonpregnant women. Indications for treatment of CMV infection during pregnancy are the same as for those in nonpregnant HIV-1--infected adults  For retinal disease, use of intraocular implants or intravitreous injections for local therapy should be considered in pregnancy if possible to limit fetal exposure to systemically administered antiviral drugs  Close ophthalmologic monitoring must be maintained, and systemic therapy should then be added as indicated after delivery. Ganciclovir is embryotoxic among rabbits and mice and teratogenic (i.e., cleft palate, anophthalmia, aplastic kidney and pancreas, and hydrocephalus) in rabbits . Safe use in human pregnancy after organ transplantation has been reported  On the basis of very limited data and weighing toxicity of the various drugs, ganciclovir is the treatment of choice during pregnancy . No experience has been reported with the use of valganciclovir in human pregnancy. Concerns are expected to be the same as with ganciclovir. The fetus should be monitored by fetal movement counting in the third trimester and by periodic ultrasound monitoring after 20 weeks of gestation to look for evidence of hydrops fetalis indicating substantial anemia. Foscarnet is associated with an increase in skeletal anomalies or variants in rats and rabbits. No experience with use early in human pregnancy has been reported. A single case report of use in the third trimester described normal infant outcome . Because primary toxicity is renal, monitoring of amniotic fluid volumes by ultrasound is recommended weekly after 20 weeks of gestation to detect oligohydramnios. Cidofovir is embryotoxic and teratogenic (i.e., meningomyelocele and skeletal abnormalities) among rats and rabbits. No experience with use in human pregnancy has been reported. Rarely, ultrasound findings in the fetus (e.g., cerebral calcifications, abdominal and liver calcifications, hydrops, microcephaly, ventriculomegaly, ascites, and echogenic fetal bowel) might indicate the possibility of in utero CMV infection among pregnant women with CMV end organ disease . In this case, consideration of invasive testing (i.e., amniocentesis and fetal umbilical blood sampling) must be individualized based on clinical history and serologic findings, gestational age, potential risk for HIV-1 transmission, and maternal preference . Referral to a maternal-fetal medicine specialist for evaluation, counseling, and potential further testing is recommended. On the basis of data in HIV-uninfected women, transmission of CMV from mother to infant might occur in utero. However, symptomatic infection in the newborn is usually related to primary CMV infection in the mother during pregnancy, and because >90% of HIV-1--infected pregnant women are CMV antibody positive in the majority of studies, the risk for symptomatic infection in the fetus is low . Therefore, treatment of maternal CMV infection, if asymptomatic, during pregnancy solely to prevent infant infection is not indicated .