Management of Intraocular Infections in HIV

Ocular Immunology and Inflammation

ISSN: 0927-3948 (Print) 1744-5078 (Online) Journal homepage: https://www.tandfonline.com/loi/ioii20

Ilaria Testi, Sarakshi Mahajan, Rupesh Agrawal, Aniruddha Agarwal, Alessandro Marchese, Andre Curi, Moncef Khairallah, Yee Sin Leo, Quan Dong Nguyen & Vishali Gupta

To cite this article: Ilaria Testi, Sarakshi Mahajan, Rupesh Agrawal, Aniruddha Agarwal, Alessandro Marchese, Andre Curi, Moncef Khairallah, Yee Sin Leo, Quan Dong Nguyen & Vishali Gupta (2020): Management of Intraocular Infections in HIV, Ocular Immunology and Inflammation, DOI: 10.1080/09273948.2020.1727533 To link to this article: https://doi.org/10.1080/09273948.2020.1727533

Published online: 12 Mar 2020.

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INVITED REVIEW Management of Intraocular Infections in HIV Ilaria Testi, MDa, Sarakshi Mahajan, MDb, Rupesh Agrawal, MD a,c,d, Aniruddha Agarwal, MD e, Alessandro Marchese, MDf, Andre Curi, MD g, Moncef Khairallah, MDh, Yee Sin Leo, MDi, Quan Dong Nguyen, MDb, and Vishali Gupta, MDe aMoorfields Eye Hospital, NHS Foundation Trust, London, UK; bByers Eye Institute, Stanford University, Palo Alto, California, USA; cNational Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore, Singapore; dSingapore Eye Research Institute, Singapore, Singapore; eAdvanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India; fDepartment of Ophthalmology, Scientific Institute San Raffaele, University Vita-Salute San Raffaele, Milan, Italy; gResearch Laboratory of Infectious Diseases in Ophthalmology, National Institute of Infectious Diseases, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; hDepartment of Ophthalmology, Fattouma Bourguiba University Hospital, Faculty of Medicine, University of Monastir, Monastir, Tunisia; iNational Center for Infectious Disease, Tan Tock Seng Hospital, Singapore, Singapore

ABSTRACT ARTICLE HISTORY Purpose: Overview of treatment options for the most common intraocular opportunistic infections in Received 3 December 2019 patients with acquired immunodeficiency syndrome (AIDS), including ocular syphilis, ocular tuberculosis, Revised 9 January 2020 toxoplasmic chorioretinitis, and viral retinitis. Accepted 5 February 2020 Method: Narrative Review. KEYWORDS Results : Despite the huge advances in the development of combined antiretroviral therapy (cART) for the Opportunistic infections; management of patients with human immunodeficiency virus (HIV) infection, opportunistic infections intraocular infections; still represent a significant diagnostic dilemma and cause of ocular morbidity in patients with HIV. human immunodeficiency Conclusion: Although the treatment of intraocular infections in patients with AIDS may be challenging, virus (HIV); combined active prompt assessment of the clinical features and appropriate aggressive management of the underlying retroviral therapy (cART); etiology are critical to avoid life and vision threatening. ocular tuberculosis; ocular syphilis; ocular toxoplasmosis; viral retinitis; treatment

Human immunodeficiency virus (HIV) progressively damages Co-infection of HIV and syphilis is well known, and an the immune system of those infected rendering them suscep- increasing number of ocular syphilis cases, particularly tible to opportunistic infections. Opportunistic infections can among homosexual males and drug users, have been recently affect every organ system, eyes are no exception. Ocular reported globally as co-infection with HIV.2,3 Syphilis, known involvement has been associated with opportunistic infections as ‘the great imitator,’ can affect any tissue of the eye with since the beginning of the HIV epidemic. In the pre- variable clinical manifestations, mimicking other uveitis combined active retroviral therapy (cART) era HIV patients entities. developed opportunistic infections in 70% of cases, and cyto- Previous case series on ocular syphilis in patients infected megalovirus (CMV) retinitis was considered the major cause with HIV identified posterior uveitis and panuveitis as the of visual loss.1 Though the advent of cART has resulted in most common manifestations of the disease and supported a decline in the incidence of some intraocular infections, such the association between posterior uveitis and low CD4 cell as CMV retinitis, the incidence of other ones like ocular count.4,5 A recent meta-nalysis reported 348 cells/μl (range syphilis has remained high, experiencing a resurgence 4–1435) as the median of CD4 lymphocyte count in patients among HIV patients.2,3 Management of intraocular infections who developed ocular syphilis, 17% of whom having a CD4 may be challenging, because of atypical clinical manifestations cell count <200 cells/μl.6 Early assessment for ocular symp- and severe course of the disease in patients often affected by toms and prompt recognition of the underlying etiology are comorbidities or presenting resistance to the therapy currently crucial to avoid delays in diagnosis and treatment, potentially in use. The aim of this review is to focus on treatment options leading to irreversible tissue damages and visual loss. of the most common ocular opportunistic infections, includ- Ocular syphilis should be treated by the ophthalmologist in ing ocular syphilis, ocular tuberculosis, toxoplasmic chorior- collaboration with infectious disease specialist. Syphilitic uvei- etinitis, and viral retinitis. tis can be associated with neurosyphilis and, since its active clinical features are considered an expression of both secondary and neurologic syphilis, all manifestations should be man- Treatment of ocular syphilis in HIV patients aged according to neurosyphilis regimens of treatment.7 HIV Ocular syphilis should always be considered in the differential patients with ocular syphilis are treated with the same neuro- diagnosis of uveitis, especially in patients infected with HIV. syphilis regimens of non-HIV infected patients.7 Although

CONTACT Vishali Gupta [email protected] Ophthalmology, Advanced Eye Center, Post Graduate Institute of Medical Education and Research (PGIMER), Sector 12, Chandigarh, 160012, India © 2020 Taylor & Francis Group, LLC 2 I. TESTI ET AL.

HIV patients with early syphilis might have an increased risk VDRL baseline values, the less likely they are to normalize.12 for both neurologic involvement and serological failure with CSF leukocyte count is a more sensitive parameter to assess standard therapy, no alternative treatment regimens have treatment efficacy, since it is more likely to normalize com- been found to prevent the risk of neurosyphilis in such pared to CSF-VDRL reactivity. If the cell count has not patients.7 Only cART has been demonstrated to improve the decreased after 6 months or normalize after 2 years, patients clinical outcome of HIV patients co-infected with syphilis.7 should be retreated. Treatment for ocular syphilis involves antibiotics crossing Systemic corticosteroids have not been proven to be ben- both blood–brain and blood–aqueous humor barriers. The eficial in neurosyphilis and their role in ocular syphilis is recommended regimen consists of intravenous aqueous crys- undefined.7 Generally, penicillin treatment leads to resolution talline penicillin G 18–24 million units per day, administered of intraocular inflammation and visual improvement within 1 – as 3–4 million units every 4 h or continuous infusion, for 10 to 3 months after starting therapy.14 16 However, in selected to 14 days.7 If compliance with treatment can be ensured, an patients, oral steroids can be administered effectively in the alternative regimen consisting of intramuscular procaine management of sight-threatening complications, such as penicillin G 2.4 million units once daily plus oral probenecid macular edema, or might be helpful in preventing Jarisch– 500 mg four times a day, both for 10 to 14 days, can be used.7 Harxheimer reaction and treating the resultant worsening of In patients with ocular syphilis and allergy to penicillin cef- ocular and neurologic manifestations.17 Topical steroids and triaxone 2 g daily, either intramuscular or intravenous, for 10 cycloplegics are commonly used in the treatment of syphilitic to 14 days, has been demonstrated to be effective.7 iridocyclitis. Serological evaluation of non-treponemal test titers Prognosis of visual acuity in HIV patients with ocular should be performed to assess treatment response in HIV manifestations of syphilis is favorable after an appropriate patientsat3,6,9,12,and24months.Failureoftesttitersto treatment. In the largest case series of HIV patients with decrease fourfold might indicate treatment failure.7 ocular syphilis, Tsuboi et al. reported that best-corrected However, it has emerged that around 20% of the subjects visual acuity (BCVA) improved after proper therapy in 89% treated with standard therapy does not achieve the non- of the 30 study eyes within 3 months.15 Presence of ocular treponemal titer decline defining treatment response at symptoms for more than 28 days before diagnosis has been – 1 year.8 10 Different factors play a role in determining ser- demonstrated to be associated with poor BCVA prognosis.15 ologic response, including the stage of syphilis and serologic This finding highlights the need for early diagnosis and titers; late stages and low serologic titers are less likely to prompt treatment in HIV patients in presence of ocular – decrease fourfold.8 10 Furthermore, unusual serologic symptoms. However, since two out of the three subjects who responses have been reported in HIV patients, involving developed recurrences of eye disease did not complain of any post-treatment serologic titers fluctuated or higher than ocular symptoms, regular ophthalmic examination and strict expected, and false-negative serologic results with or without follow-up after treatment are mandatory in HIV patients delayed appearance of seroreactivity.11 In instances of no treated for ocular syphilis, since retreatment can still improve serologic response, patients should be provided with addi- their BCVA.15 tional clinical and serologic follow-up and, if needed, retreatment (intramuscular procaine penicillin Treatment of ocular tuberculosis in HIV patients G 2.4 million units, administered once weekly for 3 conse- cutive weeks). Tuberculosis (TB) is one of the most common opportunistic Regardless of HIV infection, cerebrospinal fluid (CSF) infections in HIV-infected subjects. Ocular tuberculosis examination should always be performed in patients with (OTB) is a rare form of extrapulmonary disease, not to be suspicion of active clinical manifestations of ocular syphilis, underestimated due to its potential ocular morbidity and even in the absence of neurologic findings.7 Furthermore, CSF severe visual prognosis. Data regarding ocular involvement examination is recommended in patients who do not achieve of patients coinfected with HIV and TB are limited.18 the expected serologic titer decline after treatment to rule out Management of OTB still poses a significant challenge due neurosyphilis, and in instances of patients with abnormal test to heterogeneous and non-pathognomonic presentations, results, serial CSF examination should be repeated routinely involvement of different ocular tissues, lack of consensus on to assess treatment response. In case of pleocytosis, CSF diagnostic investigations, and lack of international agreement – evaluation should be performed every 6 months until cell on treatment regimen.18 21 Furthermore, OTB manifestations count normalization.12,13 Evaluation of the non-treponemal in HIV-infected patients can be severe, persistent, and non- CSF-Venereal Disease Research Laboratory (VDRL) reactivity responsive despite aggressive ATT. Decisions regarding initia- or CSF protein concentration might be less useful during the tion of antitubercular therapy (ATT) and treatment manage- follow-up, since these two parameters occur more slowly than ment should be undertaken by the ophthalmologist together pleocytosis and persistent alterations might be less with pulmonologists and/or infectious disease specialist. important.12,13 Marra et al. demonstrated that HIV-infected The recommended regimen for TB treatment in patients patients are 2.5 times less likely to normalize CSF-VDRL test infected with HIV is the standard four-drug ATT regimen as than HIV uninfected patients and that those with peripheral per non-HIV infected subjects, involving isoniazid (5 mg/kg/ blood CD4+T cell counts ⩽200 cells/µL are 3.7 times less day), rifampicin (450–600 mg/day), ethambutol (15 mg/kg/ likely to normalize CSF-VDRL reactivity than those with day), and pyrazinamide (25–30 mg/kg/day).22 Treatment CD4+T cell counts >200 cells/µL.12 The higher the CSF- should be prolonged in case of disease affecting OCULAR IMMUNOLOGY AND INFLAMMATION 3 extrapulmonary sites with delayed response to therapy, as in infected with HIV on cART and ATT.37 Overall, OTB was OTB.22 There is no consensus between ophthalmologists and detected in six patients, with two of them having active other physicians regarding the duration of ATT in patients intraocular inflammation in the form of choroidal tubercles with isolated OTB. In a recent meta-analysis, Kee et al. ana- despite completing anti-TB regimen. The new guidelines for lyzed 28 studies evaluating the effect of ATT on ocular out- the treatment of MDR-TB include levofloxacin or moxiflox- come of 1,917 patients diagnosed with OTB.23 The authors acin, in combination with bedaquiline and linezolid, plus one identified in 18 of the 28 studies the standard four-drug regi- agent among clofazimine and cycloserine or terizidone. The men adopted for at least 2 months, up to 4 months, followed regimen ensures that anti-TB treatment starts with at least by a two-drug treatment with isoniazid and rifampicin for at four TB drugs likely to be effective and that at least three least 4 months, up to 15 months, for a total of therapy of at agents are included for the rest of the treatment after bedaqui- least 6 months.24 line is discontinued.38 The introduction of a singular new Although simultaneous therapy of TB and HIV is asso- drug should always be avoided in patients that failed ciated with drug–drug interactions, overlapping side effects, a previous treatment, to prevent the onset of new acquired poor adherence, and increased risk of IRIS, early administra- resistance.38 tion of cART results in reduction of morbidity and mortality. All HIV patients coinfected with TB should start cART within 8 weeks of ATT initiation, irrespective of the CD4 lymphocyte Treatment of ocular toxoplasmosis in HIV patients count. Patients with CD4 cell count ≤100 cells/μl will be started on cART as soon as they are tolerating ATT, patients In immunocompetent patients, toxoplasmic retinochoroiditis with Tcell count >100 cells/μl should initiate cART within is usually a self-limiting disease, resolving spontaneously over 8 weeks and at least by the end of ATT first phase, patients weeks to months even without therapy.39 Although small with CD4 counts ≤50 cell/μl should be started on cART as peripheral lesions usually do not require any treatment, soon as possible.23 lesions involving or threatening the macula and the optic Corticosteroid agents are often used in patients with OTB disc and peripheral localizations associated with intense vitri- in combination with ATT to control intraocular inflammation tis are managed with antimicrobial therapy. As host defenses and limit the damage to ocular tissues. However, the use of are crucial for limiting the severity of the disease, the manage- – corticosteroids is controversial, and there is no consensus on ment is determined by the immune status of the patient.40 42 their effective efficacy. According to the Collaborative Ocular In immunocompromised patients ocular toxoplasmosis can be Tuberculosis Study (COTS)-1, patients started on systemic seriously aggressive, and manifest as bilateral, widespread, steroids may have a worse outcome compared to those who multifocal chorioretinitis, mimicking necrotizing herpetic are not, in contrast to the meta-analysis that did not observe retinopathies. Furthermore, the disease frequently reactivates significant differences in treatment outcome with or without if antimicrobial treatment is stopped, and nearly 30% of the oral corticosteroids.20,24 Despite these uncertainties related to affected HIV subjects can have evidence of concomitant cere- the use of corticosteroids, HIV patients co-infected with TB bral involvement.40,43-46 Any active lesion in HIV patients, are often managed with corticosteroid therapy, because of the therefore, requires immediate treatment. A prompt diagnosis higher likelihood of immune reconstitution inflammatory and an early management are crucial to avoid infection dis- syndrome (IRIS). The recovery of the host immune response semination and related tissue damages, potentially leading to following cART can lead to a paradoxical worsening of intrao- poor visual prognosis. cular inflammation, accompanied by sight-threatening seque- Although immunocompromised subjects require extended lae. Both systemic corticosteroids and more recently, local systemic therapy to avoid the risk of cerebral involvement and intravitreal therapy have been used to treat this condition reduce the frequency of relapses, standard anti-toxoplasmosis – successfully.25 35 Bansal et al. administered 1 mg/kg/day oral regimens are commonly used in HIV patients. Several drugs prednisolone in combination with ATT, to be gradually are administered for the treatment of toxoplasmic retinochor- tapered not faster than 5 mg/day every 2 weeks, based on oiditis, including pyrimethamine, sulfadiazine, azithromycin, clinical features of choroidal lesions.36 Several authors clindamycin, and trimethoprim-sulfamethoxazole, and there described the successful outcome of patients with OTB and is no evidence demonstrating that one treatment is superior to – IRIS treated with sustained-release intravitreal dexamethasone the other in improving the final outcome.47 50 – as an optional adjunctive anti–inflammatory therapy.25 27 Pyrimethamine and sulfadiazine, in combination with foli- Julian et al. and Sahin et al. successfully managed the progres- nic acid, are the most common therapeutic regimen currently sion of serpiginous-like choroiditis in patients on ATT with used for ocular toxoplasmosis, considered the standard of the use of intravitreal methotrexate.30,31 Jain et al. reported therapy.51,52 It consists of pyrimethamine 75–100 mg daily a case of intravitreal anti-vascular endothelial growth factor for 2 days, followed by a 25–50 mg dose daily, and sulfadia- (anti-VEGF) injection leading to complete resolution of ser- zine 2–4 g daily for 2 days, followed by a 500–1000 mg dose ous retinal detachment occurred as part of paradoxical wor- every 6 h, in combination with 5 mg of folinic acid daily, sening in an HIV-TB co-infected patient with choroidal administered for at least 4–6 weeks.52 Pyrimethamine and tuberculoma.34 sulfadiazine have a synergistic effect on diverse steps of Features of OTB in HIV subjects can be aggressive and nucleic acid synthesis in Toxoplasma gondii. Pyrimethamine non-responsive to ATT. Mehta et al. reported data on a large inhibits the dihydrofolic acid reductase, and sulfadiazine is cohort of 47 multidrug resistance (MDR)-TB patients co- a competitive antagonist of p-aminobenzoic acid. 4 I. TESTI ET AL.

As both pyrimethamine and sulfonamides inhibit folic acid close proximity to the fovea and optic nerve, concomitant metabolism pathway, folic acid is always added in the treat- systemic and local antimicrobial therapy could be effective ment regimen to avoid bone marrow suppression, manifesting in limiting tissue damages. as leukopenia and thrombocytopenia. Blood cell and platelet As the conventional short-term treatment of active toxo- count are always recommended as part of antiparasitic treat- plasmic retinochoroiditis does not prevent subsequent reacti- ment monitoring. Especially in HIV patients, who have been vations of the disease, a prophylactic regimen is highly demonstrated to have high rates of allergic reactions to sulfo- recommended in high-risk patients, including those with namides, sulfadiazine can induce skin rash, hives, breathing multiple and frequent relapses, or in case of critical anatomi- problems, swelling, up to sulfonamide drug hypersensitivity cal localization of the lesions, where any reactivation may lead syndrome, characterized by fever, maculopapular rash, and to severe vision loss.61,62 In addition, in HIV patients long- toxicity of one or more internal organs, and Stevens– term maintenance therapy is crucial to prevent reactivation of Johnson syndrome.53,54 In case of allergy or intolerance to the disease and dissemination of the infection until significant sulfadiazine, pyrimethamine, and clindamycin plus folinic immunologic improvement is achieved.52 Prophylactic treat- acid is the preferred alternative therapy.52 ment in immunocompromised subjects includes the double- Among all regimens used in the treatment of toxoplasmic strength-tablet daily dose of trimethoprim-sulfamethoxazole retinochoroiditis, pyrimethamine (50 mg/day) and azithromy- (160mg/800mg TMP/SMX), or, in alternative, one double- cin (250–500 mg/day) have been demonstrated to have similar strength tablet 3 times weekly.52,61-63 A lower dosage of pyr- efficacy to the classic therapy with pyrimethamine and sulfa- imethamine and sulfadiazine, combined with atovaquone that, diazine, representing a valid alternative for treating sight- acting synergically with the two drugs could help to reduce threatening lesions located in proximity to the fovea or optic toxicity, could be an additional option.52,63,64 Prophylaxis can nerve.55 Besides, it has been shown that the subjects treated be safely discontinued in patients receiving cART when CD4+ with pyrimethamine and azithromycin have a lower incidence T cell count has increased to >200 cells/µL for more than – and severity of side effects compared to those receiving the 3 months.65 68 classic regimen.55 If pyrimethamine is not available, trimethoprim- Treatment of viral retinitis in HIV patients sulfamethoxazole 160mg/800mg twice a day is a safe and effective alternative to be used in place of standard drug combina- Varicella-Zoster Virus (VZV), Herpes Simplex Virus (HSV), tions to achieve resolution of active toxoplasmic lesions.56,57 Like and Cytomegalovirus (CMV) belong to the family of Herpes pyrimethamine, trimethoprim-sulfamethoxazole can also viruses. Host immunity determines the clinical picture follow- induce bone marrow suppression, and patients require baseline ing reactivation from latency, which is usually characterized and follow-up laboratory tests, including complete blood count, by acute retinal necrosis (ARN) in immunocompetent indivi- liver enzymes, and serum creatinine levels. duals and progressive outer retinal necrosis (PORN) or CMV Alternative therapeutic strategies include clindamycin retinitis in immunocompromised patients.69 Although initi- (300 mg four times a day from 4 to 6 weeks), either alone ally thought to be associated with immune competence, or in combination with the standard regimen as quadruple authors have shown clinical features consistent with ARN – drug therapy (pyrimethamine and sulfadiazine plus clindamy- even in HIV patients.70 73 Diagnosis of ARN revolved around cin and corticosteroids). Pseudomembranous colitis is diagnostic criteria outlined by American Uveitis Society in a potential complication of the treatment.39 1994, which included one or more foci of retinal necrosis in In immunocompetent patients, systemic corticosteroids are the peripheral retina, rapid progression in the absence of widely used in combination with antitoxoplasmic drug regimens treatment, occlusive vasculopathy, circumferential spread, in preventing tissue damages by severe intraocular inflamma- and inflammatory reaction in vitreous and anterior chamber. tion. However, given the lack of normal inflammatory response PORN clinically presents as minimal ocular infection, invol- to the parasite in immunocompromised patients, steroid therapy vement of outer retinal with inner retinal, and vasculature is usually contraindicated in HIV patients.40 sparing, but rapid progressive course and poor response to – Intravitreal injections of antimicrobial drug, either clinda- intravenous therapy.74 76 mycin (1.5 mg/0.1 ml weekly) or sulfamethoxazole/trimethoprim (1.28 mg/0.08 mL weekly), together with dexamethasone Treatment of Progressive Outer Retinal Necrosis (400 g/0.1 ml), is an effective additional option for immuno- (PORN) in HIV Patients competent patients who do not tolerate or have contraindica- – tions to oral medication.58 60 Delivering high concentrations Progressive outer retinal necrosis, first described by Forster in of therapeutics directly into the vitreous and retina, the local the year 1990, is seen in profoundly immunocompromised route reduces the systemic side effects associated with oral patients, such as HIV subjects with CD4+T cell count <200 antiparasitics, increasing patient convenience, and drug avail- cells/µL.75 Once diagnosed, PORN was associated with a bad ability. Although in HIV subjects extended systemic treatment visual prognosis with two-thirds of eyes progressed to no light is highly recommended to avoid toxoplasmic reactivation in perception within 4 weeks of onset.77 the fellow eye and prevent cerebral involvement, in those Considering the rapidly destructive nature of PORN and the subjects who experience disease progression despite systemic high incidence of retinal detachment, the quick control of the conventional therapy, or in case of sight-threatening lesions in disease is essential. The aim of the treatment, therefore, revolves OCULAR IMMUNOLOGY AND INFLAMMATION 5 around minimizing ocular tissue damages, leading to irreversible to a total retinal detachment. Despite the anatomical success visual loss, as well as protecting the fellow eye from bilateraliza- achieved surgically with pars plana vitrectomy and silicone oil tion of the disease and preventing cerebral involvement. tamponade, visual acuity remains poor in a number of In patients with PORN aggressive and extensive antiviral patients, mostly depending on extensive retinal necrosis and therapy in combination with the treatment of the underlying optic atrophy.77,95 HIV infection becomes crucial to preserve visual morbidity, as cART significantly lowers the viral load and increases CD4+T cell count. Although VZV is the causative agent of PORN, Treatment of Cytomegalovirus (CMV) Retinitis in HIV treatment outcomes of patients with a rapidly progressive – patients disease treated with intravenous acyclovir were poor.79 82 Furthermore, the disease showed relapses following changes Cytomegalovirus (CMV) retinitis is the most common oppor- in the regimen, when intravenous administration was tunistic intraocular infection among patients with AIDS and switched to oral therapy or when the dosage was lowered or CD4+T cells <50 cells/µL. The incidence of CMV retinitis has – therapy discontinued. Recurrences were reported within decreased by 80% after the development of cART.96 101 a median time of 2 weeks (1–6 weeks range) after the change Treatment of CMV aims in addressing the direct damage in treatment regimen.77 A combination of factors, including caused to retinal structures as well as the immune recovery. HIV-associated enteropathy, malabsorption, and low oral As viral DNA has been demonstrated at the border of healed bioavailability of the drug or drug resistance, might be retinitis lesions without effective assembly of intact virions, if involved.77,83,84 treatment is discontinued without the immune reconstitution, Patients diagnosed with PORN who were given intra- viral assembly resumes and retinitis reactivates.102 In HIV venous ganciclovir, either alone (5 mg/kg twice each day patients, CD4+T cell count of more than 100 cells/µL for for 2 weeks for induction treatment, followed by 5 mg/kg/ longer than 3–6 months is considered adequate recovery day for maintenance therapy) or in association with fos- with a significant reduction in recurrences.98 However, in carnet (60 mg/kg each 8 h for 2 weeks of induction, the absence of immune reconstitution, life-long treatment is followed by 90–120 mg/kg/day for maintenance), showed required to avoid relapses. better clinical outcome compared those receiving acyclovir Systemic antivirals prevent infection in the fellow eye and alone.85 Combining antiviral drug regimen, including both provide systemic coverage. First-line antiviral therapy for systemic medications and intravitreal injections, has been CMV retinitis is intravenous ganciclovir (5 mg/kg twice – shown to have additive effects.86 92 In the series of Scott daily for two to 3 weeks as induction therapy then followed et al. 45% of the eyes treated with both intravenous anti- by daily 5 mg/kg infusions) or the oral pro-drug valganciclo- viral (intravenous ganciclovir and foscarnet) and intravi- vir (induction dose is 900 mg twice daily for 21 days followed treal antivirals, including either ganciclovir (2 mg/ by maintenance of 900 mg daily). In patients refractory to 0.05 mL) and foscarnet (1.2 mg/0.05 mL) or intravitreal ganciclovir, intravenous foscarnet (90 mg/kg twice daily for 2 ganciclovir only, had a final visual acuity of 20/80 or weeks followed by maintenance therapy of 90–120 mg/kg more.90 Gore et al. recently described the largest series daily) has shown positive results. Systemic anti-CMV thera- of patients with PORN treated with the local antiviral pies are usually administered initially as per induction phase therapy only.76 Subjects with active retinitis lesions with at higher doses for two to 3 weeks to control the infection, potential for visual recovery received multiple intravitreal and then at lower doses as maintenance, to prevent recurrence injections of ganciclovir, initially administered twice of clinical disease. Comparative trials of intravenous ganciclo- weekly for 2 weeks and then weekly. In the absence of vir and intravenous foscarnet and of intravenous ganciclovir any detectable signs of activity, treatment was tapered to and oral valganciclovir have demonstrated that all drug regi- – injections every other week as per maintenance phase and mens have similar efficacy in controlling CMV retinitis.103 106 continued until CD4+T cell count increased to more than The role of cidofovir (5 mg/kg weekly during induction, and 100/µL.76 Only 9 out of 50 study eyes (13%) lost light 5 mg/kg every other week during maintenance) is limited perception compared to 67% of the eyes (42 out of 63) and is recommended only after ganciclovir, valganciclovir, treated with intravenous antiviral therapy described by the and foscarnet have failed, with probenecid given pre- and early report of Engstrom et al.76,77 post-cidofovir administration for neuroprotection. The level of immune reconstitution at which antiviral Both ganciclovir and foscarnet can be administered as intra- medications might be safely stopped has not been established vitreal injections, with typical regimen being two to three times for PORN. As per CMV retinitis treatment, CD4+T cell count weekly as induction therapy and decreasing frequency to once greater than 100/µL can be considered a safe level to discon- weekly as maintenance, till control of retinitis is achieved.98 tinue the maintenance regimen.93,94 However, general recom- Recurrence rate of patients treated with local therapy has been mendations as per studies dictate monitoring disease lifelong found to be similar to those on systemic treatment.107,108 irrespective of immune recovery and continuation of main- Intravitreal use of cidofovir has been discontinued due to tenance therapy. a narrow therapeutic-toxic index and issues related to the Retinal detachment occurs in nearly 70% of patients with development of uveitis associated with hypotony. PORN, usually presenting within the first 4 weeks.76,85 The In HIV patients with CMV retinitis, intraocular inflamma- detachment tends to be rhegmatogenous, beginning from tion is not extensive due to underlying immunosuppression. retinal breaks at the margins of inactive retinitis, progressing The role of corticosteroids is therefore limited to immune 6 I. TESTI ET AL. recovery uveitis (IRU), as part of IRIS, manifesting as severe therapy, visual outcome depends on the control of intracer- anterior uveitis, vitritis, and macular edema. Normally, cART ebral pressure. Acetazolamide, relief lumbar puncture, or is started as soon as possible in HIV patients diagnosed with peritoneal ventricle shunts have been used.121 opportunistic infections. However, initiation of cART before In Cryptococcus infection associated with HIV, the timing that the induction therapy to control CMV infection is com- of cART initiation has a major impact on long-term patient pleted might result in a higher likelihood of IRU together with prognosis. Recently, the Cryptococcal Optimal ART Timing a more severe presentation. The benefic effect on intraocular Trial (COAT) recommended to defer cART initiation for at inflammation of the delay in starting cART must be counter- least 4 weeks after the initiation of antifungal treatment.122 balanced by the development of other opportunistic infections The study demonstrated better survival outcome in patients in immunocompromised patients.109 diagnosed with cryptococcal meningitis in whom ART initiation was a delay for up to 5 weeks after the diagnosis as compared with those who were started on cART within Treatment of Bartonella infection in HIV patients 1–2 weeks, suggesting that IRIS may be related to an increased Bartonella henselae is the causative agent of cat-scratch disease mortality. and, in immunocompromised patients, of bacillary angiomatosis. Ocular complications associated with the infection have Immuno recovery uveitis (IRU) been reported in immunocompetent patients and less often in – HIV patients.110 113 Bartonella infection in HIV-infected The advent of cART resulted in new challenges when facing patients usually presents differently from the typical presenta- the management of patients infected with HIV.123 Intraocular tion of neuroretinitis. Due to the relationship between the inflammation is usually not severe in immunocompromised bacteria and vascular endothelium, the response tends to be patients, due to their underlying low CD4+ cell count. vasoproliferative. Vasoproliferative lesions can be seen both in However, in HIV patients started on cART the immune the skin (bacillary angiomatosis) and in the retina.110 Diagnosis restoration might potentially lead to IRIS, manifesting as IRU. is based on serologic tests in peripheral blood and titers of IgG IRU commonly occurs in CMV retinitis and manifests with >1/256 are considered acute or recent infection.114 various degrees of intraocular inflammation, triggered by the Treatment of intraocular Bartonella infection remains presence of CMV antigens in the eyes of the patients who debatable, although most of the authors agree that treatment experience immune restoration with CD4+ cells reconstitu- with systemic antibiotics has some benefit. Several antibiotics tion. In the pre-cART era, mild or absent intraocular inflam- have been used and the most common regimen consists of mation was detected in the eyes of subjects diagnosed with doxycycline 100 mg twice a day, alone or associated with CMV retinitis, and inflammatory complications, like macular rifampicin.115 Sulfamethoxazole and ciprofloxacin are also edema, were rarely described.124,125 Anterior chamber cells, used. In immunocompetent patients duration of treatment is vitritis, and macular edema appeared in the face of immune – 1 month, but in immunocompromised patients is not well restoration with the introduction of cART.126 128 known. Like other opportunistic intraocular infections, main- Normally, cART is initiated as soon as possible in HIV tenance therapy until immune recovery occurs may be patients diagnosed with opportunistic infections. However, appropriated.116 Ortega et al. demonstrated that the administration of cART before induction therapy to control CMV retinitis leads to a higher rate of IRU, resulting in severe clinical findings with Treatment of Cryptococcus neoformans infection in risks of ocular sequelae and visual loss.109 Recently, the HIV patients COAT recommended to defer cART initiation for at least Cryptococcus neoformans is the most common life-threatening 4 weeks after the initiation of antifungal treatment in fungus that predominantly affects lungs and central nervous patients affected by cryptococcal meningitis, suggesting that system in patients infected with HIV. In severe immunocom- IRIS may be related to an increased mortality.122 Hence, promised patients, the yeast can be widely disseminated while dealing with immunocompromised patients, physi- throughout the body and infect several organs, including cians have to counterbalance the beneficial effects on intrao- eye, skin, bone, joints, and prostate. In patients diagnosed cular inflammation of the delay in starting cART with the with meningitis, ocular involvement is found in a substantial risk of new systemic opportunistic infections. For instance, proportion of cases.117 Ocular manifestations of Jabs et al. suggested that a delay in the institution of cART of C. neoformans infection include optic neuritis, optic neuro- no more than 2 weeks would seem acceptable in patients pathy, papilledema, ocular nerve palsy, and multifocal with CMV retinitis, since CMV replication is controlled choroiditis.118 Diagnosis is based on latex, direct examination, within 2 weeks after starting the antiviral induction and culture, usually in the cerebrospinal fluid.119 therapy.130 Treatment of ocular manifestations of Cryptococcus infec- IRU requires a prompt anti–inflammatory therapy. Both tion depends on clinical presentation. Multifocal choroiditis topical and systemic corticosteroids have been successfully rarely causes visual acuity impairment and specific systemic used in the management of intraocular inflammation, to treatment with antifungal drugs (amphotericin B and flucyto- avoid structural sequelae, leading to poor clinical prognosis sine) shows good results.120 Optic nerve changes are usually and severe visual loss. In HIV patients diagnosed with OTB secondary to high intracerebral pressure or fungus direct and started on cART, IRIS can lead to paradoxical worsening invasion in the optic nerve tissue, and, besides the antifungal of chorioretinal lesions. High-dose systemic corticosteroids OCULAR IMMUNOLOGY AND INFLAMMATION 7 have been demonstrated to be successful in treating the virus infection. N Engl J Med. 1997;337:307–314. doi:10.1056/ inflammatory reaction.36 Recently, several authors described NEJM199707313370504. the successful outcome of patients with OTB and IRIS treated 9. 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