Rifabutin Induced Uveitis in HIV-Dangers of Drug Interactions in Patients on ART

Acquired Immunodeficiency Syndrome (AIDS) in its advanced stages, leads to a susceptibility to opportunistic infections in the immunocompromised host. Oral candidiasis, herpetic infections and atypical Mycobacterium infections are commonly associated with AIDS. As a result of this, patients with HIV infection are commonly administered several anti microbial drugs in addition to ART. 

Mycobacterium Avium Complex (MAC) infection is a common opportunistic infection in patients with Acquired Immunodeficiency Syndrome (AIDS). Rifabutin is recommended as a prophylaxis for MAC in patients with advanced AIDS is at the dosage of 300mg/day [1]. It is also used in the treatment of tuberculosis along with drugs like INH, pyrazinamide and ethambutol in patients with active tuberculosis. It is usually well tolerated, but is known to manifest an idiosyncratic side effect commonly seen in HIV infected individuals on Rifabutin prophylaxis - i.e., rifabutin induced uveitis [2]. It can cause anterior uveitis with or without hypopyon, intermediate uveitis or posterior uveitis with or without cystoid macular edema [3]. The onset of symptoms can occur as early as 2 weeks to 7 months following initiation of therapy [4]. It can be seen with doses that range from as low as 300mg a day to 1800mg a day [4], although side effects are less common in the standard prophylactic dose of 300mg [5,6]. It is usually under diagnosed, and the patient is subjected to various laboratory tests to establish an etiology for the uveitis. Since the number of HIV infected patients all over the world is significant, clinicians need to be aware of the incidence and the consequences of HIV related conditions.

A 42 year old female was referred to our ophthalmology department with complaints of sudden onset of redness, pain and blurring of vision in the right eye of 1 week duration. It was associated with photophobia and watering. The patient was a known case of retroviral disease diagnosed in 2003 and had been on Antiretroviral Therapy (ART) since then. Her drug regimen included tenofovir 300mg, lamivudine 300mg atazanavir 300mg and ritonavir 100mg. She had a history of Pneumocystis Carinii Pneumonia (PCP) and Herpes labialis infection a year earlier and was treated for the same, and was continued on PCP prophylaxis of sulphadiazine and pyrimethamine in a fixed drug combination. She was diagnosed to have tuberculous inguinal lymphadenitis a month prior to the onset of ocular symptoms and had been started on Anti Tuberculosis Treatment (ATT), which included INH 300mg, pyrazinamide 15mg/KGB, ethambutol 800mg and rifabutin 300mg. 

Ocular examination revealed the following: Best corrected visual acuity OD -Finger Counting (FC) at ½ metre and BCVA OS - 6/6. Anterior segment examination showed circumcorneal congestion, central Descement’s membrane folds, medium sized keratic precipitates, normal anterior chamber depth with a 3+ reaction and a central dense coagulated fibrinous exudate with a 2mm hypopyon (Figure 1)

Figure 1: Dense Fibrinous exudates in the anterior chamber mimicking a lens nucleus. 

Fundoscopy through a hazy media showed exudates in the vitreous cavity (Figure 2) 

 

 

Figure 2: Hazy view of the fundus due to vitreous exudates.

The left eye anterior segment and fungus was normal at presentation, but developed an identical clinical picture within 3 days of the right eye manifestations. 

Her blood tests results were as follows : Hemoglobin 9.9g, Total count 8.940 cells/cu.mm, differential count ( N70 L25 M4 E1 B0) normocytic normochromic peripheral smear, CD 4+ = 297, CD 3+ = 1064, CD 45+ = 2126. 

After reviewing her treatment charts, a diagnosis of rifabutin induced uveitis was made and the patient was started on oral prednisolone 40mg and topical steroids (Prednisolone acetate 1% hourly ) and topical cycloplegics (atropine sulphate 1% twice daily). Immediate discontinuation of rifabutin therapy was suggested after a physician consultation. The INH, prazinamide and ethambutol were however continued. The oral and topical steroid therapy for the uveitis was slow tapered over a 3 month period. Rapid resolution of the bilateral uveitis was observed (Figure 3,4) within a fortnight and was followed by total visual recovery in 3 months.

 

Figure 3: Complete resolution following steroid therapy and cessation of rifabutin (OD).

 

Figure 4: Resolving anterior uveitis in the fellow eye (OS).

Rifabutin associated uveitis has been described in AIDS patients and is identified as a dose-dependent, idiosyncratic side effect [7]. Adverse effects are unusual at the recommended dose of 300mg/day [8], however, it can be seen with doses that range from as low as 300mg a day to higher doses of 1800mg a day [4].

Ritonavir (a component of ART) is a potent inhibitor of CYP3A4, a liver enzyme responsible for drug metabolism, and has been shown to substantially increase Rifabutin concentration in blood by indirectly inhibiting its metabolism. 

Co-administration of rifabutin with ritonavir, as is common in patients with HIV disease, increases the Area Under the Concentration–time curve (AUC) of Rifabutin by 35 times, compared with administration of rifabutin alone [5,6]. This increases the propensity for rifabutin to exert its ocular idiosyncratic effect. It has also been associated with concomitant use of clarithromycin or fluconazole, which is believed to raise serum levels through inhibition of the hepatic cytochrome p-450 system that metabolizes the drug [9].

It has also been described in immunocompetent indivuals with atypical mycobacterial infections [10]. Studies conducted by Havlir et al. [11] and Kelleher et al. [12] have shown that the interval between starting rifabutin and the onset of uveitis was 7 months and 2 months respectively. 

The dose required to cause uveitis could range anywhere from 300mg to 1800mg as established by Skolik et al. [13], The higher the dose and duration of treatment, the greater is the risk of associated uveitis [14]. Our patient developed uveitis within one month of initiation of therapy at a standard dose of 300mg, the early onset of the drug side effect is attributable to the inhibition of its metabolism by ritonavir.

The treatment is aimed at stopping the offending agent along with anti inflammatory and immunosuppressive therapy to help the inflamed uveal tissue recover. Discontinuation of rifabutin with concomitant use of topical and a short course of systemic steroids is effective in reversal of the condition. The importance of reviewing treatment charts and awareness of drug interactions in cases such as these would obviate the need for unnecessary and extensive investigations that patients of uveitis are usually subjected to. An early suspicion of rifabutin induced uveitis could also prevent invasive ocular procedures like aqueous sampling and a detailed drug history should be elicited in unexplained uveitis [15]. In our patient, rapid resolution of uveitis (Figure 3 and 4) was followed by total visual recovery within 3 months time. No invasive diagnostic procedure was carried out to confirm the diagnosis, although it is recommended to consider a blood sampling to determine serum rifabutin levels in patients with uveitis.