Cytomegalovirus (CMV) retinitis is the most common ocular infection in patients with Acquired Immune Deficiency Syndrome (AIDS), occurring in up to 40% of patients, particularly when CD4+ T lymphocyte levels decrease to less than 50 cells/mm. Before the availability of highly active antiretroviral therapy (HAART), the treatment of CMV retinitis included longterm intravenous ganciclovir. This therapy is very expensive (induction: Rs 22,000/week, approximately) and is associated with severe morbidity, including nephrotoxicity, myelosuppression, central line sepsis, malaise, and surgical complications. HAART stands for various combinations of antiretroviral drugs and consists of either two-nucleoside reverse-transcriptase inhibitors (2NRTIs), 2NRTIs plus one protease inhibitors (PI) or 2NRTIs plus one non-nucleoside reverse transcriptase inhibitors (NNRTI). With the advent of the HAART therapy, not only has the incidence of CMV retinitis decreased, but also CMV retinitis is more easily controlled with anti-CMV medications. The reports also suggest that anti-CMV medications can be omitted in patients who respond to HAART therapy. Recently, a new ocular inflammatory syndrome of immune recovery vitritis (IRV) has been described in patients with inactive CMV retinitis responding to HAART therapy. This study examined the changes in presentation and the course of CMV retinitis in patients with AIDS receiving combination antiretroviral therapy.
Materials and Methods
This was an open-label prospective study of AIDS patients with CMV retinitis on combination antiretroviral therapy who showed an increase in CD4 cell counts after the introduction of combination antiretroviral therapy. Response to combination therapy was assessed by clinical and immunological parameters (CD4 + T cells count). Treatment responders were defined as patients who maintained CD4 cell counts =100 cells/mm3 for more than 3 months following treatment. Periodic plasma viral load assays were not performed in all patients due to financial constraints and hence its analysis was not included in the study. All patients were followed up for minimum 6 months. Informed consent was taken in all patients.
All patients were subjected to complete ophthalmic examinations [vision, slitlamp examination including biomicroscopy, intraocular pressure (IOP) measurement and detailed fundus evaluation] every 4 weeks until the lesions were clinically inactive, after which they were seen monthly. Fundus photograph was taken when necessary. IRV was defined as vitritis of +1 or greater severity, which caused visually significant floaters or a decrease in vision of one or more lines. The severity of vitritis was evaluated according to the grading system of Nussenblatt et al. Anti-CMV medications were discontinued after discussion between the patient, the ophthalmologist and physician. The levels of CD4 T-cell counts were monitored every three months. Patients who had received rifabutin or cidofovir within two months of the onset of inflammation were excluded from the study.
Combination therapy consisted of either 2-nucleoside reverse-transcriptase inhibitors (2NRTIs), 2NRTIs plus 1 protease inhibitors (PI) or 2NRTIs plus 1 non-nucleoside reverse transcriptase inhibitors (NNRTI). They were in various combinations: d4T+3TC+NVP (d4T = stavudine, 3TC = lamivudine, NVP = nevirapine), or d4T+ddI+HU (ddI = didenosine, HU = hydroxyurea), or AZT+3TC+ IDV (AZT = zidovudine, IDV = indinavir) or AZT+3TC+ NVP, or d4T+ddI, or d4T+3TC+IDV. Anti-CMV treatment consisted of intravenous ganciclovir or intravitreal cidofovir (15µg/0.1ml).
Fifty six patients with AIDS-related CMV retinitis were examined from January 1998 through December 2000. Of these, 24 patients received combination antiretroviral therapy, but only 12 had a minimum follow-up of 6 months (median 16.7 months; range 6-26 months). The remaining 12 patients were excluded from the study because of inadequate follow-up. The commonly associated systemic diseases in these 12 patients were pulmonary tuberculosis in 8 (66.6%) cases, oropharyngeal candidiasis in 4 (33.6%) cases, gastroenteritis in 3 (25%) cases and pneumonia in 2 (16.6%) cases.
Cytomegalovirus retinitis remained inactive without maintenance anti-CMV therapy in all patients as long as the CD4+ cell count was higher than 100 cells/mm3, with most patients followed up for at least one year [Table - 1]. To date, CMV retinitis has re-emerged in only one of these patients (No 8, drug defaulter), who discontinued combination anti-retroviral therapy due to financial constraints. His CD4 cell count had dropped to 7/ mm3 at the time of reactivation. He was treated with a repeat intravitreal injection of cidofovir. Nine patients received a single injection of intravitreal cidofovir (15µg) while two patients received induction doses of intravenous ganciclovir (5mg/kg twice daily for 2 weeks) at the time of diagnosis of active CMV retinitis. None of these 11 patients received any further anti-CMV medications. One patient (No 4) had a very small patch of active CMV retinitis in the extreme periphery. No specific anti-CMV treatment was given and the patient was started on combination antiretroviral therapy. He had complete resolution of retinitis and remained healed throughout the follow-up period; his CD4 cell counts increased from 70/mm3 at baseline to 752/mm3 at 26 months of follow up [Figure - 1]. The visual acuity following therapy remained stable at the pre-treatment level except in some cases which developed IRV [Table - 1].
Immunological response to combination antiretroviral therapy
The median CD4 cell count at baseline was 36.5/mm3 (range, 3-74/mm3). After initiation of combination therapy, the CD4 cell counts increased. At 3 months, the median CD4 count was 175.5/mm3 (range, 97-410/mm3) while it was 374.5/mm3 (range, 7-752/mm3) at last follow-up.
Immune recovery vitritis
During the follow-up period, 5 patients (41.7%) developed immune recovery vitritis (IRV) [Figure - 2]. The mean time to IRV was 42 weeks (range: 31-46 weeks). Of these patients, four had a history of intravitreal cidofovir therapy and one patient received intravenous ganciclovir at baseline. No anti-CMV medications were repeated thereafter in any patient. All patients with IRV complained of floaters and decreased visual acuity and all had inactive CMV retinitis at the diagnosis of vitritis. Three patients had 1-line vision loss, and one patient each had 2-line and 3-line vision loss. The vitritis was of 1-3+ severity in all cases. The patient with a 3-line vision loss developed epiretinal membrane with macular oedema. All patients with IRV received 1 ml deep-posterior subtenon depomedrol injection (40mg/1ml) and all responded with clearing of vitritis and improvement in visual acuity to previous levels. The CD4 cell counts had increased in all these patients [Table - 1].
Major advances in HIV/AIDS therapy have been made during the last few years with the introduction of antiretroviral drugs. The anti-retroviral drugs disrupt the HIV life cycle by inhibiting the enzyme reverse transcriptase and thwart HIV genes before they integrate into helper T lymphocyte nucleus. These are called reverse transcriptase inhibitors, which are either nucleoside or non-nucleoside analogues. The nucleoside analogues are drugs that resemble nucleosides and when added into the developing DNA, disrupt the entire process. Non-nucleoside analogues are drugs composed of other substances, that disrupt the function of reverse transcriptase. The protease inhibitors are drugs that inhibit the protease enzyme, and thus prevent the formation of new copies of HIV proteins.
HAART represents various combinations of anti-retroviral drugs. The combination makes the therapy more potent and reduces or postpones development of drug resistance. Patients treated with HAART show a decrease in HIV viral load and increase in CD4 cell counts. HAART therapy has improved the quality of life of HIV patients, decreased morbidity due to opportunistic infections, and has led to better control of opportunistic infections. It has also affected the incidence, severity and clinical course of CMV retinitis. In some patients, retinitis did not progress even when specific anti-CMV therapy was discontinued. Since the proportion of naive T cells increases after about 3 months of therapy, patients may need to receive combination antiretroviral therapy for several months before the immune response against opportunistic infections is effectively restored. Therefore, specific anti-CMV maintenance therapy should be continued for at least 3 months after CD4+ cell counts increase, while the patient is still receiving combination antiretroviral therapy. Although the elevation in CD4+ cell counts following combination antiretroviral therapy effectively controls CMV retinitis in some patients, the rejuvenated immune response causes intraocular inflammation in many cases. This is manifested as inflammation involving both the anterior and posterior segments of the eye (anterior uveitis, cataract, vitritis, cystoid macular oedema, epiretinal membrane, and disc oedema). [6,7] The exact mechanism of immune recovery uveitis is still not known. The ocular inflammation appears to be related to the CMV infection, which causes a breakdown in the blood-ocular barrier. This may allow the CMV antigen to leak out of the eye and give the antigen access to lymphoid organs and stimulate an antigen-specific immune response.
Intravitreal cidofovir is a very potent drug for the local treatment of CMV retinitis. An earlier study has shown that use of cidofovir is not a causative factor of inflammation. Our study also illustrates these striking changes. First, retinitis did not progress in all 12 patients when specific anti-CMV therapy was discontinued following a rise in CD4 cell counts, observed for at least 3 months. Second, 41.7% patients developed substantial intraocular inflammation that resulted in reduction in vision. This is comparable to the 63% incidence of IRV recently reported by Karavellas et al. These two findings highlight both the benefits and the potential adverse effects of a rejuvenated immune response. It is important to recognise early vitritis clinically before significant visual debility occurs; this allows early institution of treatment for inflammation with good results.
The appropriate management of CMV retinitis in the setting of improved immune function is one of the crucial issues facing ophthalmologists involved in the care of patients with AIDS. This has special significance in view of rapid increase of AIDS patients and the treatment cost burden that lies on them. Until August 2001, 25,896 cases were reported to the Indian National AIDS Control Organization with an estimated 0.7% of the population being HIV infected. With the increase in the availability of antiretroviral drugs in developing countries, the lifespan of AIDS patients will be prolonged, but other inadequacies in treatment will render patients increasingly vulnerable to opportunistic infections that can impair or destroy vision. Also, the antiretroviral therapy does not provide a complete cure and the therapy needs to be continued practically throughout life. In such a scenario, we believe that some form of local treatment for CMV retinitis along with a combination antiretroviral treatment would serve as a good option. Chronic suppressive treatment for CMV retinitis can be discontinued in AIDS patients with inactive retinitis for greater than 3 months who have sustained elevation of CD4+T lymphocyte counts of greater than 100 cells/mm3 for at least 6 months.
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Conflict of Interest:
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