Over the follow-up period, 66 patients experienced a progression of their CMV retinitis, a Kaplan–Meier progression rate of 84.0% by 2.79 years after initial diagnosis (Fig. 3). In these patients the number of progressions ranged from one to eight (median, two progressions). The median time to first progression was 0.31 years. In univariate Cox regression analysis none of the factors, including the use of HAART, were associated with time to progression (Table 2). Consequently, no multivariate analyses were performed. However, no progressions of retinitis occurred in patients who had received more than 6 months of HAART.
Information on complications was available for 100 (97.1%) patients. 39 patients experienced a total of 46 complications of retinitis. The most common complication recorded was retinal detachment (19 patients, seven in the left eye only, 10 in the right eye only and two bilaterally) although uveitis (11 patients) and optic atrophy (seven patients) were also relatively common.
Vitritis was diagnosed a median of 105 days (range 91 to 237 days) after starting HAART. At the time of starting HAART, CD4 cell counts ranged from 0 to 100 × 106 cells/l (median 5 × 106 cells/l). At the time of development of vitritis CD4 cell counts had increased in four patients (increases of 29, 35, 97 and 120 × 106 cells/l) and decreased in one patient (decrease of 90 × 106 cells/l). CMO was diagnosed 162, 193, 231 and 651 days after starting HAART. CD4 cell counts were available for three of these patients. Prior to HAART, the CD4 cell counts were 3, 10 and 100 × 106 cells/l; at the time of diagnosis of CMO the counts had increased in two patients (by 113 and 197 × 106 cells/l) and decreased in one (by 46 × 106 cells/l). There were no significant differences in maximum CD4 cell counts achieved in the first 12 months after HAART between patients who developed inflammatory complications (CD4 cell range, 51–503 × 106/l; median 197 × 106/l) and those who did not (CD4 range, 8–330 × 106/l; median 142 × 106/l). Plasma HIV RNA levels were available for six of eight patients at the time of first diagnosis of vitritis or CMO. In five of these patients the HIV RNA was undetectable (< 400 copies/ml) and it was > 750 000 copies/ml in the sixth.
The incidence of CMV retinitis has declined dramatically since the introduction of HAART. The majority of recent new cases of retinitis at our hospital have occurred in individuals presenting with untreated HIV infection. This is reflected in the finding of this study that there has been no significant change in the CD4 cell count at the time of first diagnosis of retinitis over time. It can be concluded therefore that an increased CD4 cell count following HAART is protective against the development of retinitis even in patients that were previously at high risk.
Survival following a diagnosis of retinitis has improved significantly and these results suggest that this is predominantly due to the introduction of HAART. Other groups have reported similar findings . Although patients who commenced HAART after a diagnosis of retinitis did experience progression of disease, no progressions were seen after HAART had been taken for more than 6 months. This observation may be important when considering discontinuation of maintenance therapy for retinitis in patients responsive to HAART, a practice which has been successfully adopted by several groups [11–13].
The previously uncommon complications of vitritis and CMO only occurred in association with the use of HAART in this cohort. CMV retinitis in the pre-HAART era was characterized by only mild and often asymptomatic vitreous and anterior chamber inflammation. These newer manifestations of CMV retinitis are important as they can cause considerable loss of visual acuity in the absence of active retinitis . Although a direct drug effect has been suggested as a possible aetiology for these complications, it is now thought that these are inflammatory conditions resulting from immune restoration. One patient in our series developed vitritis and CMO despite a fall in the total CD4 cell count and there was no difference in maximum CD4 cell counts attained from those without inflammatory complications, suggesting that patients at risk may not be identifiable simply by considering the CD4 cell count. Our findings do not support the hypothesis that the risk of inflammatory complications is increased following the discontinuation of maintenance therapy for CMV.
The protective effect of HAART on CMV disease may be explained by the recently described reconstitution of T-lymphocyte responses to a variety of pathogens, including CMV, following HAART [15–17]. Similar effects on the incidence of other opportunistic infections such as progressive multifocal leucoencephalopathy, Kaposi's sarcoma, cryptosporidiosis and microsporidiosis have been reported [18–23]. In parallel, paradoxical inflammatory complications attributed to immune reconstitution have been described in Mycobacterium tuberculosis infection following HAART . Patients who develop vitritis have enhanced proliferative responses to antigen in vitro compared with controls and it is possible that it is the degree of recovery of these specific responses rather than the actual cell count which determines the degree of inflammatory response to intra-ocular CMV antigen . Currently, the optimal management of vitritis and CMO remains uncertain. Patients may respond to oral or ocular corticosteroids without reactivation of CMV retinitis . Alternative therapies such as oral acetazolamide and topical non-steroidal agents are of limited effectiveness . However, recovery may occur in the absence of anti-inflammatory therapy which suggests that these complications may be transient phenomena .
The introduction of HAART has made a dramatic impact on the management of HIV infection. However, it has recently become apparent that the longer-term receipt of PIs is associated with severe metabolic complications which may limit their future use in some patients . Adherence to complicated therapeutic regimens is difficult and treatment failure secondary to antiretroviral resistance is increasingly problematic in clinical practice . Interest in `PI-sparing' HAART regimens containing NNRTIs is increasing. This cohort did not contain any patients receiving such a regimen as NNRTIs came into use later than PIs. There are therefore no data on the effect of NNRTI-containing HAART regimens on CMV disease.
It remains unknown how long the beneficial effect of HAART on both the development of retinitis and risk of progression after previous disease may be sustained. It is probable that the natural history of CMV disease will continue to evolve and so further monitoring is required to document these changes.
The authors thank Dr Amanda Mocroft, Professor Clive Loveday, Dr Helen Devereux and staff in immunology for help in the collection of data for this study.
1. Centres for Disease Control and Prevention. Update: trends in AIDS incidence.
MMWR 1997, 46: 861 –867.
2. Palella FJ, Delaney KM, Moorman AC. et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection.
N Engl J Med 1998, 338: 853 –860.
3. Mocroft A, Vella S, Benfield T. et al. Changing patterns of mortality across Europe in patients infected with HIV-1.
Lancet 1998, 352: 1725 –1730.
4. Jacobson MA, Zegans M, Pavan PR. et al. Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy.
Lancet 1997, 349: 1443. 1443.
5. Gilquin J, Piketty C, Thomas V. et al. Acute cytomegalovirus infection in AIDS patients with CD4 counts above 100
×106 cells/l following combination antiretroviral therapy including protease inhibitors.
AIDS 1997, 11: 1659 –1660.
6. Mallolas J, Arrizabalga J, Loncá M. et al. Cytomegalovirus disease in HIV-infected patients treated with protease inhibitors.
AIDS 1997, 11: 1785 –1787.
7. Whitcup SM, Fortin E, Nussenblatt RB. et al. Therapeutic effect of combination antiretroviral therapy on cytomegalovirus retinitis.
JAMA 1997, 277: 1519 –1520.
8. Reed JB, Schawb IR, Gordon J. et al. Regression of cytomegalovirus retinitis associated with protease-inhibitor treatment in patients with AIDS.
Am J Ophthalmol 1997, 124: 199 –205.
9. Bowen EF, Sabin C, Wilson P. et al. Cytomegalovirus viraemia detected by polymerase chain reaction identifies a group of patients at high risk of CMV disease.
AIDS 1997, 11: 889 –893.
10. Walsh JC, Jones CD, Barnes EA. et al. Increasing survival in AIDS patients with cytomegalovirus retinitis treated with combination antiretroviral therapy including HIV protease inhibitors.
AIDS 1998, 12: 613 –618.
11. Tural C, Romeu J, Sirera G. et al. Long-lasting remission of cytomegalovirus retinitis without maintenance therapy in human immunodeficiency virus-infected patients.
J Infect Dis 1997, 177: 1080 –1083.
12. Macdonald JC, Torriani FJ, Morse LS. et al. Lack of reactivation of cytomegalovirus (CMV) retinitis after stopping CMV maintenance therapy in patients with sustained elevations in CD4 T cells in response to highly active antiretroviral therapy.
J Infect Dis 1998, 177: 1182 –1187.
13. Vrabec TR, Baldassano VF, Whitcup SM. Discontinuation of maintenance therapy in patients with quiescent cytomegalovirus retinitis and elevated CD4 counts.
Ophthalmology 1998, 105: 1259 –1264.
14. Silverstein BE, Smith JH, Hasenyager Smith J. et al. Cystoid macular edema associated with patients with the acquired immunodeficiency syndrome.
Am J Ophthalmol 1998, 125: 411 –415.
15. Autran B, Carcelain G, Li TS. et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease.
Science 1997, 277: 112 –116.
16. Li TS, Tubiana R, Katlama C. et al. Long-lasting recovery in CD4 T-cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease.
Lancet 1998, 351: 1682 –1686.
17. Komanduri KV, Viswanathan MN, Wieder ED. et al. Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1.
Nat Med 1998, 4: 953 –956.
18. Elliot B, Aromin I, Gold R. et al. 2.
:5 year remission of AIDS-associated progressive multifocal leukoencephalopathy with combined antiretroviral therapy.
Lancet 1997, 349: 850. 850.
19. Murphy M, Armstrong D, Sepkowitz KA. et al. Regression of AIDS-related Kaposi's sarcoma following treatment with an HIV-1 protease inhibitor.
AIDS 1997, 11: 261 –262.
20. Conant MA, Opp KM, Poretz D, Mills RG. Reduction of Kaposi's sarcoma lesions following treatment of AIDS with ritonavir.
AIDS 1997, 11: 1300 –1301.
21. Blum L, Pellet C, Abgalika F. et al. Complete remission of AIDS-related Kaposi's sarcoma associated with undetectable human herpesvirus-8 sequences during anti-HIV protease therapy.
AIDS 1997, 11: 1653 –1655.
22. Goguel J, Katlama C, Sarfati C. et al. Remission of AIDS-associated intestinal microsporidiosis with highly active antiretroviral therapy.
AIDS 1997, 11: 1658. 1658.
23. Carr A, Marriott D, Field A. et al. Treatment of HIV-1 associated microsporidiosis and cryptosporidiosis with combination antiretroviral therapy.
Lancet 1998, 351: 256 –261.
24. Race EM, Adelson-Mitty J, Kriegel GR. et al. Focal mycobacterial lymphadenitis following initiation of protease-inhibitor therapy in patients with advanced HIV-1 disease.
Lancet 1998, 351: 252 –255.
25. Torriani F, Durand FD, Karavellas M, et al
. Evidence that HAART induced immune recovery vitritis in CMV retinitis patients is immune mediated. XIIth World AIDS Conference.
Geneva, 1998. [Abstract 15/22240].
26. Karavellas MP, Lowder CY, Macdonald C. et al. Immune recovery vitritis associated with inactive cytomegalovirus retinitis: a new syndrome.
Arch Ophthalmol 1998, 116: 169 –175.
27. Zegans ME, Walton RC, Holland GN. et al. Transient vitreous inflammatory reactions associated with combination antiretroviral therapy in patients with AIDS and cytomegalovirus retinitis.
Am J Ophthalmol 1998, 125: 292 –300.
28. Carr A, Samaras K, Burton S. et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors.
AIDS 1998, 12: F51 –F58.
29. Ledergerber B, Egger M, Opravil M. et al. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study.
Lancet 1999, 353: 863 –868.