Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy
1997; Elsevier BV; Volume: 350; Issue: 9077 Linguagem: Inglês
10.1016/s0140-6736(05)63177-7
ISSN1474-547X
Autores Tópico(s)HIV Research and Treatment
ResumoAuthors' replySir—The effect of chronic potent combination antiretroviral therapy (also described as HAART) on the natural history of specific AIDS-related opportunistic infections such as CMV retinitis is largely undocumented. We reported five unusual cases of CMV retinitis who had in common clinical presentation soon after HAART regimens were initiated, and at a time when previously very low absolute CD4 lymphocyte counts had risen (in response to HAART) to values of 200 cells/μL or greater. These values are much higher than previously reported in patients with this AIDS-related complication. We also noted in a prospective clinical trial a temporal trend toward higher absolute CD4 counts occurring in patients with CMV retinitis diagnosed after the widespread availability of the potent HIV protease inhibitors indinavir and ritonavir than in those diagnosed before. These objective observations were the basis of our report.We, in our report, and your correspondents speculate about what these findings mean. Uthayakumar and colleagues and Stein provide additional observations to support the hypothesis that HAART does allow reconstitution of protective CMV-specific immunity. Certainly, our observations are consistent with this hypothesis, given the presence of vitritis in two of the five cases and the subsequent prolonged time without retinitis progression in all five. In fact, since publication of our report, ophthalmological examinations indicate that after 8–17 months of treatment, none of these five patients have yet to show progression of retinitis. We speculated, like Stein, that these cases could have had subclinical CMV retinal infection that was unmasked by a HAART-induced immune inflammatory response. At scientific meetings, others have also reported CMV retinitis developing in the first 2 months after the institution of HAART, but not in subsequent months.1Michelet C, Arvieux C, Aubert V, et al. Viral ocular involvement after initiation of antiprotease inhibitor therapy. 4th Conference on Retroviruses and Opportunistic Infections, Washington DC 1997 (abstr 315).Google Scholar, 2Gilquin J, Piketty C, Thomas V, et al. Acute CMV infection in AIDS patients receiving combination therapy including protease inhibitors. 4th Conference on Retroviruses and Opportunistic Infections, Washington DC 1997 (abstr 354)..Google Scholar, 3Cameron B, Heath-Chiozzi M, Kravcik S, et al. Prolongation of life and prevention of AIDS in advanced HIV immunodeficiency with ritonavir. 3rd Conference on Retroviruses and Opportunistic Infections, Washington DC 1996 (abstr LBa)..Google Scholar One would expect retinitis to occur with increasing rather than decreasing frequency after HAART-induced absolute CD4 count rises if these increases did not represent improved functional immunity. On the other hand, Mitchell and colleagues' hypothesis that functional CMV immunity takes several months to be restored and that of Carr and Cooper that improved CMV immunity may be anatomically restricted and not penetrate into the eye are equally plausible.However, to put these speculations in perspective, we note that neither we nor any of your correspondents have any direct evidence proving that HAART does or does not allow reconstitution of clinically meaningful CMV-specific protective immunity in vivo. Searching for such direct evidence should now be a high priority objective of clinical research.In response to specific questions raised, first, none of the patients described were receiving anti-CMV monoclonal antibody at the time that CMV retinitis was diagnosed. Second, routine ophthalmological monitoring began only after retinitis was diagnosed. Third, the nadir CD4 counts reported, ranging from 14 to 82 cells/μL, were obtained 1–17 weeks before HAART was initiated. And last, of the patients enrolled in ACTG protocol 266 between July, 1995, and August, 1996, four of 16 whose baseline absolute CD4 count was 50 cells/μL or greater had initiated ritonavir, indinavir, or saquinavir therapy within 8 weeks before enrolment and three of these 16 had initiated protease inhibitor therapy greater than 8 weeks before enrolment. Authors' reply Sir—The effect of chronic potent combination antiretroviral therapy (also described as HAART) on the natural history of specific AIDS-related opportunistic infections such as CMV retinitis is largely undocumented. We reported five unusual cases of CMV retinitis who had in common clinical presentation soon after HAART regimens were initiated, and at a time when previously very low absolute CD4 lymphocyte counts had risen (in response to HAART) to values of 200 cells/μL or greater. These values are much higher than previously reported in patients with this AIDS-related complication. We also noted in a prospective clinical trial a temporal trend toward higher absolute CD4 counts occurring in patients with CMV retinitis diagnosed after the widespread availability of the potent HIV protease inhibitors indinavir and ritonavir than in those diagnosed before. These objective observations were the basis of our report. We, in our report, and your correspondents speculate about what these findings mean. Uthayakumar and colleagues and Stein provide additional observations to support the hypothesis that HAART does allow reconstitution of protective CMV-specific immunity. Certainly, our observations are consistent with this hypothesis, given the presence of vitritis in two of the five cases and the subsequent prolonged time without retinitis progression in all five. In fact, since publication of our report, ophthalmological examinations indicate that after 8–17 months of treatment, none of these five patients have yet to show progression of retinitis. We speculated, like Stein, that these cases could have had subclinical CMV retinal infection that was unmasked by a HAART-induced immune inflammatory response. At scientific meetings, others have also reported CMV retinitis developing in the first 2 months after the institution of HAART, but not in subsequent months.1Michelet C, Arvieux C, Aubert V, et al. Viral ocular involvement after initiation of antiprotease inhibitor therapy. 4th Conference on Retroviruses and Opportunistic Infections, Washington DC 1997 (abstr 315).Google Scholar, 2Gilquin J, Piketty C, Thomas V, et al. Acute CMV infection in AIDS patients receiving combination therapy including protease inhibitors. 4th Conference on Retroviruses and Opportunistic Infections, Washington DC 1997 (abstr 354)..Google Scholar, 3Cameron B, Heath-Chiozzi M, Kravcik S, et al. Prolongation of life and prevention of AIDS in advanced HIV immunodeficiency with ritonavir. 3rd Conference on Retroviruses and Opportunistic Infections, Washington DC 1996 (abstr LBa)..Google Scholar One would expect retinitis to occur with increasing rather than decreasing frequency after HAART-induced absolute CD4 count rises if these increases did not represent improved functional immunity. On the other hand, Mitchell and colleagues' hypothesis that functional CMV immunity takes several months to be restored and that of Carr and Cooper that improved CMV immunity may be anatomically restricted and not penetrate into the eye are equally plausible. However, to put these speculations in perspective, we note that neither we nor any of your correspondents have any direct evidence proving that HAART does or does not allow reconstitution of clinically meaningful CMV-specific protective immunity in vivo. Searching for such direct evidence should now be a high priority objective of clinical research. In response to specific questions raised, first, none of the patients described were receiving anti-CMV monoclonal antibody at the time that CMV retinitis was diagnosed. Second, routine ophthalmological monitoring began only after retinitis was diagnosed. Third, the nadir CD4 counts reported, ranging from 14 to 82 cells/μL, were obtained 1–17 weeks before HAART was initiated. And last, of the patients enrolled in ACTG protocol 266 between July, 1995, and August, 1996, four of 16 whose baseline absolute CD4 count was 50 cells/μL or greater had initiated ritonavir, indinavir, or saquinavir therapy within 8 weeks before enrolment and three of these 16 had initiated protease inhibitor therapy greater than 8 weeks before enrolment. Cytomegalovirus retinitis after initiation of highly active antiretroviral therapyMark Jacobson and colleagues (May 17, p 1443)1 describe five patients who were newly diagnosed with cytomegalovirus (CMV) retinitis with CD4 counts above 195 cells/μL. All patients had started taking highly active antiretroviral treatment (HAART) regimens 4–7 weeks before diagnosis, but it is unclear which were taking additional monoclonal antibody specific for CMV gH surface protein or placebo in ACTG protocol 266. They state that four patients were not examined ophthalmologically either at the start of therapy or in the 3 preceding months. Full-Text PDF Cytomegalovirus retinitis after initiation of highly active antiretroviral therapyMark Jacobson and colleagues report1 CMV retinitis which developed despite rising CD4 counts. The use of triple combination antiretroviral therapy produces a striking rise in CD4 count, but concern has been expressed that the full repertoire of immune response may not be reactivated. CMV retinitis is the most common manifestation of cytomegalovirus disease and is particularly dreaded by patients because it can result in blindness. CMV retinitis usually occurs at a CD4 count less than 50 cells/μL. Full-Text PDF Cytomegalovirus retinitis after initiation of highly active antiretroviral therapyIt is surprising that Mark Jacobson and colleagues1 did not report plasma HIV RNA values in their study, since these measurements are routinely done to monitor the efficacy of HAART. A similar study from France suggested that HIV levels were decreased in HAART-treated patients who developed acute CMV complications.2 In addition, anecdotal reports of acute CMV infection in the setting of HAART have noted that plasma HIV RNA levels were very low or undetectable in these cases. Thus opportunistic infections might occur despite substantial HIV suppression, suggesting that an independent and persistent defect in cellular immunity is responsible for the infections. Full-Text PDF Cytomegalovirus retinitis after initiation of highly active antiretroviral therapyMark Jacobson and colleagues1 suggest two possible mechanisms by which treatment failure might occur: exhaustion of CMV-specific CD4 or CD8 lymphocyte clones before starting treatment or the failure of a CMV-specific immune response to penetrate into the eye. There are data suggesting that the latter mechanism is more likely. The addition of the protease inhibitor ritonavir in patients with CD4 counts less than 100 cells/μL resulted in a reduction in the number of cases of extraretinal CMV disease by 70% (five cases in the ritonavir group versus 14 in the placebo group) but not in CMV retinitis (18 cases in each group). Full-Text PDF Cytomegalovirus retinitis after initiation of highly active antiretroviral therapyMark Jacobson and colleagues'1 cases are very similar to the case that we described2 as part of a phase I/II evaluation of indinavir. Our patient had a normal dilated ophthalmological examination as part of screening but developed an intense vitritis with CMV retinitis diagnosed at week 6 of the study. His CD4 lymphocyte count had gone from a pretreatment average of 27·5 to 219 cells/μL at time of diagnosis. Response to ganciclovir was prompt, and on maintenance ganciclovir he died 2 years later (secondary to wasting, Mycobacterium avium intracellulare, and toxoplasmosis) without relapse of the retinitis. Full-Text PDF
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