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Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy
THE LANCET
count is 550 cells/µL, no detectable CMV on buffycoat, and she remains CMV IgG antibody positive. We believe that this is the first report of such a long standing remission from active CMV retinitis, and suggest that remission is due to her sustained immune restitution. We plan further studies to examine her immune response in vitro. *S Uthayakumar, K Birthistle, R Dalton, P E Hay Departments of *Genitourinary Medicine, Virology, and Ophthalmology, St Georges Hospital Medical School, London SW17 0QT, UK
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2
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Jacobson MA, Zegans M, Pavan PR, et al. Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy. Lancet 1997; 349: 1443–45. MacGregor RR, Pakola SJ, Graziani AL, et al. Evidence of active CMV infection in clinically stable HIV infected individuals with CD4 lymphocyte counts below CD4 count 100/mm3: features and relation to risk of subsequent CMV retinitis. J AIDS Humn Retrovir 1995; 10: 324–30. Drew WI, Ives D, Lalezari JP, et al. Oral Ganciclovir as maintenance treatment for CMV retinitis in patients with AIDS. N Engl J Med 1995; 333: 615–20.
S IR —It is surprising that Mark Jacobson and colleagues 1 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.3,4 The cellular immune defect in AIDS remains a formidable diagnostic and therapeutic challenge, and the article by Jacobson and colleagues underscores this fact.
4
SIR—Mark 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 CMVspecific 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).2 This differential clinical effect was seen with maximum mean CD4 and CD8 cell increases of 45 and 300 cells/µL, respectively, and a peak reduction of HIV RNA viraemia of 1·3 logs. Combination therapy including a protease inhibitor has been shown subsequently to result in complete clinical and histological remissions of HIV-related cryptosporidiosis and microsporidiosis3 and occasionally of Kaposi’s sarcoma4 and chronic hepatitis B,5 presumably by expansion of surviving pathogen-specific clones. Perhaps Jacobson and colleagues do not refer to these data because they have not been published in full, despite the trial having being terminated in December, 1995. Without rapid peerreviewed publication of clinical trials and their resultant generation of new hypotheses to be tested, clinical management is forced to rely more on subtle clinical observation with its associated lack of evidence. *Andrew Carr, David A Cooper St Vincent’s Hospital, Darlinghurst, Sydney, NSW 2010, Australia
1
*Raphael B Stricker, Billi Goldberg *California Pacific Medical Center, San Francisco, CA 94120, USA; and International DNCB Study Group, San Francisco
1
2
3
Jacobson MA, Zegans M, Pavan PR, et al. Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy. Lancet 1997; 349: 1443–45. Gilquin J, Piketty C, Thomas V, Gonzales-Canali G, Kazatchkine M. Acute CMV infection in AIDS patients receiving combination therapy including protease inhibitors. Presented at fourth conference on retroviruses and opportunistic infections, Washington, DC, 1997 (abstr 629). Goldberg B, Stricker RB. HIV protease and the pathogenesis of AIDS. Res Virol 1996; 147: 375–79.
Vol 350 • August 23, 1997
Connors M, Kovacs JA, Gea-Banacloche JC, et al. HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies. Nat Med 1997; 3: 533–40.
2
3
4
Jacobson MA, Zegans M, Pavan PR, et al. Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy. Lancet 1997; 349: 1443–45. Cameron B, Heath-Chiozzi M, Kravcik S, et al. Prolongation of life and prevention of AIDS complications in advanced HIV immunodeficiency with ritonavir: update. In: Abstracts of the XI International Conference on AIDS, Vancouver, July, 1996 (abstr MoB411). Carr A, Foudraine N, Reiss P, Marriott D, Lange J, Cooper DA. Resolution of antibiotic resistant cryptosporidiosis and microsporidiosis with potent combination antiretroviral therapy. In: Abstracts of the 4th Conference on Retroviruses and Opportunistic Infections, Washington DC, January, 1997 (abstr 688). Henry K, Worley J, Sullivan C, Stawarz K, McCabe K. Documented improvement in late stage manifestations of AIDS after
5
starting retonavir in combination with two reverse transcriptase inhibitors. In: Abstracts of the 4th Conference on Retroviruses and Opportunistic Infections, Washington DC, January, 1997 (abstr 356). Carr A, Cooper DA. Restoration of immunity to chronic hepatitis B infection in HIV-infected patient on protease inhibitor. Lancet 1997; 349: 995–96.
Sir—Mark 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. Although I agree with Jacobson and colleagues’ conclusion that the relation between CD4 cell count thresholds and development of CMV disease may be altered by protease inhibitor use I suspect that it is not attributable to insufficient immune reconstitution. All six cases had no previous clinically apparent disease, followed by a period without relapse that seems to be greater than is typically seen. Clearly, the use of protease inhibitors greatly decreases the risk of both disease progression and death in late-stage disease. This effect would have to be secondary to improvement in immune function, as has been described earlier for nucleoside analogues.3,4 Modelling of the CD4 cell turnover after initiation of protease inhibitors5 indicates an average half-life of about 10–12 days so that a new steady state would not be reached for 50–60 days, which is consistent with the time frame of these cases. Therefore I submit that the patients all had subclinical CMV disease which became clinically apparent with the sudden increase in cell mediated immunity; this would indicate that presumptive therapy of certain patients at high risk about to start protease therapy may be needed to avoid onset of clinical disease. Whether these patients can be identified by laboratory testing such as use of CMV early antigen detection (p65) by flow cytometry or quantitative serum CMV DNA polymerase chain reaction needs to be investigated. In this regard can Jacobson and colleagues tell us what percentage of patients who had newly diagnosed CMV retinitis with CD4 cell counts of 50 or 100 cells/µL or greater in their trial had started protease inhibitors within the preceding 8 weeks. Daniel S Stein Clinical Pharmacology Studies Unit, Departments of Medicine and Pharmacology, Albany Medical College, Albany, NY 12208, USA
589
count is 550 cells/µL, no detectable CMV on buffycoat, and she remains CMV IgG antibody positive. We believe that this is the first report of such a long standing remission from active CMV retinitis, and suggest that remission is due to her sustained immune restitution. We plan further studies to examine her immune response in vitro. *S Uthayakumar, K Birthistle, R Dalton, P E Hay Departments of *Genitourinary Medicine, Virology, and Ophthalmology, St Georges Hospital Medical School, London SW17 0QT, UK
1
2
3
Jacobson MA, Zegans M, Pavan PR, et al. Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy. Lancet 1997; 349: 1443–45. MacGregor RR, Pakola SJ, Graziani AL, et al. Evidence of active CMV infection in clinically stable HIV infected individuals with CD4 lymphocyte counts below CD4 count 100/mm3: features and relation to risk of subsequent CMV retinitis. J AIDS Humn Retrovir 1995; 10: 324–30. Drew WI, Ives D, Lalezari JP, et al. Oral Ganciclovir as maintenance treatment for CMV retinitis in patients with AIDS. N Engl J Med 1995; 333: 615–20.
S IR —It is surprising that Mark Jacobson and colleagues 1 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.3,4 The cellular immune defect in AIDS remains a formidable diagnostic and therapeutic challenge, and the article by Jacobson and colleagues underscores this fact.
4
SIR—Mark 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 CMVspecific 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).2 This differential clinical effect was seen with maximum mean CD4 and CD8 cell increases of 45 and 300 cells/µL, respectively, and a peak reduction of HIV RNA viraemia of 1·3 logs. Combination therapy including a protease inhibitor has been shown subsequently to result in complete clinical and histological remissions of HIV-related cryptosporidiosis and microsporidiosis3 and occasionally of Kaposi’s sarcoma4 and chronic hepatitis B,5 presumably by expansion of surviving pathogen-specific clones. Perhaps Jacobson and colleagues do not refer to these data because they have not been published in full, despite the trial having being terminated in December, 1995. Without rapid peerreviewed publication of clinical trials and their resultant generation of new hypotheses to be tested, clinical management is forced to rely more on subtle clinical observation with its associated lack of evidence. *Andrew Carr, David A Cooper St Vincent’s Hospital, Darlinghurst, Sydney, NSW 2010, Australia
1
*Raphael B Stricker, Billi Goldberg *California Pacific Medical Center, San Francisco, CA 94120, USA; and International DNCB Study Group, San Francisco
1
2
3
Jacobson MA, Zegans M, Pavan PR, et al. Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy. Lancet 1997; 349: 1443–45. Gilquin J, Piketty C, Thomas V, Gonzales-Canali G, Kazatchkine M. Acute CMV infection in AIDS patients receiving combination therapy including protease inhibitors. Presented at fourth conference on retroviruses and opportunistic infections, Washington, DC, 1997 (abstr 629). Goldberg B, Stricker RB. HIV protease and the pathogenesis of AIDS. Res Virol 1996; 147: 375–79.
Vol 350 • August 23, 1997
Connors M, Kovacs JA, Gea-Banacloche JC, et al. HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies. Nat Med 1997; 3: 533–40.
2
3
4
Jacobson MA, Zegans M, Pavan PR, et al. Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy. Lancet 1997; 349: 1443–45. Cameron B, Heath-Chiozzi M, Kravcik S, et al. Prolongation of life and prevention of AIDS complications in advanced HIV immunodeficiency with ritonavir: update. In: Abstracts of the XI International Conference on AIDS, Vancouver, July, 1996 (abstr MoB411). Carr A, Foudraine N, Reiss P, Marriott D, Lange J, Cooper DA. Resolution of antibiotic resistant cryptosporidiosis and microsporidiosis with potent combination antiretroviral therapy. In: Abstracts of the 4th Conference on Retroviruses and Opportunistic Infections, Washington DC, January, 1997 (abstr 688). Henry K, Worley J, Sullivan C, Stawarz K, McCabe K. Documented improvement in late stage manifestations of AIDS after
5
starting retonavir in combination with two reverse transcriptase inhibitors. In: Abstracts of the 4th Conference on Retroviruses and Opportunistic Infections, Washington DC, January, 1997 (abstr 356). Carr A, Cooper DA. Restoration of immunity to chronic hepatitis B infection in HIV-infected patient on protease inhibitor. Lancet 1997; 349: 995–96.
Sir—Mark 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. Although I agree with Jacobson and colleagues’ conclusion that the relation between CD4 cell count thresholds and development of CMV disease may be altered by protease inhibitor use I suspect that it is not attributable to insufficient immune reconstitution. All six cases had no previous clinically apparent disease, followed by a period without relapse that seems to be greater than is typically seen. Clearly, the use of protease inhibitors greatly decreases the risk of both disease progression and death in late-stage disease. This effect would have to be secondary to improvement in immune function, as has been described earlier for nucleoside analogues.3,4 Modelling of the CD4 cell turnover after initiation of protease inhibitors5 indicates an average half-life of about 10–12 days so that a new steady state would not be reached for 50–60 days, which is consistent with the time frame of these cases. Therefore I submit that the patients all had subclinical CMV disease which became clinically apparent with the sudden increase in cell mediated immunity; this would indicate that presumptive therapy of certain patients at high risk about to start protease therapy may be needed to avoid onset of clinical disease. Whether these patients can be identified by laboratory testing such as use of CMV early antigen detection (p65) by flow cytometry or quantitative serum CMV DNA polymerase chain reaction needs to be investigated. In this regard can Jacobson and colleagues tell us what percentage of patients who had newly diagnosed CMV retinitis with CD4 cell counts of 50 or 100 cells/µL or greater in their trial had started protease inhibitors within the preceding 8 weeks. Daniel S Stein Clinical Pharmacology Studies Unit, Departments of Medicine and Pharmacology, Albany Medical College, Albany, NY 12208, USA
589