Jpn. J. Infect. Dis., 55, 62-65, 2002

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Laboratory and Epidemiology Communications

Discordant Movement of CD4-Positive T-Cell Count in HIV-1 Infected Patients with HAART Failure

Aiko Okano, Masakazu Matsuda, Tomoko Chiba, Kenji Moriya, Kaneo Yamada¹ and Wataru Sugiura*

AIDS Research Center, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama, Tokyo 208-0011 and ¹St. Marianna University School of Medicine, Sugao 2-16-1, Miyamae-ku, Kawasaki, Kanagawa 216-8511

Communicated by Naoki Yamamoto

(Accepted June 7, 2002)

Highly active antiretroviral treatment (HAART) with at least one protease inhibitor (PI) and two nucleoside reverse transcriptase inhibitors (NRTIs) is now the recommended first-line antiretroviral prescription for HIV-1 infection (1,2). While its introduction has greatly improved the prognoses of many of patients (3-5), HAART has been unsuccessful in a considerable number of cases (6,7). This treatment failure is due mainly to the emergence of drug resistant HIV-1. Once the drug resistant virus appears, it will quickly predominate in the virus population due to selective advantage under continued drug administration. Insufficient suppression of virus replication, gradual decrease of peripheral CD4+ T-cell count, and consequent accelerated disease progression are frequent outcomes (8-10). Recently, however, several groups have reported cases in which the rise and fall of CD4+ T-cell counts and viral copy numbers during HAART did not follow the rule above (11,12).

We examined 236 HIV-1 infected patients who had been treated in 17 hospitals collaborating with our laboratory and followed up for more than 4 years (from November 1996 to September 2000).

CD4+ T-cell count and clinical data were provided by the collaborating hospitals. Viral load (VL) was measured by using AMPLOCOR HIV-1 MONITORTM Test Version 1.5 (Roche Diagnostics, Branchburg, N.J., USA).

HIV-1 pol sequences were analyzed for drug resistance genotypes. RNA was extracted form 200 mL of plasma by using an RNA purification kit (Boehringer Mannheim, Indianapolis, Ind., USA), and the 821 bp reverse transcriptase (RT) and 380 bp protease (PR) regions were reverse transcribed and amplified by nested PCR in a previously reported manner (13). The amplified fragments were directly sequenced using dye-terminator chemistry (14) and the auto-sequencer ABI-377 (Applied Biosystems, Foster City, Calif., USA).

The 236 cases were classified according to their VL response and changes in CD4+ T-cell count (Table 1). VL responses were classified into two groups, either (i) responding: VL achieved below the detectable level (<50 copies/mL) or >2 log copies/mL of reduction from the baseline before treatment, or (ii) non-responding: not applicable to category (i). Each VL response class was categorized into three according to CD4+ T-cell counts: (a) increase: absolute increase from the baseline before treatment, (b) decrease: absolute decrease from the baseline before treatment, (c) no change: no significant increase or decrease during the observation period.

As summarized in Table 1, in the VL responding group (n = 109), the number of cases applicable to categories (a), (b), and (c) were 80, 22, and 7, respectively. In the VL non-responding group (n = 127), the number of cases applicable to (a), (b), and (c) were 41, 64, and 22 cases, respectively. Thus, the responding group had a significantly high number of category (a), i.e., cases with increased CD4+ T-cell count, (P < 0.001). In contrast, the non-responding group had significantly high numbers of categories (b) + (c), cases whose CD4+ T-cell did not increase during the therapy (P < 0.001). As has been previously reported, and found as well in our samples, some cases have shown discordance between VL response and CD4+ T-cell response. Forty-one VL non-responding cases demonstrated increased CD4+ T-cell count, and seven VL responding cases showed a decrease in CD4+ T-cell count.

Patient profiles of each category are summarized in Table 2. No significant difference was seen in regard to sex, sexual behaviors and treatment protocols. Only parameter in which a significant difference could be seen was the lower median age, 30.5 years, of the patients with "VL non-responding-CD4+ increase", i.e., (ii) (a) cases.

In the drug resistance genotype comparison (Table 3), the incidence of D67N, K103N, and M184V/I RT-related resistance mutations was significantly higher in the discordant "VL non-responding-CD4+ increase" group (n = 41) than in the concordant "VL non-responding-CD4+ decrease" group (n = 22) (P = 0.045, 0.040, and 0.004, respectively). Regarding protease inhibitor-resistant mutations, no significant association could be seen between mutations and the discordance pattern.

Our results confirmed that virologic failure did not always result in acute immunologic failure. The cause of this discordance remains unclear, necessitating further research. The further study might help answer fundamental questions regarding HIV-1 pathogenesis and may provide clues to the proper timing for changing antiretroviral regimens after virologic failure.

REFERENCES

1. Kirt, O., Mocroft, A., Katzenstien, T.L., Lazzarin, A., Antunes, F., Francioli, P., Brettle, R.P., Parkin, J.M., Gonzales-Lahoz, J. and Jens D. Lundgren for the EuroSIDA Study Group (1998): Changes in use of antiretroviral therapy in regions of Europe over time. AIDS, 12, 2031-2039.
2. Carpenter, C.C., Fischl, M.A., Hammer, S.M., Hirsch, M.S., Jacobsen, D.M., Katzenstein, D.A, Montaner, J.S., Richman, D.D., Saag, M.S., Schooley, R.T, Thompson, M.A., Bella, S., Yeni, P.G. and Volberding, P.A. (1998): Antiretroviral therapy for HIV infection in 1998: updated recommendations of the International AIDS Society-USA panel. JAMA, 280, 78-86.
3. Notermans, D.W., Pakker, N.G., Hamman, D., Foudraine, N.A., Kauffmann, R.H., Meenhorst, P.L., Goudsmit, J., Roos, M.T., Schellekens, P.T., Miedema, F. and Danner, S.A. (1999): Immune reconstitution after 2 years of successful potent antiretroviral therapy in previously untreated human immunodeficiency virus type 1-infected adults. J. Infect. Dis., 180, 1050-1956.
4. Rosenberg, E.S., Billingsley, J.M., Caliendo, A.M., Boswell, S.L., Sax, P.E., Kalams, S.A. and Wakler, B.D. (1997): Vigorous HIV-1 specific CD4+ T cell responses associated with control of viremia. Science, 278, 1447-1450.
5. Li, T.S., Tubiana, R., Katlama, C., Calvez, V., Ait, Mohand, H. and Autran, B. (1998): Long-lasting recovery in CD4 T-cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease. Lancet, 351, 1682-1686.
6. O'Brien, W.A., Hartigan, P.M., Martin, D., Esinhart, J., hill, A., Benoit, S., Rubin, M., Simberkoff, M.S. and Hamilton, J.D. (1996): Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. New Engl. J. Med., 334, 426-431.
7. Chene, G., Binquet, C., Moreau, J.F., Neau, D., Pellegrin, I., Malvy, D., Ceccaldi, J., Lacoste, D., Dabis, F. and the Group d'Epidemiologie Clinique du SIDA en Aquitaine (1998): Changes in CD4+ cell count and the risk of opportunistic infection or death after highly active antiretroviral treatment. AIDS, 12, 2313-2320.
8. Lepri, A.C., Katzenstien, T.L., Ullum, H., Phillips, A.N., Skinhｿj, P., Gerstoft, J. and Pedersen, B.K. (1998): The relative prognostic value of plasma HIV RNA levels and CD4 lymphocyte counts in advanced HIV infection. AIDS, 12, 1639-1643.
9. Mellors, J.W., Rinaldo, C.R., Jr., Gupta, P., White, R.M., Todd, J.A. and Kingsley, L.A. (1996): Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science, 272, 1167-1170.
10. Grabar, S., Le Moing, V., Goujard, C., Leport, C., Kazatchkine, M.D., Costagliola, D., Weiss, L. (2000): Clinical outcome of patients with HIV-1 infection according to immunologic and virologic response after 6 months of highly active antiretroviral therapy. Ann. Intern. Med., 133, 401-410.
11. Marimoutou, C., Chene, G., Mercie, P., Neau, D., Farbos, S., Morlat, P., Ceccaldi, J., Dabis, F. and Groupe d'Epidemiologie Clinique du SIDA en Aquitaine (2001): Prognostic factors of combined viral load and CD4+ cell count responses under triple antiretroviral therapy, Aquitaine cohort, 1996-1998. J. Acquired Immune Defic. Syndr., 27, 161-167.
12. Teri, J.L., Matthew, S.H., Liegler, T.J., Hayden, M.S., Lee, K.H., Hoh, R., Deeks, S.G. and Grant, R.M. (2001): Protease inhibitor-resistant HIV-1 from patients with preserved CD4 cell counts is cytopathic in activated CD4 T lymphocytes. AIDS, 15, 179-184.
13. Kitsutani, P.T., Naganawa, S., Shiino, T., Matsuda, M., Honda, M., Yamada, K., Taki, M. and Sugiura, W. (1998): HIV Type 1 subtypes of nonhemophiliac patients in Japan. AIDS Res. Hum. Retroviruses, 14, 1099-1103.
14. Sanger, F., Nickeln, S. and Coulson, A.R. (1977): DNA sequencing with chain-terminating inhibitors. Proc. Natl. Acad. Sci. USA, 74, 5463-5467.

*Corresponding author: Fax: +81- 42-561-7746, E-mail: wsugiura@nih.go.jp

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