Jpn.J.Infect.Dis., 52, 1999

Laboratory and Epidemiology Communications

Intention-to-Treat Analysis of Anti-HIV Therapies and Incidence of Drug Resistance after a Year of Treatment

Saori Aizawa1, Setsuko Ida1, Atsuko Sakai-Hachiya1, Mari Tanaka1, Yukiko Takahashi1, Yoshihiro Hirabayashi1, Wataru Sugiura2, Satoshi Kimura1,3 and Shinichi Oka1*

1AIDS Clinical Center, International Medical Center of Japan, Toyama 1-21-1, Shinjuku-ku, Tokyo, 2AIDS Research Center, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama-shi, Tokyo and 3Department of Infectious Diseases, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo

Communicated by Hiroshi Yoshikura

(Accepted July 5, 1999)

Anti-HIV combination therapies with reversetranscriptase (RT) and/or protease (PR) inhibitors dramatically decreased serum HIV RNA level and restored CD4+ cell count. The appearance of drug-resistant HIV mutants, however, has been a problem (1). If the first therapeutic trail fails, the
second becomes much harder on account of the cross-resistance to newly introduced drugs (2). Therefore, highly active anti-retroviral therapy (HAART) is widely recommended (3). Checking the appearance of drug-resistant mutants, usually by genome sequencing (4), is becoming an
important step in determining appropriate therapies (5).

Another problem is dropout from the therapeutic regime. It is caused mainly by the drugs' side-effects and the strict dose schedules which the patients were unable to follow.

We conducted HIV drug resistance assay and intention-to-treat analysis in 95 outpatients who had been treated since April 1997 in the AIDS Clinical Center, International Medical Center of Japan. The data were collected one year later.

None of the patients had received anti-HIV drugs before the start of this study. The patients were divided into two groups; one was treated with two RT inhibitors (2RTI group) and the other with two RTIs plus PR inhibitor (2RTI+PI group). The latter group contained a higher proportion
of patients in the advanced stage (Table 1). This is because the 3-drug therapy was recommended for the advanced stage when the trial started.

Among 42 cases in the 2RTI group, 16 (39%) dropped out (Fig. 1a); 9 due to failure of controlling the viral load and 7 due to low compliance (the patients did not want the therapy). Among 53 cases in the 2RTI+PI group, 24 (45%) dropped out (Fig. 1b); 4 due to failure of viral load control, 6 to the side effects, 12 to low compliance, and 2 to unknown reasons.

Further virological and immunological analyses were restricted to 26 cases in the 2RTI group and 29 cases in the 2RTI+PI group who adhered to the treatment longer than 12 months. In 15 of 26 2RTI group patients (58%) and 24 of 29 2RTI+PI group patients (83%), the virus load was
reduced to undetectable levels (<400 copies/ml). In patients whose viral load was higher than 1,000 copies/ml, drug resistance-related mutations in the RT and PR regions (5) were detected at a high frequency (7/11, 58.3%). In patients whose viral load was reduced to <400 copies/ml, the rate of mutations was very low but not zero (3/39, 0.8%). When the incidence of the drug resistance-related mutations was compared between the 2RTI and 2RTI+PI groups, it was much higher in the 2
RTI group than in the 2RTI+PI group (10/26 vs. 2/29)(Fig. 2). Here, the patients whose HIV genomes were not detected were counted as mutation-free.

The patients' CD4+ cell count was followed for the next 12 months (Fig. 3). In the 2RT group, the CD4+ cells increased in the first 6 months (from 380 to 476/ƒÊl) and then tended to decrease gradually. In the 2RT+PI group, the CD4 count continuously increased during this period (from
293 to 430/ƒÊl).

This study was supported in part by grants-in-aid for AIDS research of the Ministry of Health and Welfare of Japan, the Organization of Pharmaceutical Safety and Research (OPSR), and the Japanese Foundation for AIDS Prevention.

REFERENCES

  1. Moyle, G.J. (1995): Resistance to antiretroviral compounds; Implications for the clinical management of HIV infection. Immunol. Infect. Dis., 5, 170-182.
  2. Palmer, S., Shafer, R.W. and Merigan, T.C. (1999): Highly drug-resistant HIV-1 clinical isolates are cross-resistant to many antiretroviral compounds in current clinical development. AIDS, 13,
    661-667.
  3. Carpenter, C.J., Fischl, M.A., Hammer S.M., Hirsch, M.S., Jacobsen, D.M., Katzenstein, D.A., Montaner, J.S.G., Richman, D.D., Saag, M.S., Schooley, R.T., Thompson, M.A., Vella, 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.
  4. Zazzi M, Riccio M.L., Venturi G., et al.(1998): Long-read direct infrared sequencing of crude PCR products for prediction of resistance to HIV-1 reverse transcriptase and protease inhibitors. Mol. Biotech., 10, 1-8.
  5. Hirsch M.S., Conway B., D'Aquila R.T., Johnson, V.A., Brun-Vezinet, F., Clotet, B., Demeter, L.M., Hammer, S.M., Jacobsen, D.M., Kuritzkes, D.R., Loveday, C., Mellors, J.W., Vella, S., Richman, D.D. and the International AIDS Society-USA Panel. (1998): Antiretroviral drug resistance testing in adults with HIV infection. JAMA, 279, 1984-1991.

*Corresponding Author: Fax: +81-3-5273-5193, E-mail: oka@imcj.hosp.go.jp

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