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

Laboratory and Epidemiology Communications

Two Possible Pathways for Acquisition of Mutations Related to Nelfinavir Resistance

Wataru Sugiura*, Tsuyoshi Oishi, Aiko Okano, Masakazu Matsuda, Hanae Abumi, Kaneo Yamada1, Mitsuru Koike1, Masashi Taki2, Masaaki Ishikawa3, Takuma Miura4, Katsuyuki Fukutake5, Kengo Gouchi6, Atsushi Ajisawa7, Aikichi Iwamoto8, Hideji Hanabusa9, Junichi Mimaya10, Junki Takamatsu11, Noboru Takata12, Eizo Kakishita13, Satoshi Higasa13, Seizaburou Kashiwagi14, Akira Shirahata15 and Yoshiyuki Nagai

AIDS Research Center, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama-shi, Tokyo, 1Institute of Medical Science and 2Department of Pediatrics, St. Marianna University School of Medicine, Sugao 2-6-1, Miyamae-ku, Kawasaki-shi, Kanagawa, 3Third Department of Internal Medicine, Tohoku University School of Medicine, Seiryo-cho 1-1, Aoba-ku, Sendai-hi, Miyagi, 4Department of Pediatrics, Haga Red Cross Hospital, Dai-machi 2461, Mooka-shi, Tochigi, 5Department of Clinical Pathology, Tokyo Medical University, Nishishinjuku 6-7-1, Shinjuku-ku, Tokyo, 6Department of Internal Medicine, Teikyo University School of Medicine, Kaga 2-11-1, Itabashi-ku, Tokyo, 7Department of Infectious Diseases, Tokyo Metropolitan Komagome Hospital, Honkomagome 3-8-22, Bunkyo-ku, Tokyo, 8Department of Infectious Diseases, Institute of Medical Science, The University of Tokyo, Shirokanedai 4-6-1, Minato-ku, Tokyo, 9Department of Hematology, Ogikubo Hospital, Imagawa 3-1-24, Suginami-ku, Tokyo, 10Division of Hematology and Oncology, ChildrenŐs Hospital of Shizuoka Prefecture, Urushiyama 860, Shizuoka-shi, Shizuoka, 11Division of Blood Transfusion, Nagoya University Hospital, Tsurumai 65, Showa-ku, Nagoya-shi, Aichi, 12Division of Blood Transfusion Services, Hiroshima University Medical Hospital, Kasumi 1-2-3, Minami-ku, Hiroshima-shi, Hiroshima, 13Second Department of Internal Medicine, Hyogo College of Medicine, Mukogawa-cho 1-1, Nishinomiya-shi, Hyogo, 14Department of General of Medicine, Kyusyu University Hospital, Maidashi 3-1-1, Higashi-ku, Fukuoka, 15Department of Pediatrics, University of Occupational and Environmental Health, Iseigaoka 1-1, Yahatanishi-ku, Kitakyusyu-shi, Fukuoka

Communicated by Hiroshi Yoshikura

(Accepted September 22, 1999)

Mutations related to resistance against reverse transcriptase inhibitors (RTI) are basically drug-specific, while those involved in resistance to protease inhibitors (PI) overlap among drugs, i.e., cross resistance is more frequent among PIs. Recently, the concept of "primary" and "secondary" drug resistance mutations was introduced by a study group in the United States (1). This group has attempted to systematize complex drug (particularly PI) resistance-related mutation patterns, but confusing features still remain. For example, some primary mutation(s) for one PI are secondary mutation(s) for another PI. This event complicates doctors' decisions regarding when they want to switch from one PI to another.

In Japan, four kinds of PIs are currently available: saquinavir (SQV), ritonavir (RTV), indinavir (IDV), and nelfinavir (NFV). We recently evaluated the efficacy of NFV in PI-naive and PI-experienced patients, particularly in relation to the appearance of the D30N mutation, which is responsible for NFV treatment failure (2). Based on this evaluation, we identified the interesting mutation patterns.

All the samples were collected at the National Institute of Infectious Diseases from November 1996 to May 1999 in collaboration with 17 hospitals in Japan. Seventy-five patients received NFV; 32 among these received NFV as their first PI (naive group), and 25 received NFV as an alternative to other PIs which had failed previously. The response to NFV was evaluated after 3 months of NFV treatment and was classified by viral load (VL), i.e., "resistant" for VL higher than 104 copies/ml, "intermediate" for VL in the range of 400-104 copies/ml, and "sensitive" for VL lower than 400 copies/ml. The protease region was sequenced as described elsewhere (3).

The relation between the response to NFV and the appearance of primary and secondary NFV-resistance mutations in PI-naive cases are summarized in Table 1. Clearly, the failure of NFV treatment depended upon the acquisition of the primary mutation D30N.

Similar studies were carried out with 25 PI-experienced cases. Nine patients received SQV, seven patients RTV, and nine patients IDV. Only one case responded to NFV, with the VL decreased to less than 400 copies/ml. In other words, once the first PI failed, the probability of success with a switch to NFV was very small.

Table 2 shows the relation between the response to NFV and the presence of primary or secondary resistance mutations related to the PIs that were administered before NFV. Eleven of the 14 cases that had exhibited primary mutations to the preceding PIs were resistant to NFV. Particularly in RTV- and IDV-experienced cases, the primary mutations appeared to predispose the patient to resistance to NFV; the incidence of resistant cases among those with the primary mutation was 5 in 5 for RTV and 3 in 4 for IDV in contrast to 3 in 6 for SQV. It was noted that there were four patients who had only a secondary mutation to the preceding IDV but resisted NFV treatment, i.e., in the case of IDV, the secondary mutation may affect the outcome of NFV treatment.

In resistant cases, viruses with primary or secondary mutations persisted throughout the NFV treatment. The NFV-related D30N mutation appeared only in a few cases, and, interestingly enough, if it ever appeared, the mutation was detected in virus genomes without primary or secondary mutations related to resistance against the preceding PIs.


Figure 1 summarizes the frequencies of known drug resistance-related mutations observed in PI-naive and experienced groups. In the naive group, 52% of the NFV failures acquired the D30N primary mutation, while in the experienced group the incidence of the D30N primary mutation was only 24%, and the incidence of the L90M mutation became high (60%). L90M is a primary mutation of SQV and a secondary mutation of RTV, IDV, and NFV. It appears there are two pathways for acquiring NFV resistance. One is the NFV primary mutation D30N, which is frequently observed in PI-naive cases. The other is the L90M mutation which appears to be selected during previous PI treatments. Probably L90M together with other primary or secondary mutations accumulated during previous PI treatment confers cross-resistance to NFV.

This study was supported by the Organization of Pharmaceutical Safety and Research (OPSR) of Japan.

REFERENCES

  1. 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. and Richman, D.D. (1998): Antiretroviral drug resistance testing in adults with
    HIV infection: implications for clinical management. International AIDS Society - USA Panel. JAMA, 279, 1984-1991.
  2. Patick, A.K., Duran, M., Cao, Y., Shugarts, D., Keller, M.R., Mazabel, E., Knowles, M., Chapman, S., Kuritzkes, D.R. and Markowitz, M. (1998): Genotypic and phenotypic characterization of human immunodeficiency virus type 1 variants isolated from patients treated with the protease inhibitor nelfinavir. Antimicrob. Agents Chemother., 42, 2637-2644.
  3. Sugiura, W., Matsuda, M., Matsuda, Z., Abumi, H., Okano, A., Oishi, T., Moriya, K., Yamamoto, Y., Fukutake, K., Mimaya, J., Ajisawa, A., Taki, M., Yamada, K. and Nagai, Y. (1999): Identification of insertion mutations in HIV-1 reverse transcriptase causing multiple drug resistance to nucleoside analogue reverse transcriptase inhibitors. J. Hum. Virol., 12,146-153.


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


Go to JJID Homepage                                Go to JJID 52(4)