Effect of introduction of highly active antiretroviral treatment and the changes in patterns of drug-resistant HIV-1 in Japan

Abstract

HIV-1 infection, which causes fatal immunodeficiency in humans, appeared in the early 1980s among homosexual men. The plague quickly spread throughout the world, and today 36.1 million people are living with HIV/AIDS. The first inhibitory compound, “zidovudine”, was discovered in 1985, only a few years after the identification of HIV-1, and many other inhibitory compounds have been developed successfully in the past decade. In Japan, three classes of inhibitors are available today: nucleoside inhibitors, non-nucleoside inhibitors, and protease inhibitors (Table 1). The availability of multiple classes of compounds opened the way to the combined use of the inhibitors, in particular, to the use of highly active anti-retroviral therapy (HAART). HAART is powerful enough to suppress virus replication in vivo almost completely, and it is accepted as a standard treatment strategy for HIV-1 infection. After HAART was introduced, deaths caused by AIDS decreased dramatically in the United States, although the number of cases of HIV-1 infection increased (Fig. 1a). This same pattern was also observed in Japan after 1997 (Fig. 1b). However, treating patients with HAART was not always successful, and the number of cases in which the treatment was unsuccessful was reported to be 30% to 50% of the total HAART cases in two studies. In 1998, we collected data from hospitals with a substantial number of HIV-1 patients in order to more fully understand the state of treatment of HIV-1 in Japan. The hospitals were surveyed in regard to the number of HIV1-infected patients, the number of patients receiving HAART, the treatment history of patients prior to HAART, and the number of cases successfully treated with HAART. Replies were received from 16 hospitals regarding a total of 809 cases. As shown in Fig. 2a, 446 of the 809 patients (55.1%) were undergoing HAART at the time the data was collected. Of the 446 patients receiving HAART, 301 had a history of previous anti-HIV-1 treatment (termed “experienced”), and 145 were treatment-naive until the initiation of HAART (“naive”). Success rates were 50% in “experienced” patients and 60% in “naive” patients; the HAART response was significantly better in “naive” patients (Fig. 2b). Generally, treatment failure could be caused by the discontinuation of treatment because of adverse effects of the inhibitors, or virological unresponsiveness to the treatment. The emergence of mutant viruses with decreased susceptibility to inhibitors is the most critical factor leading to virological unresponsiveness. This emergence of drug-resistant variants is not an issue specific to HIV-1 infection, as there is a similar problem with most pathogens treated by antiviral or antibacterial compounds. However, the impact of drug resistance in HIV-1 treatment is significant, as, to date, the virus cannot be eliminated completely despite HAART, and continuation of treatment is necessary throughout a patient’s life.