Transmission of drug-resistant HIV-1 has paralleled the expansion of treatment indications for HIV-infected patients over the past dozen years. Each time the indications for therapy have been broadened to include a larger portion of HIV-infected persons, the rate of drug-resistant transmission has increased, following a lag period of one to two years. This lag period is determined by the time it takes for a significant percentage of the treated population to develop drug-resistant HIV, which is then passed on to the next generation of infected persons.

In 1993, there were initial reports of primary infections with AZT-resistant HIV via both sexual and percutaneous routes of transmission [1,2]. Prior to 1987, the T215Y/F mutation associated with AZT resistance had never been detected in HIV isolates. In 1987, AZT was introduced into clinical practice for the treatment of patients with advanced HIV disease (AIDS or CD4 cell counts less than 200 cells/mm³). This meant that approximately 20% of HIV-infected persons were potentially eligible to receive AZT. In 1990, as a result of the ACTG 016/019 trials, the indication for AZT was broadened to include patients with less than 500 CD4 cells/mm³, which increased the AZT-eligible population to 60% of HIV-infected persons. In a retrospective analysis of blood from new seroconverters in the United States, Switzerland and Australia during the period from 1987 to 1991, AZT-resistant primary HIV infection was very infrequent, being detected in only 1.4% (1 of 69) recently infected persons [3]. In 1992, two years after the expanded indications for AZT therapy, the rate of primary infection with AZT-resistant virus increased to 7.5% (4 of 53 recently infected persons). This rate increased to 10% between 1993 and 1998 [3]. The rates of primary infection with drug-resistant HIV-1 have been remarkably consistent between the United States, Europe and Australia over the past decade.

Lamivudine (3TC) was introduced into clinical practice in 1996. This potent nucleoside agent was quickly added to patients’ antiretroviral drug regimens. The M184V point mutation in HIV reverse transcriptase (RT) produces high-level 3TC resistance and rapidly emerges with incompletely suppressive drug regimens containing 3TC. This mutation rapidly overtook the T215Y/F mutation associated with AZT resistance to become the most prevalent mutation in patients failing on combination antiretroviral therapy. By 1997, one year after its introduction into broad clinical practice, 3TC-resistant primary HIV infection was documented in 2 of 35 (5.7%) patient samples from Vancouver, Canada [4].

HIV protease inhibitors (PI) were also introduced into clinical practice in 1996. In 1997, due to the success of combination therapy in preventing progression of HIV disease and significant reductions in HIV-associated mortality, the indications for antiretroviral drug use were expanded to include the majority of HIV-infected persons ("hit early, hit hard"). In early 1998, there were initial reports of primary infection with multidrug-resistant HIV (virus with resistance to both RT inhibitors and HIV PIs) from both San Francisco and Geneva [5]. Primary infection with PI-resistant virus was seen in 3-5% of newly infected persons. By the end of 1998, primary infection with drug-resistant HIV-1 was documented in 21-28% of recently infected persons in two large cohorts [6,7]. Furthermore, the incidence of multidrug-resistant virus in primary infection appears be rising in some areas of the United States and Canada.

Transmission of drug-resistant HIV has mirrored the broadening of antiretroviral treatment indications with a lag period related to the time it takes for a significant proportion of treated persons to develop and transmit drug-resistant virus. Recent reports of patients with primary HIV infection with multidrug-resistant virus raise concerns regarding how long current triple-drug regimens will remain effective for drug-naïve patients, and emphasize the need to develop a standardized, reproducible HIV drug resistance assay for clinical use. It is also critical to develop patient-friendly once- or twice-a-day drug regimens and to develop methods to enhance patient adherence in drug-naïve HIV-infected persons, while simultaneously developing new drugs that are active against drug-resistant HIV in order to treat the increasing number of persons with multidrug-resistant HIV.