Patients Who Use Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Before HAART Experience an Increased Rate of Virus Rebound

“Patients who use nucleoside reverse-transcriptase inhibitors (NRTIs) before HAART have an increased rate of virus rebound,” write the authors of a study appearing in the August 15, 2004 issue of The Journal of Infectious Diseases.

An examination of rebound according to specific NRTIs used might inform which NRTIs retain activity once others have failed. In this study, the researchers focused on 2280 patients.

These patients had received zidovudine/AZT (Retrovir) and either didanosine/ddI (Videx) or lamivudine/3TC (Epivir) before starting HAART, started HAART that included zidovudine with didanosine or lamivudine or stavudine/d4T (Zerit) with didanosine or lamivudine, and had virus loads <500 copies/mL within 24 weeks.

Results

In a Cox model, the relative hazard (RH) of virus rebound for having switched from zidovudine to stavudine (vs. retaining zidovudine) was 0.94, which suggests little or no benefit in terms of reduced rebound rate.

Conclusions

Having switched from didanosine to lamivudine, or vice versa, was associated with a reduced rebound rate, which suggests that these drugs retain appreciable activity after use of the other and of zidovudine.

Discussion

Among patients receiving HAART regimens whose virus loads are suppressed to < or =500 copies/mL, the history of nucleoside use before starting HAART and the changes in nucleosides made at the start of HAART appear to influence the risk of virus rebound for a period of at least 3 years after viral suppression has been achieved.

This intriguing observation prompted researchers to investigate whether useful insights into nucleoside drug sequencing could be obtained by looking at specific permutations of nucleoside use before and during HAART.

Nucleosides used before starting HAART tended not to result in viral suppression to very low levels, so the evolution of resistance was relatively common, at least for zidovudine and lamivudine.

For this reason, most physicians tend to equate use of nucleosides before starting HAART in a non suppressive regimen with virologic failure of these drugs. In the patients we studied who used > or =1 nucleoside before starting HAART, zidovudine was almost universally included.

A common practice when HAART regimens were being constructed between 1996 and 1998 was to substitute this thymidine analogue drug with another, stavudine, at the time of starting HAART, largely in the belief that it would retain activity if virus with resistance to zidovudine was present.

During the past few years, this belief has been questioned, and there is increasing evidence that thymidine analogue mutations (TAMs) are associated with reduced susceptibility to stavudine as well as to zidovudine.

In analyses based on >4000 patients who received zidovudine before starting HAART, the authors found no evidence of a reduction in risk of virus rebound associated with having made a switch from zidovudine to stavudine when starting HAART. This may relate to cross-resistance between the 2 drugs and/or the fact that significant levels of intracellular stavudine-triphosphate are actually found in zidovudine-treated individuals or other pharmacological issues, such as a reduction in the phosphorylation of thymidine analogue drugs in general.

“In conclusion,” write the authors, “Having switched from zidovudine to stavudine when starting HAART appears to be associated with little lowering of risk of virus rebound.”

“In contrast, having switched from didanosine to lamivudine, or vice versa, was associated with a significantly reduced rebound rate, which suggests that, in the majority of individuals, at least these drugs retain appreciable activity after previous use or failure of the other and of zidovudine.”

“These findings are consistent with those from earlier smaller studies. They emphasize the importance of decisions on sequencing of nucleoside drugs within HAART regimens and should prove to be useful when configuring such sequences.”

08/16/04

Reference
Collaboration of HIV Cohorts (19 cohorts worldwide). Nucleoside Analogue Use Before and During Highly Active Antiretroviral Therapy and Virus Load Rebound. The Journal of Infectious Diseases 190(4): 675-687. August 15, 2004.