Introduction
Among the first lines of defense in the prevention of the exacerbation of Human Immunodeficiency Virus to “full-blown” CDC-defined AIDS among HIV infected individuals is the prevention of or the reduction of the virus’ ability to replicate its genetic material, RNA. Certain RNA protease inhibitors and nucleosides are among the antiretroviral compounds which have been shown to be effective medications in achieving this goal.
Indinavir (an HIV RNA protease inhibitor) and abacavir (a nucleoside analogue and inhibitor of HIV RNA reverse transcriptase) have been shown to be effective both alone and in combination with lamivudine and zidovudine nucleosides in the suppression of human immunodeficiency virus (HIV) replication. Abacavir is marketed in the United States as abacavir, (abacavir sulfate), trizivir (the triple nucleoside combination), or the trade name Ziagen (Glaxo-Smith-Kline). Indinavir (indinavir sulfate) is marketed in the United States as Crixivan (Merck & Co., Inc., PDR, 2005).
This report addresses some of the safety and efficacy considerations in prescribing indinavir vs. abacavir in combination with lamivudine and zidovudine nucleosides in the virologic suppression of HIV.
A Clinical Trial
In a multicenter, phase 3, randomized, double-blind, placebo-controlled study, Staszewski et al. (2001) evaluated the safety and efficacy of these two regimens for the initial antiretroviral treatment of 562 antiretroviral-nave patients diagnosed with HIV and whose plasma concentrations of HIV RNA were at least 10,000 copies per milliliter (mL) and who had CD4 cell counts of at least 100X106/L. Virologic suppression was defined as achieving HIV RNA concentrations of 400 copies/mL or fewer at week 48 of the study.
Findings and Conclusions
The study concluded that the triple-nucleoside regimen of abacavir-lamivudine-zidovudine (triziver) was equivalent to the protease inhibitor-containing regimen of indinavir-lamivudine-zidovudine in reducing plasma concentrations of HIV RNA to fewer than 400 copies/mL at 48 weeks in antiretroviral-naive HIV-infected adults. The authors concluded that there were no significant differences between the two treatment groups in effects on CD4 cell counts, in adverse events, in overall genotypic resistance-conferring mutagenesis, or in laboratory abnormalities.
Among high baseline patients whose baseline HIV RNA concentrations were initially greater than 100,000 copies/mL, the proportion ultimately achieving fewer than 50 copies/mL was 14% greater in the indinavir group than in the abacavir group. Among the 59 patients who experienced viral rebound to HIV RNA levels exceeding 400 copies/mL by week 48 of the study, the proportion of RT M184V mutations was greater in the abacavir group (21/27=78%) as compared to the indinavir group (10/20=50%).
Four of the 562 patients in the study experienced AIDS-defining (Centers For Disease Control, CDC Category C) events. Three of these were from the abacavir group (2 with Kaposi sarcoma and one with cryptococcosis). One patient from the indinavir group experienced progression to CDC Category-C lymphoma.
Of the four patient deaths that occurred during the study, three were among the abacavir group. One death in the indinavir group was attributed to a heroin/cocaine overdose six weeks into the study. Two cardiac-related deaths in the abacavir group (one myocardial infarction and one cardiac arrhythmia) were not attributed to the abacavir by the authors. One death was attributed to a hypersensitivity reaction following abacavir rechallenge after 3 weeks in the study.
Possible Weaknesses of the Study
Due to the placebo-controlled nature of the investigation, all patients were required to receive 16 tablets per day along with the diet restrictions and fluid requirements for indinavir treatment. The authors suggest that the large number of pills to be taken may have lead to decreased treatment adherence in this study as has been shown in other studies. They propose that taking 16 tablets daily as opposed to 4 tablets daily may have caused the potential impact of the abacavir regimen to be underestimated in this investigation.
One study patient’s death was due to a hypersensitivity reaction upon abacavir rechallenge. Rechallenge was not supposed to be part of the study protocol.
Disadvantages of the Abacavir-Lamivudine-Zidovudine (Triziver) Regimen
– 14% Less Effective among High Baseline Patients (100,000 HIV RNA copies/mL)
– Smaller Number of High Baseline Patients Achieved Undetectable HIV RNA Levels
– 28% more M184V RT mutations among viral rebound patients
– Greater Number of Patients Experience Hypersensitivity Reactions
– Greater Number of Patients Report Headaches
– Greater Number of Patients Progress to CDC-defined AIDS
– Greater Number of Patient Deaths
Physicians are recommended to and encouraged to register patients to whom they are prescribing abacavir, triziver, or Ziagen (Glaxo-Smith-Kline) by calling the toll free phone number: 800-270-0425 (PDR, 2005).
Advantages of the Indinavir-Lamivudine-Zidovudine Regimen
– 14% More Effective Among High Baseline Patients (100,000 copies/mL)
– Greater Number of High Baseline Patients Achieved Undetectable HIV RNA Levels
– 28% fewer M184V RT mutations among viral rebound patients
– Fewer Patients Experience Hypersensitivity Reactions
– Fewer Patients Report Headaches
– Fewer Patients Progress to CDC-defined AIDS
– Fewer Patient Deaths
Indinavir is marketed in the United States as Crixivan (Merck)
References
Medical Economics Company, Inc. Physician’s Desk Reference (PDR). 2005. Medical Economics Company, Inc. Montvale, NJ.
Staszewski, S. et al. (2001) Abacavir-Lamivudine-Zidovudine vs. Indinavir-Lamivudine-Zidovudine in Antiretroviral-Naive HIV Infected Adults. Staszewski et al. JAMA. 2001; 285: 1155-1163.
