Medical Inspection – Health Blog

The history of antiretroviral agents that have been approved by the Food and Drug Administration (FDA) dates from March 19, 1987, when generic zidovudine (ZDV), also known as AZT (Retrovir canadian, GlaxoSmithKline), became the first drug to be used to treat patients with acquired immunodeficiency syndrome (AIDS). Since that time, the therapy for patients with human immunodeficiency virus (HIV) has grown increasingly complex. A total of 17 new agents, many with more than one formulation, have been added to the anti-HIV arsenal.
Part 1 of this two-part series (P&T, August 2003) detailed the fundamental aspects of HIV therapy, namely goals, resistance, and patient adherence to treatment. Part 2 focuses on selected agents approved within each drug class.

Given the considerable breadth of literature on antiretroviral therapy and the rapidity with which new information is published in journals and presented at professional meetings, we have not provided a systematic Medline search strategy. After conducting initial and follow-up Medline searches, we have included abstracts from the current literature and conferences. A comprehensive review of all available literature on antiretroviral therapy, however, is beyond the scope of this series.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

The NRTIs are synthetic nucleoside analogues of the naturally occurring nucleosides (Table 1). Within cells, these drugs are converted to their active triphosphate forms by cellular enzymes. The active forms are capable of competing with the natural substrate for utilization and can be incorporated into viral DNA. Once incorporated, the NRTI prevents the formation of essential 5′ to 3′ phosphodiester bonds because the NRTI lacks a 3′-OH group. Thus, DNA chain elongation is terminated and proviral DNA synthesis is halted.
Patients who are discontinuing therapy should be advised that antiretroviral drug resistance is less likely to occur if all antiretroviral therapy is temporarily stopped than if one component (e.g., abacavir sulfate) of an effective suppressive regimen is withheld.

Table 1   Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and Their Corresponding Nucleosides

All of the currently approved NRTIs have been associated with lactic acidosis and severe hepatomegaly with steatosis, both of which are potentially fatal.

Abacavir

Abacavir sulfate (ABC) (Ziagen®, GlaxoSmithKline) is indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents.

Resistance

The most frequently observed viral mutations relating to abacavir generic have been K65R, L74V, Y155F, and M184V. In this nomenclature, the first letter represents the wild-type amino acid, the number indicates the amino acid position, and the subsequent letter corresponds to the amino acid of the mutant strain.

In the K65R mutation, the mutant viral strain contains the amino acid arginine instead of lysine at position 65. Different mutations confer variable amounts of resistance to drug therapy, and multiple mutations may be necessary to confer significant resistance to drug therapy. Key primary mutations conferring resistance to ABC occur at positions 65, 74, 151, and 184. Multiple amino acid substitutions at positions 41, 67, 69, 70, 115, 210, 215, and 219 have also been associated with decreased susceptibility to ABC. Didanosine tablet (ddI, Videx®, Bristol-Myers Squibb), zalcitabine (ddC, HIVID®, Roche), and lamivudine (3TC, Epivir®, GlaxoSmithKline) can select for overlapping mutations that can lead to decreased sensitivity to ABC in patients who have been previously treated with these drugs.

Cross-resistance occurs to a lesser degree between ABC and stavudine canadian (d4T, Zerit®, Bristol-Myers Squibb) or zidovudine (ZDV). Foster and Faulds reported that when resistance occurred to two or more nucleoside analogues, one of which was ZDV or 3TC, sensitivity to ABC was reduced.

Cross-resistance between ABC and HIV protease inhibitors is also unlikely because of the different enzyme targets involved. Cross-resistance between ABC and the NNRTIs is unlikely because of different binding sites on reverse tran-scriptase.

Table 2 Pharmacokinetics of Abacavir (ABC)

Warnings and Precautions

Abacavir (ABC) therapy has been associated with a potentially fatal hypersensitivity reaction. It is recommended that ABC be discontinued as soon as a hypersensitivity reaction is first suspected and that patients seek medical evaluation immediately. Although hypersensitivity reactions occur more frequently within the first six weeks of therapy, they may occur at any time.

Drug product information warns that patients should not be rechallenged with ABC because more severe symptoms have been shown to recur and may include life-threatening hypotension and death. The incidence of hypersensitivity in clinical trials has been reported to be approximately 5% for adult patients receiving ABC.5 centrations and a 26% increase in the elimination half-life of ABC. This drug did not have any effect on the pharmaco-kinetics of ethanol in men and has not been studied in women.

Pharmacokinetics

A summary of the pharmacokinetic properties of ABC is presented in Table 2.

Clinical Trials with Abacavir

Therapy-Naive Patients CNAA3003. A randomized, double-blind study of 173 therapy-naive patients was conducted to compare abacavir + lamivu-dine + zidovudine canadian (ABC + 3TC + ZDV) and lamivudine canadian + zido-vudine (3TC + ZDV) in terms of efficacy and safety. Although the study was 48 weeks in duration, patients had the option of switching to open-label ABC + 3TC + ZDV at 16 weeks if they were experiencing incomplete viral suppression on the two-drug regimen. At the time of enrollment, the median baseline viral load was 4.6 log10 copies/ml and the median baseline CD4 count was 427 to 473 cells/mm.

Interim results at week 16 showed that 75% of the triple-therapy (ABC + 3TC + ZDV) arm and 35% of the 3TC + ZDV arm achieved a viral load of less than 400 copies/ml according to an intent-to-treat analysis (P < .001). Of the patients in the ABC + 3TC + ZDV arm, 59% retained viral load suppression below 400 copies/ml through 48 weeks. There was no significant difference between the CD4 count change from baseline in the two treatment groups at 48 weeks.

Adverse Effects

The most common adverse events occurring in 5% of patients (or more) taking ABC were nausea, vomiting, diarrhea, anorexia, insomnia, and other sleep disorders. Less common adverse side effects during therapy with ABC included pancreatitis, anemia, neutropenia, and abnormal liver function test findings.

Drug Interactions

ABC does not appear to interact with cytochrome P-450 (CYP-450) isoenzymes 2C9, 2D6, or 3A4.5 Coadministration of ethanol and 600 mg of ABC in 24 HIV-infected men resulted in a 41% increase in ABC area-under-the-curve (AUC) con-CNA3005. This ongoing multicenter, randomized, double-blind study includes 562 antiretroviral therapy-naive patients. It is being conducted to compare the antiviral effect and CD4 count response of the three-drug regimen of ABC, 3TC, and ZDV with generic indinavir sulfate (IDV, Crixivan medication, Merck), 3TC, and ZDV. Enrolled patients had a baseline viral load of more than 10,000 copies/ml and a CD4 count above 100 cells/mm3.

Interim 24-week results from an intent-to-treat analysis showed that 64% of patients in the ABC group and 65% of patients in the IDV group achieved a plasma HIV RNA below 400 copies/ml. The median increase in CD4 counts in both groups was 98 cells/mm3. Therapy-Experienced Patients

CNA3009. This study enrolled 52 patients with a median of 119 days of previous treatment with ZDV and 3TC. Patients had a median baseline plasma viral load of 2.88 log10 copies/ml, although 29% of patients already had a viral load of less than 400 copies/ml with the ZDV + 3TC regimen alone. The median baseline CD4 count was 543 cells/mm3. Twice-daily ABC 300 mg was added to the patients’ current regimen of ZDV + 3TC.

Results were reported at 48 weeks after initiation of ABC therapy. According to an intent-to-treat analysis, 72% of patients had viral loads below 400 copies/ml and 49% of patients had viral loads below 20 copies/ml. The median decrease in plasma HIV RNA was 0.84 log10 copies/ml; the median CD4 cell count increase was 118 cells/mm3.

Related Posts

• Antiretroviral Therapy in HIV-infected Adults: Clinical Trials
• Antiretroviral Therapy in HIV-infected Adults: Protease Inhibitors
• Antiretroviral Therapy in HIV-infected Adults: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
• Antiretroviral Therapy in HIV-infected Adults: Nucleotide Reverse Transcriptase Inhibitors (NtRTIs)