At week 4, 28 and 45% of subjects on abacavir monotherapy who were subsequently assigned to receive placebo or ZDV, respectively, had plasma HIV-1 RNA levels of below 400 copies/ml (Fig. 1b). At week 12, 28 and 69% of subjects on abacavir or abacavir-ZDV, respectively, had plasma HIV-1 RNA levels below 400 copies/ml. The percentage of subjects who had viral loads below 40 copies/ml were 5 and 11% at week 4, and 11 and 22% at week 12, on abacavir monotherapy and abacavir-ZDV therapy, respectively.
CD4+ cell counts
Treatment with abacavir alone or in combination with ZDV resulted in a sustained increase in CD4+ cell counts in all groups (Fig. 2). At week 4, abacavir elicited a median CD4+ cell count increase of 63–111 × 106/l (Table 2). At week 12, median CD4+ cell count increased by 79–195 × 106/l and 93–142 × 106/l, respectively, after treatment with abacavir or abacavir-ZDV. For the combined cohorts, the change in median CD4+ cell count from baseline to week 12 was not significantly different for the abacavir-ZDV group compared with the abacavir monotherapy group (P > 0.05).
Abacavir monotherapy and abacavir-ZDV combination therapy were generally well tolerated. Adverse events were usually mild and reversible, with the most common adverse events being nausea (57%), headache (41%), and asthenia (29%; Table 3). Severe adverse events (attributable to abacavir) were infrequent and tended to be observed primarily in the higher dose cohorts (cohorts II and IV).
Eight subjects (10%) discontinued the study prematurely because of adverse events, all of which were considered by the investigator to be attributable to abacavir. None of these subjects were on 300 mg twice daily. Four subjects were withdrawn because of nausea, two receiving abacavir-ZDV therapy [200 mg three times daily (cohort I) and 400 mg three times daily (cohort II)] and two receiving abacavir alone [400 mg three times daily (cohort II) and 600 mg three times daily (cohort IV)]. One subject was withdrawn due to dizziness, photophobia, and palpitations (cohort IV). Three subjects, one on abacavir-ZDV (cohort I) and two on abacavir alone (cohort IV), were withdrawn within 4 weeks of dosing because of hypersensitivity reaction (erythematous generalized rash, low-grade fever, malaise and nausea). After a temporary interruption of study drugs due to hypersensitivity, subjects were rechallenged at least once. Rechallenge with abacavir resulted in rapid onset of hypersensitivity. There were no deaths among the study subjects.
Four additional subjects experienced a serious adverse event but remained in the study through week 12. Amongst abacavir-ZDV subjects, one experienced headache (cohort I) and another reported depression [300 mg twice daily (cohort III)]. Amongst abacavir monotherapy subjects, one experienced leukopenia (cohort II) and another had a syncopal episode (cohort III).
Five subjects (6%) experienced grade 3 or 4 laboratory abnormalities. Three cases of hematological abnormalities were reported: amongst subjects receiving ZDV monotherapy, one had leukopenia (grade 3, but grade 4 at one evaluation) and another had decreased hemoglobin count (grade 4); one subject receiving abacavir-ZDV therapy had decreased platelet count (grade 3). Two cases of clinical chemistry abnormalities were reported: one subject receiving ZDV monotherapy had elevated alanine aminotransferase levels (grade 3), and one subject receiving abacavir-ZDV therapy had hypoglycemia (grade 3). The one report of grade 4 leukopenia was also noted as a serious adverse event. In all cases, laboratory values had returned to within normal limits at the scheduled follow-up visit.
In this 12-week study, treatment with abacavir both as monotherapy and in combination with ZDV resulted in sustained reductions in plasma HIV-1 RNA and marked increases in median CD4+ lymphocyte counts in HIV-infected subjects with limited or no previous use of ZDV. However, the study did not identify clear differences between different dosing regimens.
Abacavir monotherapy demonstrated a median viral load reduction of 1.11–1.77 log10 copies/ml at week 4 to 1.02–2.24 log10 copies/ml at week 12, and a median increase in CD4+ cell count of at least 79 × 106/l sustained over 12 weeks. In contrast, other RT inhibitor monotherapy regimens have demonstrated smaller viral load reductions during the first 12 weeks of therapy (0.5–0.8 log10 copies/ml at week 4 to 0.3–0.6 log10 copies/ml by week 12), with less pronounced reductions observed thereafter [6–9]. Median CD4+ cell count increases have also been modest (20–30 × 106/l at week 4), and this effect wanes over time [7–11]. These findings suggest that abacavir is more potent than currently available nucleoside RT inhibitors.
Our results also suggest that subjects who received abacavir with ZDV had a greater and more consistent improvement in plasma HIV-1 RNA levels than subjects receiving abacavir alone. However, with the limited sample size in our study, small differences in CD4+ cell count changes from baseline between the abacavir-ZDV and abacavir monotherapy groups could not be detected. In addition, although 69% of subjects receiving abacavir-ZDV therapy achieved reduction in HIV-1 RNA level below the limit of detection of the Roche Amplicor assay, only 22% were able to achieve values below the limit of detection using the ultrasensitive assay. Thus, like other antiretroviral agents, abacavir will most likely exhibit highest potency as part of a three-drug (or more) antiretroviral regimen.
A key finding of this study is that the reductions in viral load and increases in CD4+ cell count achieved with abacavir monotherapy were of comparable magnitude to those achieved with protease inhibitors. With protease inhibitor monotherapy, studies have reported reductions in HIV-1 RNA levels of 0.5–2.3 log10 copies/ml and increases in CD4+ cell counts of 68–104 × 106/l in antiretroviral-naive subjects [12–15]. In contrast, combination regimens involving two currently available nucleoside RT inhibitors (ZDV with lamivudine, didanosine, or zalcitabine) have yielded viral load reductions of 1.1–1.7 log10 copies/ml and CD4+ cell count increases of 55–90 × 106/l in anti-retroviral-naive subjects [6–11].
The present study investigated three escalating three times daily dosing regimens and one twice daily dosing regimen. The 200 mg three times daily and 300 mg twice daily regimens produced similar activity with fewer adverse events compared with the other dosing regimens. Considering the increased adherence to treatment achieved with lower pill burdens and twice daily dosing, the 300 mg twice daily dosing regimen was therefore selected for evaluation in subsequent clinical trials. The potency of abacavir combined with the convenience of twice daily dosing should facilitate patient adherence to therapy.
Abacavir was generally well tolerated. Five subjects (6%) experienced a grade 3/4 laboratory abnormality (none of which resulted in premature treatment discontinuation), and eight subjects (10%) withdrew because of an adverse event. Three patients treated with abacavir in this study experienced a hypersensitivity reaction. A broader experience with the use of abacavir from the treatment of over 5000 patients in subsequent clinical trials of this drug has revealed a hypersensitivity syndrome in approximately 3% of recipients worldwide. The hallmark of this syndrome is fever, varyingly accompanied by rash, weakness, nausea, and vomiting. The drug must be discontinued in order to achieve resolution of the symptoms, which usually resolve quickly. The symptoms universally recur rapidly upon rechallenge with the drug. Rechallenge following the occurrence of this reaction has resulted in severe manifestations of the original syndrome, in addition to hypotension, respiratory distress, and in one instance, death. No deaths occurred in this study despite rechallenge in each of the three cases of hypersensitivity.
Nonetheless, it is imperative that individuals who discontinue abacavir due to hypersensitivity syndrome should not be rechallenged with the drug.
Abacavir represents an important new agent for use in subjects with HIV infection. The precise role of abacavir in clinical practice remains to be determined. Future studies are needed to assess its activity in nucleoside-experienced subjects and those who are failing existing therapy with other nucleoside agents, protease inhibitors, and non-nucleoside agents. Studies are underway to evaluate the role of triple nucleoside therapeutic regimens that represents a ‘convergent’ approach to antiretroviral treatment via multiple attack of a single target.
The investigators gratefully acknowledge the contributions of the Abacavir Phase 2 Clinical Team members: Richard D'Aquila (Massachusetts General Hospital, Boston, Massachusetts), Judith Feinberg (University of Cincinnati, Cinicinnati, Ohio), William Lang (ViRx, Inc., San Francisco, California), Melanie Thompson (AIDS Research Consortium of Atlanta, Atlanta, Georgia), Jan W. Mulder (Slotervaartziekenhuis, Amsterdam, The Netherlands), Merce Gurgui Ferrer (Hospital de Santa Creu i Sant Pau, Barcelona, Spain) and Miguel Santin Cerezales (Hospital de Bellvitge, Barcelona, Spain), and the Glaxo Wellcome team members: William Symonds, Stephanie Tortell, Gillian Pearce, Seth Hetherington, and Helen Steel for the clinical conduct of the study, Randall Lanier and Richard Harrigan for virologic support, Amy Cutrell for statistical analysis, and Teri Lorbacher for data entry and editing.
1. Daluge SM, Good SS, Faletto MB, et al.
: 1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity
. Antimicrob Agents Chemother
2. Faletto MB, Miller WH, Garvey EP, St Clair MH, Daluge SM, Good SS: Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89
. Antimicrob Agents Chemother
3. Tisdale M, Alnadaf T, Cousens D: Combination of mutations in human immunodeficiency virus type 1 reverse transcriptase required for resistance to the carbocyclic nucleoside 1592U89
. Antimicrob Agents Chemother
4. Ravitch JR, Sadler BM, McDowell JP, Walsh JS: In vivo and in vitro studies of the potential for drug interactions involving the anti-retroviral 1592 in humans
. Fifth Conference on Retroviruses and Opportunistic Infections
. Chicago, February 1998 [abstract 634].
5. Kumar PN, Sweet DE, McDowell JA, et al.
: Safety and pharmacokinetics of abacavir (1592U89), a nucleoside analog, following oral administration of escalating single doses
. Submitted to Antimicrob Agents Chemother
6. Brun-Vezinet F, Boucher C, Loveday C, et al.
: HIV-1 viral load, phenotype, and resistance in a subset of drug-naive participants from the Delta trial. The National Virology Groups. Delta Virology Working Group and Coordinating Committee
7. Eron JJ: The treatment of antiretroviral-naive subjects with the 3TC/zidovudine combination: a review of North American (NUCA 3001) and European (NUCB 3001) trials
8. Katlama C, Ingrand D, Loveday C, et al.
: Safety and efficacy of lamivudine-zidovudine combination therapy in antiretroviralnaive patients. A randomized controlled comparison with zidovudine monotherapy. Lamivudine European HIV Working Group
9. Eron JJ, Benoit SL, Jemsek J, et al.
: Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. North American HIV Working Party
. N Engl J Med
10. Hammer SM, Katzenstein DA, Hughes MD, et al.
: A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter
. N Engl J Med
11. Delta Coordinating Committee: Delta: a randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals
12. Kitchen VS, Skinner C, Ariyoshi K, et al.
: Safety and activity of saquinavir in HIV infection
13. Massari F, Conant M, Mellors J, et al.
: A phase II open-label, randomized study of the triple combination of indinavir, zidovudine (ZDV) and didanosine (DDI) versus indinavir alone and zidovudine/didanosine in antiretroviral naive patients
. Third Conference on Retroviruses and Opportunistic Infections
. Washington, DC, January-February 1996 [abstract 200].
14. Chodakewitz JA, Leavitt R, Massari F, et al.
: Crixivan: summary of 24-week experience with Crixivan at 2.4g/d in phase II trials
. XI International Conference on AIDS
. Vancouver, July 1996 [abstract MoB1144].
15. Pym AS, Churchill DR, Galpin S, et al.
: Sustained benefit after four years of saquinavir monotherapy
. XI International Conference on AIDS.
Vancouver, July 1996 [abstract TuB2123].
Keywords:© 1998 Lippincott Williams & Wilkins, Inc.
Abacavir; zidovudine; combination drug therapy; reverse transcriptase inhibitors; HIV infection