Short-term safety and tolerability of a once-daily fixed-dose abacavir-lamivudine combination versus twice-daily dosing of abacavir and lamivudine as separate components: findings from the ALOHA study.

STUDY OBJECTIVE: To evaluate the short-term (12 wks) safety and tolerability of a once-daily, fixed-dose abacavir-lamivudine combination versus twice-daily dosing of the separate components, both with background antiretroviral therapy. DESIGN: Phase IIIB, randomized, open-label, parallel-group, multicenter study. SETTING: One hundred forty-six human immunodeficiency virus (HIV) clinics. PATIENTS: Six hundred eighty antiretroviral therapy-naïve patients with HIV type 1 RNA greater than 1000 copies/ml at baseline. INTERVENTION: Patients were randomly assigned in a 2:1 manner to receive either abacavir 600 mg-lamivudine 300 mg once/day or abacavir 300 mg twice/day and lamivudine 150 mg twice/day. Subjects were stratified based on choice of third or fourth antiretroviral drug (nucleoside reverse transcriptase inhibitor [NRTI], NNRTI, or protease inhibitor), assigned before randomization. MEASUREMENTS AND MAIN RESULTS: The primary end point was occurrence of grades 2-4 adverse events and serious adverse events; abacavir hypersensitivity reactions were considered serious adverse events. Baseline characteristics were similar between the once-daily (455 patients) and twice-daily (225 patients) groups. The rates of all grades 2-4 adverse events were similar: once-daily 33% (150 patients), twice-daily 31% (69). A slightly larger proportion of patients in the twice-daily group experienced drug-related grades 2-4 adverse events: once-daily 10% (47), twice-daily 16% (36). Rates of all serious adverse events (once-daily 11% [49], twice-daily 10% [22]) and drug-related serious adverse events (once-daily 5% [21], twice-daily 8% [17]) were similar. The rate of suspected abacavir hypersensitivity reaction was 5.3% (once-daily 4.4% [20], twice-daily 7.1% [16]), with a higher rate for the NNRTI stratum of the twice-daily group (8.6% [10]) than in any other stratum (once-daily, NNRTI 4.3% [10]; twice-daily, protease inhibitor 5.6% [6]; once-daily, protease inhibitor 4.6% [10]). CONCLUSION: In the short-term, the rates of adverse events in the once-daily and twice-daily groups appeared to be similar. The rate of suspected abacavir hypersensitivity reaction in the once-daily group was lower than the rate in the twice-daily group.

CHOP Chemotherapy Followed by Tositumomab and Iodine-131 Tositumomab for Previously Untreated Diffuse Large B-cell Lymphoma.

The efficacy and safety of tositumomab/iodine-131 tositumomab (TST/I-131 TST) were evaluated in diffuse large B-cell lymphoma patients who responded to first-line cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Fifteen patients (median age, 52 years) received dosimetric and therapeutic doses of TST/I-131 TST. The most common Grade 3/4 hematologic adverse events were decreased absolute neutrophil count (47%), white blood cell count (40%), platelet count (27%), and hemoglobin (20%). The complete response (CR) rate increased from 60% post-CHOP to 80% post TST / I-131 TST. With a median follow-up of 120.0 months (range, 14-130 months), median duration of response (95% confidence intervals) was 58.4 months (12.0-not reached [NR]) for patients with confirmed complete response and 58.4 months (20.9-NR) for all confirmed responders. Median progression-free survival and time to treatment failure were 63.0 months (16.1-NR). Median overall survival was not reached; 2 patients died on study. CHOP and TST/I-131 TST demonstrated clinical activity with acceptable toxicity.

Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine.

OBJECTIVE: To determine if stavudine (alpha4T)-associated mitochondrial toxicity could be reversed by substitution with another nucleoside reverse transcriptase inhibitor. As apoptosis and dysfunction of electron transport chain (ETC) activities may underlie mitochondrial toxicity, these parameters were also evaluated. DESIGN: The 16 participants (on d4T for >3 years; with lipoatrophy and/or hyperlactatemia) substituted abacavir or zidovudine for stavudine in their antiretroviral regimen. Key parameters including dual-energy X-ray absorptiometry (DEXA) scans, fat apoptosis, mitochondrial DNA (mtDNA) content in peripheral blood mononuclear cells (PBMC), skeletal muscle and fat, as well as skeletal muscle mitochondrial ETC activities were evaluated at study entry and at 48 weeks after the substitution. METHODS: Quantitative PCR was used to evaluate mtDNA levels and the presence of deletions/rearrangements; CLIA-validated methods for ETC activities; terminal deoxynucleotidyl transferase dUTP-digoxigenin nick-end labeling assays to evaluate adipocyte apoptosis; and DEXA scans to measure changes in body fat. RESULTS: MtDNA was depleted at study entry in muscle, adipose tissue and PBMC but levels rebounded with respective mean increases of 141%, 146%, and 369% at week 48. Corresponding fat improvements were noted with DEXA increases of 21%, 11%, and 16% in arm, leg, and trunk, respectively. Quantitative adipocyte apoptosis were significantly increased at baseline (P < 0.01 versus HIV-negative controls), with a significant reduction at week 48 (P < 0.05 versus baseline). Mean values for seven mitochondrial enzyme activities assays at entry indicated substantial loss of function (48% to 85% of controls) with significant improvement of complex I activity by week 48. CONCLUSIONS: Substitution of stavudine with abacavir or zidovudine improves mitochondrial indices and fat apoptosis in the setting of lipoatrophy.

Substituting abacavir for hyperlipidemia-associated protease inhibitors in HAART regimens improves fasting lipid profiles, maintains virologic suppression, and simplifies treatment.

BACKGROUND: Hyperlipidemia secondary to protease inhibitors (PI) may abate by switching to anti-HIV medications without lipid effects. METHOD: An open-label, randomized pilot study compared changes in fasting lipids and HIV-1 RNA in 104 HIV-infected adults with PI-associated hyperlipidemia (fasting serum total cholesterol >200 mg/dL) who were randomized either to a regimen in which their PI was replaced by abacavir 300 mg twice daily (n = 52) or a regimen in which their PI was continued (n = 52) for 28 weeks. All patients had undetectable viral loads (HIV-1 RNA <50 copies/mL) at baseline and were naive to abacavir and non-nucleoside reverse transcriptase inhibitors. RESULTS: At baseline, the mean total cholesterol was 243 mg/dL, low density lipoprotein (LDL)-cholesterol 149 mg/dL, high density lipoprotein (HDL)-cholesterol 41 mg/dL, and triglycerides 310 mg/dL. Mean CD4+ cell counts were 551 and 531 cells/mm3 in the abacavir-switch and PI-continuation arms, respectively. At week 28, the abacavir-switch arm had significantly greater least square mean reduction from baseline in total cholesterol (-42 vs -10 mg/dL, P < 0.001), LDL-cholesterol (-14 vs +5 mg/dL, P = 0.016), and triglycerides (-134 vs -36 mg/dL, P = 0.019) than the PI-continuation arm, with no differences in HDL-cholesterol (+0.2 vs +1.3 mg/dL, P = 0.583). A higher proportion of patients in the abacavir-switch arm had decreases in protocol-defined total cholesterol and triglyceride toxicity grades, whereas a smaller proportion had increases in these toxicity grades. At week 28, an intent-to treat: missing = failure analysis showed that the abacavir-switch and PI-continuation arms did not differ significantly with respect to proportion of patients maintaining HIV-1 RNA <400 or <50 copies/mL or adjusted mean change from baseline in CD4+ cell count. Two possible abacavir-related hypersensitivity reactions were reported. No significant changes in glucose, insulin, insulin resistance, C-peptide, or waist-to-hip ratios were observed in either treatment arm, nor were differences in these parameters noted between treatments. CONCLUSION: In hyperlipidemic, antiretroviral-experienced patients with HIV-1 RNA levels <50 copies/mL and CD4+ cell counts >500 cells/mm3, substituting abacavir for hyperlipidemia-associated PIs in combination antiretroviral regimens improves lipid profiles and maintains virologic suppression over a 28-week period, and it simplifies treatment.

Improvement in lipoatrophy associated with highly active antiretroviral therapy in human immunodeficiency virus-infected patients switched from stavudine to abacavir or zidovudine: the results of the TARHEEL study.

Stavudine use is a contributing factor for lipoatrophy, whereas use of abacavir or zidovudine is less likely to cause this complication. The TARHEEL study was a 48-week, open-label study that assessed changes in lipoatrophy after abacavir (86 patients [73%]) or zidovudine (32 patients [27%]), 300 mg twice daily, was substituted for stavudine for 118 human immunodeficiency virus (HIV)-infected patients (HIV type 1 RNA level, <400 copies/mL) with virological suppression who had developed lipoatrophy after > or =6 months of stavudine-based treatment. At week 48, full-body dual-energy x-ray absorptiometry demonstrated a median increase in arm fat of 35%, leg fat of 12%, and trunk fat of 18%, compared with the baseline level. These improvements coincided with fat gain in lipoatrophic areas that was documented by computerized tomography. Results of a "body image" questionnaire showed that a substantial percentage of patients reported some or a lot of fat gain in the arms (22%), legs (18%), buttocks (19%), and face (27%). HIV suppression was maintained over the study period. In conclusion, replacing stavudine with abacavir or zidovudine resulted in improvement in stavudine-induced lipoatrophy.

Twice-daily Trizivir versus Combivir-abacavir in antiretroviral-experienced adults with human immunodeficiency virus-1 infection: a formulation-switch trial.

STUDY OBJECTIVE: To establish the clinical equivalence (noninferiority) of one tablet containing abacavir 300 mg-lamivudine 150 mg-zidovudine 300 mg (Trizivir) versus a tablet containing lamivudine 150 mg-zidovudine 300 mg (Combivir) given with one abacavir (ABC) 300-mg tablet, administered twice/day, in antiretroviral-experienced, human immunodeficiency virus (HIV)-1-infected patients. DESIGN: Randomized, open-label, parallel-group, multicenter, formulation-switch study. SETTING: Twenty seven outpatient treatment sites. PATIENTS: Adults with HIV-1 RNA levels of 400 copies/ml or less and CD4+ cell counts above 200 cells/mm3 who had been treated for 16 weeks or more with highly active antiretroviral therapy containing Combivir-ABC. INTERVENTION: Patients were randomized 1:1 to Trizivir (97 patients) or Combivir-ABC (98) for 24 weeks. MEASUREMENTS AND MAIN RESULTS: The primary study end point was the proportion of patients who maintained less than a 0.5-log10 increase from baseline in HIV-1 RNA (virologic success) through week 24. Clinical equivalence of the treatments was established if the 95.1% lower confidence limit (LCL) for the difference in proportion of virologic success with Trizivir minus Combivir-ABC was -0.12 or greater. Trizivir was clinically equivalent to Combivir-ABC. The intent-to-treat observed analysis at week 24 with Trizivir and Combivir-ABC showed a similar rate of virologic success (83% [80/97] and 77% [75/98], respectively, 95.1% LCL -0.026), of patients with HIV-1 RNA levels of 400 or fewer copies/ml (99% [82/83] and 93% [77/83], respectively, 95.1% LCL 0.021), and of patients with HIV-1 RNA levels of fewer than 50 copies/ml (89% [74/83] and 77% [64/83], respectively, 95.1% LCL 0.038). The intent-to-treat missing = failure analysis showed comparable results. Changes in CD4+ cell count from baseline, overall mean self-reported adherence (Trizivir 97%, Combivir-ABC 92%), and adverse events did not differ significantly between treatments. No ABC-related hypersensitivity reactions occurred. CONCLUSION: Trizivir was clinically equivalent to Combivir-ABC and may be substituted for the latter to simplify treatment and reduce pill burden.

Lack of recurrence of hyperlactatemia in HIV-infected patients switched from stavudine to abacavir or zidovudine.

Stavudine (d4T) has been observed in clinical trials and cohort studies to be more often implicated in cases of hyperlactatemia than other nucleoside reverse transcriptase inhibitors, possibly because of its relatively greater propensity to induce mitochondrial toxicity. The ESS40010 study was a 48-week, open-label, switch study that assessed changes in serum lactate levels and signs/symptoms of hyperlactatemia after substitution of abacavir (n = 86) or zidovudine (n = 32) for d4T in 118 virologically suppressed HIV-infected patients (HIV-1 RNA <400 copies/mL) who had developed serum lactate concentrations > or =2.2 mmol/L (n = 16) or had remained normolactatemic (n = 102) after receiving > or =6 months of d4T-based treatment. Median serum lactate decreased significantly below baseline at week 24 (-0.15 mmol/L, P = 0.0002) and week 48 (-0.15 mmol/L, P = 0.0015). In 10 hyperlactatemic patients in whom d4T was discontinued, serum HIV-1 RNA levels rebounded over the ensuing 31 days, but virologic suppression (HIV-1 RNA <400 copies/mL) was regained when treatment using abacavir or zidovudine was subsequently instituted. In the group with elevated lactate at baseline, symptoms of hyperlactatemia improved in 8% to 23% of patients, did not change in 69%, and worsened in 8%. Serum transaminases, which had been elevated while patients received d4T, normalized after d4T discontinuation and remained in the normal range after the switch to abacavir or zidovudine. Overall, in patients with d4T-associated hyperlactatemia, stopping d4T results in normalization of lactate and a rebound in viral load; restarting treatment using abacavir or zidovudine subsequently maintains normal lactate levels and rapidly leads to a return of virologic suppression.

Impact of an educational program on efficacy and adherence with a twice-daily lamivudine/zidovudine/abacavir regimen in underrepresented HIV-infected patients.

A 24-week open-label clinical trial was conducted in 195 HIV-infected adults commonly underrepresented in research (35% female, 71% African American, 21% Hispanic, and 20% injection drug users [IDUs]) to evaluate the effect of an HIV educational program on efficacy and adherence with a simple, compact, twice-daily triple nucleoside regimen containing a lamivudine (150 mg)/zidovudine (300 mg) combination (COM) tablet plus abacavir (ABC), 300 mg. At baseline, the patients' median plasma HIV-1 RNA level was 4.18 log10 copies/mL and the median CD4+ cell count was 379 cells/mm3. Patients were randomized 1:1 to 4 modules of the Tools for Health and Empowerment HIV education intervention plus routine counseling (EI + RC; n = 96) or to routine counseling alone (RC; n = 99). No differences between the EI + RC and RC treatment arms were observed with respect to the proportion of patients achieving plasma HIV-1 RNA levels <40 copies/mL (60% [33/55] vs. 55% [38/69]; P = 0.529) or <400 copies/mL (80% [44/55] vs. 80% [55/69]; P = 0.689) at week 24 (intent-to-treat observed analysis), increase in median CD4 cell count above baseline at week 24 (78.3 vs. 104.8 cells/mm3; P = 0.498), or mean overall adherence rates as measured by the Medication Event Monitoring System (MEMS) (70% vs. 74%). COM + ABC was generally well tolerated, and no association was observed between interruptions in treatment and the development of ABC hypersensitivity (5 suspected cases). In conclusion, in underrepresented patients, the EI used in this study did not affect the efficacy and adherence results with ABC + COM to any greater degree than did RC.