Jaime E. Hernandez

Abacavir versus Zidovudine Combined with Lamivudine and Efavirenz, for the Treatment of Antiretroviral-Naive HIV-Infected Adults

BACKGROUND Zidovudine, lamivudine, and efavirenz comprise a highly effective and well-tolerated triple regimen for antiretroviral-naive patients. Evaluating other unique nucleoside reverse-transcriptase inhibitor (NRTI) combinations for long-term viral suppression is desirable. METHODS This multicenter, randomized, double-blind noninferiority clinical trial compared the efficacy and safety of abacavir with that of zidovudine plus lamivudine and efavirenz in 649 antiretroviral-naive HIV-infected patients. The primary objective was a comparison of proportions of patients achieving plasma HIV-1 RNA levels <or=50 copies/mL through week 48 of the study. RESULTS At study week 48, 70% of patients in the abacavir group, compared with 69% in the zidovudine group, maintained confirmed plasma HIV-1 RNA levels of <or=50 copies/mL (in the intent-to-treat exposed population). Virologic failure was infrequent (6% in the abacavir group and 4% in the zidovudine group). There was a significant CD4(+) cell response (209 cells/mm(3) in the abacavir group and 155 cells/mm(3) in the zidovudine group). Safety profiles were as expected. CONCLUSION Abacavir provided an effective and durable antiretroviral response that was noninferior to zidovudine, when combined with lamivudine and efavirenz.

Risk of Myocardial Infarction and Abacavir Therapy: No Increased Risk Across 52 Glaxosmithkline-sponsored Clinical Trials in Adult Subjects

Background:Recently, the Data collection of Adverse events of Anti-HIV Drugs Group (D:A:D) described results from their international observational cohort of 33,347 HIV-1-infected individuals, suggesting unexpected increased risk of myocardial infarction (MI) associated with abacavir (ABC) therapy [relative rate 1.9, 95% confidence interval (CI): 1.47 to 2.45; P = 0.0001]. To contribute to the scientific question, we summarized GlaxoSmithKline HIV clinical trial data to determine if a similar signal emerged. Methods:We compiled data from GlaxoSmithKline-sponsored clinical trials with ≥24 weeks of combination antiretroviral therapy comprising 14,174 HIV-infected adults who received ABC (n = 9502; 7641 person-years) or not (n = 4672; 4267 person-years). Findings:Baseline demographics and HIV disease characteristics, including lipids and glucose values, were similar. MI rates were comparable among subjects exposed [n = 16 (0.168%; CI: 0.096 to 0.273; 2.09 per 1000 person-years)] or not [n = 11 (0.235%; CI: 0.118 to 0.421; 2.57 per 1000 person-years)] to ABC-containing therapy. Results of 12 trials with randomization to ABC or not were consistent (2.15 per 1000 person-years vs. 4.10 per 1000 person-years). Interpretations:In this pooled summary, we observed few MI events overall and no excess risk of MI with ABC therapy. It is unclear why results from this data set seem discrepant to the Data collection of Adverse events of Anti-HIV Drugs data set, particularly, as the non-ABC MI event rate is similar. Further data are needed to evaluate any association between ABC and increased risk of MI.

Updated clinical risk factor analysis of suspected hypersensitivity reactions to abacavir

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Response to Lamivudine-Zidovudine plus Abacavir Twice Daily in Antiretroviral-Naive, Incarcerated Patients with HIV Infection Taking Directly Observed Treatment

Prison inmates with human immunodeficiency virus (HIV) infection can be difficult to treat because of the complexity and intrusiveness of many combination antiretroviral therapy regimens. NZTA4007, a 24-week open-label, single-arm clinical trial involving 108 antiretroviral therapy-naive, incarcerated, HIV-infected persons, was conducted to evaluate a compact regimen (4 tablets per day) consisting of 1 lamivudine-zidovudine (150 mg/300 mg) combination tablet (COM) and one 300-mg abacavir tablet administered twice daily under directly observed treatment conditions. In the intent-to-treat observed analysis, the plasma HIV type 1 (HIV-1) RNA level remained at < or =400 copies/mL in 85% of the patients and at < 50 copies/mL in 75% of the patients. Median change from baseline was -2.41 log(10) copies/mL for the HIV-1 RNA level and +111 cells/mm(3) for the CD4 cell count. The overall adherence to prescribed doses was 94% for patients who remained enrolled in the study. COM-abacavir given twice daily was generally well tolerated, and adverse events prompted only 4 patients to withdraw from the study.

Thymidine Analog and Multinucleoside Resistance Mutations Are Associated with Decreased Phenotypic Susceptibility to Stavudine in HIV Type 1 Isolated from Zidovudine-Naive Patients Experiencing Viremia on Stavudine-Containing Regimens

Studies have demonstrated that HIV-1 isolated from subjects experiencing virologic failure on stavudine (d4T)-containing regimens often contains thymidine analog mutations (TAMs), consisting of reverse transcriptase (RT) mutations M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E, previously associated only with zidovudine (ZDV) resistance. In clinical study NZT40012, HIV-1 was isolated from 86 ZDV-naive subjects experiencing viremia on d4T-based therapies (plasma HIV-1 RNA > or =1000 copies/ml) and analyzed to examine the association between RT mutations and phenotypic resistance to d4T. Resistance-associated mutations were analyzed from HIV-1 isolated from 85 subjects. Of these, 24 samples (28%) had TAMs, and 30 samples (35%) had either TAMs and/or the Q151M multinucleoside resistance (MNR) mutation. Phenotypic susceptibility to d4T was determined by two commercially available methods. Statistically significant increases (p < 0.001) in phenotypic fold resistance to d4T were observed in virus with at least one TAM or MNR mutation. However, the mean increases in phenotypic resistance were 4-fold for the Antivirogram assay and 3-fold for the Phenosense HIV assay, only slightly above the levels used to designate decreased susceptibility to d4T. Subjects can experience viremia on d4T-containing regimens with virus exhibiting only small increases in IC(50), suggesting that relatively small changes in viral susceptibility to d4T may influence drug efficacy.

Stavudine-associated peripheral neuropathy in zidovudine-naïve patients: effect of stavudine exposure and antiretroviral experience.

A post hoc analysis of safety data from study protocol NZT40012 assessed the incidence of conditions defined by the Centers for Disease Control and Prevention in 86 zidovudine-naïve, antiretroviral-experienced patients with HIV-1 infection who responded poorly (plasma HIV-1 RNA >1000 copies/mL) despite at least 4 months’ treatment with stavudine-containing regimens. Peripheral neuropathy occurred in 21%; other conditions were seen less frequently (candidiasis [13%], herpes zoster [12%], diarrhea lasting >1 month [9%],Pneumocystis carinii pneumonia [9%], and wasting syndrome [8%]). The incidence of peripheral neuropathy rose significantly with the number of drugs comprising treatment regimens (≥ vs 1–3;P = .013) and tended to be higher in patients with longer exposure to stavudine (29% with ≥24 months’ exposure vs 13% with <24 months). Because peripheral neuropathy was observed with such high frequency, vigilance for signs and symptoms of this condition appears warranted if stavudine-containing regimens are to be continued.

Long-Term Safety and Tolerability of the Lamivudine/Abacavir Combination as Components of Highly Active Antiretroviral Therapy

AbstractBackground: Numerous large, long-term clinical trials have assessed the safety and efficacy of the two antiretroviral nucleoside analogs lamivudine and abacavir as components of highly active antiretroviral therapy for the treatment of patients with HIV-1 infection. This analysis pools the safety data on multi-drug regimens containing lamivudine/abacavir in combination with a protease inhibitor, non-nucleoside reverse transcriptase inhibitor, or nucleoside reverse transcriptase inhibitor. Methods: Data are presented from 2279 treatment-naive HIV-1-infected patients who were enrolled in one of five clinical trials that assessed the safety and tolerability of lamivudine/abacavir in combination with a third antiretroviral agent. The well characterised combination of lamivudine/zidovudine plus efavirenz was used as the comparator arm. All available safety data (including data beyond 48 weeks) were used in all analyses, which included calculation of treatment emergent laboratory values, adverse events (AEs), serious AEs, fatalities, drug discontinuations and any summaries by study week of safety data. Results: In the total lamivudine/abacavir group, 1585 of 2229 (71%) patients experienced at least one drug-related AE during the study compared with 247 of 325 (76%) patients in the lamivudine/zidovudine/efavirenz treatment group. The most common drug-related AEs reported during the study were diarrhoea (19%), nausea (18%) and dizziness (12%) in patients treated with lamivudine/abacavir plus a third agent, and nausea (31%), dizziness (27%) and headache (16%) in the comparator group. Overall, in the total lamivudine/abacavir group there were only three severe (Division of AIDS 1992 toxicity table grade 3 or 4) AEs that were reported in >1% of subjects: drug hypersensitivity, elevated ALT levels and elevated AST levels. In the lamivudine/zidovudine/efavirenz group, six severe AEs that occurred in >1% of the safety population were reported. The abacavir hypersensitivity reaction rate reported in these five studies was comparable with the previously reported rate. In addition, there were no patient fatalities attributed by investigators to the study drugs. Conclusion: This analysis indicates that the combination of lamivudine/abacavir is generally safe for the majority of patients when used as part of combination therapy.

Changes in thrombolytic and inflammatory markers after initiation of indinavir- or amprenavir-based antiretroviral therapy

HIV-infected subjects who have lipodystrophy and insulin resistance on prolonged antiretroviral therapy have elevated levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAl-1) antigens, markers of impaired thrombolysis that are associated with hyperinsulinemia and increased cardiovascular risk. We studied HIV-infected, protease inhibitor (PI)-naive adults treated with indinavir (n=11) or amprenavir (n=14) plus two nucleoside reverse transcriptase inhibitors enrolled in two independent prospective trials. Antiretroviral and immune responses were similar in both studies. Over 8 wk, indinavir was associated with decreased insulin sensitivity, whereas amprenavir was not. Levels of tPA antigen declined by approx 25% with both treatments (p<0.05 for each); levels of PAl-1 antigen did not change. Levels of the inflammatory marker soluble tumor necrosis factor-alpha receptor II (sTNFr2) correlated positively with tPA antigen (r=0.33, p=0.02), and mean (±SD) plasma concentrations of sTNFr also declined with treatment (4.44±1.11 ng/mL pretherapy, 3.75±1.21 posttherapy, p=0.007). Short-term improvement in a marker of impaired thrombolysis and increased vascular risk can occur during PI-based antiretroviral therapy, perhaps as a consequence of improvement in HIV-related inflammation. This improvement occurred independent of development of insulin resistance, which occurred only with indivinavir.

Twice-daily amprenavir 1200 mg versus amprenavir 600 mg/ritonavir 100 mg, in combination with at least 2 other antiretroviral drugs, in HIV-1-infected patients

BackgroundLow-dose ritonavir (RTV) boosts plasma amprenavir (APV) exposure. Little has been published on the efficacy, tolerability, and safety of APV 600 mg/RTV 100 mg (APV600/RTV) twice daily (BID) compared to APV 1200 mg BID (APV1200).MethodsESS40011 was a 24-week, multicenter, open-label, clinical trial in which antiretroviral therapy-naïve and -experienced HIV-1-infected adults were randomized 3:1 to receive either APV600/RTV BID or APV1200 BID, in combination with ≥ 2 non-protease inhibitor antiretroviral drugs. Non-inferiority of the APV600/RTV regimen to the APV1200 regimen was established if the 95% lower confidence limit for the difference in proportion of patients achieving HIV-1 RNA <200 copies/mL at week 24 with APV 600/RTV minus APV1200 was ≥-0.12. Late in the conduct of the trial, patients not yet completing 24 weeks of therapy were given the option of continuing treatment for an additional 24-week period.Results211 patients were randomized, 158 to APV600/RTV and 53 to APV1200. At week 24, APV600/RTV was similar to or better than APV1200 (HIV-1 RNA <200 copies/mL in 62% [73/118] vs 53% [20/38] of patients; intent-to-treat: observed analysis). In the APV600/RTV arm, significantly more patients achieved HIV-1 RNA <50 copies/mL (48% [57/118] vs 29% [11/38] with APV1200, P = 0.04), and greater mean reduction from baseline in HIV-1 RNA was observed (-2.21 vs -1.59 log10 copies/mL, P = 0.028). The two treatment arms were similar with respect to mean overall change from baseline in CD4+ count, frequency of drug-related grade 1–4 adverse events, and frequency of discontinuing treatment due to adverse events (most commonly nausea, diarrhea, vomiting or fatigue; 7% vs 8%), although a lower proportion of patients in the APV600/RTV arm experienced drug-related oral/perioral paresthesia (2% vs 8%). Eleven (73%) of 15 patients who had HIV-1 RNA <200 copies/mL at week 24 and chose to continue study treatment maintained this level of virologic suppression at follow-up 24 weeks later.ConclusionsAPV600 RTV BID was similar to or better than APV1200 BID in virologic response. Virologic results in a small number of patients who continued treatment for 24 weeks post-study suggest that virologic suppression with APV600 RTV BID is durable.

Anaphylactoid Reaction to Ciprofloxacin versus Toxic Shock Syndrome

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