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Analysis of a US hospitalization database demonstrated that more influenza patients were hospitalized and the age distribution of hospitalizations was younger during the 2009 (H1N1) influenza A pandemic compared with the three previous influenza seasons. The duration of hospital stay remained stable in all four seasons. A higher proportion of patients was treated with antivirals (P < 0·0001), comprised almost entirely of neuraminidase inhibitors, and the proportion was highest in those with influenza confirmed by diagnostic testing (P < 0·0001). Approximately one-third remained untreated. Young children had the lowest rate of neuraminidase-inhibitor treatment during the 2009 pandemic (P < 0·05).

(See the editorial commentary by Jain et al, on pages 707–709.) Background. Peramivir, an investigational intravenous neuraminidase inhibitor in Phase 3 trials for hospitalized patients, was made available during the 2009 H1N1 influenza pandemic under the Emergency Investigational New Drug (eIND) regulations. We describe the clinical characteristics and outcomes of all patients for whom peramivir was requested under the eIND. Methods. After obtaining eIND approval from the Food and Drug Administration and local institutional review board approval, clinicians caring for hospitalized patients with influenza administered intravenous peramivir and collected information on demographic characteristics, clinical characteristics, and outcomes. Results. From April through October 2009, peramivir was requested for 42 patients and administered to 20 adults and 11 children. At hospitalization, all patients had rapidly progressing, radiographically confirmed viral pneumonia with respiratory failure, and all but 1 patient required mechanical ventilation. In most patients, including 1 person with documented oseltamivir-resistant infection, the illness had progressed despite oseltamivir treatment. Peramivir was administered for 1–14 days (median duration, 10 days). The 14-day, 28-day, and 56-day survival rates were 76.7%, 66.7%, and 59.0%, respectively. Peramivir was generally well tolerated. Conclusions. Intravenous peramivir was well tolerated and was associated with recovery in most patients hospitalized with severe 2009 H1N1 influenza viral pneumonia and treated under an eIND.

While African Americans in the United States are disproportionately affected by HIV, they are less likely to take antiretroviral therapies. Different first-line antiretroviral therapies are associated with short-term and long-term adverse event (AE) risks. We estimated the willingness of antiretroviral-naïve, HIV-positive African Americans to accept risks of acute AEs with known outcomes and long-term AEs with uncertain outcomes in exchange for virologic suppression. We estimated the relative importance of short-term and long-term AE risks. Two hundred thirty-five subjects were recruited through eight clinics in the United States. One hundred fifty-eight subjects met study inclusion criteria. One hundred fifty-three subjects completed a series of choice-format conjoint trade-off tasks. In each task, subjects were asked to choose between two hypothetical treatments with varying levels of virologic failure, risks of hypersensitivity reaction, decreases in bone mineral density (BMD), and renal impairment, and outcome uncertainty associated with the risks of decreased BMD and renal impairment. Attributes were expressed as probabilities of occurrence. We calculated the relative importance of each AE and the level of risk subjects would accept to reduce the risk of virologic failure. Subjects indicated that short-term AEs with relatively certain outcomes are preferred to long-term AEs with uncertain outcomes. Subjects were strongly averse to the risk of decreased BMD that could not be treated successfully or when the outcome was uncertain and to the risk of renal impairment that could not be treated successfully. Subjects were willing to accept increased risks of AEs in exchange for lower risk of virologic failure.

Background: 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.

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 afteror =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.

Information about the nucleoside analogue abacavir has been based primarily on the results of clinical trials, rather than on experience in the clinical practice setting. The Ziagen Optimal Regimen and Resistance Observational (ZORRO) trial was a Phase IV, open-label, community-based. study conducted over 16 weeks at 265 U.S. clinical practice sites to assess the real-world safety/tolerability and efficacy of abacavir-containing combination regimens. Of 833 HIV-infected patients enrolled, 791 had documented evidence of having taken abacavir (298 antiretroviral-naive, 490 antiretroviral-experienced, and 3 with missing data). Mean age was 40.3 years, 84% were male, 48% were Caucasian, and 33% were African-American. At baseline, the median plasma HIV-1 RNA was 4.34 log 1 0 copies/ mL and CD4 cell count was 321 cells/mm 3 . Adverse events were primarily gastrointestinal and transient. A suspected abacavir-related hypersensitivity reaction was reported in 7% of patients. Week 16, data in the total antiretroviral-naive and antiretroviral-experienced groups showed that median HIV-1 RNA was reduced by 1.64, 2.40, and 1.05 logo copies/mL below baseline, viral load was < 400 copies/mL in 68%, 69%, and 67% of patients (intent-to-treat: observed analysis), and median CD4 cell count was increased by 78, 120, and 54 cells/mm 3 above baseline. Overall, the safety and efficacy profile of abacavir-containing combination regimens in clinical practice patients appeared similar to that previously reported in clinical trials.

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.

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 RNA1000 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 lasting1 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 (or = 4 vs 1-3; P = .013) and tended to be higher in patients with longer exposure to stavudine (29% withor = 24 months' exposure vs 13% with24 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.

Background Influenza causes over 200,000 hospitalizations a year in the United States, but few antiviral treatment studies have focused on patients hospitalized with influenza. This open-label, randomized study was initiated during the 2009 H1N1 pandemic to help assess the antiviral activity, safety and tolerability of 5–10 days treatment with two different dosing regimens of the intravenous neuraminidase inhibitor, peramivir, in hospitalized subjects with influenza. Methods Quantitative virology was done on nasopharyngeal swab specimens from subjects ≥6 years of age to measure change from baseline in tissue culture infective dose (primary end point) and quantitative viral RNA levels by real-time PCR. Clinical end points included time to clinical resolution, a composite end point of four vital signs and oxygen saturation. Results A total of 234 hospitalized patients were randomized to peramivir 300 mg twice daily or 600 mg once daily; 127 had laboratory confirmed influenza. In those with detectable virus at baseline, viral titres declined without differences between regimens. There were no significant differences in clinical or virological end points between treatment arms, and apparent differences were explained by baseline disease severity differences in the groups. Peramivir was generally safe and well tolerated for treated patients hospitalized with pandemic influenza with outcomes similar to those described in the literature. Conclusions This open-label trial of intravenous peramivir in subjects hospitalized predominantly with 2009 influenza A (H1N1) demonstrated that once- or twice-daily administration was associated with decreases in viral shedding and clinical improvement. ClinicalTrials.gov number NCT00957996.

Peramivir, an intravenously administered neuraminidase inhibitor, may be used concomitantly with other influenza antivirals. Two studies were conducted to assess the potential for pharmacokinetic interactions of peramivir when coadministered with oseltamivir or rimantadine. Twenty-one healthy subjects were enrolled in each randomized, open-label, crossover study, and they received 1 intravenous dose of peramivir (600 mg), 1 oral dose of oseltamivir (75 mg) or rimantadine (100 mg), or a combination of peramivir with oseltamivir or rimantadine. Assessment of the 90% confidence interval for the geometric mean ratio of peramivir and oseltamivir carboxylate or rimantadine pharmacokinetic parameters showed no effect of oseltamivir or rimantadine on the pharmacokinetics of peramivir and no effect of peramivir on the pharmacokinetics of oseltamivir carboxylate or rimantadine. The drugs were well tolerated. These results suggest no reason to expect an effect of concomitant administration of oseltamivir or rimantadine on the safety profile of peramivir in patients with influenza.

Background. The 2009 influenza A(H1N1) pandemic called attention to the limited influenza treatment options available, especially in individuals at high risk of severe disease. Neuraminidase inhibitor–resistant seasonal H1N1 viruses have demonstrated the ability to transmit well despite early data indicating that resistance reduces viral fitness. 2009 H1N1 pandemic viruses have sporadically appeared containing resistance to neuraminidase inhibitors and the adamantanes, but the ability of these viruses to replicate, transmit, and cause disease in mammalian hosts has not been fully characterized.

Other researchers have found that diethylcarbamazine (DEC) is effective treatment for filariasis despite a lack of demonstrated in vitro antifilarial activity. The results of our previous investigations using feline and murine leukemia virus models encouraged us to investigate the use of DEC with other infections. In the current experiments, DEC treatmentS was associated with (a) increased survival and decreased brain Streptococcus pneumoniae levels following S. pneumoniae challenge in previously immunized mice; (b) increased serum antibody levels to S. pneumoniae, Escherichia coli, and Haemophilus influenzae following inoculation of live bacteria; and (c) lower brain fungal levels following intravenous injection of Aspergillus fumigatus or increasing numbers of Cryptococcus neoformans organisms, and lower brain and kidney levels of Candida albicans following intravenous injection of increasing numbers of C. albicans.

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.We compiled data from GlaxoSmithKline-sponsored clinical trials withor = 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).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).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.

HIV-1 drug resistance methodologies are being increasingly utilized to guide treatment decisions; however, information comparing the various assays is limited. Duplicate plasma samples from 70 ART-experienced subjects were analyzed by both the Antivirogram and PhenoSense phenotypic assays and the results compared. HIV genotypes were also obtained and analyzed using seven different resistance algorithms. These results were also compared with the phenotypic assay results. Concordances between the phenotypic tests and between each algorithm, and between the two phenotypic assays were calculated and kappa coefficients (KC) determined. Overall agreement between the two phenotypic assays was good (86.9% concordance; KC 0.621). The highest concordance by drug class was seen for protease inhibitors (93.4%; KC 0.679) and the lowest (79.8%; KC 0.549) for nucleoside reverse transcriptase inhibitors. Concordance between the two phenotypic assays, when evaluating individual drugs, was good for all drugs tested except for abacavir, zalcitabine, and indinavir. Agreement between the seven algorithms and each phenotypic assay was variable, though most had good or excellent agreement. The highest overall level of agreement for an individual drug was observed when comparing lamivudine susceptibility to either assay. Concordance for abacavir, didanosine, zalcitabine, and saquinavir was generally problematic when comparing one or more phenotypic assays to the drug resistance predictive algorithms. In conclusion, results comparing these two phenotypic tests were mostly similar, but comparisons of the predictive resistance algorithms for specific drugs, as well as to specific phenotypic assays, were more inconsistent.

Background Hydroxyurea (HU) is an immunomodulatory agent that has been documented to enhance the antiretroviral activity of nucleoside reverse transcriptase inhibitors, such as abacavir (ABC) and didanosine (ddI), and would be expected to improve virologic efficacy. Methods A 48-week, phase IV, multicenter, open-label, proof-of-concept clinical trial was conducted to evaluate second-line, protease inhibitor (PI)-sparing therapy with ABC/efavirenz (EFV)/ddI plus HU or without HU in HIV-infected subjects failing to achieve HIV-1 RNA ≤ 400 copies/mL after ≥ 16 weeks of treatment with lamivudine/zidovudine or lamivudine/stavudine, plus 1 or 2 PIs. Subjects were assigned to ABC (300 mg twice daily)/ EFV (600 mg once daily)/ ddI (400 mg once daily) plus HU (500 mg twice daily) (n = 30) or this regimen without HU (n = 24). Results Baseline mean HIV-1 RNA was 3.86 log10 copies/mL and CD4+ cell count was 345 cells/mm3. A similar percentage of subjects in the non-HU arm (58%) and HU arm (53%) completed the study. Intent-to-treat: missing = failure analysis showed no differences in proportions of subjects in the non-HU and HU arms achieving undetectable plasma HIV-1 RNA levels at week 24 (P = 0.899; P = 0.780). Median change from baseline in CD4+ cell count in the non-HU and HU arms at week 48 was +114 cells/mm3 and -63 cells/mm3 (P = 0.007), respectively. Both regimens were generally well tolerated, although more subjects in the HU arm withdrew prematurely from the study due to adverse events (23% vs 4%). Four cases of possible ABC-related hypersensitivity were observed. Conclusion ABC/EFV/ddI was an effective and well-tolerated second-line regimen for nucleoside/PI-experienced HIV-infected subjects. The addition of HU blunted the CD4+ cell response, did not appear to enhance antiviral activity, and resulted in more treatment-limiting adverse events.

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 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 Conclusion In hyperlipidemic, antiretroviral-experienced patients with HIV-1 RNA levels 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.

Objective: To determine if stavudine (a4T)-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.

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

Background Low-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). Methods ESS40011 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 Results 211 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 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 Conclusions APV600 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.

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.

Previous reports suggest that diethylcarbamazine citrate (DEC) could be useful in the treatment of retroviral, bacterial, and fungal infections [1]. In an additional experiment, DEC (25 mg by mouth twice daily) was administered concurrently with oral Zidovudine (20 mg/kg twice daily, later changed to 10 mg/kg, then 15 mg/kg oral Videx twice daily) to a chronically FeLV-infected 18-month-old female domestic shorthair cat (cat S). FeLV serum p27 levels were lowered (by a factor of 10) with no apparent adverse effects or notable changes in serum alanine aminotransferase and creatinine levels, and a weight gain of 0.5 kg was noted over 4 months. Another study indicated that 1 month of oral DEC (10 mg/kg day -~) given to 12 FeLV-infected cats did not significantly alter serum alanine aminotransferase and

Other researchers have found that diethylcarbamazine (DEC) is effective treatment for filariasis despite a lack of demonstrated in vitro antifilarial activity. The results of our previous investigations using feline and murine leukemia virus models encouraged us to investigate the use of DEC with other infections. In our current experiments, DEC treatment was associated with lower brain fungal burden in fluconazole-treated mice following intravenous injection of Aspergillus fumigatus or increasing numbers of Cryptococcus neoformans organisms, and lower brain and kidney levels of Candida albicans following intravenous injection of increasing numbers of C. albicans. Further investigation of combined DEC and fluconazole treatment of fungal infections is warranted.

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 (PAI-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 (p0.05 for each); levels of PAI-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 indinavir.