Therapeutic drug monitoring in treatment-experienced HIV-infected patients receiving darunavir-based salvage regimens: A case series.

Therapeutic drug monitoring (TDM) constitutes a compelling approach for the optimization of antiretroviral therapy in treatment-experienced HIV-1 patients. While various inhibitory indices have been proposed to predict virologic outcome, there is a lack of consensus on the clinical value of TDM. Here, we report the comparative results of TDM in 14 HIV-1-infected patients who had previously received at least two different PI-based regimens and who initiated darunavir (DRV)-based salvage therapy. Pharmacokinetic/pharmacodynamics (PK/PD) parameters were calculated for each subject. Seventy-nine percent of subjects had a viral load <50 copies/mL at 48 weeks. The only subject with two consecutive viral loads >50 copies/mL at the end of the study period was the patient with the lowest instantaneous inhibitory potential (IIP). The sample size was insufficient to show an association between any of the PK/PD parameters and virologic response. Based on our observations, we suggest that the utility of IIP for antiretroviral combinations for the prediction of virologic outcome in HIV-1 drug-experienced patients should be studied further.

The effect of ß-carotene supplementation on the pharmacokinetics of nelfinavir and its active metabolite M8 in HIV-1-infected patients.

ß-Carotene supplements are often taken by individuals living with HIV-1. Contradictory results from in vitro studies suggest that ß-carotene may inhibit or induce cytochrome P450 enzymes and transporters. The study objective was to investigate the effect of ß-carotene on the steady-state pharmacokinetics of nelfinavir and its active metabolite M8 in HIV-1 infected individuals. Twelve hour nelfinavir pharmacokinetic analysis was conducted at baseline and after 28 days of ß-carotene supplementation (25,000 IU twice daily). Nelfinavir and M8 concentrations were measured with validated assays. Non-compartmental methods were used to calculate the pharmacokinetic parameters. Geometric mean ratios comparing day 28 to day 1 area under the plasma concentration-time curve (AUC(0-12 h)), maximum (C(max)) and minimum (C(min)) concentrations of nelfinavir and M8 are presented with 90% confidence intervals. Eleven subjects completed the study and were included in the analysis. There were no significant differences in nelfinavir AUC(0-12 h) and C(min) (-10%, +4%) after ß-carotene supplementation. The M8 C(min) was increased by 31% while the M8 AUC(0-12 h) and C(max) were unchanged. During the 28 day period, mean CD4+ % and CD4+:CD8+ ratio increased significantly (p < 0.01). ß-carotene supplementation increased serum carotene levels but did not cause any clinically significant difference in the nelfinavir and M8 exposure.

Impact of HIV-1 viral subtype on CD4+ T-cell decline and clinical outcomes in antiretroviral naive patients receiving universal healthcare.

OBJECTIVE: The influence of viral subtype on the natural history of HIV is unclear and confounded by socioeconomic and host factors that vary between groups harboring different clades. We compared Canadians (clade B), with recent immigrants from Haiti (clade B) and sub-Saharan Africa (clades non-B) to determine whether there were differences in disease progression attributable to viral subtype. METHODS: We conducted a retrospective cohort study in a universal healthcare setting between 1996 and 2007. The rate of CD4+ T-lymphocyte decline prior to initiation of antiretroviral therapy was determined in all participants with at least two CD4+ T-lymphocyte measures using mixed linear regression models. Time to first AIDS-defining illness was compared using adjusted Cox proportional hazards models. RESULTS: Two hundred and eighty-nine Canadians, 44 Haitians, and 123 Africans were studied for a median of 260 days (2 days-11 years). Africans and Haitians were demographically and clinically similar. However, the adjusted slope of square root CD4+ T-lymphocyte decline was significantly lower in Africans [-0.04/year; 95% confidence interval (CI) = -0.08 to -0.003] compared with Canadians (-0.07/year; 95% CI = -0.11 to -0.03; P = 0.02), and Haitians (-0.10/year; 95% CI = -0.12 to -0.07; P = 0.001). Africans were also less likely to develop AIDS. CONCLUSION: Despite having similar demographic, socioeconomic, and nutritional status to Haitians, Africans infected with non-B clade HIV had slower rates of disease progression compared with both Haitians and Canadians, with both groups being infected by the clade B virus. Our findings suggest that viral subtype may be an important predictor of HIV natural history in a developed medical setting.

Tuberculosis screening and active tuberculosis among HIV-infected persons in a Canadian tertiary care centre.

RATIONALE: HIV infection increases the risk of reactivation of latent tuberculosis (TB). The present study evaluates how latent TB is detected and treated to determine the effectiveness of screening in HIV-infected patients with diverse risk profiles. METHOD: A retrospective medical record database review (1988 to 2007) was conducted at a tertiary care HIV clinic. The proportion of patients receiving tuberculin skin tests (TSTs) and the rate of active TB at each stage of screening and prevention were estimated. Predictors of receiving a TST at baseline, testing positive by TST and developing active TB were evaluated. RESULTS: In the present study, 2123 patients were observed for a total of 9412 person-years. Four hundred seventy-six (22.4%) patients were tested by TST within 90 days of first clinic visit. Having a first clinic visit during the highly active antiretroviral therapy era (OR 3.64; 95% CI 2.66 to 4.99), country of birth (ORs: Africa 3.11, Asia 2.79, Haiti 3.14, and Latin America and the Caribbean 2.38), time between HIV diagnosis and first visit (OR per one-year change 0.97; 95% CI 0.94 to 0.99) and previous antiretroviral exposure (OR 0.61; 95% CI 0.45 to 0.81) were independent predictors of receiving a TST at baseline. Of the 17 patients who developed active TB during follow-up, nine (53%) had no documented TSTs at baseline or during follow-up. Forty-one per cent of all TB patients and 56% of TB patients who were not screened were born in Canada. CONCLUSION: The administration of TSTs to newly diagnosed HIV patients was inconsistent and differential according to country of birth, among other factors, resulting in missed opportunities for TB prevention.

Efficacy and safety of three doses of tipranavir boosted with ritonavir in treatment-experienced HIV type-1 infected patients.

The efficacy, safety, and pharmacokinetics of three doses of tipranavir/ritonavir (TPV/r) in highly treatment-experienced human immunodeficiency virus (HIV)-1-infected patients with protease inhibitor (PI)-resistant isolates were evaluated. A 24-week multicenter, double-blind, randomized, dose-finding trial was conducted. All patients were three-drug class experienced and had taken at least two PI-based regimens. All had at least one primary PI mutation and had plasma HIV-RNA > 1000 copies/ml. Patients remained on their background non-PI antiretroviral medications for the first 14 days. After this 14-day period of functional TPV/r monotherapy, the background antiretroviral medications were optimized based on treatment history and the screening genotype. A total of 216 patients were randomized. All groups [TPV/r 500 mg/100 mg (n = 73), 500 mg/200 mg (n = 72), and 750 mg/200 mg (n = 71) twice daily] achieved an approximate 1 log10 reduction in the median HIV-RNA at week 2. A significant reduction was sustained through 24 weeks in the TPV/r 500 mg/200 mg and 750 mg/200 mg groups. The 500 mg/200 mg dose achieved optimal median TPV trough concentrations and lower interpatient variability. The most frequently reported adverse events (AEs) were diarrhea, nausea, vomiting, fatigue, and headache. The TPV/r 750 mg/200 mg group had the highest rate of grade 3 or 4 laboratory abnormalities and study discontinuations due to AEs. All doses of TPV/r tested in this study were associated with HIV-1 viral load reductions through 24 weeks. The 500 mg/200 mg dose achieved the best efficacy, safety, and pharmacokinetic profile in this highly treatment-experienced population and was selected for the pivotal phase 3 studies.

Evaluating liver fibrosis progression and the impact of antiretroviral therapy in HIV and hepatitis C coinfection using a noninvasive marker.

The effects of highly active antiretroviral therapy (HAART) on progression of hepatic fibrosis in hepatitis C virus (HCV) coinfection with HIV are not well understood and are difficult to measure because of the need for repeated liver biopsy. We evaluated the evolution of a noninvasive measure of liver fibrosis, the alanine aspartyl transferase (AST)-to-platelet ratio index (APRI), longitudinally and determined its predictive value for hepatic outcomes in HIV-positive patients with and without HCV coinfection. A total of 673 HIV-positive patients without liver complications at baseline (540 with HIV only, 133 with HIV-HCV coinfection) were followed between 1991 and 2004 for a median of 4.6 years (3524 person-years). At baseline, HIV-HCV coinfection had a higher median APRI compared with HIV infection alone (0.59 vs. 0.33; P < 0.0001). The natural logarithm of the APRI [ln(APRI)] changed significantly over time, particularly among patients with HIV-HCV coinfection. The baseline ln(APRI) was predictive of liver complications (hazard ratio [HR] = 4.0, 95% confidence interval [CI]: 2.5 to 6.4 per log), as was HCV (HR = 4.5, 95% CI: 1.5 to 14). Cumulative HAART did not protect against liver complications, although it was significantly associated with progression of APRI scores in HIV-HCV coinfection and in HIV alone. In conclusion, the APRI may be a useful marker for longitudinal evaluation of the progression of liver disease in HIV-HCV coinfection.

Gender and long-term metabolic toxicities from antiretroviral therapy in HIV-1 infected persons.

Gender differences in a large population-based cohort of HIV-1 infected patients (245 women and 723 men) were examined with respect to the incidence of metabolic and morphologic alterations after initiation of highly active antiretroviral therapy (HAART). Patients initiated HAART between January 1996 and December 2003. The outcome measures were the incidence of hyperglycemia, hypercholesterolemia, symptomatic lactic acidosis, treatment-limiting lipodystrophy, and hypersensitivity reaction. Cox proportional hazards models were used to estimate the crude and adjusted hazard ratios of reaching the endpoints for exposures and covariates. Women were younger than men (35 +/- 9.8 vs. 40 +/- 8.2 years, P < 0.001) and more frequently from Haiti or Africa (59%), whereas 76% of men were Canadian-born. Type of initial HAART regimen did not differ between women and men. There were no gender differences in the overall incidence of hyperglycemia, hypercholesterolemia, or treatment-limiting lipodystrophy, even after adjusting for age, CD4 cell count, viral load, time since HIV diagnosis, history of AIDS-defining illness and year of HAART initiation. In contrast, women had significantly higher risk of developing lactic acidosis than men (P = 0.0009). Hypersensitivity reactions were also more frequent in women than men (adjusted hazard ratio = 4.4 (95% CI: 2.1-9.3)). Collectively, these data suggest that metabolic toxicities after HAART do not differ by gender but that lactic acidosis and hypersensitivity reactions are more frequent in women than men.

Progressive loss of echinocandin activity following prolonged use for treatment of Candida albicans oesophagitis.

OBJECTIVES: To illustrate the progressive loss of cross-echinocandin activity on Candida albicans isolates with strong clonal homology from a patient with advanced HIV infection and chronic oesophagitis progressively resistant to uninterrupted micafungin treatment. METHODS: Antifungal susceptibility profiles for different antifungal agents were determined against serial C. albicans isolates retrieved before and during therapy. Multilocus sequencing typing (MLST) was performed on each of the isolates. FKS1 mutations conferring reduced susceptibility to echinocandin drugs were determined by DNA sequence analysis. RESULTS: Four C. albicans isolates showing identical allelic homology were retrieved from the patient at the initiation and during therapy with micafungin. The progressive lack of clinical response to micafungin therapy was associated with increased MICs of all three echinocandin drugs (caspofungin, micafungin and anidulafungin) in association with the acquisition of mutations in the FKS1 gene. CONCLUSIONS: This report documents for the first time a progressive loss of activity of all three echinocandin drugs against clonally related C. albicans isolates following long-term clinical exposure to this new class of antifungal agents.

Virologic and immunologic response to a boosted double-protease inhibitor-based therapy in highly pretreated HIV-1-infected patients.

PURPOSE: To assess the virologic and immunologic response to a boosted double-protease inhibitor (PI) regimen of highly pretreated patients infected with HIV-1 and to examine the role of PI resistance and concentration of serum saquinavir. METHOD: In an open-label prospective study, lopinavir/ritonavir, saquinavir-sgc, lamivudine, and other nucleoside analogues were offered to highly pretreated patients who had advanced HIV-1 infection and who had failed at least 2 previous highly active antiretroviral therapy regimens including at least 1 nonnucleoside reverse transcriptase inhibitor. The relationship between baseline drug resistance and steady-state saquinavir serum levels and early (week 4) and sustained (week 48) virologic response was documented. RESULTS: 35 advanced HIV-1 patients were enrolled. The boosted double-PI regimen was well tolerated. Twenty-two (63%) of the 35 patients had a > 0.8 log(10) decrease in HIV viral load at week 4. After 48 weeks of follow-up, the 22 patients who remained on the study therapy had an average decrease in viral load of 1 log(10) and had a median increase in CD4 cells of 60 cell/microL. Multiple logistic regression analysis indicated that genotypic resistance to both PIs and the week-3 trough concentrations of saquinavir were associated with virologic outcome at week 4. The presence of > or = 6 lopinavir mutations [odds ratio (OR) 0.03; 95% CI 0.01 to 0.79] and the 48V mutation (OR 0.01; 95%CI <0.01 to 0.88) was independently associated with lower odds of achieving an early response, whereas a higher saquinavir concentration at week 3 (OR 8.36; 95% CI 1.28 to 54.70) was associated with greater odds of an early response. CONCLUSION: These findings suggest that baseline PI resistance and saquinavir concentration were associated with virologic response and should be considered when planning salvage therapy.

The impact of initial highly active antiretroviral therapy on future treatment sequences in HIV infection.

OBJECTIVES: To determine whether the initial use of non-nucleoside reverse transcriptase inhibitors (NNRTI) or protease inhibitors (PI) differentially influences subsequent HIV therapy. DESIGN: A cohort study using a prospective clinical database in a university-based HIV clinic. SUBJECTS: A total of 440 HIV-seropositive patients, naive or nucleoside experienced, initiating therapy with either an NNRTI or PI between January 1998 and July 2003 and followed to December 2003. MAIN OUTCOME MEASURES: Time until stopping the first regimen and until exposure to all antiretroviral classes (excluding tenofovir and enfuvirtide) according to the type of initial regimen. RESULTS: A total of 291 subjects initiated HAART with PI and 149 with NNRTI; median follow-up 3.1 and 2.3 years, respectively. Subjects starting NNRTI remained on their initial regimens longer (median time to change 2.1 versus 1.6 years; log rank P = 0.03). Overall, subjects initiating NNRTI-based regimens were less likely to alter their therapy. Previous nucleoside exposure was an important predictor of treatment modification. Subjects initiating NNRTI-based HAART were also less likely to experience virological failure than those initiating PI-based HAART. Individuals starting with NNRTI were exposed to fewer regimens (15 versus 25% received three or fewer regimens), and showed a trend towards lower rates of three-class exposure (7 versus 12%). CONCLUSION: There is a high rate of treatment modification among patients initiating HAART. The initial use of NNRTI-based HAART was associated with more durable treatment and lower rates of virological failure, which may translate into a reduced need for multiple salvage therapies.

Clinical risk factors for cytomegalovirus retinitis in patients with AIDS.

PURPOSE: To determine the clinical risk factors for cytomegalovirus (CMV) retinitis in patients with AIDS. DESIGN: A case-control study. PARTICIPANTS: The study included 120 patients in whom CMV retinitis had been diagnosed from 1990 through 1999 (cases) and 159 patients without CMV retinitis from the same period (controls). All individuals had AIDS and CD4 counts less than 50 cells/microl at the time of diagnosis of retinitis in the cases or on the corresponding date for the controls. METHODS: Clinical risk factors were determined by history or physical examination. Confounders controlled for included CD4 count, hospital center, and a series of variables to control for confounding by drug treatment. Statistical analysis was performed by multivariate logistic regression. A systematic model-building strategy was developed from assumption testing to model building to model checking. MAIN VARIABLES MEASURED: Presence of visual symptoms, retinal microinfarctions (cotton-wool spots), history of opportunistic infections, and risk factors for human immunodeficiency virus acquisition were determined and compared in both groups. RESULTS: The following clinical risk factors were significant predictors of CMV retinitis: flashing lights or floaters (odds ratio [OR], 11.42; 95% confidence interval [CI], 3.43 to 38.01), cotton-wool spots (OR, 2.90; 95% CI, 1.01 to 8.29), number of previous opportunistic infections (OR, 1.81; 95% CI, 1.24 to 2.64), previous nonocular CMV infection (OR, 82.99; 95% CI, 6.86 to 1004.58), previous Mycobacterium infection (OR, 3.41; 95% CI, 0.99 to 11.85), and homosexuality (OR, 2.83; 95% CI, 1.13 to 7.12). CONCLUSIONS: Based on this study, clinical variables have been identified that elevate the risk of CMV retinitis. These findings may be useful to clinicians and health policy experts in developing rational guidelines for screening, examination frequency, and targeted prophylaxis for CMV retinitis in patients with AIDS.

Canadian consensus guidelines for the management of cytomegalovirus disease in HIV/AIDS.

BACKGROUND: The management of HIV-infected patients with cytomegalovirus (CMV) disease has changed significantly with the availability of highly active antiretroviral therapy (HAART). OBJECTIVES: These updated guidelines are intended to provide practical help to physicians managing HIV-positive patients with or at risk for CMV disease. METHODS: The 10 members of the Canadian CMV Disease in HIV/AIDS Consensus Group were infectious disease specialists, a primary care physician and ophthalmologists with expertise in HIV and CMV infection. Financial support by Hoffmann-La Roche Canada Ltd was unrestricted, and was limited to travel expenses and honoraria. The consensus group met in June and October 2002. Key areas to be considered were identified, and group members selected, reviewed and presented relevant recent literature for their assigned section for the group's consideration. Evidence was assessed based on established criteria, which were expert opinions of the members. Draft documents were circulated to the entire group and modified until consensus was reached. The final guidelines represent the group's consensus agreement. The guidelines were approved by the Canadian Infectious Disease Society. RESULTS AND CONCLUSIONS: The guidelines address symptom monitoring, screening for early detection and prevention, and treatment using oral, intravenous and intraocular anti-CMV therapies in conjunction with HAART.

Laboratory-based risk factors for cytomegalovirus retinitis.

BACKGROUND: Very few studies have investigated risk factors for cytomegalovirus (CMV) retinitis. Identifying these risk factors will have many benefits, including helping establish screening regimens, examination frequency regimens, and targeted prophylaxis with oral therapy with valganciclovir or other anti-CMV agents. The purpose of this study was to determine the laboratory-based risk factors for CMV retinitis in patients with AIDS. METHODS: We conducted a case-control study involving 120 patients in whom CMV retinitis had been diagnosed in 1990-99 and 159 patients without CMV retinitis from the same period. The sampling was from a primary study base in eastern Ontario and western Quebec of patients with AIDS and CD4 counts less than 50 cells/microL at the time of diagnosis of retinitis in the case subjects or an analogous date for the control subjects. There were two components to the study. In the first component (n = 279) we examined standard-of-care laboratory tests (hematologic and nutrition variables) done during the study period. In the second component (n = 57), which was a subset of the first, we examined laboratory tests (HLA type, qualitative and quantitative CMV polymerase chain reaction [PCR] and HIV load) on stored blood samples from the eastern Ontario site. Multivariate logistic regression was used to model the data and control for confounding. We developed a systematic model-building strategy, from assumption testing to model building to model checking. RESULTS: A low hemoglobin concentration was a statistically significant predictor of CMV retinitis (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.94-0.98). Both qualitative CMV PCR (OR 21.71, 95% CI 1.80-261.67) and quantitative CMV PCR (OR 33.03,95% CI 2.32-469.39) were strong predictors of CMV retinitis. Among the 80 HLA types tested, HLA-Bw4 (OR 11.68, 95% CI 1.29-105.82) and HLA-DRB115 (OR 9.34, 95% CI 1.14-76.41) were significant predictors of CMV retinitis, whereas HLA-Cw7 was protective against CMV retinitis (OR 0.09, 95% CI 0.01-0.67). INTERPRETATION: We have identified laboratory variables that elevate (or decrease) the risk of CMV retinitis. These findings may be useful to clinicians and health policy experts in developing rational guidelines for screening, examination frequency and targeted prophylaxis for patients with AIDS.

The impact of hepatitis C virus coinfection on HIV progression before and after highly active antiretroviral therapy.

To compare the impact of hepatitis C virus (HCV) coinfection on progression of HIV infection in the eras before and after the introduction of highly active antiretroviral therapy (HAART), the authors conducted a retrospective cohort study. One hundred twenty-five HCV+ patients and 1076 HCV- patients were studied; 83% of HCV+ patients were injection drug users. HCV+ subjects experienced no clear benefit from HAART. The adjusted hazard ratios (HRs) of opportunistic infection, death, and hospitalization were 0.74 (95% CI: 0.31-1.78), 1.78 (95% CI: 0.59-5.37), and 2.1 (95% CI: 0.90-4.90), respectively, comparing the post-HAART era with the pre-HAART era. In contrast, HCV- subjects experienced rate reductions for all outcomes. Comparable HRs for opportunistic infection, death, and hospitalization were 0.49 (95% CI: 0.37-0.64), 0.28 (95% CI: 0.19-0.41), and 0.51 (95% CI: 0.38-0.67), respectively. HCV+ subjects remained at increased risk for death and hospitalization post-HAART even after additional adjustment for antiretroviral use and time-updated CD4 cell and viral load measures. Deaths and hospitalizations in HCV+ patients were primarily for non-AIDS-defining infections and complications of injection drug use. HCV coinfection and comorbidity associated with injection drug use are preventing the realization of substantial health benefits associated with HAART.

Didanosine, interferon-alfa and ribavirin: a highly synergistic combination with potential activity against HIV-1 and hepatitis C virus.

OBJECTIVE: To evaluate the antiviral triple combination didanosine (ddI), interferon-alfa (IFN-alpha), and ribavirin for potential synergy in inhibition of HIV-1 replication in vitro. METHODS: Phytohaemagglutinin-stimulated cord blood mononuclear cells were infected with HIV-1(IIIB) or the HXB2D molecular clone of HIV-1 then cultured with interleukin-2 with ddI, ribavirin or IFN-alpha, alone and in combination. Reverse transcriptase activity was measured after 7 days to determine the inhibitory concentration of 50% (IC(50)) for the various drugs in replicate assays. Analysis of combined effects was performed using both the median effect principle (CalcuSyn, Biosoft) and three-dimensional modelling (MacSynergy II). RESULTS: The triple combination was highly synergistic against HIV-1 in vitro with combination indices < 1. The mean IC(50) was reduced from 6.85 to 0.90 micromol/l (P < 0.001) for ddI and from 6.58 to 1.00 micromol/l (P < 0.001) for IFN-alpha. No increased cytotoxicity was observed. Results were similar with both viral strains and using both analyses. In the triple combination, increasing concentrations of IFN-alpha resulted only a slight enhancement of synergy: synergy volumes were 134 [95% confidence limit (CL), 77-191] with 5 U IFN-alpha and 214.92 (95% CL, 116-314) with 10 U. This supporting the observation that the majority of the synergistic activity was derived from the combination of ddI and ribavirin, with IFN-alpha providing additional additive suppression. CONCLUSIONS: This novel triple combination has the potential to provide simultaneous activity against both HIV and hepatitis C and deserves further study to determine if can be safely administered in the clinical setting.

Nelfinavir and non-nucleoside reverse transcriptase inhibitor-based salvage regimens in heavily HIV pretreated patients.

OBJECTIVE: To assess the efficacy of nelfinavir mesylate (NFV) in combination with delavirdine mesylate (DLV) or efavirenz (EFV) and other antiretroviral agents following virological failure on other protease inhibitor (PI)-based regimens. DESIGN: Multicentre, retrospective chart review. METHODS: One hundred-one patients who were naive to both NFV and non-nucleoside reverse transcriptase inhibitors (NNRTIs) and who initiated NFV plus DLV or EFV-based salvage regimens were reviewed. Response to treatment was defined as a reduction in HIV ribonucleic acid (RNA) levels to unquantifiable levels (less than 50 copies/mL, less than 400 copies/mL, less than 500 copies/mL) on at least one occasion after the initiation of salvage therapy. Baseline correlates of response, including prior duration of HIV infection, prior number of regimens, viral load and CD4 cell counts were also evaluated. RESULTS: Patients had a mean duration of HIV infection of 10 years, a mean duration of prior therapy of four years, a median of four prior nucleoside reverse transcriptase inhibitors and a median of two prior PIs. At the time of review the mean duration of salvage therapy was 63.4 weeks. Virological suppression was achieved in 59 (58.4%) patients within a mean of eight weeks and maintained for a mean of 44.9 weeks (the mean follow-up was 78 weeks). Of the non-responders, 16 (38%) achieved a less than 1 log(10) decrease in HIV RNA levels. Although there was no association between baseline correlates, response rate (75.7%) was significantly higher in patients with HIV RNA levels of 50,000 copies/mL or lower and CD4 counts greater than 200 cells/mm(3). CONCLUSION: NFV/NNRTI-based highly active antiretroviral therapy regimens are an effective therapy in many patients who have experienced virological breakthroughs on at least one prior PI-based regimen.

Successful discontinuation of therapy for disseminated Mycobacterium avium complex infection after effective antiretroviral therapy.

BACKGROUND: Highly active antiretroviral therapy (HAART) is associated with improvement or resolution of several HIV-associated opportunistic infections. Although prophylaxis against disseminated Mycobacterium avium complex infection may be successfully discontinued after a favorable response to HAART, the 1999 guidelines from the U.S. Public Health Service/Infectious Diseases Society of America recommend continuing therapy for disseminated M. avium complex infection, regardless of the response to HAART. OBJECTIVE: To examine the outcome among patients with disseminated M. avium complex infection whose antimycobacterial therapy was discontinued after a favorable response to HAART. DESIGN: Retrospective chart review between May 2000 and May 2001. SETTING: 13 Canadian HIV clinics. PATIENTS: 52 HIV-infected adults (43 men; mean age, 37.3 years) in whom successful antimycobacterial therapy for disseminated M. avium complex infection was discontinued after a favorable virologic response to HAART. MEASUREMENTS: Survival, survival free of disseminated M. avium complex infection, and CD4(+) cell count responses. RESULTS: At the time of diagnosis of disseminated M. avium complex infection, the median CD4(+) cell count was 0.016 x 10(9) cells/L, and the median plasma HIV RNA level was 90 000 copies/mL (plasma HIV RNA levels were available for only 21 patients). The patients received a median of 32 months of antimycobacterial therapy that included ethambutol plus either clarithromycin or azithromycin. When antimycobacterial therapy was discontinued, the median CD4(+) cell count was 0.23 x 10(9) cells/L and the median plasma HIV RNA level was less than 50 copies/mL. A median of 20 months after discontinuation of antimycobacterial therapy, only 1 patient had developed recurrent M. avium complex disease (37 months after stopping antimycobacterial therapy). This patient had stopped HAART 2 months earlier because of uncontrolled HIV viremia. Twenty months after stopping antimycobacterial therapy, the other 51 patients had a median CD4(+) cell count of 0.288 x 10(9) cells/L; 34 (67%) had undetectable plasma HIV RNA levels, and 8 (15%) had plasma HIV RNA levels of 50 to 1000 copies/mL. CONCLUSIONS: Discontinuation of successful disseminated M. avium complex therapy after a successful response to HAART is safe and reduces patients' pill burdens, potential drug adverse effects, drug interactions, and costs of therapy.

Field evaluation of the Merlin immediate HIV-1 and -2 test for point-of-care detection of human immunodeficiency virus antibodies.

The Merlin Immediate HIV-1 and -2 Test (Merlin point-of-care [POC] test; Merlin Biomedical & Pharmaceutical) is a nitrocellulose membrane flow immunoassay performed at the POC with the use of blood obtained from a fingerprick. The results of this test were compared with those of enzyme immunoassay (EIA) performed on venous blood samples in the laboratory. Positive results of both tests were confirmed by a Western blot (WB). The study included 553 adults with known HIV (human immunodeficiency virus) seropositivity (all of whom had positive Merlin POC test results) and 2659 adults with unknown HIV serostatus (20 of whom had positive EIA/WB results; 19 of the 20 also had positive Merlin-POC test results). The sensitivity of the Merlin POC test was 95.0% for patients with an unknown HIV serostatus and 99.83% for those with a positive serostatus. For previously untested subjects, the test's specificity and positive predictive value were 100%, its negative predictive value was 99.96%, and its overall accuracy was 99.96%. The Merlin POC test is highly accurate for the detection of HIV antibodies.

Associations between dietary antioxidant intake and oxidative stress in HIV-seropositive and HIV-seronegative men and women.

OBJECTIVE: To describe the relationship between dietary antioxidant intake and oxidative stress in clinically stable HIV-positive and HIV-negative adults. DESIGN: A cross-sectional study. METHODS: Average total daily dietary intakes of vitamin C, beta-carotene, alpha-tocopherol, selenium, and zinc from foods and nutritional supplements were estimated in noninstitutionalized individuals using the dietary history method. Plasma malondialdehyde (MDA) concentrations were measured by high-performance-liquid-chromatography (HPLC) whereas peripheral blood mononuclear cell glutathione (PBMC GSH) concentrations were determined spectrophotometrically by an enzymatic recycling assay. Data were analyzed in multiple linear regression models to investigate these relationships. RESULTS: Regression analysis revealed an inverse relationship between selenium intake and plasma MDA in a model that included the five dietary antioxidants ( R 2 = 0.25; p < .02) and with selenium only ( R 2 = 0.19; p < .01). Both models were adjusted for gender, smoking status, and HIV seropositivity. Antioxidant intake was not associated with PBMC GSH ( R 2 = 0.12, p = .36). In univariate analyses, oxidative stress did not significantly differ between clinically stable HIV-positive and healthy HIV-negative study subjects. CONCLUSIONS: This is the first study to characterize the relationship between dietary antioxidant intake from food and supplements with oxidative stress. The results suggested dietary selenium intake was strongly and inversely associated with plasma MDA, but dietary antioxidant intakes were not related to PBMC GSH. This study also provides evidence that HIV infection was not specifically associated with oxidative stress among clinically stable individuals.