Gastrointestinal intolerance is a limitation of boosted saquinavir antiretroviral treatment. We present three HIV-infected individuals whose severe toxicity symptoms started directly after initiation of a standard dose saquinavir hard-gel capsule-containing regimen (saquinavir/ritonavir 1000/100 mg). All patients underwent immediate 12 h pharmacokinetic (PK) assessment and showed extraordinarily high saquinavir plasma exposure. All three patients did not recover until the saquinavir exposure was decreased. This pilot case study anticipates a new concept of 'direct PK'-guided individual dose interventions under close viral load monitoring. Two major reasons for symptomatic saquinavir overexposure were defined: impaired liver function in a chronic hepatitis C virus co-infected individual at normal liver performance parameters and a delayed cytochrome p450 enzyme autoinduction. Overexposure seems to be an independent intolerance factor. Although delayed autoinduction is not well established as a reason for adverse events in saquinavir therapy, this observation may be confirmed in the near future by increased use.

OBJECTIVES:The authors evaluated the pharmacokinetics and tolerability of indinavir/lopinavir/ritonavir in a protease inhibitor only combination. METHODS:Plasma drug levels of patients taking indinavir/lopinavir/ritonavir 800/400/100mg twice daily (n = 24, group 1) were compared to patients taking either lopinavir/ritonavir 400/100mg (n = 35, group2) or indinavir/ritonavir 800/100mg (n = 33, group3) twice daily plus nucleos(t)ide reverse transcriptase inhibitors (NRTI). Steady-state drug concentrations were measured by LC/MS/MS. Minimum and maximum concentrations (C subsetmin, C subsetmax), area under the concentration-time curve (AUC subset0-12h), total clearance (CL subsettot) and half-life (t1/2) were calculated. HIV viral load, CD4 cell count and adverse events causing early termination of therapy were correlated over a period of 48 weeks. RESULTS:Plasma levels of lopinavir/ritonavir were significantly enhanced when combined with indinavir compared to a regimen of lopinavir/ritonavir+NRTI: Mean lopinavir AUC subset(0-12h) 80,912 ng*h/mL vs. 60,548 ng*h/mL; C subsetmin 4,633 ng/mL vs. 3,258 ng/mL; C subsetmax 8,023 ng/mL vs. 6,710 ng/mL. Mean ritonavir AUC(0-12h) 6,907 ng*h/mL vs. 3,467 ng*h/mL; Cmin 220 ng/mL vs. 125 ng/mL; C subsetmax 1,059 ng/mL vs. 522 ng/mL. Indinavir levels were comparable for both indinavir containing regimen. A significantly smaller number of patients stopped indinavir/lopinavir/ritonavir therapy (group1: 16.7%) than indinavir/ritonavir + NRTI treatment (group3: 45.5%) due to adverse events. Virological failure was the main reason for early termination of treatment with indinavir/lopinavir/ ritonavir before week 48 (group1: 50%). CONCLUSIONS:indinavir/lopinavir/ritonavir 800/400/ 100mg twice daily represents a therapy option with an adequate safety but only short term efficacy for extensively pretreated patients.

BACKGROUND:We obtained estimates of the incidence of tuberculosis (TB) among patients receiving HAART and identified determinants of the incidence. METHODS:We analyzed the incidence of TB during the first 3 years after initiation of HAART among 17,142 treatment-naive, AIDS-free persons starting HAART who were enrolled in 12 cohorts from Europe and North America. We used univariable and multivariable Poisson regression models to identify factors associated with the incidence. RESULTS:During the first 3 years (36,906 person-years), 173 patients developed TB (incidence, 4.69 cases per 1000 person-years). In multivariable analysis, the incidence rate was lower for men who have sex with men, compared with injection drug users (relative rate, 2.46; 95% confidence interval [CI], 1.51-4.01), heterosexuals (relative rate, 2.42; 95% CI, 1.64-3.59), those with other suspected modes of transmission (relative rate, 1.66; 95% CI, 0.91-3.06), and those with a higher CD4+ count at the time of HAART initiation (relative rate per log2 cells/microL, 0.87; 95% CI, 0.84-0.91). During 28,846 person-years of follow-up after the first 6 months of HAART, 88 patients developed TB (incidence, 3.1 cases per 1000 person-years of follow-up). In multivariable analyses, a low baseline CD4+ count (relative rate per log2 cells/microL, 0.89; 95% CI, 0.83-0.96), 6-month CD4+ count (relative rate per log2 cells/microL, 0.90; 95% CI, 0.81-0.99), and a 6-month HIV RNA level >400 copies/mL (relative rate, 2.21; 95% CI, 1.33-3.67) were significantly associated with the risk of acquiring TB after 6 months of HAART. CONCLUSION:The level of immunodeficiency at which HAART is initiated and the response to HAART are important determinants of the risk of TB. However, this risk remains appreciable even among those with a good response to HAART, suggesting that other interventions may be needed to control the TB epidemic in the HIV-infected population.

Objectives The aim of the study was to evaluate the safety and efficacy of abacavir (ABC) and efavirenz (EFV) instead of a protease inhibitor (PI) in HIV-1-infected subjects treated with two nucleoside reverse transcriptase inhibitors (NRTIs) and one PI with undetectable viral loads (< 50 HIV-1 RNA copies/mL). To be eligible for inclusion, patients had to have a history of viral load < 400 copies/mL for at least 3 months and had to be naive to treatment with nonnucleoside reverse transcriptase inhibitors (NNRTIs) and ABC, but multiple pretreatment and treatment failure were allowed.Design An open-label, single-centre pilot study of duration 48 weeks was conducted. ABC was added to the original treatment with two NRTIs and one PI at baseline, and at week 6 the PI was replaced by EFV. At each study visit, CD4 cell count, viral load [measured by polymerase chain reaction (PCR)] and clinical chemistry were measured. Fasting blood samples were taken at baseline and at weeks 12, 24, 36 and 48 to measure levels of cholesterol [high-density lipoprotein (HDL)/low- density lipoprotein (LDL)], triglycerides, insulin and C-peptide. Additionally, an oral glucose tolerance test (OGTT) was performed. A bioelectric impedance analysis (BIA) and a single slice abdominal and mid-thigh computed tomography (CT) scan were carried out to assess changes in body composition.Results Thirty patients were included in the study. Three patients experienced ABC-hypersensitivity and one patient demonstrated virological failure caused by nonadherence. At week 48, all remaining patients had viral loads < 50 copies/mL with stable CD4 counts. The fasting metabolic parameters and abdominal fat distribution remained unchanged.Conclusions In heavily pretreated patients, ABC and EFV in combination provide an effective, simplified and well-tolerated alternative to PI treatment.

Hintergrund und Fragestellung: Patienten und Methodik: Ergebnisse: Folgerung: Background and objective: Patients and methods: Results: Conclusion:

Objective To compare the rate of disease progression according to viral load and CD4 cell count in patients receiving or not receiving highly active antiretroviral therapy (HAART), defined as protease inhibitor-containing regimens. Design An observational study, with prospectively collected data. Methods All patients attending the HIV Outpatient clinic as of 1 January 1995 (n = 2083) were included. Follow-up was until the first AIDS-defining event or death. Associations between viral load or CD4 cell count and disease progression were assessed using a person–years approach. Event rates were compared using Poisson regression analysis; a multivariate model was used to assess the independent effects of CD4, viral load and treatment group on event rates and to consider interactions between these variables. Results The event rates increased with lower CD4 cell count and higher viral load for both treatment groups and were generally lower in the HAART group. In a multivariate analysis, lower CD4 cell counts and higher viral loads remained significantly associated with disease progression, irrespective of treatment group. However, the event rate was significantly lower for the HAART group compared with the control group (relative rate 0.53, P < 0.001). Conclusions HAART-treated patients with high viral loads and CD4 cell counts experienced reduced disease progression compared with individuals with the same CD4 cell count and viral load not receiving HAART. Consequently, the short-term prognosis associated with viral load levels and CD4 cell counts may differ in patients on HAART. Whether this effect will be observed with non-protease-inhibitor-containing HAART is not known at this time.

Combination antiretroviral therapy has been proven to be effective in suppressing plasma viral load (pVL) in patients infected with human immunodeficiency virus (HIV), but adherence to the antiretroviral regimen is crucial in order to maintain viral suppression. Simplified regimens are needed to improve adherence, especially in populations such as intravenous drug users (IVDUs). Triple combination regimens consisting of the non-nucleoside reverse transcriptase inhibitor nevirapine, with two nucleoside reverse transcriptase inhibitors, have shown efficacy in a range of patient populations[1-3]. A once-daily regimen comprising nevirapine (NVP), didanosine (ddI) and lamivudine (3TC) was administered to 70 IVDUs in an open-label, non-comparative pilot study[4]. The daily dosages were 400 mg NVP, 400 mg ddI and 300 mg 3TC. All drugs were taken simultaneously once a day. The majority of patients (56/70) were using methadone, polamidone or codeine substitution. The median baseline CD4 cell count was 247 cells/mm3 and the median plasma viral load (pVL) was 124 000 copies/mL. Forty-five patients (32%) had received a range of antiretroviral agents prior to enrolment for various periods of time. Approximately half (33/70) of patients discontinued therapy due to loss of follow-up (n = 12); rash (n = 5); side effects of methadone (n = 5); therapy failure (n = 4); or other reasons (n = 7). At week 8, 60% of the 39 patients on treatment had pVLs of <500 copies/mL. By week 24, approximately 70% of the 22 patients still on therapy had undetectable pVLs (<500 copies/mL) and this had risen to 100% by week 40 (10 patients) ( Fig. 1). At week 24, the ultrasensitive HIV–RNA–PCR assay was performed on samples from 11 patients, nine of which were below the limit of detection of 20 copies/mL (Roche Amplicor® Assay 1.5). By week 36, nine of 10 patients had pVLs below the limit of detection of the ultrasensitive test. CD4 count increased a median of 225 cells/μL from baseline ( Fig. 2). H)IV–RNA–PCR: percentage of patients with pVLs below limit of detection (< 500 copies/mL). CD4 count median change from baseline. Due to the high dropout rate in this patient population, it was not appropriate to perform an intent-to-treat analysis on the efficacy data. Pharmacological interactions between NVP and methadone/polamidone may lead to symptoms of methadone/polamidone withdrawal[5]. These effects were also observed in this study and the dose of methadone/polamidone had to be increased in 54% of the patients using these compounds. The average increase of methadone dosage was 45% (range 0–140%) ( Fig. 3). There was no need to increase the dosage of codeine. Five patients could not achieve a satisfactory methadone level and had to discontinue their antiretroviral therapy. Ten patients had to take their daily methadone dosage in more than one intake. For all patients who needed to increase their substitute dosage, it was important to increase the dosage immediately after starting therapy with NVP/ddI/3TC. Median increase of methadone/polamidone dosage with ddI, NVP, 3TC once-daily therapy. □, Baseline; ▪, during study. Despite the expected high dropout rate in this study, the once-daily NVP/ddI/3TC regimen appeared to be effective therapy in this ‘hard-to-reach’ patient population of IVDUs. This regimen has potential as part of a directly-observed-treatment (DOT) programme for HIV-infected IVDUs.

This is a brief report of preliminary results of the assessment of the correlation between baseline viral drug susceptibility and virological response in patients receiving mega-HAART. A total of 37 patients received > or = 6 drugs with a median follow-up of 8 months. There was evidence of extensive loss of viral drug susceptibility at baseline among the 24 patients analysed. Results showed that the magnitude and duration of virological response was associated with phenotypic viral drug resistance, although resistance did not lead to virological failure in all cases, and susceptibility did not lead to response in all cases.

The association between CD4 cell count and duration of virus load suppression was investigated in 558 patients in the Frankfurt HIV Clinic Cohort who had begun highly active antiretroviral therapy and who had virus load declines to =500 copies/mL. The Kaplan-Meier method estimated viral rebound in 42.5% of patients by 24 weeks and in 64.3% by 84 weeks. Risk of viral rebound was independently associated with baseline and changes from baseline CD4 cell count. The achieved CD4 cell count was the most important factor for prediction of viral rebound (relative hazard, 5.4 for an updated CD4 cell count of <20 vs. >500 copies/mL; P=.0001). Baseline virus load was not associated with virus load rebound. Lower baseline CD4 cell counts were associated with increased risk of viral rebound; however, this risk was significantly reduced in persons with low baseline CD4 cell counts who experienced substantial increases in CD4 cell counts during follow-up.

Human immunodeficiency virus type 1 (HIV-1) strains dually resistant to zidovudine and lamivudine (3TC) may arise during zidovudine-3TC combination therapy. The objective of this cross-sectional study (n = 43 patients) was to test the association between therapy response (clinical and immunologic) to zidovudine-3TC and the level of phenotypic zidovudine resistance and zidovudine resistance-associated genotype of 3TC-resistant isolates. Other variables included were baseline CD4+ cell count, baseline Centers for Disease Control and Prevention (CDC) classification, virus load, and time receiving zidovudine. Phenotypic resistance was assessed using a recombinant virus assay. Genotypic analysis was based on population sequencing of plasma HIV-1. In a univariate analysis using a logistic regression model, it was found that therapy response was significantly associated with phenotypic and genotypic zidovudine resistance, baseline CD4+ cell count, and virus load. After adjustment for all variables, phenotypic resistance to zidovudine remained the only significantly associated factor, independent of baseline CD4+ cell count, baseline CDC classification, and virus load.