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We studied 382 multiexperienced HIV-infected patients followed up for > or =3 months after starting lopinavir/ritonavir (LPV/r) to identify the factors predicting hypertriglyceridemia and high non-HDL cholesterol levels (triglycerides > or =200 mg/dl and/or non-HDL cholesterol > or =190 mg/dl) after 6 and 12 months of LPV/r exposure. The predictors of hypertriglyceridemia were higher baseline triglyceride levels [OR: 2.28 (95% CI: 1.67-3.12) for each additional 100 mg/dl; p = 0.001], the total duration of antiretroviral treatment [OR: 1.26 (95% CI: 1.12-1.41) for each additional year; p = 0.01], CDC stage C (OR: 2.06; 95% CI: 1.24-3.88; p = 0.02), and male gender (OR: 2.52; 95% CI: 1.42-4.74; p = 0.02); intravenous drug abusers seem less likely to develop the event (OR: 0.52; 95% CI: 0.37-0.92; p = 0.03). The predictors of high non-HDL cholesterol levels were higher baseline levels [OR: 3.92 (95% CI: 1.92-6.24) for each additional 100 mg/dl; p = 0.001) and the combination of NRTIs and NNRTIs with LPV/r (OR: 1.83; 95% CI: 1.10-3.69; p = 0.03). The 75 patients stopping LPV/r showed a significant reduction in median triglyceride and non-HDL cholesterol levels after 3 months of 39 mg/dl and 20 mg/dl (p = 0.01 for both), respectively. Patients with high triglyceride and non- HDL cholesterol levels at the start of LPV/r treatment are at higher risk of developing hyperlipidemia.

The objective of this study was to find predictive factors of lopinavir/ritonavir (LPV/r) discontinuation for drug-related toxicities in highly pre-treated human immunodeficiency virus (HIV)-infected subjects. The study was an observational study of HIV patients starting LPV/r with HIV RNA > 3log10 copies/mL and a follow-up > or = 6 months. Parameters studied were HIV RNA, CD4+ cell counts, metabolic parameters and drug-related adverse events. Acquired immune deficiency syndrome (AIDS) events and deaths were recorded. The Kaplan-Meier (KM) model was used to estimate time-dependent probability, and the multivariable Cox model to identify predictors of LPV/r discontinuation for adverse events. The study evaluated 416 HIV-infected patients. Seventy-seven patients (18.5%) discontinued LPV/r for toxicities. Adverse events leading to LPV/r discontinuation were gastrointestinal symptoms in 40 cases, hyperlipidaemia in 27 and increase of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) in 10 patients. Nineteen patients (4.6%) developed an AIDS event during observation and 15 (3.6%) died. The KM probability of LPV/r discontinuation for toxicities was 5.3% (range 3.1-7.5%) at month 12 and 15.7% (range 12.1-19.3%) at month 24. Subjects with hepatitis C virus (HCV)-HIV co-infection (odds ratio (OR) 7.40; 95% confidence interval (CI) 3.73-14.66 versus HCV-negative; P = 0.001) and receiving LPV/r plus nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitor (PI)/non-nucleoside reverse transcriptase inhibitor (NNRTI) (OR 1.74; 95% CI 1.04-2.91 versus LPV/r plus only NRTIs; P = 0.04) showed a higher risk of LPV/r discontinuation by a Cox analysis, whereas non-intravenous drug abusers (IVDUs) (OR 0.40; 95% CI 0.24-0.67 versus IVDUs; P = 0.001) had a lower risk. The rate of discontinuation for toxicity decreased by 17% for each additional month of LPV/r exposure (OR 0.83; 95% CI 0.80-0.86 for each additional month; P < 0.001). LPV/r was substantially well tolerated. Diarrhoea was the most frequent adverse event leading to discontinuation. HCV-HIV co-infected patients and patients with a short exposure to LPV/r have a higher risk of discontinuing LPV/r and should be strictly monitored.

Objectives: The long-term virological efficacy of lopinavir/ritonavir-containing highly active antiretroviral therapy (HAART) in HIV-infected patients failing a first-line protease inhibitor (PI)-based regimen is still unclear., Methods: An observational study was carried out from December 2000-December 2002 on 111 consecutive patients starting lopinavir/ritonavir. The primary end-point was virological success (HIV RNA <50 copies/mL in two consecutive determinations). CD4 outcome, lipid levels and adverse events were recorded. The Kaplan-Meier method and log-rank test were used to estimate the time-dependent probability of reaching the end-point using intention-to-treat and on-treatment approaches., Results: Ninety-six patients obtained virological success during follow-up; Kaplan-Meier analysis showed that the time-dependent probability of obtaining this end-point was 78.4% at month 12 and 85.8% at month 24. The median CD4+cell count increased by 118 cells/mm(3) from baseline to month 12 and by 153 cells/mm(3) to month 24. Thirty-one patients discontinued lopinavir/ritonavir: 16 because of drug-related toxicities, six for simplification, five because of virological failure, one patient was lost at follow-up and three died. An elevation in lipid parameters was observed, but only a minority of patients developed a grade 3 or higher hypertriglyceridaemia and/or hypercholesterolaemia. Among the 15 patients not reaching virological success, five had < or =5 mutations in the protease region known to reduce susceptibility to lopinavir/ritonavir (one discontinued lopinavir/ritonavir because of gastrointestinal intolerance), five had no mutations (two discontinued lopinavir/ritonavir because of gastrointestinal intolerance) and five showed > or =6 mutations (all discontinued lopinavir/ritonavir); however, of the patients who discontinued lopinavir/ritonavir none achieved HIV RNA <50 copies/mL on subsequent regimens., Conclusions: Lopinavir/ritonavir was highly effective and well tolerated in HIV-infected patients failing a first-line PI-based HAART.

We compared immunovirological outcomes and toxicities of HAART regimens including LPV/r and IDV/r in antiretroviral naïve HIV-1 patients. We retrospectively selected 55 patients starting LPV/r and 52 starting IDV/r as first-line HAART. Immunovirological and metabolic parameters were recorded at baseline and every 3 months as were side effects, AIDS-defining events and deaths. Demographic characteristics and NRTIs included in the regimens were comparable. Both groups reached undetectable HIV-RNA plasma viremia from third month and maintained during follow-up. However, patients receiving IDV/r had a lower probability to obtain virological success (RH: 0.46). Patients receiving IDV/r patients showed a greater increase of total cholesterol (P = 0.01). Three patients on LPV/r and 21 on IDV/r discontinued the drug for toxicity, leading to a 8.40 higher risk of discontinuation in the latter group. In our clinical setting IDV/r showed to be less effective and more toxic than LPV/RTV as first-line HAART.

The wide use of protease inhibitors (PI) as part of a highly active antiretroviral (HAART) regimen is associated with the development of several side effects. Among these, the development of avascular necrosis (AVN) of the bone is being reported more frequently and it has been related both to the use of PI and to HIV-1 infection itself. We report here a case of AVN of the bone in a patient taking the new PI lopinavir (LPV)/ritonavir (RTV) as part of a HAART regimen.

We evaluated the virological outcome of lopinavir/ritonavir (LPV/RTV) in 224 HIV-1-infected and protease inhibitor (PI)-experienced patients showing virological failure to a highly active antiretroviral therapy (HAART) regimen and followed up for at least 3 months. At baseline, the median level of plasma viraemia was 4.61 log10 copies/ml (range 3-6.48) and the median CD4 cell count was 219 cells/mm3 (range 1-836). During a median follow-up of 272 days (range 92-635), we observed an increase in the number of CD4 cells (P=0.02) and a dramatic decrease in plasma viraemia levels (P=0.0001), which became undetectable in 122 patients (54.5%). The closely related predictive factors were baseline plasma viraemia levels and the number of mutations known to reduce susceptibility to LPV/RTV. Thirty-one patients (13.8%) discontinued LPV/RTV during the follow-up, and one AIDS event and three deaths were recorded. Of the 134 patients (59.8%) who underwent a baseline genotype resistance test, 22 (16.4%) had > or = 6 mutations known to reduce LPV/RTV susceptibility; plasma viraemia became undetectable in 76 patients (56.7%), only five of whom harboured > or = 6 mutations at baseline (P=0.0001). The independent predictive factors related to virological success were plasma viraemia levels and the number of mutations reducing susceptibility to LPV/RTV at baseline; each additional log10 copies/ml of HIV RNA reduced the probability of virological success by 34.0% and each extra mutation by 14.5%.

The outcome of second-line protease inhibitor (PI)-containing highly active antiretroviral therapy (HAART) was investigated in 263 patients who were failed by (n = 148) or intolerant of (n = 115) a first HAART regimen. The endpoints were virologic failure (decline in HIV RNA < 1 log10 copies/ml after > or = 2 months) and discontinuation due to intolerance/toxicity. During a median follow-up of 483 days (33-1087 days), 154 patients (59%) discontinued the second regimen, 86 (33%) because of intolerance/toxicity; another 135 patients (51.3%) showed virologic failure. Independent factors associated with virologic failure (Cox's model) were 7 to 12 months of first HAART (hazard ratio [HR] 1.70 versus < or = 6 months: 95% confidence interval [CI], 1.08-2.70) and gender (HR 1.58 males versus females: 95% CI, 1.04-2.30); the negatively associated factors were advanced age (HR 0.61 > 34 years versus < or = 34 years: 95% CI, 0.42-0.88), a saquinavir-containing first HAART (HR 0.57 versus indinavir: 95% CI, 0.34-0.93) and change due to intolerance/toxicity (HR 0.58 versus failure: 95% CI, 0.35-0.98). The independent variables predictive of discontinuation due to intolerance/toxicity were the reason for switching (HR 1.79 intolerance versus failure: 95% CI, 1.02-3.16) and the first protease inhibitor (PI) regimen (HR 0.42 ritonavir versus indinavir: 95% CI, 0.22-0.80). Given that patients who are failed by a first regimen are at high risk of having rescue therapy fail as well, second-line regimens including therapies directed by testing of drug resistance patterns of clinical viral isolates are warranted. Patients experiencing toxicity due to a first PI-containing regimen are at risk of toxicity to other PIs and should be addressed to PI-sparing HAART.

Objective: To verify the effectiveness of highly active antiretroviral therapy (HAART) and to identify any factors predictive of clinical outcome in a clinical setting., Design: Observational study., Methods: Treatment failure (i.e., the occurrence of new or recurrent AIDS-defining events, death or any definitive discontinuation) and the course of CD4+ cell counts and HIV RNA copies were evaluated in 250 heavily pretreated HIV-infected patients starting HAART [153 with indinavir (IDV), 55 with ritonavir (RTV), 43 with saquinavir (SQV)]. Univariate and multivariate analyses were performed to identify predictors of worse outcome., Results: During a median follow-up of 8 months, 75 patients (30%) had treatment failure because of the occurrence of an AIDS-defining event or death (n = 24), inefficacy (n = 24), or severe intolerance (n = 27). Twenty new and six recurrent AIDS-defining events, and nine deaths occurred (six out of 20 AIDS-defining events and two out of nine deaths within 1 month of treatment). CD4+ counts were above 200 x 10(6)/l at AIDS diagnosis in only two patients. None of the SQV patients, 12 (7.8%) of the IDV patients, and 15 (27.3%) of the RTV-treated patients were considered non-compliant. The SQV-containing regimens independently correlated with treatment failure (relative risk, 2.46; 95% confidence interval, 1.20-5.03; versus IDV). Low compliance partially determined outcome in RTV-treated patients; both severe immunodepression and AIDS at baseline were predictive of treatment failure. There was a 10-fold increase in CD4+ cell counts in the patients treated with IDV and RTV; the best virological outcome occurred in IDV-treated patients, with 68.4% of patients showing undetectable HIV RNA copies after 6 months., Conclusions: HAART was effective in 70% of patients; low compliance and previous AIDS diagnosis represented predictive factors of therapy failure.