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Objective To assess the baseline factors associated with haematological toxicity that lead to ribavirin or pegylated interferon (peginterferon) dosage reductions in hepatitis C and human immunodeficiency virus (HCV/HIV)-coinfected patients.Design Multicentre, prospective, observational study.Setting Eleven hospitals in Spain during the period 2002–2003.Subjects and methods One-hundred and forty-two HIV/HCV-coinfected patients received peginterferon-a2a plus ribavirin. Baseline characteristics and haematological parameters were recorded at baseline, week 4, 8, 12, 24 and 48. Cox's regression model was used to study the factors associated with the appearance of a haemoglobin level below 10g/dl (haemoglobin-endpoint), a neutrophil count below 750/mm3(neutrophil-endpoint) and a platelet count below 50,000/mm3(platelet-endpoint).Results Nineteen patients (13.4%) reached the haemoglobin-endpoint, 22.5% the neutrophil-endpoint and 7% the platelet-endpoint. Mean time of follow-up was 8 months (±3.5). A baseline haemoglobin level below 14g/dl [hazard ratio (HR): 3.65; 95% confidence interval (CI): 1.46–9.06] and treatment with zidovudine (HR: 3.25; 95% CI: 1.31–8.11) were the independent factors associated with the appearance of the haemoglobin-endpoint. A baseline neutrophil below 2050/mm3(HR: 3.59; 95% CI: 1.77–7.28) and baseline weight <60 kg (HR: 2.21; 95% CI: 1.04–4.56) were independently associated with the appearance of the neutrophil-endpoint. Baseline platelet count (x1000/mm3decrease) (HR: 1.074; 95% CI: 1.04-1.11) was independently associated with the appearance of the platelet-endpoint.Conclusions Baseline factors allow the identification of a subset of HIV/HCV-coinfected patients who are prone to experience haematological toxicity during HCV antiviral therapy.

Mitochondrial parameters in peripheral blood mononuclear cells (PBMC) and their relationship with mitochondrially- driven PBMC apoptosis were investigated in a group of HIV-1-infected long-term nonprogressors (LTNP) and compared with untreated asymptomatic HIV-1 infected typical progressors (TP) and uninfected healthy controls (HC). Twenty-six LTNP, 27 TP and 31 HC were evaluated. Studies were performed in PBMCs. Mitochondrial DNA content (mtDNA) was assessed by quantitative real-time PCR. Activities of mitochondrial respiratory chain complexes (MRC) II, III and IV were determined by spectrophotometry. Caspase-3 activity was assessed by fluorimetry, and caspase-9 activation and Bcl-2 levels were assessed by immunoblotting. mtDNA abundance (p &lt; 0.05), MRC complex II (p &lt; 0.001), complex III (p &lt; 0.01) and complex IV (p=0.01) were lower in the TP group than in the HC group. In the LTNP group these parameters were similar to those of the HC group except for complex II, which was decreased (p &lt; 0.01). The PBMC of TP showed the highest overall apoptotic activation, since their caspase-3 activity was greater than that of HC (p &lt; 0.05) and LTNP. In the case of LTNP, however, the difference was non-significant. Caspase-9 and the caspase-9/Bcl-2 ratio were both over-expressed in TP compared to HC (p &lt; 0.01) and LTNP (p &lt; 0.05). Both of these measurements indicate that mitochondrially- driven apoptosis in TP is greater than in LTNP and HC. A relationship between mitochondrial damage and apoptotic activation was found in TP. Mitochondrial damage is associated with increased PBMC apoptosis in patients with active HIV-1 replication (TP). These abnormalities are slight or not present in LTNP.

Objective Investigate the metabolic and mitochondrial effects of switching a highly active antiretroviral therapy (HAART) regimen with a high mitochondrial toxicity profile to a HAART with a theoretically low mitochondrial toxicity.Patients and Methods Six consecutive HAART-experienced patients receiving at least one dideoxy-nucleoside reverse transcriptase inhibitor (NRTI) switched to enfuvirtide plus tenofovir plus saquinavir/ritonavir (T20+TDF+SQV/r). Blood samples were collected at baseline, 12 and 24 weeks after the switch, and viral load (VL) and lymphocyte CD4+T-cell count were determined. Metabolic parameters consisted of fasting serum triglycerides, cholesterol (total and fractions), glucose, insulin, C-peptide and lactate. Mitochondrial assessment consisted on mitochondrial DNA (mtDNA) quantification, COX-II mitochondrial protein expression rate, mitochondrial respiratory chain complex III and IV activities, and oxygen consumption in peripheral blood mononuclear cells. For baseline mitochondrial comparisons, we included six HIV-infected patients naive for ART.Results Switched patients exhibited a mean increase of 26 CD4+T-cells/mm3and a mean decrease of 1.1 log in VL (P=NS for both). Lactate, lipids and glycaemia remained stable during the study; only insulin levels increased significantly (P<0.05). Switched patients exhibited, at baseline, low mitochondrial measurements, being significant only for complex III and IV activities with respect to naive patients (P<0.05 for both). MtDNA content did not rise significantly during the study. However, we observed increases in COX-II mitochondrial protein synthesis (124%, P<0.05), complex III activity (127%, P<0.05), complex IV activity (86%, P=0.37) and oxygen consumption (194%, P<0.05).Conclusion Switching a HAART-containing dideoxy-NRTI to T20+TDF+SQV/r minimally alters metabolic parameters and exerts beneficial effects on mitochondrial function at 24 weeks. Mitochondrial improvement should be considered as an additional advantage of this rescue therapy.

Objective To assess the efficacy and safety of an extended treatment period in HIV/hepatitis C virus (HCV)-coinfected patients without early virological response (EVR).Methods Patients received pegylated interferon (peg-INF)-a2a 180 µg/week plus ribavirin 800 mg/d for 12 weeks. Patients achieving EVR at week 12 continued under therapy for an additional 12 or 36 weeks depending on genotype. Patients without EVR were randomized to complete the standard treatment or treatment lasting 72 weeks (extension arm).Results One hundred and ten patients were included (mean age 38.7 years, mean weight 68 kg, 74% males, 74% on highly active antiretroviral therapy, mean CD4+T-cell count 564 cells/mm3). Fifty-one patients harboured genotype 1, 44 genotype 2/3, and 15 genotype 4. Fifty-three had an HCV load >800,000 IU/ml. Premature interruptions occurred in 32.7%. EVR was achieved in 63.6% (51% in genotype 1, 88.6% in genotype 2/3, 33.3% in genotype 4). End-of-treatment response was 52.7% (47.2% in genotype 1, 68.2% in genotype 2/3, 26.7% in genotype 4). Sustained virological response (SVR) was achieved in 41.8% (37.3% in genotype 1, 54.6% in genotype 2/3, 20% in genotype 4). Only one patient allocated to the extended arm achieved SVR. The rate of drop-outs in the extension arm was 68%. The negative predictive value of EVR was 97.5%.Conclusions This study shows no benefit of extending therapy in patients without EVR at week 12. Measures to improve adherence to HCV antiviral therapy should be considered when new approaches based on extended periods of treatment are investigated.

Using a multicenter, cross-sectional, observation study, the long-term safety, metabolic profile, and viral efficacy of nevirapine (NVP)-based approaches in HIV-1-infected patients treated for at least 2 years were assessed. For 4 months, all consecutive HIV-1-infected patients who had been receiving an NVP-containing regimen for at least 2 years were recruited. A total of 613 patients were included with a median follow-up period of 43 months (IQR: 31–51). At baseline, 24.5% (150 patients) were treatment naive, 41.5% (254 patients) switched for simplification purposes, and 34% (209 patients) were failing HAART. Increases by five times or more in AST/ALT values were observed in fewer than 2% of patients. Only 5.7% of all adverse events reported during the investigation were attributable to NVP. The percentage of patients with normal HDL cholesterol levels rose from 17.7% at baseline to 35.4% at the last visit. At the latest time point available for analysis, 76% of naive and 74% of those who had switched had HIV-1 RNA loads of <50 copies/ml, while 59% of salvage patients achieved this level of viral suppression. Factors associated with viral suppression at the latest visit were adequate adherence (OR: 2.58, 95% CI: 0.85–7.78, p < 0.001), first-line treatment (OR: 3.02, 95% CI: 1.52–6.00, p = 0.002), and baseline CD4 cells >400 cells/µl (OR: 2.34, 95% CI: 1.22–4.47, p = 0.010). Exposure to nevirapine for up to 4 years is safe. Liver toxicity is infrequent and generally mild. HDL cholesterol levels consistently increase over time and viral suppression is maintained.

Background In vitrostudies have reported controversial effects of protease inhibitors (PIs) on mitochondrially driven apoptosis. Additionally, since PIs in the clinical setting are almost always given in combination with nucleoside analogues, which may have negative effects on mitochondrial DNA (mtDNA), the impact of PI-containing highly active antiretroviral therapy (HAART) on apoptosis and mtDNA content is unclear.Patients and methods A cross-sectional study was performed including 20 HIV-negative (HIV-) patients, 16 HIV-positive, antiretroviral-naive (HIV+) patients and 17 HIV-positive patients receiving the PI nelfinavir (NFV) plus zidovudine and lamivudine (AZT+3TC) or didanosine and stavudine (ddI+d4T) - collectively known as HIV+PI - as first-line antiretroviral treatment for at least 12 months. Peripheral blood mononuclear cells (PBMCs) were isolated. BCL2 expression (anti-apoptotic) and the levels of the cleaved, active form of caspase-9 (pro-apoptotic) were determined by western blot. An index of mitochondrially driven apoptotic activation was estimated calculating the ratio caspase-9:BCL2. Mitochondrial DNA content was measured by real-time PCR.Results BCL2 expression was lower in HIV+ than in HIV-patients (P<0.01), whereas levels of caspase-9 were higher (P=0.001). The caspase-9:BCL2 ratio was significantly increased in HIV+ compared with HIV- individuals (P<0.001). Mitochondrial DNA content was also decreased in HIV+ compared with HIV- patients (P<0.001). The HIV+PI group exhibited a trend to normalization for BCL2 expression and caspase-9 compared with the HIV+ group, whereas the caspase-9:BCL2 ratio significantly improved (decreased, P<0.05 compared with HIV+ group). The mtDNA content in the HIV+PI group was similar to that of the HIV+ group, although the results of mtDNA content differed depending on whether NFV was combined with AZT+3TC (preserved) or with ddI+d4T (depleted). Conversely, no differences were found in apoptotic markers between the two subgroups of HIV+PI.Conclusions NFV-based PI-containing HAART regimens may exert some beneficial effects counteracting the increased mitochondrially driven apoptosis present in HIV-infected people.

Increased apoptosis in CD4+ T lymphocytes plays an important role in the pathogenesis of HIV infection and it has also invoked some HIV-related as well as antiretroviral-related adverse events. We assessed whether increased apoptosis is also present in the skeletal muscle of HIV-infected patients. We included 36 consecutive individuals, 18 without (group A) and 18 with HIV infection. The latter group consisted of five asymptomatic antiretroviral-naive HIV-infected individuals (group B), six asymptomatic HIV-infected individuals on highly active antiretroviral therapy (HAART, group C), and seven HIV-infected individuals on HAART with lipodystrophy (group D). Immunohistochemical reaction using deoxyribonucleotidyltransferase-mediated- dUTP-biotin nick-end labeling (TUNEL) was performed on skeletal muscle samples. None of the uninfected patients (group A) showed data of increased apoptosis, while 16 out of 18 infected patients did (p < 0.001). All subgroups of infected subjects (groups B–D) showed a significant increase of apoptosis in TUNEL with respect to uninfected individuals, but the comparison between the different subgroups of infected patients did not reveal significant differences. We conclude that skeletal muscle of HIV-infected patients exhibits increased apoptosis compared with that of uninfected patients, but the role of HAART in inducing apoptosis remains to be established.

Background Simplified antiretroviral regimens are needed to improve patient adherence and quality of life. The purpose of this study was to evaluate the efficacy and safety of a once-daily regimen consisting of didanosine (ddI), lamivudine (3TC) and nevirapine (NVP) for adult antiretroviral-naive patients with HIV-1 infection.Methods This was a prospective, one-arm, multicentre pilot study. Daily drug dosage was 250 or 400 mg didanosine, 300 mg lamivudine and 400 mg nevirapine. The primary outcome measure was the percentage of patients with a plasma HIV-RNA level <50 copies/ml at 12 months on an intention-to-treat (ITT) basis.Results Seventy patients were enrolled in the study. At baseline, mean plasma HIV-1 RNA was 5.10 log10copies/ml, and mean CD4 cell count was 262 cells/µl. At month 12, 67% (95% CI: 56–78) of patients maintained a viral load of <50 copies/ml in the ITT analysis and CD4 counts increased a median of 201 cells/µl. The treatment was more effective in patients with baseline CD4 counts >100 cells/µl than in those with a poorer immunological status at baseline, although the number of patients with CD4 counts <100 was low. Four patients died during the study period. Therapy was discontinued in 18 patients due to virological failure in 11, adverse events in seven, loss to follow-up or withdrawal of consent in four and death in one. Eight out of nine patients with available genotype after virological failure showed resistance mutations to NVP (Y181C and others) and 3TC (M184V/I), and four of them also had ddI resistance (L74V). The lipid profile was favourable, with a decrease in the ratio of total-to-high density lipoprotein cholesterol.Conclusion A once-daily combination of ddI, 3TC and NVP seems to be an effective, safe and easy-to-take regimen in antiretroviral-naive patients, at least in those who do not have severe immunodepression at baseline.

Introduction Alternation of antiretroviral drug regimens has been proposed as a novel treatment strategy for HIV infection. However, some concerns persist regarding antiviral efficacy, adherence, toxicity and resistance evolution in the long term.Methods A total of 161 antiretroviral-naive HIV-1-infected patients were randomized to receive stavudine/ didanosine/efavirenz (group A) or zidovudine/lamivudine/ nelfinavir (group B) or to alternate between the two regimens every 3 months starting with regimen A (group C). Antiviral efficacy, adherence, safety and tolerability were analysed every 12 weeks.Results After 96 weeks, time to virological failure was significantly delayed in the alternating regimen compared with the standards of care regimens. Virological suppression was seen in 46%, 48% and 58% of patients in groups A, B and C, respectively, in the intention-to-treat analysis and in 75%, 76% and 97% in the on-treatment analysis (A vs C: P=0.014; B vs C: P=0.016; A vs B: P=0.849). At the end of the study, 94% of patients in group A and 92% in groups B and C reported an adherence greater than 95%. Alternating therapy was associated with a similar impact on CD4+ counts in comparison with the standards of care regimens, as well as a lower mitochondrial DNA/nuclear DNA (mtDNA/nDNA) ratio decrease in the mitochondrial substudy performed on 37 patients. The frequency and intensity of adverse events in the alternating group decreased during subsequent cycles.Discussion Our results favour the hypothesis that proactive therapy switching may delay the accumulation of resistance mutations. Moreover, the alternating regimen was well tolerated and adherence remained comparably high in all treatment groups. The lower mtDNA/nDNA ratio decrease observed in this group may imply a lower impact on mitochondrial toxicity than in standard regimens.

Objective To assess the efficacy and safety of a once-daily antiretroviral regimen in HAART-experienced subjects with long-lasting viral suppression.Methods One-hundred-and-sixty-nine patients with chronically suppressed viral load (limit of detection <50 copies/ml) were recruited. Based on patient willingness to simplify treatment, 84 of them continued receiving their usual treatment (BID Group) and 85 switched to once-daily didanosine/tenofovir/nevirapine (QD Group) in a non-randomized fashion.Results At week 48, the proportion of patients with viral suppression in the QD and in the BID Group, respectively, was 97 vs 100% in the per-protocol analysis (P=0.497), and 76 vs 86% for the intention-to-treat analysis (P=0.176). Nevertheless, CD4 count decreased in the QD Group, with a mean decline of 95 cells/mm3(95% CI: 45–145). Twelve subjects in the QD Group (14%) discontinued treatment due to adverse events, mainly nevirapine-related hepatitis (6%). No significant differences regarding the rate of acute pancreatitis or peripheral neuropathy were observed between both groups. A significant improvement in the lipid profile was only seen in the QD Group. High levels of adherence were observed in both groups during follow-up, as well as a good quality of life. At week 48, a reduction in effort to take medication (P=0.001) and an increment in the satisfaction with the treatment (P<0.001) was only seen in the QD group. No differences were observed in median nevirapine trough levels between patients on twice-daily nevirapine at baseline (4820 ng/ml) and subjects in the QD Group (6090 ng/ml, P=0.30).Conclusion Treatment simplification to a once-daily antiretroviral regimen based on didanosine, tenofovir and nevirapine may be a valid approach in HIV-infected subjects with long-lasting viral suppression. Combination of standard doses of didanosine and tenofovir may have contributed to the CD4 cell decline observed with this QD regimen.

Background A decrease in the mitochondrial (mt) DNA to nuclear DNA ratio has gained acceptance as a marker of mitochondrial toxicity in treated HIV-infected patients, but the functional meaning of this alteration is unclear.Methods We assessed mtDNA content, mitochondrial content and function in peripheral blood mononuclear cells (PBMCs) of consecutive asymptomatic HIV-infected patients. Patients selected had been receiving a first-line highly active antiretroviral therapy (HAART) regimen for at least 6 months, consisting of zidovudine plus lamivudine or stavudine plus didanosine plus either nelfinavir or nevirapine, or were antiretroviral-naive. The mtDNA content was assessed by quantitative real-time PCR, mitochondrial content by citrate synthase activity, enzyme activity of complexes III and IV (both partially encoded by mtDNA) of the electron transport chain by spectrophotometry, oxygen consumption by polarography, and oxidative damage in cell membranes by monitoring cis-parinaric acid fluorescence.Results Mitochondrial content was significantly lower in all treated groups. Patients receiving stavudine plus didanosine had mtDNA depletion and a decrease in complex IV activity. However, oxygen consumption capacity and lipid peroxidation were unaffected in all groups.Conclusion Long-term HAART may induce mitochondrial abnormalities in PBMC mitochondria, which do not necessarily translate into functional abnormalities, at least in asymptomatic patients. This study was presented in the 4th International Workshop on Adverse Drug Reactions & Lipodystrophyin HIV (San Diego, Calif., USA, September 2002) and in ‘Late Breakers & Hot Topics’ session in the 6th International Congress on Drug Therapy in HIV Infection(Glasgow, UK, November 2002).

The main objective of the present study was to ascertain if mitochondrial DNA (mtDNA) depletion as reported in HIV-infected patients with highly active antiretroviral therapy (HAART)-related lipodystrophy (LD) implies any degree of mitochondrial respiratory chain (MRC) dysfunction. For this purpose, we evaluated HIV patients on different HAART schedules with LD (group A; n=12) and on HAART but without LD (group B; n=12), and untreated HIV-infected patients as controls (group C; n=24). mtDNA content was determined on peripheral blood mononuclear cells (PBMCs) with a real-time PCR method. Complex II, III and IV activities of the MRC were simultaneously measured spectrophotometrically, as were spontaneous and stimulated oxygen consumption by PBMCs. Compared to controls (group C, 100%), patients with LD (group A) showed a decreased mtDNA content (54%, P<0.001), which was associated with a decline in complex III (62%, P<0.05) and IV activity (69%, P<0.05) (both complexes partially encoded by mtDNA), but not in complex II activity (exclusively encoded by nuclear DNA). Patients in group B showed a similar pattern of mitochondrial dysfunction but to a lesser extent and without statistical significance. Respiratory activities in both treated groups (A and B) did not differ in comparison with controls. We conclude that mtDNA depletion occurring during HAART is associated with deficiencies in MRC complexes partially encoded by mtDNA, which are detectable by PBMCs. Presented in ‘Late Breakers and Hot Topics’ session at 6th International Congress on Drug Therapy in HIV Infection, Glasgow, UK, 17–21 November 2002.

Background Non-nucleoside reverse transcriptase inhibitor-containing regimens may be a valid alternative to protease inhibitor-containing regimens for initial antiretroviral therapy, but to date few studies comparing these two strategies have been performed.Objective To evaluate the efficacy and safety of nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients.Design Randomized, open-label, multicentre trial.Setting Twelve centres in Spain (9) and Argentina (3).Patients One hundred and forty-two HIV-infected naive patients without AIDS.Interventions Patients received combivir (zidovudine 300 mg/lamivudine 150 mg, twice-daily) plus either nelfinavir (1250 mg) twice-daily (zidovudine/lamivudine/nelfinavir, n=70) or nevirapine (200 mg) twice-daily (zidovudine/lamivudine/nevirapine, n=72), and were followed for 12 months. The primary endpoint was the proportion of patients with a plasma HIV-1 RNA (pVL) of less than 200 copies/ml by PCR at 12 months. pVL of less than 20 copies/ml (PCR), changes in CD4 counts, clinical progression and adverse events were also evaluated. Efficacy was assessed using intent-to-treat (ITT) (missing=failure) and on-treatment analysis.Results At 12 months in the ITT analysis the proportion of patients with pVL below 200 copies/ml was 60% (95% CI 48.5–71.5) in the zidovudine/lamivudine/nelfinavir arm and 75% (95% CI 65–85) in the zidovudine/lamivudine/nevirapine arm (P=0.06), and the proportion below 20 copies/ml was 50% (95% CI 38.3–61.7) and 65% (95% CI 54.2–76.2), respectively (P=0.06). No differences were found when comparing the subgroup of patients with baseline pVL of more than 100 000 copies/ml. A gain of +173 and +162 CD4 cells/mm3, respectively, was observed. Zidovudine/lamivudine/nelfinavir was discontinued in 21% of patients, and zidovudine/lamivudine/ nevirapine in 25%, due to toxicity (P>0.2).Conclusions Our results suggest that zidovudine/ lamivudine/nevirapine is at least as effective as zidovudine/lamivudine/nelfinavir as first-line therapy for HIV disease.

The aim of the current study was to analyze the frequency and characteristics ofsymptomatic myopathies occurring in rheumatoid arthritis (RA) patients, to correlate these findings with clinical data, and to evaluate their therapeutic implications. All RA patients from a cohort of 350 RA patients from a single institution who developed muscular symptomatology during an 8-year period were included in the study (n = 21). Clinical and laboratory data and electromyographic results were recorded in all cases, and an open muscle biopsy was performed. Weakness and muscle atrophy were the most common symptoms. Serum creatine kinase was increased in 8 cases (38%). Histopathologic study showed type 2 atrophy in 12 cases. In 13 cases, a treatable disease was diagnosed: dermatomyositis (n = 2), d-penicillamine-related dermatomyositis (n = 2), polymyositis (n = 1), muscular mononuclear cell infiltration (n = 3), polyarteritis nodosa (n = 1), glucocorticoid myopathy (n = 3), and toxic chloroquine myopathy (n = 1). In all but 1 patient, muscular clinical response to new therapy and/or drug withdrawal was satisfactory. Although symptomatic muscular involvement in RA is low (6% in the current series), we have found that nearly two thirds of cases were caused by potentially treatable conditions, mainly myositis or toxic myopathies.