Enric Pedrol

Mitochondrial Effects of HIV Infection on the Peripheral Blood Mononuclear Cells of HIV-Infected Patients Who Were Never Treated with Antiretrovirals

To investigate the effects of HIV infection on mitochondrial DNA (mtDNA) content and other mitochondrial parameters, we used peripheral blood mononuclear cells (PBMCs) from 25 asymptomatic antiretroviral-naive human immunodeficiency virus (HIV)-infected patients and from 25 healthy control subjects. HIV-infected patients had significant decreases in mtDNA content (decrease, 23%; P<.05) and in the activities of mitochondrial respiratory chain (MRC) complex II (decrease, 41%; P<.001), MRC complex III (decrease, 38%; P<.001), MRC complex IV (decrease, 19%; P=.001), and glycerol-3-phosphate dehydrogenase (decrease, 22%; P<.001), along with increased lipid peroxidation of PBMC membranes (P=.007). Therefore, HIV infection is associated not only with mtDNA depletion, but also with extensive MRC disturbances and increased oxidative damage.

Mitochondrial involvement in antiretroviral therapy-related lipodystrophy

ObjectivesThe management of HIV infection has greatly improved during recent years essentially because of the appearance of new antiretroviral drugs. Highly active antiretroviral therapy (HAART) has achieved important reductions of viraemia and significant recoveries of CD4+ cell counts in HIV-infected patients. Nonetheless, cases of HIV-infected individuals experiencing lipodystrophy (LD) are being increasingly reported. The purpose of this work was to analyse whether the presence of mitochondrial abnormalities is a frequent feature in LD, since we previously detected mitochondrial abnormalities in an HIV-patient. The second main objective was to study whether LD could be associated with a specific drug. DesignSeven HIV patients presenting LD and five HIV non-LD controls participated in the study. LD patients met the following criteria: (1) LD was their only clinical abnormality, (2) LD was clinically relevant, (3) compliance with antiretroviral treatment was higher than 90% and (4) patients did not have personal or familial history suggestive of mitochondrial disease or neuromuscular disorder. MethodsHistological stainings, histo-enzymatic reactions, enzymatic and respiratory activities of mitochondrial respiratory chain complexes, and mitochondrial DNA (mtDNA) depletion and rearrangements were examined on muscle mitochondria. ResultsStructural muscle abnormalities, mitochondrial respiratory chain dysfunction or mtDNA deletions were detected in all HIV lipodystrophic patients. ConclusionsThe mitochondrial abnormalities found suggest that mitochondrial dysfunction could play a role in the development of antiretroviral therapy-related lipodystrophy.

Efficacy and safety of switching from boosted lopinavir to boosted atazanavir in patients with virological suppression receiving a LPV/r-containing HAART: the ATAZIP study.

Objectives:To evaluate the efficacy and safety of switching from boosted lopinavir (LPV/r) to boosted atazanavir (ATV/r) in virologically suppressed HIV-1-infected patients versus continuing LPV/r. Methods:Forty-eight weeks analysis of a randomized, open-label, noninferiority trial including patients with virological suppression (≤200 copies/mL for ≥6 months) on LPV/r-containing triple highly active antiretroviral therapy. Patients (n = 248) were randomized 1:1 either to continue LPV/r twice a day (n = 127) or to switch to ATV/r every day (ATV/r; n = 121), with no change in nucleoside reverse transcriptase inhibitor backbone. Those known to have >4 protease inhibitor (PI)-associated mutations and/or who had failed >2 PI-containing regimens were excluded. Results:Baseline characteristics were balanced. 30% harboured ≥1 PI-associated mutation (10% harboured ≥1 major mutation). Treatment failure at 48 weeks (primary end point) occurred in 20% (25 of 127) of the LPV/r arm and in 17% (21 of 121) of the ATV/r arm (difference −2.3%; 95% confidence interval: −12.0 to 8.0; P = 0.0018). Virological failure occurred in 7% (9 of 127) of the LPV/r arm and in 5% (6 of 121) of the ATV/r arm (difference −2.1%; 95% confidence interval: −8.7% to 4.2%, P < 0.0001 for noninferiorating). CD4+ changes from baseline were similar in each arm (approximately 40 cells/mm3). Adverse event rate leading to study drug discontinuation was 5% in both arms. Median fasting triglycerides and total cholesterol decreased significantly in the ATV/r arm (−53 and −19 mg/dL, respectively versus −4 and −4 mg/dL in the LPV/r arm; P < 0.001 in both comparisons). Alanine aminotransferase/aspartate aminotransferase hepatic abnormalities were similar in the 2 arms. Conclusions:Switching to ATV/r in virologically suppressed patients who were receiving a LPV/r-containing highly active antiretroviral therapy provided comparable (noninferior) efficacy and a safety profile with improved lipid parameters [ISRCTN24813210].

Influence of HAART on the Clinical Course of HIV-1-Infected Patients With Progressive Multifocal Leukoencephalopathy : Results of an Observational Multicenter Study

Background:The aim of this study was to analyze the incidence of new cases, survival of HIV-1-infected patients with progressive multifocal leukoencephalopathy (PML), and the characteristics of PML-associated immune reconstitution inflammatory syndrome (IRIS). Methods:Multicenter observational cohort study of all HIV-1-infected patients newly diagnosed of PML in 7 hospitals in Barcelona (Spain) from 2002 to 2006. The annual incidence of PML was calculated. Survival was estimated using the Kaplan-Meier method. IRIS was defined as new onset or rapid worsening of PML shortly after initiation of highly active antiretroviral therapy together with a decline in HIV-1 viral load and rising of CD4 lymphocytes. Results:Sixty-one new cases of PML were diagnosed. The mean survival time was 15 months [95% confidence interval (CI), 11 to 19]. The Kaplan-Meier estimates of the probability of survival were 47.7% (95% CI, 35 to 59) at 6 months, 38.6% (95% CI, 25 to 51) at 12 months, 35.1% (95% CI, 22 to 48) at 24 months, and 25.1% (95% CI, 10 to 40) at 36 months. IRIS was diagnosed in 14 (23%) cases. Mortality was similar in patients with and without IRIS. Conclusions:PML continues to be one of the deadliest opportunistic infections in acquired immunodeficiency syndrome patients. The development of PML-associated IRIS has no influence on prognosis.

Central nervous system toxoplasmosis in AIDS patients: efficacy of an intermittent maintenance therapy.

Fifty-five episodes of central nervous system (CNS) toxoplasmosis developing in 43 of the 329 AIDS cases seen at our institution were diagnosed during a 34-month period and were prospectively studied. Acute episodes were treated with a pyrimethamine/sulfadiazine (P/S) combination for a mean of 21 days. Because of a previously known major allergy to sulfonamides, three episodes were treated with clindamycin instead of sulphadiazine. In those patients who accepted maintenance therapy, a combination of P/S or pyrimethamine and clindamycin (P/C) was administered 2 days per week. Thirty-six patients (83.7%) survived the first episode. Four of these 36 were lost to further study. Six of the 12 (50%) who decided not to undergo maintenance therapy relapsed (mean follow-up: 12 months). Fourteen patients were given P/S and none relapsed while they were on maintenance therapy (mean follow-up: 10.3 months). Six patients received an intermittent maintenance treatment with P/C and one relapsed 2 months after starting the maintenance therapy (mean follow-up: 13.7 months). We conclude that an intermittent (2 days per week) maintenance treatment for CNS toxoplasmosis with P/S was effective in preventing relapses, although prospective randomized studies remain to be done.

Skeletal muscle studies in patients with HIV-related wasting syndrome

Previous reports have suggested that HIV-related wasting syndrome may be considered as a form of myopathy. The aim of the present study was to investigate histopathological muscle changes in HIV-related wasting syndrome in order to know if there is a common substrate and whether muscle plays a primary or secondary role in its development. Patients with wasting syndrome diagnosed by Centers for Disease Control (CDC) criteria were prospectively evaluated. Clinical, analytical, nutritional, anthropometrical and muscular data were recorded. The patients were subdivided into two groups: group A was constituted by patients in whom wasting syndrome was the AIDS-defining illness, and group B by patients in whom AIDS diagnosis was previously made. In all cases muscle biopsy was performed and processed for conventional stainings and histochemical reactions. Thirty patients were included (group A, 12; group B, 18). Clinical, analytical, nutritional and anthropometrical data did not essentially differ between the two groups. All patients were malnourished with respect to controls. Histopathological findings in muscle biopsy were heterogeneous and similar in both groups, except for HIV-related myopathies, which were more frequently seen in the patients from group A (P=0.05). In five cases (17%) an unsuspected and potentially treatable myopathy was diagnosed. Patients with polyarteritis nodosa (two) or polymyositis (one) were treated with prednisone, which improved their wasting syndrome. By contrast, patients with AZT-myopathy (two) did not improve when the drug was discontinued. We conclude that in most cases the wasting syndrome cannot be considered as a true myopathy, and probably metabolic and/or nutritional factors may account for wasting development. However, in a subset of patients muscle biopsy allows the diagnosis of a treatable myopathy leading to the improvement of wasting syndrome.

Muscle involvement in rheumatoid arthritis : Clinicopathological study of 21 symptomatic cases

The aim of the current study was to analyze the frequency and characteristics of symptomatic 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.

Clinical, histological and molecular reversibility of zidovudine myopathy.

The use of zidovudine in the treatment of human immunodeficiency virus infection has been associated with toxic mitochondrial myopathy. There are some reported cases of improvement after stopping the drug, but in only one were molecular studies performed. We therefore studied three patients with toxic AZT myopathy during AZT treatment and after drug withdrawal. Clinical complaints disappeared within the next three months after drug cessation. In all cases, histological data of mitochondrial abnormalities also disappeared. Molecular studies showed an initial depletion of the total amount of mitochondrial DNA with respect to healthy controls which was reversible after AZT withdrawal. This work demonstrates that AZT myopathy is reversible not only at a clinical and histological, but also at a molecular level.

Didanosine, Lamivudine, and Efavirenz versus Zidovudine, Lamivudine, and Efavirenz for the Initial Treatment of HIV Type 1 Infection : Final Analysis (48 Weeks) of a Prospective, Randomized, Noninferiority Clinical Trial, GESIDA 3903

BACKGROUND The combination of didanosine, lamivudine, and efavirenz (ddI/3TC/EFV) for the initial treatment of human immunodeficiency virus type 1 (HIV-1) infection has been insufficiently analyzed in clinical trials. METHODS We conducted an open-label, randomized study to compare the noninferiority of ddI/3TC/EFV with the lamivudine-zidovudine tablet and EFV (COM/EFV), both administered with food to improve tolerability and convenience. Patients were stratified by HIV-1 RNA level of <5.0 log(10) or > or =5.0 log(10) copies/mL. The primary end point was the percentage of patients with an HIV-1 RNA level of <50 copies/mL at week 48, determined by intention-to-treat analysis. RESULTS Three hundred sixty-nine patients were randomized: 186 for ddI/3TC/EFV treatment and 183 for COM/EFV treatment. Both groups were well matched in terms of baseline characteristics; 19.3% of patients received a Centers for Disease Control and Prevention assessment of clinical category C, median HIV RNA level was 5.0 log(10) copies/mL, and median CD4(+) cell count was 208 cells/microL. At week 48, by intention-to-treat analysis, 70% of patients in the ddI/3TC/EFV group and 63% of patients in the COM/EFV group had an HIV-1 RNA level of <50 copies/mL (treatment difference, 7.1%; 95% confidence interval, -2.39% to 16.59%). Fourteen patients (8%) in the ddI/3TC/EFV arm (not the COM/EFV arm) and 26 patients (14%) in the COM/EFV arm (not the ddI/3TC/EFV arm) [corrected] discontinued the study medication because of adverse events (P = .046). One patient (1%) in the ddI/3TC/EFV arm and 11 patients (6%) in the COM/EFV arm discontinued medication because of hematological toxicity (P = .003). CONCLUSIONS At week 48, ddI/3TC/EFV administered once per day with food did not have results inferior to those of COM/EFV treatment. A statistically significantly higher proportion of patients in the COM/EFV arm than in the ddI/3TC/EFV arm discontinued therapy because of adverse events, mainly because of hematological toxicity. CLINICAL TRIALS REGISTRATION NCT00256828.

Three-year follow-up of protease inhibitor-based regimen simplification in HIV-infected patients

Patients with sustained virological suppression on protease inhibitor (PI)-based therapy were randomly assigned to switch the PI to nevirapine (n = 155), efavirenz (n = 156), or abacavir (n = 149) and were followed for at least 3 years regardless of the discontinuation of assigned therapy. There was a higher probability of maintaining virological suppression after 3 years of follow-up with nevirapine or efavirenz than with abacavir. In contrast, abacavir showed a lower incidence of adverse effects leading to drug discontinuation.