Jaime Cosín

Treatment of Aids-associated progressive multifocal leukoencephalopathy with highly active antiretroviral therapy

Objectives:To evaluate the efficacy of highly active antiretroviral therapy (HAART) in 12 patients with AIDS-associated progressive multifocal leukoencephalopathy (PML). Patients and methods:The diagnosis of PML was established by brain biopsy in six patients and by neuroimaging findings and PCR detection of JC virus in cerebrospinal fluid (CSF) in six patients. We also studied 13 consecutive AIDS patients with biopsy-proven PML cared for in the same institution before HAART was available. Eleven patients of the HAART group and eight patients of the control group received intravenous arabinoside cytosine cycles. Results:With HAART, the median decrease in the HIV viral load was 3.58 log10 copies/ml and the median increase in the CD4 cell count was 74 × 106/l. The median survival time after PML diagnosis was 545 days in the HAART group and 60 days in the control group (P < 0.001, log-rank test). In the HAART group, the neurological deficits improved substantially in six patients and stabilized in six patients. Eleven patients underwent follow-up cranial computed tomography or magnetic resonance scan that showed improvement of PML lesions in 10 patients and stabilization in one patient. Follow-up CSF analysis showed clearance of JC virus in six out of seven patients who had an initial positive result. Conclusions:This study shows that HAART may increase the survival, clinical status and radiological features of AIDS patients with PML. Clearance of JC virus from CSF has been found, suggesting that immune reconstitution can interrupt the JC virus lytic cycle.

Inflammatory reactions in progressive multifocal leukoencephalopathy after highly active antiretroviral therapy.

Three patients with progressive multifocal leukoencephalopathy (PML) treated with highly active antiretroviral therapy (HAART) worsened clinically and radiologically. At the time of deterioration all three had reduced HIV viraemia and increased CD4 cell counts. Brain biopsy in all three disclosed PML and marked perivascular lymphoplasmacytic infiltration. We reviewed the slides of 28 brain biopsies diagnostic of PML. Inflammatory changes were observed in four out of nine patients on HAART and in one out of 19 patients not on HAART.

Recurrent pericarditis. Relief with colchicine.

Recurrence is one of the major complications of pericarditis. Treatment of recurrence is often difficult, and immunosuppressive drugs or surgery may be necessary. We conducted an open-label prospective study of nine patients (seven men and two women; age, 18-64 years; mean age, 41.7 +/- 13.7 years). Patients were treated with colchicine (1 mg/day) to prevent recurrences. All patients had suffered at least three relapses despite treatment with acetylsalicylic acid, indomethacin, prednisone, or a combination. Pericarditis was classified as idiopathic in five patients, postpericardiotomy in two, post-myocardial infarction in one, and associated with disseminated lupus erythematosus in one. For statistical analysis, we conducted a paired comparison design (Students t test). All patients treated with colchicine responded favorably to therapy. Prednisone was discontinued in all patients after 2-6 weeks (mean, 26.33 +/- 10.9 days), and colchicine alone was continued. After a mean follow-up of 24.3 months (minimum, 10 months; maximum, 54 months), no recurrences were observed in any patient; there was a significant difference between the symptom-free periods before and after treatment with colchicine (p less than 0.002). Our study suggests that colchicine may be useful in avoiding recurrence of pericarditis, although these results need to be confirmed in a larger, double-blind study.

A simplification trial switching from nucleoside reverse transcriptase inhibitors to once-daily fixed-dose abacavir/lamivudine or tenofovir/emtricitabine in HIV-1-infected patients with virological suppression.

Background:Data comparing abacavir/lamivudine versus tenofovir/emtricitabine in antiretroviral-naive patients are controversial. We compared 48-week efficacy and safety of these combinations as substitutes of nucleosides in patients with virological suppression. Methods:We randomly assigned 333 HIV-1-infected patients on lamivudine-containing triple regimens with <200 copies per milliliter for at least 6 months to switch their nucleosides to either abacavir/lamivudine (n = 167) or tenofovir/emtricitabine (n = 166). The primary outcome was treatment failure [“switching = failure” intention to treat (ITT) analysis, noninferiority margin 12.5%]. Secondary outcomes were time to treatment failure, virological failure, adverse events, and changes in CD4 count, fasting plasma lipids, lipodystrophy, body fat, bone mineral density, and renal function. Results:Treatment failure occurred in 32 patients (19%) on abacavir/lamivudine and 22 patients (13%) on tenofovir/emtricitabine [difference 5.9%; (95% confidence interval −2.1% to 14.0%), P = 0.06]. Four patients in the abacavir/lamivudine group versus none in the tenofovir/emtricitabine group developed virological failure [difference 2.4; (95% confidence interval 0.05 to 6.0), P = 0.04]. Twenty-three patients (14%) assigned to abacavir/lamivudine and 10 (6%) to tenofovir/lamivudine experienced grade 3 or 4 adverse effects (P = 0.03). CD4 counts and plasma lipids showed higher increments in the abacavir/lamivudine group than in the tenofovir/emtricitabine group. Conclusions:In HIV-1-infected patients with virological suppression, abacavir/lamivudine did not meet the noninferiority outcome for treatment efficacy compared with tenofovir/emtricitabine.

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].

Use of transient elastography (FibroScan®) for the noninvasive assessment of portal hypertension in HIV/HCV-coinfected patients

Summary.  The hepatic venous pressure gradient (HVPG) is the gold standard for assessing portal pressure and correlates with the occurrence of portal hypertension (PH)–related complications. Transient elastography (TE) is a new, highly accurate noninvasive technique, which enables us to evaluate hepatic fibrosis to detect advanced fibrosis and cirrhosis. We performed a hepatic haemodynamic study and TE in 38 HIV/HCV‐coinfected patients. The association between HVPG and liver stiffness was assessed by linear regression. The diagnostic value of TE was assessed by receiver operating characteristic (ROC) curves. We considered clinically significant PH as an HVPG ≥10 mmHg and severe PH as an HVPG ≥12 mmHg. A total of 38 HIV/HCV‐coinfected patients were included. Twenty‐eight patients (73.7%) had clinically significant PH (HVPG ≥10 mmHg), and 23 (60.5%) of these had severe PH (HVPG ≥12 mmHg). We found a statistically significant association between liver stiffness (kPa) and HVPG (r2 = 0.46, P < 0.001, straight line equation HVPG=7.4 + 0.204*TE). The areas under the ROC curves were 0.80 [95% confidence interval (CI), 0.64–0.97] and 0.80 (95% CI, 0.66–0.94) for the prediction of HVPG ≥10 and ≥12 mmHg, respectively. Our data suggest that TE can predict the presence of clinically significant and severe PH in HIV/HCV‐coinfected patients.

Liver Biopsy Findings for HIV-Infected Patients with Chronic Hepatitis C and Persistently Normal Levels of Alanine Aminotransferase

BACKGROUND Severe liver fibrosis is common in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) who have a high alanine aminotransferase (ALT) level. However, little is known about the frequency, liver biopsy findings, and significance of a persistently normal ALT level in coinfected patients. METHODS We analyzed clinical data and histological findings for 256 patients coinfected with HIV and HCV, 24 (9.4%) of whom had an ALT level within the normal range on > or =2 separate occasions within a 6-month period. RESULTS The proportion of patients demonstrating advanced stages of fibrosis (F3 and F4) was 78 (33.7%) of 232 patients in the high ALT level group, compared with 0 (0%) of 24 patients in the persistently normal ALT level group (P<.001). Among patients with persistently normal ALT levels, 23 (96%) had any grade of fibrosis, and 7 (29%) had stage F2 of fibrosis. No differences were found between both groups with respect to age, sex, HIV transmission category, Centers for Disease Control and Prevention clinical category, CD4+ cell count (both nadir and baseline values), type of antiretroviral therapy, years since onset of HCV infection, alcohol use, or HCV load. However, the proportion of patients infected with HCV genotype 3 was significantly higher among patients with high ALT levels than in patients with persistently normal ALT levels (61 [26.9%] of 232 patients vs. 1 [4.2%] of 24 patients; P=.04). CONCLUSIONS Histological abnormalities are significantly milder in patients coinfected with HIV and HCV who have persistently normal ALT levels than those found in patients with high ALT levels. However, a subgroup of patients with persistently normal ALT levels may have significant cases of fibrosis. Liver biopsy may be recommendable in patients coinfected with HIV and HCV who have persistently normal ALT levels, to determine the extent of liver fibrosis and, consequently, to assess suitability for treatment.

High prevalence of tuberculosis in AIDS patients in Spain

A total of 67 cases of tuberculosis was diagnosed in the first 100 cases of AIDS, diagnosed according to the former CDC criteria, at a hospital in Madrid, Spain. This is the highest known prevalence of tuberculosis in AIDS patients both within and outside Spain. The clinical manifestations of tuberculosis were very variable and atypical. The rate of isolation ofMycobacterium tuberculosis from blood was particularly high: of 25 patients in whom blood cultures were performed, 16 were positive. In a third of the patients with proven mycobacteremia, blood was the first or the only positive specimen. In general, therapy resulted in rapid clinical improvement, but in some cases mycobacteria were isolated from clinical or necroscopy specimens months after what was considered adequate therapy.

Hepatitis C virus and human immunodeficiency virus coinfection in Spain

OBJECTIVE AND METHODS In a cross-sectional study, based on a cohort composed of HIV-infected patients of fifteen tertiary level institutions of Spain, the main data of the entire cohort are described, characteristics of patients with or without hepatitis C coinfection are compared, and the possible association of hepatitis C virus coinfection with socioeconomic, HIV-related, and hepatitis B-related variables is assessed. RESULTS A total of 4,709 patients are studied. Median of age is 37 years, 78.3% are male. HIV risk behaviours are: parenteral drug use in 63.8% of patients, heterosexual in 22.3%, and homosexual in 10.8%. Serology of hepatitis C is positive in 69.2% of participants. The following variables are associated with increased prevalence of hepatitis C coinfection, both in univariate and in multivariate analysis: HIV risk behaviour, positive anti-HBs, longer time elapsed since HIV infection diagnosis, younger age, lower social status, lower CD4 cell count increase between nadir and last available result, and lower educational level (all P<0.001). Patients with heterosexual behaviour are more frequently coinfected than patients with homosexual behaviour (P<0.001). CONCLUSION This study highlights that, in Spain, more than two thirds of patients with HIV infection are coinfected with hepatitis C virus.

Association between Exposure to Nevirapine and Reduced Liver Fibrosis Progression in Patients with HIV and Hepatitis C Virus Coinfection

BACKGROUND We analyzed the effect of exposure to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) on the progression of liver fibrosis in patients with human immunodeficiency virus (HIV) and hepatitis C virus coinfection. METHODS We analyzed data and liver biopsy findings for 201 coinfected patients. Fibrosis was scored following the French METAVIR Cooperative Study Group. We used multinomial logistic regression analysis and the fibrosis progression rate to assess the association between cumulative exposure to antiretroviral drugs and stage of fibrosis. RESULTS The adjusted odds ratio (AOR) and 95% confidence interval (CI) of having a fibrosis stage score of 0 or 1, compared with 3 or 4, increased with each additional year of exposure to HAART (AOR, 1.32; 95% CI, 1.04-1,67), to NNRTIs as a class (AOR, 1.64; 95% CI, 1.18-2.27), to efavirenz (AOR, 1.54; 95% CI, 1.03-2.30), and to nevirapine (AOR, 1.72; 95% CI, 1.15-2.78). This effect was not found with PIs as a class. The AOR (95% CI) of having a fibrosis stage score of 2 versus 3 or 4 increased with each additional year of exposure to NNRTIs (AOR, 1.51; 95% CI, 1.08-2.10) and nevirapine (AOR, 1.58; 95% CI, 1.06-2.37). This effect was not found with highly active antiretroviral therapy, PIs, or efavirenz. The AOR (95% CI) of having a fibrosis progression rate < or = 0.1 versus > 0.1 increased with each additional year of exposure to highly active antiretroviral therapy (AOR, 1.31; 95% CI, 1.07-1.60), to NNRTIs (AOR, 1.33; 95% CI, 1.03-1.70), and to nevirapine (AOR, 1.44; 95% CI, 1.07-1.95). This effect was not found with PIs or with efavirenz. CONCLUSIONS In contrast with previous studies, we found that exposure to NNRTIs was clearly associated with a reduction in fibrosis progression, whereas exposure to PIs was not. Of note, exposure to nevirapine was more consistently associated with a reduction in fibrosis progression than was exposure to efavirenz. Prospective work is needed in this area.