Juan Berenguer

Tuberculous meningitis in patients infected with the human immunodeficiency virus.

BACKGROUND AND METHODS Tuberculosis is a frequent complication of human immunodeficiency virus (HIV) infection. We describe the clinical manifestations and outcomes of tuberculous meningitis in patients with HIV infection, and compare them with those in non-HIV-infected patients. We reviewed the records from 1985 through 1990 at two large referral hospitals in Madrid for patients who had Mycobacterium tuberculosis isolated from cerebrospinal fluid. RESULTS Of 2205 patients with tuberculosis, 455 (21 percent) also had HIV infection, of whom 45 had M. tuberculosis isolated from the cerebrospinal fluid. Of the 37 HIV-infected patients with tuberculous meningitis for whom records were available, 24 (65 percent) had clinical or radiologic evidence of extrameningeal tuberculosis at the time of admission. In 18 of 26 patients (69 percent), a CT scan of the head was abnormal. In most patients, analysis of cerebrospinal fluid showed pleocytosis (median white-cell count, 0.234 x 10(9) per liter) and hypoglycorrhachia (median glucose level, 1.3 mmol per liter), but in 43 percent (15 of 35), the level of protein in cerebrospinal fluid was normal. In four patients with HIV infection, tuberculosis was only discovered after their deaths. Of the 33 patients who received antituberculous treatment, 7 died (in-hospital mortality, 21 percent). Illness lasting more than 14 days before admission and a CD4+ cell count of less than 0.2 x 10(9) per liter (200 per cubic millimeter) were associated with a poor prognosis. Comparison with tuberculous meningitis in patients without HIV infection showed that the presentation, clinical manifestations, cerebrospinal fluid findings, and mortality were generally similar in the two groups. However, of the 1750 patients without HIV infection, only 2 percent (38 patients) had tuberculous meningitis, as compared with 10 percent of the HIV-infected patients (P less than 0.001). CONCLUSIONS HIV-infected patients with tuberculosis are at increased risk for meningitis, but infection with HIV does not appear to change the clinical manifestations or the outcome of tuberculous meningitis.

Sustained virological response to interferon plus ribavirin reduces liver‐related complications and mortality in patients coinfected with human immunodeficiency virus and hepatitis C virus

Human immunodeficiency virus (HIV) infection modifies the natural history of chronic hepatitis C, thus promoting more rapid progression to cirrhosis and end‐stage liver disease. The objective of our study was to determine whether hepatitis C virus (HCV) clearance is associated with improved clinical outcomes in patients positive for HIV and HCV. It was an ambispective cohort study carried out in 11 HIV units in Spain and involved 711 consecutive patients positive for HIV/HCV who started interferon plus ribavirin therapy between 2000 and 2005. We measured sustained virologic response (SVR), i.e., undetectable HCV RNA at 24 weeks after the end of treatment, and clinical outcomes, defined as death (liver‐related or non–liver‐related), liver decompensation, hepatocellular carcinoma, and liver transplantation. Of 711 patients who were positive for HIV/HCV, 31% had SVR. During a mean follow‐up of 20.8 months (interquartile range: 12.2‐38.7), the incidence rates per 100 person‐years of overall mortality, liver‐related mortality, and liver decompensation were 0.46, 0.23, and 0.23 among patients with SVR and 3.12, 1.65, and 4.33 among those without SVR (P = 0.003, 0.028, and <0.001 by the log‐rank test), respectively. Cox regression analysis adjusted for fibrosis, HCV genotype, HCV RNA viral load, Centers for Disease Control and Prevention clinical category, and nadir CD4+ cell count showed that the adjusted hazard ratio of liver‐related events was 8.92 (95% confidence interval, 1.20; 66.11, P = 0.032) for nonresponders in comparison with responders and 4.96 (95% confidence interval, 2.27; 10.85, P < 0.001) for patients with fibrosis grade of F3‐F4 versus those with F0‐F2.Because this was not a prospective study, selection and survival biases may influence estimates of effect. Conclusion: Our results suggest that the achievement of an SVR after interferon‐ribavirin therapy in patients coinfected with HIV/HCV reduces liver‐related complications and mortality. (HEPATOLOGY 2009.)

Incidence and Predictors of Severe Liver Fibrosis in Human Immunodeficiency Virus—Infected Patients with Chronic Hepatitis C: A European Collaborative Study

A study was performed in 10 European health care centers in which 914 patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) who had elevated serum alanine aminotransferase (ALT) levels underwent liver biopsy during the period of 1992 through 2002. Overall, the METAVIR liver fibrosis stage was F0 in 10% of patients, F1 in 33%, F2 in 22%, F3 in 22%, and F4 in 13%. Predictors of severe liver fibrosis (METAVIR stage, F3 or F4) in multivariate analysis were age of >35 years (odds ratio [OR], 2.95; 95% confidence interval [CI], 2.08-4.18), alcohol consumption of >50 g/day (OR, 1.61; 95% CI, 1.1-2.35), and CD4+ T cell count of <500 cells/mm3 (OR, 1.43; 95% CI, 1.03-1.98). Forty-six percent of patients aged >40 years had severe liver fibrosis, compared with 15% of subjects aged <30 years. The use of antiretroviral therapy was not associated with the severity of liver fibrosis. In summary, severe liver fibrosis is frequently found in HCV-HIV-coinfected patients with elevated serum ALT levels, and its severity increases significantly with age. The rate of complications due to end-stage liver disease will inevitably increase in this population, for whom anti-HCV therapy should be considered a priority.

Lysis-centrifugation blood cultures in the detection of tissue-proven invasive candidiasis : disseminated versus single-organ infection

Several studies have demonstrated significantly higher frequency and more rapid detection of candidemia with blood culture methods performed by lysis-centrifugation (LC) in comparison with other techniques. Little is known, however, about the ability of LC blood culture methods to detect tissue-proven invasive candidiasis. We therefore investigated the sensitivity of LC blood cultures in the detection of tissue-proven invasive candidiasis. Between 1985 and 1991, invasive candidiasis was detected in 41 (5.1%) of 803 autopsies at the Clinical Center of the National Institutes of Health (Bethesda, MD, USA). Cases were classified as single-organ (SO) candidiasis (n = 20) and as disseminated candidiasis (DI) (n = 21). Patients with DI were more likely than those with SO to have a hematologic malignancy (71% vs 15%, P < 0.001) and to have gastrointestinal mucosal candidiasis (76% vs 25%, P = 0.003). LC detected fungemia in 16 (43%) of all 37 cases with blood cultures. When analyzed by classification, Candida spp. were isolated from blood in 11 (58%) of 19 patients with DI and in five (28%) of 18 patients with SO (P = 0.13). When analyzed by number of organs infected, blood cultures were positive in seven (78%) of nine patients with > 3 organs infected by Candida in comparison to five (28%) of 18 patients with one organ infected (P = 0.024). The mean recovery time for Candida in blood cultures was 2.6 days in DI and 3.2 days in SO (P = 0.017). There was no difference in colonies of organisms per LC tube between patients with DI and those with SO.(ABSTRACT TRUNCATED AT 250 WORDS)

Liposomal Amphotericin B for the Treatment of Visceral Leishmaniasis

During the past decade, liposomal amphotericin B has been used with increasing frequency to treat visceral leishmaniasis (VL). The World Health Organization convened a workshop to review current knowledge and to develop guidelines for liposomal amphotericin B use for VL. In Europe, liposomal amphotericin B is widely used to treat VL. In Africa and Asia, the VL disease burden is high and drug access is poor; liposomal amphotericin B is available only through preferential pricing for nonprofit groups in East Africa. Clinical trials and experience demonstrate high efficacy and low toxicity for liposomal amphotericin B (total dose, 20 mg/kg) in immunocompetent patients with VL. Combination trials in areas with antileishmanial drug resistance, and treatment and secondary prophylaxis trials in VL-human immunodeficiency virus-coinfected patients, are important to safeguard the current armamentarium and to optimize regimens. The public health community should work to broaden access to preferential liposomal amphotericin B pricing by public sector VL treatment programs.

Hepatocellular carcinoma in HIV-infected patients with chronic hepatitis C

OBJECTIVES:Chronic hepatitis C is frequently seen in HIV-positive subjects infected through needle sharing or transfusion of contaminated blood products. Progression to end-stage liver disease seems to occur faster in these patients. As the life expectancy of HIV-infected persons has dramatically improved since the introduction of highly active antiretroviral therapies, cirrhosis and eventually hepatocellular carcinoma (HCC) may be recognized at an increasing rate in patients coinfected with HIV and hepatitis C virus (HCV).METHODS:We identified the main features of HIV-infected individuals with end-stage liver disease due to HCV infection and diagnosed with HCC in three HIV/AIDS referral centers, and compared these features to those of a control group of patients with HCV-related HCC but without HIV infection.RESULTS:Seven HIV-infected patients were identified. Of these, six were <45 yr of age and had been intravenous drug users. The mean time between exposure to HCV and the development of HCC was estimated to be 17.8 yr. Two subjects were coinfected with hepatitis B and delta viruses, respectively. Only one individual had been diagnosed of an AIDS-defining condition before the diagnosis of HCC was made. However, all subjects had <500 CD4+ T cells at the time of HCC diagnosis. Five died within the first 4 months of follow-up. Patients in the control group (n = 31) were significantly older (68.9 ± 8.9 vs 42.2 ± 10.4; p < 0.001) and the duration of HCV infection was significantly longer (28.1 ± 10.9 vs 17.8 ± 2.7; p < 0.05) than in those with HIV-HCV coinfection.CONCLUSIONS:HCC seems to occur at a younger age and after a shorter period of HCV infection in subjects coinfected with HIV. Thus, treatment of CHC should be encouraged in HIV-positive patients, and in those with HCV-related cirrhosis the periodic monitoring of α-fetoprotein and abdominal ultrasonography should be recommended.

Fast fibrosis progression between repeated liver biopsies in patients coinfected with human immunodeficiency virus/hepatitis C virus

A few studies have assessed the observed fibrosis progression between serial liver biopsies (LB) in human immunodeficiency virus (HIV) / hepatitis C virus (HCV)‐coinfected patients. Approximately half of the patients progressed at least one fibrosis stage over a short period of time. The risk factors for this fast progression need clarification. Because of this, we evaluated the observed fibrosis progression rates of HIV/HCV‐coinfected patients and the risk factors for accelerated progression. Overall, 135 HIV‐infected patients with positive serum HCV RNA, without other possible causes of liver disease, who underwent two LB, separated at least by 1 year, were included in this retrospective cohort study. The median (Q1‐Q3) time between both LBs was 3.3 (2.0‐5.2) years. Patients showed the following changes in fibrosis stage: regression ≥1 stage: 23 (17%), no change: 52 (39%), progression 1 stage: 38 (28%), and progression ≥2 stages: 22 (16%). Seventeen (13%) patients had cirrhosis in the second biopsy. Factors independently associated with progression ≥1 stage were undetectable plasma HIV RNA during the follow‐up (relative risk [RR] [95% confidence interval, 95% CI] 0.61 [0.39‐0.93], P = 0.03), moderate‐to‐severe lobular necroinflammation (1.77 [1.16‐2.7], P = 0.009), time between biopsies (1.11 [1.08‐1.2], P = 0.01), and end of treatment response to anti‐HCV therapy (0.41 [0.19‐0.88], P = 0.02). Conclusion: Fibrosis progresses with high frequency in HIV/HCV‐coinfected patients over a period of time of 3 years. Absent‐to‐mild lobular necroinflammation at baseline, achievement of response with anti‐HCV treatment, and effective antiretroviral therapy are associated with slower fibrosis progression. (HEPATOLOGY 2009.)

Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: the SPIRAL study

Background:Switching to raltegravir in selected patients treated with ritonavir-boosted protease inhibitors may result in similar efficacy and lower plasma lipids. Methods:SPIRAL is a 48-week multicentre, open-label trial in which HIV-infected adults with less than 50 copies/ml of plasma HIV RNA for at least the previous 6 months on ritonavir-boosted protease inhibitor-based therapy were randomized (1: 1) to switch from the ritonavir-boosted protease inhibitor to raltegravir or to continue on ritonavir-boosted protease inhibitor-based therapy. Primary endpoint was the proportion of patients free of treatment failure (noncompleter = failure) at 48 weeks. SPIRAL study was powered to show noninferior efficacy of raltegravir-based therapy with a margin of −12.5%. Results:Two hundred and seventy-three patients assigned to switch to raltegravir (n = 139) or to continue ritonavir-boosted protease inhibitor (n = 134) were included in the efficacy analysis. At 48 weeks, 89.2% (raltegravir-based therapy) and 86.6% (ritonavir-boosted protease inhibitor-based therapy) of the patients remained free of treatment failure [difference 2.6%; 95% confidence interval (CI) −5.2 to 10.6]. A total of 96.9% (raltegravir-based therapy) and 95.1% (ritonavir-boosted protease inhibitor-based therapy) of the patients remained free of virological failure (difference 1.8%; 95% CI −3.5 to 7.5). Switching to raltegravir was associated with significant decreases in plasma lipids and total-to-HDL cholesterol ratio relative to continuing ritonavir-boosted protease inhibitor. Severe adverse events and study drug discontinuations due to any adverse event occurred in 4 and 2% of the patients in each group. Conclusion:In patients with sustained virological suppression on ritonavir-boosted protease inhibitor-based therapy, switching from ritonavir-boosted protease inhibitor to raltegravir demonstrated noninferior efficacy and resulted in a better lipid profile at 48 weeks than continuing ritonavir-boosted protease inhibitor.

Less lipoatrophy and better lipid profile with abacavir as compared to stavudine: 96-week results of a randomized study.

Objective:To assess lipoatrophy, other toxicities, and efficacy associated with abacavir as compared with stavudine in HIV-infected antiretroviral-naive patients. Methods:This was a prospective, randomized, open trial, stratified by viral load and CD4 cell count, conducted January 2001 to July 2004. Two hundred thirty-seven adult patients with HIV infection initiating antiretroviral therapy were assigned to receive abacavir (n = 115) or stavudine (n = 122), both combined with lamivudine and efavirenz. The primary endpoint was the proportion of patients with lipoatrophy as assessed by physician and patient observation at 96 weeks. Results:A lower proportion of patients assigned to abacavir developed clinical signs of lipoatrophy (4.8% vs. 38.3%; P < 0.001). These observations were confirmed by anthropometric data. Dual energy x-ray absorptiometry (DEXA) scans performed in 57 patients showed significantly greater total limb fat loss in the stavudine arm (−1579 vs. 913 g; P < 0.001). The lipid profile in abacavir patients presented more favorable changes in the levels of triglycerides (P = 0.03), high-density lipoprotein cholesterol (HDLc; P < 0.001), and apolipoprotein A1 (P < 0.001) as well as in the ratio between total cholesterol and HDLc (P = 0.005). Throughout the study, a higher proportion of patients in the stavudine group received lipid-lowering agents as compared to the abacavir group (17% vs. 4%; P = 0.002). Similar virologic and immunologic responses were observed. Conclusions:Assuming the limitations inherent to clinical assessment, this study shows a notably weaker association of abacavir with lipoatrophy than stavudine. DEXA scans and anthropometric measurements supported the clinical findings. In addition, the lipid changes that occurred were more favorable in patients receiving abacavir.

Visceral Leishmaniasis in Patients Infected with Human Immunodeficiency Virus (HIV)

In an 8-month period nine patients with human immunodeficiency virus (HIV) infection were diagnosed as having visceral leishmaniasis; all diagnoses were based on cultures (eight from bone marrow and one from the skin). Visceral leishmaniasis developed before full-blown acquired immunodeficiency syndrome (AIDS) in seven patients and at the same time as or after AIDS in the other two patients. Three patients had a history of leishmaniasis. Clinical manifestations and laboratory findings were atypical. Leishmania species were cultured from samples taken from all patients; however, six patients had an insignificant antileishmanial antibody titer and Leishmania amastigotes were not seen in their bone marrow smears. Four isolates were identified by isoenzyme analysis as Leishmania donovani infantum. Five patients died, including two patients who had completed at least one 3-week course of therapy with N-methylglucamine antimoniate. Screening should be done for visceral leishmaniasis in patients with HIV infection who live or travel in areas where the disease is endemic. The diagnosis of visceral leishmaniasis may frequently be missed if cultures are not done.