Juan González-Lahoz

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.

Increasing impact of chronic viral hepatitis on hospital admissions and mortality among HIV-infected patients.

To assess the impact of chronic viral liver disease (CVLD) on hospital admissions and death in HIV-infected patients since the introduction of highly active antiretroviral therapy, all hospital charts, from January 1996 to December 2000, in a large HIV/AIDS reference center in Madrid were reviewed. Discharge diagnosis, complications during the inpatient period, and number and causes of death were recorded. A total of 1334 hospital admissions involving 875 HIV-infected individuals was recorded. Up to 82% of them were either active or former intravenous drug users. Overall, 158 (11.8%) were admitted because of complications of CVLD, or developed complications of CVLD during their admission for another reason. The absolute number and proportion of admissions caused by CVLD increased over time, from 9.4% (31 of 330) in 1996 to 16% (46 of 287) in 2000 (p < 0.05). Likewise, the total number and proportion of deaths due to CVLD increased from 9.3% (5 of 54) in 1996 to 45% (9 of 20) in 2000 (p < 0.05). Chronic hepatitis C was the only etiology in nearly three-quarters of patients who were admitted or died of CVLD. In conclusion, the proportion of hospital admissions caused by liver failure in HIV-infected patients has increased in the last 5 years, accounting for 16% of cases in 2000. End-stage liver disease currently represents 45% of causes of in-hospital death among HIV-infected individuals. Therefore, strategies to prevent infection by hepatitis viruses (hepatitis B vaccine) and specific treatment (interferon plus ribavirin for hepatitis C virus) should be encouraged among HIV-infected persons.

Zidovudine in persons with asymptomatic HIV infection and CD4+ cell counts greater than 400 per cubic millimeter

BACKGROUND Zidovudine therapy is of benefit in the treatment of symptomatic and asymptomatic human immunodeficiency virus (HIV) infection in persons with CD4+ cell counts of less than 500 per cubic millimeter. The efficacy, safety, and duration of benefit of zidovudine in those with 500 or more CD4+ cells per cubic millimeter are uncertain. METHODS In a double-blind, placebo-controlled trial, 993 patients with asymptomatic HIV infection and CD4+ cell counts above 400 per cubic millimeter were randomly assigned to receive zidovudine (500 mg twice daily) or placebo for three years. The primary end point was progression of disease, as defined by the development of Centers for Disease Control and Prevention (CDC) group IV disease (including recurrent oral candidiasis, hairy leukoplakia, or progressive diarrhea) or two CD4+ cell counts below 350 per cubic millimeter. This outcome measure was changed from the original end point of the acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex to reflect changes in recommendations for management. The study was terminated after the first interim analysis. RESULTS Disease progression was significantly less frequent in the zidovudine group (relative risk, 0.56; 95 percent confidence interval, 0.43 to 0.75; P < 0.001 by the log-rank test). The probability of disease progression at two years was 0.19 with zidovudine, as compared with 0.34 with placebo (95 percent confidence interval for the difference, -0.21 to -0.08). Progression to CDC group IV disease was reduced by half in the zidovudine recipients (relative risk, 0.49; P = 0.049) and decline in CD4+ cell counts to below 350 per cubic millimeter was reduced by 40 percent (relative risk, 0.60; P < 0.001). The inclusion of early HIV disease events (oral candidiasis, oral hairy leukoplakia, and herpes zoster) as end points confirmed the effects of zidovudine on the progression of clinical disease (relative risk, 0.55; 95 percent confidence interval, 0.37 to 0.84; P = 0.004). The median duration of treatment was 94 weeks. Severe hematologic or clinical side effects were rare. CONCLUSIONS Treatment with zidovudine benefits HIV-infected persons with CD4+ cell counts above 400 per cubic millimeter. Despite the use of doses larger than those now generally prescribed, zidovudine was well tolerated for up to three years by most of our patients.

Influence of 516G>T Polymorphisms at the Gene Encoding the CYP450-2B6 Isoenzyme on Efavirenz Plasma Concentrations in HIV-Infected Subjects

We examined 516G>T polymorphisms at the gene encoding the cytochrome P450 in 100 human immunodeficiency virus-positive subjects who were receiving efavirenz (EFV). Elevated plasma EFV concentrations were found in 40% of subjects with the polymorphic homozygous genotype and 19% of subjects with the heterozygous genotype. Conversely, 20% of subjects with the wild-type genotype had subtherapeutic concentrations of EFV. CYP2B6-516 genotyping may help to identify subjects who have plasma EFV concentrations that are outside of the therapeutic range.

Impact of chronic liver disease due to hepatitis viruses as cause of hospital admission and death in HIV-infected drug users

The life expectancy of HIV-positive individuals has been prolonged in recent years, as a consequence of the wide use of antiretroviral drugs and primary prophylaxis for the most common opportunistic infections. In HIV-positive persons infected parenterally, chronic viral liver disease (CVLD), mainly that caused by hepatitis C virus (HCV), is frequently seen. Moreover, chronic hepatitis C seems to present a more accelerated course in HIV-infected patients, leading to cirrhosis and liver failure in a shorter period of time. The aim of the present study was to investigate the impact of CVLD on the morbidity and mortality of HIV-positive patients. A retrospective analysis of the causes of hospital admission during a 4.5-year period in a reference centre for AIDS situated in Madrid was performed. Decompensated liver disease (encephalopathy, ascites, jaundice), or complications directly related to it (gastrointestinal bleeding, hepatorenal syndrome, peritonitis) were diagnosed in 143 (8.6%) of 1670 hospital admissions. These episodes of CVLD corresponded to 105 different individuals, a quarter of whom had two or more re- admissions. HCV alone or in combination with other hepatotropic viruses was involved in 93 (88.6%) patients admitted for CVLD. Death directly associated with CVLD occurred in 15 individuals, which represented 4.8% of the total causes of inhospital mortality during the study period, and represented the fifth cause of death in hospital for HIV-infected patients. In conclusion, CVLD represents an important cause of hospital admission and death in HIV-infected drug users.

Risks and benefits of replacing protease inhibitors by nevirapine in HIV-infected subjects under long-term successful triple combination therapy.

ObjectiveTo analyse the safety and efficacy of replacing the protease inhibitor (PI) by nevirapine (NVP) in subjects experiencing a long-term control of virus replication under a triple PI-containing antiretroviral combination. DesignProspective evaluation of 138 HIV-positive subjects with plasma viral load below 50 HIV-RNA copies/ml for the last 6 months under a triple PI-containing regimen, who were randomly assigned to either replace the PI by NVP (n = 104) or continue on the same treatment (n = 34). MethodsViral load, CD4 count, lipid profile, body-shape features, and quality of life parameters were all assessed at the time of randomization and every 3 months thereafter. ResultsIn an intent-to-treat analysis, a rebound in viral load occurred in 11% of subjects during the first 6 months after replacing the PI by NVP, whereas it appeared in 29% of those who remained on PI (P = 0.007). Treatment failure was related to lack of adherence in 90% of subjects on PI, but only in 22% of those receiving NVP (P = 0.006). The CD4 cell count outcome did not differ significantly comparing both groups at 6 months, although in patients receiving NVP an average reduction of 35 × 106 cells/l was observed, whereas in those on PI a positive trend was still recorded (+54 × 106 cells/l). At the time of randomization, 77.5 and 57.5% of subjects had cholesterol and triglyceride values above 200 mg/dl, respectively. No significant changes in the lipid profile were observed in any of the groups thereafter. Body-shape abnormalities were recorded in 70% of persons at the time of randomization, and partially reversed at 6 months in 50% of subjects who replaced the PI by NVP. A quality of life score recorded a significant improvement in subjects who switched to NVP compared with those who continued on PI. ConclusionsThe replacement of PI by NVP seems to be safe both virologically and immunologically, provides a significant improvement in the quality of life and in half of patients ameliorate lipodystrophic body-shape changes at 6 months, although serum lipid abnormalities still remain unmodified.

Severe liver disease associated with prolonged exposure to antiretroviral drugs

Background: Liver damage is frequently seen in HIV-positive subjects, often resulting from coinfection with hepatitis B and/or C viruses (HCV), alcohol abuse, etc. However, the etiology of liver disease still remains unknown for a small subset of individuals. Methods: Cryptogenic liver disease (CLD) was defined as persistently elevated aminotransferases levels in the absence of hepatitis C and/or B viruses replication and of other common causes of liver disease (alcohol, medications, etc). We identified cases initially meeting this definition by examining all HIV-positive subjects attended during the year 2004 in 2 large HIV clinics in Spain. Their clinical charts were retrospectively reviewed, and their assessment completed when needed to rule out other less frequent causes of liver disease. The stage of liver fibrosis was assessed by liver biopsy and/or elastography. To assess which factors could be associated with CLD, HIV-positive controls were chosen and matched by age, gender, and CD4 status. Results: CLD was diagnosed in 17 (0.5%) out of 3200 HIV-positive patients. Their mean age was 43 years, 82.4% were male, and 76% had acquired HIV through homosexual relationships. The mean time from HIV diagnosis was >15 years, and all patients had been exposed to antiretroviral therapy. Nevirapine, stavudine, and didanosine were the drugs more frequently used by this subset of patients. None of them had liver function test abnormalities before initiating antiretroviral therapy. Advanced liver fibrosis (F3-F4 Metavir scores) was recognized in 10 (58.8%) individuals, and 9 (52.9%) had developed symptomatic liver complications, including ascites (8), portal thrombosis (6), variceal bleeding (5), and encephalopathy (2). In the case-control analysis, prolonged didanosine exposure was the only independent predictor of developing CLD in this population. Conclusions: CLD is an uncommon condition in HIV-positive individuals and might be associated with prolonged didanosine exposure. It may evolve causing severe liver complications, with variceal bleeding and portal thrombosis being particularly frequent.

Genetic factors influencing atazanavir plasma concentrations and the risk of severe hyperbilirubinemia.

Background:Hyperbilirubinemia is frequently seen in patients treated with atazanavir (ATV). Polymorphisms at the uridin-glucoronosyl-transferase 1A1 (UGT1A1) and multidrug resistance 1 (MDR1) genes may influence, respectively, bilirubin and ATV plasma concentrations. Patients and methods:HIV-infected individuals receiving ATV 300 mg daily plus ritonavir 100 mg daily at one clinic were examined. ATV plasma concentrations were measured at steady state. MDR1-3435C>T and UGT1A1 polymorphisms were examined in DNA extracted from blood mononuclear cells. Results:A total of 118 patients (all Caucasian) were analysed. The median ATV plasma concentration was 465 ng/ml [interquartile range (IQR), 233–958]. MDR1-3435 genotypes were as follows: CC (32%), CT (47%) and TT (21%). CC patients showed higher ATV minimum concentration than those with CT/TT genotypes: 939 ng/ml (IQR, 492–1266) versus 376 ng/ml (IQR, 221–722) (P = 0.001). In multivariate analyses, having at least one T allele at MDR1-3435 was independently associated with lower ATV plasma concentrations (β: –427 [95% confidence interval (CI), −633 to −223]; P < 0.001). The proportion of patients with grade 3-4 hyperbilirubinemia varied with distinct UGT1A1 genotypes: 80% for 7/7, 29% for 6/7 and 18% for 6/6 (P = 0.012). In the multivariate analysis, having at least one 7 allele at UGT1A1 was independently associated with severe hyperbilirubinemia (odds ratio, 2.96; 95% CI, 1.29–6.78; P = 0.01). Conclusions:Polymorphisms at MDR1-3435 significantly influence ATV plasma concentrations, as does being Caucasian patients with CT/TT genotypes, having lower ATV levels, even using ritonavir boosting. On the other hand, although ATV plasma concentrations directly correlate with bilirubin levels, the risk of severe hyperbilirubinemia is further increased in the presence of the UGT1A1-TA7 allele.

Plasma Levels of Atazanavir and the Risk of Hyperbilirubinemia Are Predicted by the 3435C→T Polymorphism at the Multidrug Resistance Gene 1

The 3435C-->T polymorphism at the multidrug resistance gene 1 (MDR1) was examined in 74 patients with human immunodeficiency virus who initiated atazanavir therapy. The MDR1 genotype distribution at position 3435 was 28% CC, 45% CT, and 27% TT. Plasma levels of atazanavir were significantly higher in patients with genotype CC than in those with CT or TT, and bilirubin levels correlated with atazanavir concentrations.

Discontinuation of secondary prophylaxis for opportunistic infections in HIV-infected patients receiving highly active antiretroviral therapy.

BackgroundImmune reconstitution following the introduction of highly active antiretroviral therapies (HAART) has lead to a remarkable reduction in the incidence of opportunistic infections (OI) in subjects with advanced HIV disease. Moreover, discontinuation of primary prophylaxis for some OI can be attempted without risk in patients experiencing a favourable response to treatment. However, data on the feasibility of discontinuing secondary prophylaxis are much more scarce, and restricted mainly to the withdrawal of maintenance treatment for cytomegalovirus (CMV) retinitis. Patients and methodsRetrospective review of the clinical outcome at 18 months in HIV-infected patients in whom discontinuation of secondary prophylaxis, for different OI, was recommended 3 months after the introduction of HAART, if both CD4 counts > 100 × 106 CD4 lymphocytes/l and plasma HIV-RNA < 500 copies/ml had been achieved. ResultsFifty-three subjects were analysed. Secondary chemoprophylaxis was discontinued for the following OI:Pneumocystis carinii pneumonia (PCP) (n = 29), cerebral toxoplasmosis (n = 9), disseminated Mycobacterium avium complex infection (n = 7), CMV retinitis (n = 5), recurrent oroesophageal candidiasis (n = 5), Visceral leishmaniasis (n = 2), recurrent herpes zoster (n = 2), and chronic mucocutaneous herpes simplex infection (n = 1). In six individuals, OI prophylaxis was discontinued for two or more entities. Only two episodes of OI were recorded in these individuals during 18 months of follow-up. One developed tuberculous lymphadenitis despite having a good response to treatment, and another suffered a new episode of PCP after voluntary treatment interruption for 6 weeks. ConclusionSecondary prophylaxis for OI can be attempted without major risk in HIV-infected patients experiencing a favourable response to HAART. The benefit of this intervention should reduce costs, drug side-effects and pharmacologic interactions, and indirectly will improve patients quality of life and adherence to antiretroviral treatment.