Marco Bongiovanni

Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: Data from the Italian Registry Investigative Neuro AIDS (IRINA)

Human immunodeficiency virus (HIV)-associated progressive multifocal leukoencephalopathy (PML) remains a relevant clinical problem even in the era of highly active antiretroviral therapy (HAART). Aims of the study were to analyze clinical and treatment-related features and the survival probability of PML patients observed within the Italian Registry Investigative Neuro AIDS (IRINA) during a 29-month period of HAART. Intravenous drug use, the presence of focal signs, and the involvement of white matter at neuroradiology increased the risk of having PML. A reduced probability of PML was observed when meningeal signs were reported. Patients starting HAART at PML diagnosis and previously naïve for antiretrovirals showed significantly higher 1-year probability of survival (.58), compared to those continuing HAART (.24), or never receiving HAART (.00). Higher CD4 cell count were associated with a higher survival probability (.45). At multivariate analysis, a younger age, higher CD4, starting HAART at PML diagnosis, the absence of previous acquired immunodeficiency syndrome (AIDS)-defining events, and the absence of a severe neurologic impairment were all associated with a reduced hazard of death. The use of cidofovir showed a trend towards a reduced risk of death.

Prevalence, associated factors, and prognostic determinants of AIDS-related toxoplasmic encephalitis in the era of advanced highly active antiretroviral therapy

BACKGROUND Characteristics, associated factors, and survival probability of toxoplasmic encephalitis (TE) in the era of advanced highly active antiretroviral therapy (HAART) have not been fully clarified. METHODS Data for 205 individuals with acquired immunodeficiency syndrome (AIDS)-related TE were derived from the Italian Registry Investigative NeuroAIDS database, and the cases were studied longitudinally to evaluate prevalence, clinical characteristics, and survival. Moreover, the relationship between the occurrence of TE and exposure to antiretroviral therapy and to TE prophylaxis was evaluated. RESULTS With an overall prevalence of 26%, TE represented the most frequent neurological disorder in the cohort. Female sex, severe immunodeficiency, and absence of primary TE prophylaxis significantly increased the risk of TE, and previous exposure to antiretroviral therapy reduced the probability of disease occurrence. Thirty-six percent of patients who had received antiretroviral therapy developed TE, although in most of these cases, the patient experienced failure of antiretroviral therapy. Of note, 66% of patients who had experienced antiretroviral therapy did not receive prophylaxis for TE at TE diagnosis. The 1-year probability of that infection with human immunodeficiency virus (HIV) would progress or that death would occur after TE was 40% and 23%, respectively. Cognitive symptoms, low CD4(+) cell count, not receiving HAART after TE, and initiating HAART >2 months after TE diagnosis were all significantly associated with an increased probability of progression of HIV infection. Not receiving HAART after diagnosis negatively affected survival. CONCLUSIONS TE remains a highly prevalent disorder of the central nervous system, even in the late HAART era, particularly among severely immunosuppressed patients and in absence of prophylaxis. Considering that persons with TE have a high probability of early death, prophylaxis should be maintained in immunosuppressed patients who experience failure of antiretroviral therapy, and HAART should be initiated as soon as possible after TE diagnosis.

Lopinavir/ritonavir treatment in HIV antiretroviral-experienced patients: evaluation of risk factors for liver enzyme elevation

To evaluate the risk factors for lopinavir/ritonavir (LPV/r)‐related liver enzyme elevation (LEE) in HIV antiretroviral‐experienced patients.

Outcome of a second-line protease inhibitor-containing regimen in patients failing or intolerant of a first highly active antiretroviral therapy.

Summary: The outcome of second‐line protease inhibitor (PI)‐containing highly active antiretroviral therapy (HAART) was investigated in 263 patients who were failed by (n = 148) or intolerant of (n = 115) a first HAART regimen. The endpoints were virologic failure (decline in HIV RNA <1 log10 copies/ml after ≥2 months) and discontinuation due to intolerance/toxicity. During a median follow‐up of 483 days (33‐1087 days), 154 patients (59%) discontinued the second regimen, 86 (33%) because of intolerance/toxicity; another 135 patients (51.3%) showed virologic failure. Independent factors associated with virologic failure (Coxs model) were 7 to 12 months of first HAART (hazard ratio [HR] 1.70 versus ≥6 months: 95% confidence interval [CI], 1.08‐2.70) and gender (HR 1.58 males versus females: 95% CI, 1.04‐2.30); the negatively associated factors were advanced age (HR 0.61 >34 years versus ≤34 years: 95% CI, 0.42‐0.88), a saquinavir‐containing first HAART (HR 0.57 versus indinavir: 95% CI, 0.34‐0.93) and change due to intolerance/toxicity (HR 0.58 versus failure: 95% CI, 0.35‐0.98). The independent variables predictive of discontinuation due to intolerance/toxicity were the reason for switching (HR 1.79 intolerance versus failure: 95% CI, 1.02‐3.16) and the first protease inhibitor (PI) regimen (HR 0.42 ritonavir versus indinavir: 95% CI, 0.22‐0.80). Given that patients who are failed by a first regimen are at high risk of having rescue therapy fail as well, second‐line regimens including therapies directed by testing of drug resistance patterns of clinical viral isolates are warranted. Patients experiencing toxicity due to a first PI‐containing regimen are at risk of toxicity to other PIs and should be addressed to PI‐sparing HAART.

Bone Diseases Associated with Human Immunodeficiency Virus Infection: Pathogenesis, Risk Factors and Clinical Management

Bone disorders such as osteopenia and osteoporosis have been recently reported in patients infected with the human immunodeficiency virus (HIV), but their etiology remains still unknown. The prevalence estimates vary widely among the different studies and can be affected by concomitant factors such as the overlapping of other possible conditions inducing bone loss as lypodystrophy, advanced HIV-disease, advanced age, low body weight or concomitant use of other drugs. All the reports at the moment available in the literature showed a higher than expected prevalence of reduced bone mineral density (BMD) in HIV-infected subjects both naïve and receiving potent antiretroviral therapy compared to healthy controls. This controversial can suggest a double role played by both antiretroviral drugs and HIV itself due to immune activation and/or cytokines disregulation. An improved understanding of the pathogenesis of bone disorders can result in better preventative and therapeutic measures. However, the clinical relevance and the risk of fractures remains undefined in HIV-population. The clinical management of osteopenia and osteoporosis in HIV-infected subjects is still being evaluated. Addressing potential underlying bone disease risk factors (e.g., smoking and alcohol intake, use of corticosteroids, advanced age, low body weight), evaluating calcium and vitamin D intake, and performing dual x-ray absorptiometry in HIV-infected individuals who have risk factors for bone disease can be important strategies to prevent osteopenia and osteoporosis in this population. The administration of bisphosphonates (e.g., alendronate), with calcium and vitamin D supplementation, may be a reasonable and effective option to treat osteoporosis in these subjects.

Steatohepatitis in HIV-infected subjects: pathogenesis, clinical impact and implications in clinical management.

Antiretroviral medications have significantly improved the prognosis of subjects infected by human immunodeficiency virus (HIV). However, long-term complications of these drugs are increasingly recognized as significant causes of morbidity and mortality. Non-alcoholic fatty liver disease (NAFLD), which can evolve into non-alcoholic steato-hepatitis (NASH), cirrhosis and ultimately hepatic failure is one of the more often observed complications in the current clinical practice and the correlation with liver enzyme elevations is controversial. Multiple factors have been considered as possibly correlated to this event in the HIV-infected population, including metabolic abnormalities (such as hyperlipidaemia, hyperglycaemia and being overweight), chronic inflammation, concurrent infection with hepatitis C and B viruses, and treatment with certain nucleoside reverse transcriptase inhibitors (NRTI). HIV-associated syndromes such as lactic acidosis and lypodystrophy are frequently associated with fatty liver disease and a mitochondrial injury has been considered as its possible pathogenetic factor. In particular, treatment containing stavudine and didanosine have proven to be the most commonly implicated in the occurrence of mitochondrial abnormalities. Epidemiologic data to better define the role of predictive factors and drugs associated with the development of NAFLD are still lacking. Furthermore, it remains unclear the better therapeutic management for this condition, even if the current best therapeutic option for NAFLD is the treatment of the underlying disease. Other studies are mandatory to better elucidate the pathogenesis of NAFLD and the optimal therapeutic strategy for the underlying conditions.

Insulin resistance affects early virologic response in HIV-infected subjects treated for hepatitis C infection.

To the Editor: The use of highly active antiretroviral therapy (HAART) has been associated with an increased frequency of insulin resistance (IR) and of its clinical correlates, such as glucose intolerance and type-2 diabetes. A direct role of protease inhibitors (PIs) has been proposed; however, traditional risk factors for IR other than HIV infection and HAART use may also predict glucose intolerance or type-2 diabetes in HIVinfected population. In the general population, a correlation between hepatitis C virus (HCV) infection and IR has been demonstrated; the possible mechanisms at the basis of this finding seem to be increased tumor necrosis factor (TNF) production, together with the enhancement of suppressor cytokines (SOC-3), both blocking PI3K and Akt phosphorylation. In HIVnegative patients with chronic HCV receiving pegylated interferon plus ribavirin, IR, as measured by the hemostatic model of assessment (HOMA) index, has been related to the 6-month virologic response. In addition, subjects with a sustained virologic response had lower HOMA values compared with others. Whether IR represents a marker of difficult-to-cure subjects or whether it acts through a pathogenic mechanism by blocking the antiviral activity of interferon is unknown. HCV infection is often a comorbidity in HIV-infected subjects, especially if they are intravenous drug abusers. It has often been associated with IR and hyperglycemia in HIVinfected patients receiving HAART. At the moment, few data are available on the role of IR in influencing the virologic response to anti-HCV treatment in the HIV-infected population. The aim of this study is to evaluate the correlation between IR and early virologic response (EVR) in HIV/HCVcoinfected subjects receiving pegylated interferon plus ribavirin. We included in this study 29 consecutive HIV-infected subjects followed at our clinic who started an antiHCV treatment with pegylated interferon a-2a plus ribavirin (at a dosage of 1000 to 1200 mg according to body weight) in January 2006. The following variables were collected at baseline (time of starting anti-HCV treatment): gender, age, race, body mass index (BMI), platelet count, aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum glucose, insulin, total cholesterol, triglycerides, CD4 cell count, HIV RNA level, HCV RNA level, HCV genotype, and use of HAART (defined as use of

Is the CD4 Cell Percentage a Better Marker of Immunosuppression than the Absolute CD4 Cell Count in HIV-Infected Patients with Cirrhosis?

2 nucleoside reverse transcriptase inhibitors with any PI or nonnucleoside reverse transcriptase inhibitors). Serum insulin levels were measured by electrochemiluminescence immunoassay using an autoanalyser (Elecsys 1010/2010; Elecsys Modular Analytics E170; Roche, Basel, Switzerland). HIV-RNA load was assessed using the reverse transcriptase (RT) polymerase chain reaction (PCR), with a detection limit <60 copies/mL (Arthus Qiagen, Heiden, Germany). Qualitative PCR analysis for HCV was performed by nested PCR (Amplicor Roche, Basel, Switzerland; detection limit <15 IU/L). HCV genotyping was performed using a line-probe assay (INNOLiPA HCV II; Immunogenetics, Belgium). IR was calculated through the HOMA equation: fasting insulin (mIU/L) 3 fasting glucose (mmol/L)/22.5. IR was defined as a HOMAvalue >3.8, according to other studies on white populations with low risk for diabetes. EVR was defined as HCV RNA level <15 IU/mL after 3 months of anti-HCV treatment; additionally, we evaluated the rapid virologic response (RVR), defined as HCV RNA level <15 IU/L after 1 month of anti-HCV treatment. Differences between variables were calculated using the x and Student t tests when appropriate. Table 1 shows the demographics and clinical characteristics of the subjects included in our study according to the HOMA values at baseline. All the patients were white. Ten subjects (34.5%) had a HOMA index >3.8, and 19 (65.5%) had values #3.8. No statistically significant differences were observed in the 2 groups according to the variables considered. After 3 months of anti-HCV treatment, median AST and ALT levels decreased in both groups. In subjects with IR at baseline, median AST and ALT levels decreased from 109 (interquartile range [IQR]: 60 to 141) IU/ L to 54 (IQR: 42 to 65) IU/L (P < 0.01) and from 105 (IQR: 76 to 124) IU/L to 53 (IQR: 45 to 88) IU/L (P < 0.01), whereas in subjects without IR, AST and ALT levels decreased from 108 (IQR: 61 to 147) IU/L to 37 (IQR: 30 to 50) IU/L (P < 0.01) and from 101 (IQR: 68 to 109) IU/L to 33 (IQR: 27 to 48) IU/L (P < 0.01), respectively. RVR was achieved in 8 (42.1%) of 19 subjects without IR and in 0 of 10 with IR at baseline (P < 0.001); EVR was observed in 16 (84.2%) of 19 subjects without IR and in 0 of 10 with IR (P < 0.001). The 3 subjects who did not achieve EVR had genotype 1a, 3a, and 4c/4d, respectively. HCV infection and HAART are conditions associated with a higher probability of developing IR. Such a condition is a known predictor of reduced sustained virologic response to anti-HCV treatment in HCV-infected subjects. Conversely, the achievement of RVR and EVR is a strong predictor of recovery from HCV infection; therefore, subjects who do not achieve this endpoint may be discontinued from anti-HCV treatment because of a low probability of sustained virologic response. In the present study, including only HIV/HCV-coinfected subjects, we found that subjects without IR at baseline are more likely to reach RVR and EVR than the others. Also, in subjects with genotype 3, which is known to respond better to anti-HCV treatments, the presence of IR does not allow for the achievement of RVR or EVR. These results, obtained on a limited number of subjects, suggest that IR should always be evaluated before starting anti-HCV treatment. Therefore, the correction of IR, and the consequent recovery of insulin sensitivity, could improve RVR and EVR in the HIV/ HCV-coinfected population treated with pegylated interferon and ribavirin, and

A Comparison between Abacavir and Efavirenz as the Third Drug Used in Combination with a Background Therapy Regimen of 2 Nucleoside Reverse-Transcriptase Inhibitors in Patients with Initially Suppressed Viral Loads

Recently, it was shown that cirrhotic patients without human immunodeficiency virus (HIV) infection had low CD4 cell counts and normal CD4 cell percentages, suggesting that, for HIV-infected persons, the CD4 cell percentage might be a more accurate marker of disease progression than the absolute CD4 cell count. In cirrhotic HIV-infected persons in the Italian Cohort of Antiretroviral-Naive Patients, the absolute CD4 cell count seemed to be better predictor of the risk of developing an acquired immunodeficiency syndrome-defining illness than the CD4 cell percentage.

Non-invasive markers of liver fibrosis in HCV mono-infected and in HIV/HCV co-infected subjects.

BACKGROUND Our objective was to compare the rate of viral rebound and therapy failure in patients receiving abacavir or efavirenz as the third drug (in addition to 2 non-abacavir nucleosides) in combination antiretroviral therapy (cART) and to compare the rate of metabolic alteration associated with these regimens. METHODS We conducted a multicohort prospective observational study of human immunodeficiency virus-infected patients who had attained viral loads < or = 80 copies/mL while receiving cART, without having previously received antiretrovirals. The rates of virological rebound, therapy failure, and lipid-level alteration during follow-up were calculated as the number of events divided by person-years of follow-up (PYFU). A multivariable analysis was performed using a Poisson regression model. RESULTS We studied a total of 744 patients; the median age was 37 years, 27% of the patients were female, and 41% were heterosexual. There was a total of 854 PYFU spent receiving efavirenz and 285 spent receiving abacavir. The nucleoside reverse-transcriptase inhibitor pairs most frequently used were zidovudine/lamivudine (66% of PYFU), stavudine/lamivudine (17.6%), and stavudine/didanosine (5.4%). The adjusted relative rates of virological failure and therapy failure for abacavir, compared with those for efavirenz, were 2.17 (95% confidence interval [CI], 1.12-4.18; P = .02) and 1.41 (95% CI, 1.01-2.01; P = .05), respectively. CONCLUSIONS Patients with virological suppression while receiving regimens containing abacavir appear more likely to experience virological and therapy failure than those receiving efavirenz as their third drug. Although this is a selected group of adherent patients, bias cannot be ruled out, because this is a nonrandomized comparison.