Francesco Baldini

Usefulness of monitoring HIV drug resistance and adherence in individuals failing highly active antiretroviral therapy: a randomized study (ARGENTA).

Objective To establish the influence of genotypic resistance-guided treatment decisions and patient-reported adherence on the virological and immunological responses in patients failing a potent antiretroviral regimen in a randomized, controlled trial in a tertiary care infectious diseases department. Patients A total of 174 patients with virological failure were randomly assigned to receive standard of care (SOC) or additional genotypic resistance information (G). Adherence was measured by a self-administered questionnaire. Main outcomes measures Primary endpoints were the proportion with HIV-RNA < 500 copies/ml at 3 and 6 months by intention-to-treat analysis. Secondary endpoints were changes from baseline HIV-RNA levels and CD4 cell counts. Results At entry, 25% had failed three or more highly active antiretroviral therapy (HAART) regimens and 41% three drug classes; there were more resistance mutations in G. In 127 evaluable questionnaires, 43% reported last missed dose during the previous week. At 3 months, 11 of 89 patients (12%) in SOC and 23 of 85 (27%) in G had HIV-RNA < 500 copies/ml (OR 2.63, 95% CI 1.12–6.26); the relative proportions were 17 and 21% at 6 months. CD4 cell changes did not differ between arms. Six month CD4 cell changes were +62 in adherent and −13 cells/μl in non-adherent patients (P < 0.01). Being assigned to G, good adherence, previous history of virological success, fewer experienced HAART regimens and lower baseline viral load were independently predictive of 3 month virological success. Conclusion The virological benefit of genotype-guided treatment decisions in heavily pre-exposed patients was short term. Patients adherence and residual treatment options influenced outcomes.

Variable Prediction of Antiretroviral Treatment Outcome by Different Systems for Interpreting Genotypic Human Immunodeficiency Virus Type 1 Drug Resistance

To determine the variability of genotypic human immunodeficiency virus (HIV) type 1 drug-resistance interpretation by available expert systems and its clinical implications, 261 subjects for whom a potent antiretroviral regimen was failing who were starting salvage therapy were evaluated. The association of the genotypic susceptibility score (GSS) of the salvage regimen, according to 11 interpretation systems, with HIV RNA outcomes for 6 months was examined. GSS was highly variable, as determined by the different interpretation systems, and showed independent correlation with changes from baseline HIV RNA levels at 6 months with 5 systems--Stanford hivdb, GuideLines 3.0, Retrogram 1.4, HIVresistanceWeb, and São Paulo University. Most GSSs predicted virologic response in regimens containing stavudine, lamivudine, efavirenz, or indinavir. Selected systems predicted response in regimens containing didanosine, abacavir, or nelfinavir, and no system predicted outcome of boosted protease inhibitors. GSSs predicted changes in HIV RNA levels better in adherent patients than in nonadherent individuals. Interpretation may be improved, and knowledge should be used uniformly throughout different expert systems.

Female sex and the use of anti-allergic agents increase the risk of developing cutaneous rash associated with nevirapine therapy

To identify factors associated with cutaneous rash, we performed a retrospective multicentre analysis of HIV outpatients starting a highly active antiretroviral therapy regimen containing nevirapine. A total of 62 cutaneous adverse events were observed in 429 patients. Rash hazard was increased in women, by the prophylactic use of glucocorticoids or antihistaminics, and was reduced by escalating the initial dose of nevirapine. Women receiving glucocorticoids had a 3 month cumulative probability of rash of 0.41.

Neuroactive antiretroviral drugs do not influence neurocognitive performance in less advanced HIV-infected patients responding to highly active antiretroviral therapy

Objective: To analyze the effect of antiretroviral therapy, including drugs that have good penetration in cerebrospinal fluid (CSF), on neuropsychologic performance. Methods: One hundred sixty-five HIV-1-infected patients exposed to a stable highly active antiretroviral therapy (HAART) regimen were studied. Neuropsychologic examinations were performed for all patients. Results: A total of 50.3% of patients were impaired. In multivariate analysis, older age (for 10-year increase, odds ratio [OR] = 4.8, 95% confidence interval [CI]: 2.2 to 10.4; P< 0.0001) and higher plasma HIV-1 RNA levels (OR = 1.90, 95% CI: 1.1 to 3.2; P = 0.021) at testing were independently associated with an increased probability of impaired neurocognitive performance, whereas higher educational level was a protective factor (OR = 0.76, 95% CI: 0.65 to 0.90; P=0.001). A significant linear correlation was observed between the neuropsychologic z score for 8 tests (NPZ8) score, a quantitative parameter of neurocognitive impairment, and CD4 cell count at neuropsychologic testing (R = 0.273, P = 0.001) and between the NPZ8 score and the patients age (R = 0.288, P = 0.001). Conclusions: Our study indicates that the use of stable HAART, including multiple drugs that have good CSF penetration, was not associated with neuropsychologic performance. To prevent independent replication of HIV in CSF with better control of a relevant reservoir of HIV is one of the crucial aims of therapeutic strategy.

Deep salvage with amprenavir and lopinavir/ritonavir: Correlation of pharmacokinetics and drug resistance with pharmacodynamics

Abstract:The safety, efficacy, and mutual interactions of combination amprenavir with lopinavir/ritonavir as deep salvage treatment were investigated in a prospective 24-week pilot study. HIV-infected patients (n = 22) with virologic failure to nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs, and at least 2 protease inhibitors received 400/100 mg of lopinavir/ritonavir with 600 mg of amprenavir every 12 hours combined with NRTIs. Patients receiving the same doses of lopinavir/ritonavir (n = 10) or amprenavir with ritonavir (n = 8) were chosen as controls for pharmacokinetic analyses. Mean changes from baseline HIV RNA levels and CD4 counts after 24 weeks were −1.13 log10 copies/mL and +88 × 106 cells/L, respectively. The mean plasma trough concentration (Cmin)and peak concentration (Cmax) of amprenavir were 104% and 228% lower and the Cmin of lopinavir was 46% lower in patients in whom the drugs were coadministered than in controls. There were 4 permanent drug discontinuations because of toxicity. An inhibitory quotient (IQ) of amprenavir higher than 0.8 was the best predictor of virologic outcome at 24 weeks, even after adjusting for amprenavir Cmin or phenotypic susceptibility. Deep salvage therapy using lopinavir/ritonavir with amprenavir is sufficiently safe and shows partial efficacy. When these drugs are coadministered, therapeutic drug monitoring should be employed and the IQ can be used to determine target drug levels.

Progressive Multifocal Leukoencephalopathy in HIV-Infected Patients in the Era of HAART: Radiological Features at Diagnosis and Follow-Up and Correlation with Clinical Variables

The magnetic resonance (MR) imaging patterns of HIV-infected patients affected by progressive multifocal leukoencephalopathy (PML) in the HAART era have not been extensively documented. The aim of the present study is to describe the MR features of PML in HIV-infected patients at diagnosis, and the evolution during follow-up, evaluating the impact of HAART on imaging, and to correlate the MR pattern with the virological and immunological levels and with survival. We retrospectively reviewed MR imaging at baseline and at the last available follow-up within 6 months of diagnosis (median 4 months, range 1-6) of 31 HIV-positive patients affected by PML. A closer follow-up [median interval from diagnosis 39 days (range 20-139)] was also reported. At the onset of neurological disorder, 19 patients were naive for antiretroviral therapy, 7 patients were on HAART, and 5 patients were experienced but were not taking antiretroviral therapy. Upon PML diagnosis no significant differences at imaging were observed between naive and experienced patients and HAART-treated or non-HAART-treated patients. MR findings were not related to immunological status, either at baseline or at follow-up. A radiological improvement within 6 months was associated with a higher probability of a more favorable clinical evolution [OR 14.0 (2.2-87.2), p = 0.003]. The overall probability of survival at 6 months was 61.5%. A better survival was observed in patients with stable or improved MR imaging findings within 6 months [HR 4.55 (95%CI 1.36-15.19, p = 0.009]. Although HAART prolonged the survival of HIV-positive patients affected by PML, it did not seem to influence the PML MR pattern of presentation and the imaging evolution. Only the radiological outcome was predictive of clinical outcome.

Virological Response in Cerebrospinal Fluid to Antiretroviral Therapy in a Large Italian Cohort of HIV-Infected Patients with Neurological Disorders

The aim of the present study was to analyse the effect of antiretroviral (ARV) therapy and single antiretroviral drugs on cerebrospinal fluid (CSF) HIV-RNA burden in HIV-infected patients affected by neurological disorders enrolled in a multicentric Italian cohort. ARVs were considered “neuroactive” from literature reports. Three hundred sixty-three HIV-positive patients with available data from paired plasma and CSF samples, were selected. One hundred twenty patients (33.1%) were taking ARVs at diagnosis of neurological disorder. Mean CSF HIV-RNA was significantly higher in naïve than in experienced patients, and in patients not taking ARV than in those on ARV. A linear correlation between CSF HIV-RNA levels and number of neuroactive drugs included in the regimen was also found (r = −0.44, P < 0.001). Low -plasma HIV-RNA and the lack of neurocognitive impairment resulted in independently associated to undetectable HIV-RNA. Taking nevirapine or efavirenz, or regimen including NNRTI, NNRTI plus PI or boosted PI, was independently associated to an increased probability to have undetectable HIV-RNA in CSF. The inclusion of two or three neuroactive drugs in the ARV regimen was independently associated to undetectable viral load in CSF. Our data could be helpful in identifying ARV regimens able to better control HIV replication in the CNS sanctuary, and could be a historical reference for further analyses.

Brain tuberculosis-associated immune reconstitution inflammatory syndrome in an HIV-positive patient: a biopsy-proven case

The case of an HIV-infected man from Eritrea previously diagnosed with tuberculosis, who presented neurological impairment and cerebral lesion after having voluntarily stopped anti-tubercular and antiretroviral therapies, is here reported. Treatments associated with steroids and mannitol were administered. The patients condition improved, but neuroimaging showed a continuous worsening of the lesion, while a great immunological reconstitution was observed. Brain microsurgery was performed. A tuberculosis diagnosis was supported by pathological and microbiological examinations. Tuberculosis arising during immune reconstitution inflammatory syndrome is a complication of antiretroviral treatment and is considered to be an emerging disorder, especially in countries highly endemic for tuberculosis.