Gene flow analysis is used to identify the migration patterns of viruses within a geographical ar... more Gene flow analysis is used to identify the migration patterns of viruses within a geographical area and /or in different populations. 883 HIV-1 B subtype pol gene sequences were analyzed. The gene analysis among different geographical areas of the Bergamo district and from different transmission risk groups showed 25% of the observed gene flow was from people living in the north valleys to lowland and 40.5% from a heterosexual risk group to injecting drug users. Injecting drug users seem to be the central link, mercenary sex being the common route of transmission (and gene flow) between this group and both heterosexual and homosexual individuals.
Journal of acquired immune deficiency syndromes (1999), Jan 20, 2016
Dual treatments could help clinicians to avoid drawbacks and toxicities due to the nucleosidic ba... more Dual treatments could help clinicians to avoid drawbacks and toxicities due to the nucleosidic backbone, while maintaining the efficacy and convenience of robust cART. We explored the combination of rilpivirine plus boosted darunavir as an option when switching from standard cART in patients who are virologically suppressed. In this randomized, open-label, proof-of-concept, non-inferiority trial, we recruited patients aged 18 years or older with chronic HIV-1 infection and on a stable, effective (> 6 months) PI-based cART including a nucleosidic backbone. The primary endpoint was non-inferiority of the virological response between treatment groups, according to FDA snapshot approach.Sixty patients were randomly allocated to dual treatment with rilpivirine plus boosted darunavir or to continue their ongoing triple treatment.Non-inferiority was shown at the pre-specified level of -12% both at 24 and 48 weeks. At week 24, 100% of patients in the dual arm presented a blood HIV-RNA le...
Two commercial assays that detect Mycobacterium tuberculosis complex (MTB) in clinical specimens ... more Two commercial assays that detect Mycobacterium tuberculosis complex (MTB) in clinical specimens by rRNA target amplification (AMTDII) and ligase chain reaction (LCx) were evaluated. The tests were applied to 457 respiratory (n = 273) and extrapulmonary (n = 184) specimens collected from 357 patients. The results were compared with those of acid-fast staining and culture. The combination of culture and clinical diagnosis was considered to be the "gold standard." Seventy specimens were from patients with pulmonary tuberculosis and 28 specimens were from patients with extrapulmonary tuberculosis. After resolution of discrepant results, the overall sensitivities, specificities, and positive and negative predictive values for respiratory specimens were 92.8, 99.4, 98.5, and 97%, respectively, for AMTDII and 75.7, 98.8, 96.4, and 90.5%, respectively, for LCx. With extrapulmonary specimens, the overall sensitivities, specificities, and positive and negative predictive values wer...
Twenty-one pediatric liver transplant recipients were enrolled in a study comparing prophylaxis f... more Twenty-one pediatric liver transplant recipients were enrolled in a study comparing prophylaxis followed by preemptive therapy (10 patients) versus preemptive therapy alone (11 patients) for prevention of human cytomegalovirus (HCMV) disease. In the prophylaxis arm, patients were treated with ganciclovir for 30 days, then preemptive therapy was initiated with virologic monitoring for pp65 antigenemia. In the preemptive therapy arm, patients were treated on reaching 100,000 DNA copies/mL whole blood. An interim analysis showed that, although numbers of both infected and treated patients were comparable in the two arms, the median number of total days of antiviral therapy per patient (30 vs. 18, P<0.01) was significantly higher in the prophylaxis arm. No case of HCMV disease occurred in either arm. Therefore, the trial was interrupted and prophylaxis replaced with preemptive therapy alone. In parallel, the development of T-cell-mediated immune response was found to be comparable in both arms.
We evaluated the emergence of drug resistance in patients failing first-line regimens containing ... more We evaluated the emergence of drug resistance in patients failing first-line regimens containing one nonnucleoside reverse transcriptase inhibitor (NNRTI) administered with zidovudine (ZDV) + lamivudine (the ZDV group) or non-thymidine analogues (non-TAs) (tenofovir or abacavir, + lamivudine or emtricitabine; the non-TA group). Three hundred HIV-1-infected patients failing a first-line NNRTI-containing regimen (nevirapine, n = 148; efavirenz, n = 152) were included in the analysis. Virological failure was defined as viraemia ≥ 400 HIV-1 RNA copies/mL for the first time at least 6 months after starting the NNRTI-based regimen. For each patient, a genotypic resistance test at failure was available. The presence of drug-resistance mutations in HIV-1 reverse transcriptase was evaluated by comparing patients treated with NNRTI + zidovudine + lamivudine vs. those treated with NNRTI + non-TA. A total of 208 patients were failing with NNRTI + zidovudine + lamivudine and 92 with NNRTI + non-TA. No significant differences were observed between the non-TA group and the ZDV group regarding the time of virological failure [median (interquartile range): 12 (8-25) vs. 13 (9-32) months, respectively; P = 0.119] and viraemia [median (interquartile range): 4.0 (3.2-4.9) vs. 4.0 (3.3-4.7) log₁₀ copies/mL, respectively; P = 0.894]. Resistance to reverse transcriptase inhibitors (RTIs) occurred at a significant lower frequency in the non-TA group than in the ZDV group (54.3 vs. 75.5%, respectively; P = 0.001). This difference was mainly attributable to a significantly lower prevalence of NNRTI resistance (54.3 vs. 74.0%, respectively; P = 0.002) and of the nucleoside reverse transcriptase inhibitor (NRTI) mutation M184V (23.9 vs. 63.5%, respectively; P < 0.001) in the non-TA group compared with the ZDV group. As expected, the mutation K65R was found only in the non-TA group (18.5%; P < 0.001). At first-line regimen failure, a lower prevalence of RTI resistance was found in patients treated with NNRTI + non-TA compared with those treated with NNRTI + zidovudine + lamivudine. These results confirm that the choice of backbone may influence the prevalence of drug resistance at virological failure.
The effect of adherence on the risk of virologic failure and mutations selection was verified in ... more The effect of adherence on the risk of virologic failure and mutations selection was verified in a prospective study. At baseline, all patients had a viral load (VL) <50 copies/mL and completed a self-reported questionnaire. Patients were followed for the subsequent 4 months to document virologic rebound (VL > 50 copies/mL). 1,133 patients completed 2,240 questionnaires/follow-up (non-nucleoside reverse transcriptase inhibitor [NNRTI] = 1,479; single protease inhibitor [PI] = 200; boosted PI = 561). Only the type of treatment and the baseline adherence rate were significantly associated with the virologic endpoint. A viral rebound rate >10% was observed in patients treated with single PI (14.7%) or boosted PI (11.7%) up to an adherence rate of 95%, whereas a similar (17.6%) rebound rate was observed only in NNRTI-treated patients with very low adherence (<55%). After adjustment for other baseline predictors of adherence, patients on NNRTIs showed a higher adherence rate than those on PIs but not higher than those on boosted PIs. The same adherence rate did not have the same result, in terms of virologic rebound, in patients on the same HAART for shorter or longer periods of time. Overall, the risk of virologic rebound for patients with >95% adherence rate was 6.2% in the first 6 months of therapy, lowered to 5.0% in the following 6 months, and was 3.2% thereafter. The risk of selecting for resistance-inducing viral mutation for NNRTI-treated patients was higher (4.9%) at very low adherence rates (<75%); the opposite was true for single PI-treated patients (4.2% for adherence >95%). Boosted PI-treated patients showed an intermediate pattern, even if at a much lower level of risk. Low adherence is a major determinant of virologic failure, however different therapies have different adherence cutoffs determining a significant increment of risk.
24-week analysis 48-week analysis Main pharmacokinetic parameters in 21/27 patients on dual regim... more 24-week analysis 48-week analysis Main pharmacokinetic parameters in 21/27 patients on dual regimen with ATV plus RAL, who underwent 12h intensive PK (from reference: Ripamonti D) RAL 400mg BID ATV 200mg BID AUC 0-12h (ng·h/ml) GM (%CV) (Range) C12h a (ng/ml) GM (%CV) (Range) C0 b (ng/ml) GM (%CV) (Range) ATV= atazanavir, RGV= raltegravir, GM= geometric mean, CV= coefficient of variation, IQR= interquartile a: C12h is defined as concentration before PM dose. b: C0 is defined as concentration before AM dose Table 2: Proportion of patients with HIV RNA < 50 copies/μl over 24 weeks Safety and tolerability Rationale for combining ATV and RAL in a dual regimen • NRTI-sparing regimens are attractive options to avoid NRTI-associated toxicity and to provide a full active regimen in patients with extensive NRTI resistance. • Raltegravir (RAL) and atazanavir (ATV) are potent "third drugs" and they provide a synergistic inhibition of 2 different steps in HIV replication. • ATV may...
Gene flow analysis is used to identify the migration patterns of viruses within a geographical ar... more Gene flow analysis is used to identify the migration patterns of viruses within a geographical area and /or in different populations. 883 HIV-1 B subtype pol gene sequences were analyzed. The gene analysis among different geographical areas of the Bergamo district and from different transmission risk groups showed 25% of the observed gene flow was from people living in the north valleys to lowland and 40.5% from a heterosexual risk group to injecting drug users. Injecting drug users seem to be the central link, mercenary sex being the common route of transmission (and gene flow) between this group and both heterosexual and homosexual individuals.
Journal of acquired immune deficiency syndromes (1999), Jan 20, 2016
Dual treatments could help clinicians to avoid drawbacks and toxicities due to the nucleosidic ba... more Dual treatments could help clinicians to avoid drawbacks and toxicities due to the nucleosidic backbone, while maintaining the efficacy and convenience of robust cART. We explored the combination of rilpivirine plus boosted darunavir as an option when switching from standard cART in patients who are virologically suppressed. In this randomized, open-label, proof-of-concept, non-inferiority trial, we recruited patients aged 18 years or older with chronic HIV-1 infection and on a stable, effective (> 6 months) PI-based cART including a nucleosidic backbone. The primary endpoint was non-inferiority of the virological response between treatment groups, according to FDA snapshot approach.Sixty patients were randomly allocated to dual treatment with rilpivirine plus boosted darunavir or to continue their ongoing triple treatment.Non-inferiority was shown at the pre-specified level of -12% both at 24 and 48 weeks. At week 24, 100% of patients in the dual arm presented a blood HIV-RNA le...
Two commercial assays that detect Mycobacterium tuberculosis complex (MTB) in clinical specimens ... more Two commercial assays that detect Mycobacterium tuberculosis complex (MTB) in clinical specimens by rRNA target amplification (AMTDII) and ligase chain reaction (LCx) were evaluated. The tests were applied to 457 respiratory (n = 273) and extrapulmonary (n = 184) specimens collected from 357 patients. The results were compared with those of acid-fast staining and culture. The combination of culture and clinical diagnosis was considered to be the "gold standard." Seventy specimens were from patients with pulmonary tuberculosis and 28 specimens were from patients with extrapulmonary tuberculosis. After resolution of discrepant results, the overall sensitivities, specificities, and positive and negative predictive values for respiratory specimens were 92.8, 99.4, 98.5, and 97%, respectively, for AMTDII and 75.7, 98.8, 96.4, and 90.5%, respectively, for LCx. With extrapulmonary specimens, the overall sensitivities, specificities, and positive and negative predictive values wer...
Twenty-one pediatric liver transplant recipients were enrolled in a study comparing prophylaxis f... more Twenty-one pediatric liver transplant recipients were enrolled in a study comparing prophylaxis followed by preemptive therapy (10 patients) versus preemptive therapy alone (11 patients) for prevention of human cytomegalovirus (HCMV) disease. In the prophylaxis arm, patients were treated with ganciclovir for 30 days, then preemptive therapy was initiated with virologic monitoring for pp65 antigenemia. In the preemptive therapy arm, patients were treated on reaching 100,000 DNA copies/mL whole blood. An interim analysis showed that, although numbers of both infected and treated patients were comparable in the two arms, the median number of total days of antiviral therapy per patient (30 vs. 18, P&amp;amp;amp;amp;amp;amp;lt;0.01) was significantly higher in the prophylaxis arm. No case of HCMV disease occurred in either arm. Therefore, the trial was interrupted and prophylaxis replaced with preemptive therapy alone. In parallel, the development of T-cell-mediated immune response was found to be comparable in both arms.
We evaluated the emergence of drug resistance in patients failing first-line regimens containing ... more We evaluated the emergence of drug resistance in patients failing first-line regimens containing one nonnucleoside reverse transcriptase inhibitor (NNRTI) administered with zidovudine (ZDV) + lamivudine (the ZDV group) or non-thymidine analogues (non-TAs) (tenofovir or abacavir, + lamivudine or emtricitabine; the non-TA group). Three hundred HIV-1-infected patients failing a first-line NNRTI-containing regimen (nevirapine, n = 148; efavirenz, n = 152) were included in the analysis. Virological failure was defined as viraemia ≥ 400 HIV-1 RNA copies/mL for the first time at least 6 months after starting the NNRTI-based regimen. For each patient, a genotypic resistance test at failure was available. The presence of drug-resistance mutations in HIV-1 reverse transcriptase was evaluated by comparing patients treated with NNRTI + zidovudine + lamivudine vs. those treated with NNRTI + non-TA. A total of 208 patients were failing with NNRTI + zidovudine + lamivudine and 92 with NNRTI + non-TA. No significant differences were observed between the non-TA group and the ZDV group regarding the time of virological failure [median (interquartile range): 12 (8-25) vs. 13 (9-32) months, respectively; P = 0.119] and viraemia [median (interquartile range): 4.0 (3.2-4.9) vs. 4.0 (3.3-4.7) log₁₀ copies/mL, respectively; P = 0.894]. Resistance to reverse transcriptase inhibitors (RTIs) occurred at a significant lower frequency in the non-TA group than in the ZDV group (54.3 vs. 75.5%, respectively; P = 0.001). This difference was mainly attributable to a significantly lower prevalence of NNRTI resistance (54.3 vs. 74.0%, respectively; P = 0.002) and of the nucleoside reverse transcriptase inhibitor (NRTI) mutation M184V (23.9 vs. 63.5%, respectively; P &lt; 0.001) in the non-TA group compared with the ZDV group. As expected, the mutation K65R was found only in the non-TA group (18.5%; P &lt; 0.001). At first-line regimen failure, a lower prevalence of RTI resistance was found in patients treated with NNRTI + non-TA compared with those treated with NNRTI + zidovudine + lamivudine. These results confirm that the choice of backbone may influence the prevalence of drug resistance at virological failure.
The effect of adherence on the risk of virologic failure and mutations selection was verified in ... more The effect of adherence on the risk of virologic failure and mutations selection was verified in a prospective study. At baseline, all patients had a viral load (VL) &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;50 copies/mL and completed a self-reported questionnaire. Patients were followed for the subsequent 4 months to document virologic rebound (VL &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 50 copies/mL). 1,133 patients completed 2,240 questionnaires/follow-up (non-nucleoside reverse transcriptase inhibitor [NNRTI] = 1,479; single protease inhibitor [PI] = 200; boosted PI = 561). Only the type of treatment and the baseline adherence rate were significantly associated with the virologic endpoint. A viral rebound rate &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;10% was observed in patients treated with single PI (14.7%) or boosted PI (11.7%) up to an adherence rate of 95%, whereas a similar (17.6%) rebound rate was observed only in NNRTI-treated patients with very low adherence (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;55%). After adjustment for other baseline predictors of adherence, patients on NNRTIs showed a higher adherence rate than those on PIs but not higher than those on boosted PIs. The same adherence rate did not have the same result, in terms of virologic rebound, in patients on the same HAART for shorter or longer periods of time. Overall, the risk of virologic rebound for patients with &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;95% adherence rate was 6.2% in the first 6 months of therapy, lowered to 5.0% in the following 6 months, and was 3.2% thereafter. The risk of selecting for resistance-inducing viral mutation for NNRTI-treated patients was higher (4.9%) at very low adherence rates (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;75%); the opposite was true for single PI-treated patients (4.2% for adherence &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;95%). Boosted PI-treated patients showed an intermediate pattern, even if at a much lower level of risk. Low adherence is a major determinant of virologic failure, however different therapies have different adherence cutoffs determining a significant increment of risk.
24-week analysis 48-week analysis Main pharmacokinetic parameters in 21/27 patients on dual regim... more 24-week analysis 48-week analysis Main pharmacokinetic parameters in 21/27 patients on dual regimen with ATV plus RAL, who underwent 12h intensive PK (from reference: Ripamonti D) RAL 400mg BID ATV 200mg BID AUC 0-12h (ng·h/ml) GM (%CV) (Range) C12h a (ng/ml) GM (%CV) (Range) C0 b (ng/ml) GM (%CV) (Range) ATV= atazanavir, RGV= raltegravir, GM= geometric mean, CV= coefficient of variation, IQR= interquartile a: C12h is defined as concentration before PM dose. b: C0 is defined as concentration before AM dose Table 2: Proportion of patients with HIV RNA < 50 copies/μl over 24 weeks Safety and tolerability Rationale for combining ATV and RAL in a dual regimen • NRTI-sparing regimens are attractive options to avoid NRTI-associated toxicity and to provide a full active regimen in patients with extensive NRTI resistance. • Raltegravir (RAL) and atazanavir (ATV) are potent "third drugs" and they provide a synergistic inhibition of 2 different steps in HIV replication. • ATV may...
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