Direct-acting antivirals in hepatitis C virus (HCV)-infected and HCV/HIV-coinfected patients: real-life safety and efficacy.

OBJECTIVES: Clinical trials of all-oral direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection reported high response rates in HCV/HIV coinfection, similar to those obtained in HCV monoinfection. We evaluated the safety and efficacy of these regimens in a clinical practice setting. METHODS: In this prospective observational study, all the HCV-monoinfected and HCV/HIV-coinfected patients undergoing HCV treatment with all-oral DAA regimens in a routine clinical setting from December 2014 to December 2015 were included in the analysis. Sustained virological response 12 weeks after the end of therapy (SVR12) and reported adverse events (AEs) were evaluated. Resistance-associated variants (RAVs) were analysed in a subgroup of patients at baseline and at the time of viral rebound in those with virological failure. RESULTS: One-hundred and nine patients (51 HCV-infected and 58 HCV/HIV-coinfected) were enrolled in the study. Sixty per cent had cirrhosis and 52% were pegylated interferon and ribavirin (pegIFN/RBV)-experienced. Thirty-six per cent received ombitasvir + paritaprevir/ritonavir + dasabuvir, 25% sofosbuvir + daclatasvir, 16% sofosbuvir + simeprevir, 17% sofosbuvir + ribavirin and 6% sofosbuvir + ledipasvir; ribavirin was used in 57% of subjects. The SVR12 rate was 91% and 96% in HIV-infected and uninfected patients, respectively (P = 0.44). The 4-week HCV viral decline was similar in the two groups. RAVs were found at baseline in 23 of 49 patients and did not affect SVR12. No predictors of SVR12 were identified in our cohort. CONCLUSIONS: Treatment with all-oral DAA combinations of patients infected with HCV and with HCV/HIV under real-life conditions led to high and similar rates of SVR12. Moreover, the historical factors associated with a sustained virological response to pegIFN/RBV were not predictive of the response to all-oral DAAs.

AIDS-associated cryptococcosis: a comparison of epidemiology, clinical features and outcome in the pre- and post-HAART eras. Experience of a single centre in Italy.

Objectives To assess the prevalence, clinical and immunological characteristics, risk factors and survival of patients with AIDS-related cryptococcosis in the era of highly active antiretroviral therapy (HAART). Methods All newly diagnosed cryptococcosis cases identified retrospectively from among a series of AIDS patients hospitalized consecutively at a single institution in Italy in 1985-1996 (pre-HAART period, n=165) and 1997-2006 (post-HAART period, n=40) were analysed comparatively. Results The prevalence of cryptococcosis decreased from 4.7% (165/3543) to 2.2% (40/1805) between the pre- and post-HAART periods (P=0.0001). There were no differences in the clinical features or immunological status of the patients between the two cohorts. The variables associated with the occurrence of cryptococcosis in the post-HAART era were older age (P<0.001), no previous diagnosis of HIV infection (P<0.001) and infection in homosexual males (P=0.004). During the post-HAART period, immune reconstitution inflammatory syndrome associated with cryptococcosis was observed in five patients (19.3%) a median of 15 weeks after the start of HAART. Thirty-day survival (P=0.045) and overall survival (P=0.0001) were significantly better among patients diagnosed with cryptococcosis in the post-HAART compared to those diagnosed in the pre-HAART era. Conclusions The AIDS-associated cryptococcosis observed in Western countries in the HAART era has similar clinical and immunological characteristics to that observed in the pre-HAART era, but a significantly better outcome.

Predictive role of the three-month CD4 cell count in the long-term clinical outcome of the first HAART regimen.

The aim was to evaluate whether the three-month CD4 cell counts are a reliable predictor of the long-term clinical outcome of HAART-treated patients, by an observational study of 585 patients initiating HAART in a clinical setting. Clinical failure was defined as the occurrence of new or recurrent AIDS-defining events or death, and was analysed by means of intention-to-treat, univariate and multivariate analyses. An adjusted Cox regression model was used to evaluate the effect of three-month CD4+ counts on clinical outcome. Clinical failure occurred in 65 patients (11.1%) during a median follow-up of 31 months (1-65) as a result of new AIDS-defining events (ADEs) in 48 patients, ADE recurrence in six, and death in 11. The mean (median; range) CD4+ counts were 156/microL (155; 4--529) in patients with and 362/microL (326; 18--1162) in patients without clinical failure (P < .0001). Moreover, the proportion of patients with mean CD4+ counts < 200 microL was higher in those experiencing subsequent clinical failure (chi2: 41.11; P< .00001). Multivariate analysis showed that baseline CD4+ counts < 50 microL, HIV-RNA > 100,000 copies/mL and AIDS at baseline predicted failure; after adjusting for three-month CD4+ counts, this marker was the only one independently associated with clinical failure (HR 2.93; 95% Cl: 1.16--7.38). The three-month immunologic response is a reliable predictor of long-term clinical outcome.

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

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 > or = 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 (Cox's model) were 7 to 12 months of first HAART (hazard ratio [HR] 1.70 versus < or = 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 < or = 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.

CD4 cell counts at the third month of HAART may predict clinical failure.

OBJECTIVE: To evaluate the influence of immunological and virological markers on clinical outcome in patients receiving their first highly active antiretroviral therapy (HAART) regimen. DESIGN AND METHODS: Observational study of 585 patients initiating HAART in a clinical setting. Clinical failure was defined as the occurrence of new or recurrent AIDS-defining events or death, and was analysed by means of intention-to-treat, univariate and multivariate analyses. An adjusted Cox regression model was used to evaluate the effect of 3-month CD4 cell counts on clinical outcome. RESULTS: Clinical failure occurred in 55 patients (9.4%) during a median follow-up of 483 days (range 33-1334 days): 45 new AIDS-defining events (ADEs) in 38, ADE recurrence in six, and death in 11. Twenty-four of the 45 new ADEs (53.4%) occurred during the first 3 months of HAART, and 11 of 45 (24.4%) in the presence of CD4 cell counts > 200 x 10(6) cells/l. The mean (median, range) CD4 counts were 144 x 10(6) cells/l (128, 4-529) in patients with and 322 x 10(6) cells/l (288, 14-1162) in patients without clinical failure (P < 0.0001). Moreover, the proportion of patients with mean CD4 cell counts < 200 x 10(6) cells/l was higher in those experiencing subsequent clinical failure (X2 test: 26.75; P < 0.00001). Multivariate analysis showed that baseline CD4 cell counts < 50 x 10(6) cells/l and AIDS at enrolment predicted failure; after adjusting for 3-month CD4 cell counts, this marker was the only one independently associated with clinical failure (hazard risk, 4.79; 95% confidence interval, 1.40-16.47). CONCLUSIONS: The 3-month immunological response is a reliable predictor of long-term clinical outcome.

Clinical outcome and predictive factors of failure of highly active antiretroviral therapy in antiretroviral-experienced patients in advanced stages of HIV-1 infection.

OBJECTIVE: To verify the effectiveness of highly active antiretroviral therapy (HAART) and to identify any factors predictive of clinical outcome in a clinical setting. DESIGN: Observational study. METHODS: Treatment failure (i.e., the occurrence of new or recurrent AIDS-defining events, death or any definitive discontinuation) and the course of CD4+ cell counts and HIV RNA copies were evaluated in 250 heavily pretreated HIV-infected patients starting HAART [153 with indinavir (IDV), 55 with ritonavir (RTV), 43 with saquinavir (SQV)]. Univariate and multivariate analyses were performed to identify predictors of worse outcome. RESULTS: During a median follow-up of 8 months, 75 patients (30%) had treatment failure because of the occurrence of an AIDS-defining event or death (n = 24), inefficacy (n = 24), or severe intolerance (n = 27). Twenty new and six recurrent AIDS-defining events, and nine deaths occurred (six out of 20 AIDS-defining events and two out of nine deaths within 1 month of treatment). CD4+ counts were above 200 x 10(6)/l at AIDS diagnosis in only two patients. None of the SQV patients, 12 (7.8%) of the IDV patients, and 15 (27.3%) of the RTV-treated patients were considered non-compliant. The SQV-containing regimens independently correlated with treatment failure (relative risk, 2.46; 95% confidence interval, 1.20-5.03; versus IDV). Low compliance partially determined outcome in RTV-treated patients; both severe immunodepression and AIDS at baseline were predictive of treatment failure. There was a 10-fold increase in CD4+ cell counts in the patients treated with IDV and RTV; the best virological outcome occurred in IDV-treated patients, with 68.4% of patients showing undetectable HIV RNA copies after 6 months. CONCLUSIONS: HAART was effective in 70% of patients; low compliance and previous AIDS diagnosis represented predictive factors of therapy failure.