Tenofovir renal safety in HIV-infected patients: results from the SCOLTA Project.

OBJECTIVE: To evaluate the prevalence and incidence of nephrotoxicity in HIV-infected patients enrolled in the SCOLTA Project tenofovir cohort and to identify possible risk factors. DESIGN: The SCOLTA Project is a prospective, observational, multicenter study involving 25 infectious disease departments in Italy created to assess the incidence of severe adverse events in patients receiving new antiretroviral drugs. PATIENTS: The SCOLTA Project tenofovir cohort includes a total of 754 HIV infected patients. RESULTS: Data including grade II-IV creatinine elevations according to ACTG scale were available in 354 patients, 237 (67%) males with a mean age of 40.1+/-7.6 years enrolled in the SCOLTA Project tenofovir cohort. During a mean follow up of 19.5+/-11.5 months creatinine elevations were reported in 9/354 (2.5%) patients, all males. Mean duration of tenofovir therapy at the event was 9.5+/-5 months. The overall incidence was 1.6 (95% CI 1.5-1.7) per 100 person-years (p-y) and 0.5 (95% CI 0.4-0.6) p-y for grade III. No grade IV creatinine elevations were reported. Patients with nephrotoxicity were older and more frequently male, HCV infected, in CDC stage C and their CD4 cell count was significantly lower than those without nephrotoxicity. No significant difference was found between tenofovir co-administered antiretroviral drugs. CONCLUSIONS: Both prevalence and incidence of nephrotoxicity were low in patients receiving tenofovir in a non-selected clinical setting. Renal injury in patients receiving tenofovir seems associated with the presence of co-morbidities and with advanced HIV infection.

Potential predictive factors of osteoporosis in HIV-positive subjects.

Recent reports showed a high frequency of osteopenia/osteoporosis in HIV-infected subjects. Mechanism on the basis of this alteration is still unclear, as the direct effect of virus or of antiretroviral drugs. One hundred sixty-one consecutive HIV-infected outpatients aged 30-50 years, both naive and HAART-treated for >1 year, were included. An interview questionnaire was performed to establish prior pathological, toxic, epidemiological histories, medications intake, physical activity and eating habits. Blood and urinary tests were checked to exclude concomitant diseases, as were markers of bone metabolism and vitamin D3-metabolites. Each subject underwent to a lumbar spine and left hipbone mineral density by DEXA, using WHO criteria for diagnosis of osteopenia/osteoporosis. Radiologist was unaware if the subject was receiving HAART or not. For groups' homogeneity Chi-square, Fisher's exact and Student's t tests were used. Logistic regression analysis was used to find predictors of osteopenia/osteoporosis and linear regression model to find differences in bone mass density. The demographic characteristics of the 48 naive subjects and the 113 on HAART were comparable. Eighty subjects (49.7%) showed osteopenia/osteoporosis: 22 (45.8%) naive and 58 (51.3%) on HAART (P = 0.46). Independent predictors of osteopenia/osteoporosis were female gender (OR: 3.02, 95% CI: 1.26-7.25, P = 0.01 vs. male), older age (OR: 1.10, 95% CI: 1.01-1.20, P = 0.03, for each additional year), low body mass index (OR: 0.78, 95% CI: 0.68-0.91, P = 0.001 for each additional unit) and higher HIV-RNA levels at DEXA (OR: 1.97, 95% CI: 1.16-3.34, P = 0.01 for each additional Log(10)), whereas the use of HAART (OR: 2.61, 95% CI: 0.66-10.27, P = 0.17 vs. naive) and the alterations of markers of bone metabolism were not significantly related to osteopenia/osteoporosis. Similar findings were obtained using linear regression model analysis. HIV-infected subjects have a high frequency of osteopenia/osteoporosis. Traditional risk factors are predictive of osteopenia/osteoporosis also in HIV-subjects; the association with higher HIV-RNA levels can suggest a direct role of HIV itself in the occurrence of bone disease.

[Renal toxicity in HIV-infected patients receiving HAART including tenofovir]. / Tossicità renale in pazienti con infezione da HIV in trattamento con HAART contenente tenofovir.

HIV-infected patients may undergo renal damage related to the HIV infection itself, to the presence of co-infections, arterial hypertension, diabetes or to the exposure to nephrotoxic drugs. Tenofovir has been associated with the development of acute renal failure with Fanconi syndrome and acute tubular necrosis and, albeit rarely, with chronic liver disease. Patients with low CD4 cell count, low body weight and with concomitant diseases such as arterial hypertension and diabetes or co-infections with HCV, HBV or Treponema pallidum seem at higher risk of tenofovir-related nephrotoxicity. Other risk factors include previous exposure to nephrotoxic drugs and the association of tenofovir with boosted protease inhibitors or with didanosine. However, from the analysis of published papers the incidence of tenofovir-related renal toxicity seems low, as confirmed also by our personal casuistry (SCOLTA Project). Thus, a careful selection of patients including the evaluation of existent renal disease before starting an antiretroviral regimen including tenofovir is necessary to prevent renal damage. Furthermore, frequent monitoring of renal function in patients at higher risk of renal damage is strongly recommended, as well as a tenofovir dose adjustment if an alteration of renal function is detected.

Adherence to highly active antiretroviral therapy is better in patients receiving non-nucleoside reverse transcriptase inhibitor-containing regimens than in those receiving protease inhibitor-containing regimens.

The difference between adherence to non- nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI)-based regimens was investigated. Better adherence was found in NNRTI-treated patients, especially when efavirenz was included in the regimen, compared with single PI-treated patients and in those with CD4 cell counts less than 200 x 10(6)/l. By contrast, younger age, self-report of active drug use, fatigue or vomiting negatively affected adherence. Self-reported sexual dysfunction was significantly associated with non-adherence only in PI-treated individuals.

Simplification of protease inhibitor-containing regimens with efavirenz, nevirapine or abacavir: safety and efficacy outcomes.

OBJECTIVE: To describe the immunological and virological outcome, and the factors associated to discontinuation in patients switching to a regimen containing efavirenz (EFV), nevirapine (NVP) or abacavir (ABC) after long-term viral suppression under protease inhibitor-including HAART. DESIGN: Observational study at three outpatient clinics for HIV care in Italy. METHODS: Patients with HIV RNA <80 copies/ml and CD4 >200 cells/ml for at least 6 months on a protease inhibitor-containing treatment who switched to NVP, EFV or ABC were included in the study. End-points were immunological failure, virological failure and discontinuation due to toxicity. Survival analyses were performed to find out any independent variables predictive of reaching the end-points. RESULTS: 177 patients were enrolled; 85 started EFV, 54 NVP and 38 ABC as part of the simplification regimen. 16/159 patients experienced immunological failure: the variables associated to CD4 count decrease were HIV RNA set point value (HR 2.32 for each log10 copies more, P=0.040) and intolerance/toxicity as reason for simplification (HR 3.96, P=0.05). 13/151 subjects showed virological failure; an AIDS diagnosis (HR 6.04, P=0.021) and the use of NVP (HR 7.98, P=0.027) were associated to a worse virological outcome, while patients naive before HAART showed a lower risk of failure (HR 0.008, P=0.007). 16/177 patients discontinued simplification regimen due to toxicity; longer HAART duration before switch was associated to risk reduction (HR 0.92, P=0.004). CONCLUSIONS: Simplification is safe and effective, but it should be offered to patients with shorter treatment duration, and in good clinical and immunovirological conditions.

Relative prognostic value of self-reported adherence and plasma NNRTI/PI concentrations to predict virological rebound in patients initially responding to HAART.

We studied the predictive value of self-reported adherence and plasma drug concentrations on virological rebound to HAART. Among 238 participants in the AdICoNA study who had viral load < or = 500 copies/ml, 42 (17.6%) experienced virological rebound by 96 weeks. Both self-reported non-adherence and sub-optimal concentration were independently associated with a higher risk of virological rebound.

Four years data of raltegravir-based salvage therapy in HIV-1-infected, treatment-experienced patients: the SALIR-E Study.

Apart from the BENCHMRK study, there are no large observational experiences describing the long-term efficacy and safety of rescue regimens for human immunodeficiency virus type 1 (HIV-1) infection. Antiretroviral-experienced patients with detectable viraemia starting a raltegravir (RAL)-based regimen between March 2007 and June 2009 were consecutively enrolled and followed for ≥4 years. Data were censored at Week 206 for homogeneity. Of 333 patients, 258 (77.5%) were still on RAL-based therapy at Week 206, and 241 had undetectable HIV-1 RNA (73% in intention-to-treat analysis). Of the 75 subjects who discontinued RAL therapy, 36 were lost to follow-up, 15 changed their regimen due to virological failure, 2 simplified their regimen stopping RAL, 9 stopped all antiretrovirals and 13 died. Overall, 100 subjects (30.0%) had at least one detectable viraemia, but only 32 (9.6%) had true viral failure. Seventeen patients continued their failing regimen. 'Blips' were experienced by 53 patients (15.9%), whilst 15 (4.5%) had confirmed viral rebound due to adherence issues and were re-suppressed upon treatment re-introduction. In a multivariate analysis of predictors of interruption or failure, each baseline HIV-1 RNA log10 increase was associated with an adjusted hazard ratio for failure of 1.6; having more than 13 previous treatment courses also emerged as a predictor. Overall, adverse events were rare (n=64), with 13 deaths. Tumours were mainly early events, often fatal (7/15), mainly non-Hodgkin's lymphomas (8), followed by hepatocarcinoma (2). RAL proved effective and well tolerated in this cohort, and few patients experienced viral failure after 4 years.

96 Week follow-up of HIV-infected patients in rescue with raltegravir plus optimized backbone regimens: a multicentre Italian experience.

BACKGROUND: Long term efficacy of raltegravir (RAL)-including regimens in highly pre-treated HIV-1-infected patients has been demonstrated in registration trials. However, few studies have assessed durability in routine clinical settings. METHODS: Antiretroviral treatment-experienced patients initiating a RAL-containing salvage regimen were enrolled. Routine clinical and laboratory follow-up was performed at baseline, week 4, 12, and every 12 weeks thereafter. Data were censored at week 96. RESULTS: Out of 320 patients enrolled, 292 (91.25%) subjects maintained their initial regimen for 96 weeks; 28 discontinued prematurely for various reasons: death (11), viral failure (8), adverse events (5), loss to follow-up (3), consent withdrawal (1). Eight among these 28 subjects maintained RAL but changed the accompanying drugs. The mean CD4+ T-cell increase at week 96 was 227/mm(3); 273 out of 300 patients (91%), who were still receiving RAL at week 96, achieved viral suppression (HIV-1 RNA <50 copies/mL). When analyzing the immuno-virologic outcome according to the number of drugs used in the regimen, 2 (n = 45), 3 (n = 111), 4 (n = 124), or >4 (n = 40), CD4+ T-cell gain was similar across strata: +270, +214, +216, and +240 cells/mm(3), respectively, as was the proportion of subjects with undetectable viral load. Laboratory abnormalities (elevation of liver enzymes, total cholesterol and triglycerides) were rare, ranging from 0.9 to 3.1%. The mean 96-week total cholesterol increase was 23.6 mg/dL. CONCLUSIONS: In a routine clinical setting, a RAL-based regimen allowed most patients in salvage therapy to achieve optimal viral suppression for at least 96 weeks, with relevant immunologic gain and very few adverse events.

Lipid Metabolism and Cardiovascular Risk in HIV-1 Infection and HAART: Present and Future Problems.

Many infections favor or are directly implicated with lipid metabolism perturbations and/or increased risk of coronary heart disease (CHD). HIV itself has been shown to increase lipogenesis in the liver and to alter the lipid profile, while the presence of unsafe habits, addiction, comorbidities, and AIDS-related diseases increases substantially the risk of cardiovascular disease (CVD) in the HIV-infected population. Antiretroviral therapy reduces such stimuli but many drugs have intrinsic toxicity profiles impacting on metabolism or potential direct cardiotoxicity. In a moment when the main guidelines of HIV therapy are predating the point when to start treating, we mean to highlight the contribution of HIV-1 to lipid alteration and inflammation, the impact of antiretroviral therapy, the decisions on what drugs to use to reduce the probability of having a cardiovascular event, the increasing use of statins and fibrates in HIV-1 infected subjects, and finally the switch strategies, that balance effectiveness and toxicity to move the decision to change HIV drugs. Early treatment might reduce the negative effect of HIV on overall cardiovascular risk but may also evidence the impact of drugs, and the final balance (reduction or increase in CHD and lipid abnormalities) is not known up to date.

Treatment-related factors and highly active antiretroviral therapy adherence.

Adherence to highly active antiretroviral therapy (HAART) plays a critical role in the effectiveness of HIV treatment. Nevertheless, the complexity of regimens and frequent side effects make HAART extraordinarily difficult to take, and many HIV-infected persons fail to adhere. The current study offers an overview of the relationship between adherence and antiretroviral treatment-related variables. As for other chronic diseases, medication regimen complexity also has an impact on adherence in the management of HIV infection. In particular, the authors discuss the effect of pill burden, dosing frequency, dietary instructions, number and type of different medications prescribed, short- and long-term side effects, convenience, and ability to incorporate the treatment regimen into a daily routine. Medication side effects are common in HAART-treated persons and are associated with concurrent and future nonadherence. Simplification of regimens, adjustment of the drug schedule to the patient's specific lifestyle, and anticipation and self-management of side effects are treatment-based strategies to optimize HAART adherence and ensure the most effective, convenient, safe, and well-tolerated antiretroviral treatment.

Immunovirological outcomes in 70 HIV-1-infected patients who switched to lopinavir/ritonavir after failing at least one protease inhibitor-containing regimen: a retrospective cohort study.

The immunovirological outcome of lopinavir/ritonavir was evaluated in 70 antiretroviral-experienced HIV patients; at baseline, median CD4+ cell count was 218 cells/mm(3) and median plasma viraemia 4.58 log(10) copies/mL. After 12 months, we observed an increase in CD4+ cell count to 322 cells/mm(3) (P = 0.0001) and a decrease in plasma viraemia to 2.35 log(10) copies/mL (P = 0.0001). Four patients discontinued lopinavir/ritonavir during observation. Among metabolic parameters, only triglyceride concentrations increased during treatment (P = 0.02). Twenty-six patients had a genotypic resistance test at baseline; four had > or =6 mutations known to reduce susceptibility to lopinavir/ritonavir. Undetectable plasma viraemia was obtained only in patients with < or =5 mutations (61.9%).

Patient-reported and physician-estimated adherence to HAART: social and clinic center-related factors are associated with discordance.

OBJECTIVES: To evaluate the rate of discordance between patients and physicians on adherence to highly active antiretroviral therapy (HAART) and identify factors related to discordance in these two assessments. DESIGN: Prospective, multicenter, cohort study (AdICONA) nested within the Italian Cohort Naive Antiretrovirals (ICONA) study. SETTING: Tertiary clinical centers. PARTICIPANTS: The patients filled out a 16-item self-administered questionnaire on adherence to HAART. At the same time, physicians estimated the current HAART adherence of their patient. MAIN OUTCOME MEASURE: Discordance between patient and physician on adherence to antiretroviral therapy. RESULTS: From May 1999 to March 2000, 320 paired patient-physician assessments were obtained. Patients had a mean plasma HIV RNA of 315 copies/ml (64% had undetectable HIV RNA) and a mean CD4+ cell count of 577 cells x 10(6)/L. Nonadherence was reported by 30.9% of patients and estimated by physicians in 45.0% cases. In 111 cases (34.7%), patients and physicians were discordant on adherence to HAART. Kappa statistics was 0.27. Using patient-assessed adherence as reference, sensitivity, specificity, positive predictive value, and negative predictive value of physician-estimated adherence were 64.7%, 66.6%, 81.2%, and 45.8%, respectively. On multivariable analysis, low education level, unemployment, absence of a social worker in the clinical center, and unavailability of afternoon visits were significantly correlated with patient-physician discordance on adherence to antiretrovirals. CONCLUSIONS: Physicians did not correctly estimate patient-reported adherence to HAART in more than one third of patients. Both social variables and factors related to the clinical center were important predictors of discordance between patients and physicians. Interventions to enhance adherence should include strategies addressed to improve patient-physician relationship.