Dyslipidaemia after switch to tenofovir alafenamide (TAF)-based cART regimens in a cohort of HIV-positive patients: what clinical relevance?

OBJECTIVES: Switching from tenofovir (TDF) to tenofovir alafenamide (TAF) affects lipid profile. The aim of this study was to evaluate whether this results in an increased frequency of patients with low-density lipoprotein (LDL) above their cardiovascular-related target. METHODS: All HIV patients switching from TDF to TAF, with no changes of the anchor drug, and with plasma lipids available within 6 months before and after the switch, were included. Demographic, HIV-related parameters, cardiovascular (CV) risk factors and lipid profile on both TDF and TAF were collected. The CV risk score and the relative target of LDL for each patient were calculated according to 2016 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines for the management of dyslipidaemias. Modifications in lipid profiles and in the prevalence of patients with LDL above their CV-related target were evaluated after switch to TAF. RESULTS: Overall, 221 HIV patients were included, according to CV risk: 55% at low risk, 34% at moderate risk, and 11% at high/very high risk. By analysing lipid profiles according to CV risk, 38% of patients on TDF had LDL above their CV target; this prevalence increases to 60% after switching to TAF (P < 0.0001). The presence of cobicistat in the combination antiretroviral therapy (cART) regimen was associated with an increased risk of LDL above the CV-related target after switch to TAF [adjusted odds ratio (aOR) = 2.4, 95% confidence interval (CI): 1-5.1], P = 0.03) and with an increased prescription of lifestyle/therapeutic intervention (OR = 3.0, 95% CI: 1.7-5.3, P < 0.0001). DISCUSSION: Switching from TDF to TAF affects lipid parameters, and data from real life suggest a clinical relevance of this worsening that often leads clinicians to implement lifestyle/therapeutic interventions.

Cardiovascular adverse events during treatment with darunavir-based regimens in an Italian observational study.

Background: The protease inhibitor (PI) darunavir (DRV) has proven to be highly effective and well tolerated for HIV treatment. The DAD (Data collection on Adverse Effects of Anti-HIV Drugs) cohort showed an increased 5-year cumulative cardiovascular (CV) risk in patients given various PIs, including DRV, whereas two other recent studies found no association between DRV and CV diseases. Methods: We performed a post-hoc analysis of CV adverse events (CVAEs) in an Italian cohort, the TMC114-HIV4042 observational study, where 875 patients treated with ritonavir-boosted DRV-based regimens were followed for a total of 1,566 patient-years. Results: We observed 23 CVAEs of any type, including 17 [12 (95%CI, 7-19) per 1,000 patient-years] primary; 14 [10 (95%CI, 5-17) per 1,000 patient-years] were primary Framingham-type general CVAEs, close to what expected according to the Framingham algorithm based on traditional risk factors. Age and systolic blood pressure (SBP) at the time of study enrolment were the only relevant (p<0.01) independent predictors of CVAEs in all models; patients with any CVAE were on average 10 years older and had an SBP 14 mmHg higher than patients without CVAEs. When controlling for age and SBP, the association with other traditional factors, including serum lipids, and with HIV-specific factors was not statistically significant (p>0.05). Models that also adjusted for previous ARV exposure showed no statistically significant association between any-type CVAEs and either DRV doses, 1,200 or 800 mg/daily (as also suggested by propensity score stratification), or previous DRV exposure duration. Conclusion : We found no evidence of a relationship between DRV use and increased CV risk.

Assessment of radiological vertebral fractures in HIV-infected patients: clinical implications and predictive factors.

OBJECTIVES: The aim of this study was to evaluate the clinical impact of including lateral spine X-ray in the screening of bone diseases in HIV-positive patients. METHODS: A total of 194 HIV-positive patients underwent dual-energy X-ray absorptiometry (DEXA), lateral spine X-ray and bone biochemical analysis. Vertebral fractures were identified using a morphometric analysis of X-rays and classified using the semiquantitative scoring system of Genant et al. For each patient, a spine deformity index (SDI) score was calculated by summing the grades of vertebral deformities. Reductions in vertebral body height of > 25% were considered vertebral fractures, and those < 25% were considered vertebral deformities. Risk factors associated with vertebral fractures were evaluated by univariate and multivariate analysis. RESULTS: Vertebral fractures were detected in 24 patients (12.4%) and vertebral deformities in 17 patients (8.7%); 153 patients (78.9%) did not show any vertebral deformity. Among patients with fractures, only two with SDI > 10 reported lumbar pain; the remaining were asymptomatic. Patients over 50 years old showed a higher prevalence of vertebral fracture [24.4% versus 11.8% in patients 41-50 years old (P = 0.05) and 1.9% in patients ≤ 40 years old (P = 0.04)]. No significant increase in the prevalence according to bone mineral density (BMD) reduction was observed, and 70% of fractures were diagnosed in nonosteoporotic patients. Older age [adjusted odds ratio 1.09; 95% confidence interval (CI) 1.03-1.13; P = 0.001] and steroid use (adjusted odds ratio 3.64; 95% CI 1.29-10.3; P = 0.01) were independently associated with vertebral fracture; no association was found with HIV- or highly active antiretroviral therapy (HAART)-related variables. CONCLUSIONS: A prevalence of vertebral fractures of 12.4% was observed in our HIV-positive cohort. Given that two-thirds of fractures occurred in nonosteoporotic patients, spine X-ray may be considered in patients at increased risk, irrespective of BMD; that is, in elderly patients and/or patients using steroids.

Induced first abortion rates before and after HIV diagnosis: results of an Italian self-administered questionnaire survey carried out in 585 women living with HIV.

OBJECTIVES: The aim of the study was to investigate whether HIV diagnosis affected reproductive planning over time and to assess independent predictors of abortion overall and following HIV diagnosis. METHODS: Donne con Infezione da HIV (DIDI) is an Italian multicentre study based on a questionnaire survey carried out in 585 HIV-positive women between November 2010 and February 2011. The incidence and predictors of abortion were measured by person-years analysis and Poisson regression. RESULTS: The crude incidence rate of abortion was 18.8 [95% confidence interval (CI) 16.5-21.4] per 1000 person-years of follow-up (PYFU). Compared with women who terminated their pregnancy before HIV diagnosis, women who terminated their pregnancy after HIV diagnosis but before 1990 showed a 2.56-fold (95% CI 1.41-4.65) higher risk. During 1990-1999 and 2000-2010, HIV diagnosis was not significantly associated with outcome [adjusted rate ratio (ARR) 0.93 (95% CI 0.55-1.59) and ARR 0.69 (95% CI 0.32-1.48), respectively]. Age [ARR 0.96 (95% CI 0.94-0.99) per 1 year older] and injecting drug use [ARR 1.38 (95% CI 0.98-1.94)] were found to be predictors of abortion overall. After HIV diagnosis, being on combination antiretroviral therapy [ARR 0.54 (95% CI 0.28-1.02)], monthly income < €800 [ARR 1.76 (95% CI 0.99-3.12)], younger age [ARR 0.95 (95% CI 0.91-1.00) per 1 year older] and fear of vertical transmission [ARR 1.95 (95% CI 1.04-3.67)] were found to be independently associated with abortion. CONCLUSIONS: We observed a higher incidence of abortion compared with data available for the general Italian population. Awareness of HIV diagnosis was predictive of abortion only in the 1980s. Women with HIV infection are still worried about vertical HIV transmission. Interventions promoting HIV screening among women who plan to have an abortion and informative counselling on motherhood planning in the setting of HIV care are needed.

Women facing HIV. Key question on women with HIV infection: Italian consensus workshop.

A panel of leading Italian specialists in infectious diseases, obstetrics and gynaecology met in a national consensus workshop on women facing HIV to review critical aspects and discuss recommendations for selected key questions on four issues: (1) women and highly active antiretroviral therapy (HAART): access to care and adherence to therapy, side effects and drug-drug interaction; (2) HIV-infected pregnant women: prevention of mother to child transmission; (3) desire for children among women living with HIV: assisted reproduction; (4) sexually transmitted diseases and genital disturbances. The method of a nominal group meeting was used, and recommendations were graded for their strength and quality of evidence using a system based on the one adopted by the Infectious Diseases Society of America. Main conclusions are summarized and critically discussed, and some of the most recent data supporting recommendations are provided.

Two different patterns of mutations are involved in the genotypic resistance score for atazanavir boosted versus unboosted by ritonavir in multiple failing patients.

OBJECTIVES: The protease inhibitor atazanavir (ATV) can be used either boosted by ritonavir (ATV300/r) or unboosted (ATV400). To date, however, genotypic resistance scores (GRSs) have been developed only for boosted-ATV. We have determined GRS associated with virologic response (VR) for both ATV300/r and ATV400 in highly pre-treated HIV-1 infected patients. PATIENTS AND METHODS: We analyzed the results of genotypic tests available 0-3 months before the initiation of an ATV-containing regimen in 159 patients with HIV-RNA >or= 500 copies/ml (ATV300/r group: 74; ATV400 group: 85) who were enrolled in the CARe study through an Early Access Program. The impact of baseline protease mutations on VR (>or= 1 log(10)copies/ml HIV-RNA decrease at 12-24 weeks) was analyzed using Fisher's exact test. Mutated protease amino acid positions (MPP) with p < 0.20 were retained for further analysis. The GRSs were determined by a step-by-step analysis using the chi(2) test for trend. RESULTS: The GRSs for ATV300/r and ATV400 revealed differing sets of mutations. For ATV300/r, 12 MPPs (10C/I/V + 32I + 34Q + 46I/L + 53L + 54A/M/V + 82A/F/I/T + 84V + 90M - 15E/G/L/V - 69K/M/N/Q/R/T/Y - 72M/ T/V; p = 1.38 x 10(-9)) were the most strongly associated with VR (VR: 100%, 78.3%, 83.3%, 75% and 0% of patients with a score of -2/-1, 0, 1, 2, and >or= 3, respectively); the last three MPPs (I15/H69/I72) were associated with a better VR. For ATV400, nine MPPs (16E + 20I/M/R/T/V + 32I + 33F/I/V + 53L/Y + 64L/M/ V + 71I/T/V + 85V + 93L/M; p = 9.42 x 10(-8)) were most strongly associated with VR (VR: 83.3%, 66.7%, 5.9%, 0% of patients with 0, 1/2, 3, and >or= 4 MPP, respectively). Differences between GRSs for ATV300/r and ATV400 may be due to different ATV drug levels (boosted vs unboosted), favoring different pathways of escape from antiviral pressure. CONCLUSIONS: Both GRSs were independent predictors of response in a multivariable logistic regression model. Nevertheless, cross-validation of these GRSs on different patient databases is required before their implementation in clinical practice.

Predictive factors of vascular intima media thickness in HIV-positive subjects.

BACKGROUND: The predictive factors of intima media thickness (IMT) in the HIV-infected population are still poorly understood. PATIENTS AND METHODS: We studied three groups of subjects, aged 30-50 years, to find potential predictive factors of carotid and/or femoral thickening (IMT > 1 mm in at least one area): healthy controls (G1, n = 54), HIV-infected naive (G2, n = 53) and highly active antiretroviral treatment (HAART)-treated subjects (G3, n = 133). All the subjects underwent ultrasonography of the carotid and femoral vessels to evaluate IMT. RESULTS: Demographic characteristics of the three groups were comparable, except for gender (G1 had a higher percentage of females) and lipid levels (higher in G3). A total of 115 subjects (47.9%) had carotid and/or femoral IMT: 26 in G1 (48.1%), 21 in G2 (39.6%) and 68 in G3 (51.1%). Independent predictive factors of carotid and/or femoral IMT were older age (OR: 2.81, 95% CI: 1.95-4.04, P < 0.01, for each additional 5 years), triglycerides >or=150 mg/dL (OR: 2.66, 95% CI: 1.27-5.57, P < 0.001), serum glucose >or=110 mg/dL (OR: 5.24, 95% CI: 1.02-27.05, P = 0.04), high homocysteinaemia (OR: 2.75, 95% CI: 1.17-6.46, P = 0.02) and high body mass index (OR: 1.10, 95% CI: 1-1.22, P = 0.05 for each additional unit); females had a lower risk (OR: 0.38, 95% CI: 0.18-0.79, P < 0.01 versus males). HAART use was not associated with IMT (OR: 0.64, 95% CI: 0.27-1.53, P = 0.32 and OR: 0.80, 95% CI: 0.30-2.13, P = 0.20 for G3 and G2 versus G1, respectively). CONCLUSIONS: This study demonstrates that traditional risk factors for cardiovascular diseases overshadow the role of HAART in determining premature vascular lesions.

Access to gynecological services and Papanicolau tests in HIV-infected Italian women: a questionnaire survey.

The objective of the study was to evaluate the access to Papanicolau (Pap) tests of HIV-infected women in Italy. A cross-sectional survey on a cohort of HIV-infected women seen at 27 HIV clinics was performed. At each clinic a female physician involved in the care of HIV-infected women was asked questions on clinic and patients' characteristics and on access to Pap tests. The outcome of the study was to find the percentage of women who had not had a Pap test before coming to the HIV clinic and the percentage having had a Pap test in 2001. In the survey, 7,600 HIV-infected women were represented. Women who came to the clinic without having ever had a Pap test were 62+/-22%, while women who had had a Pap test in 2001 were 43+/-36%. Women who reported never having had a Pap test before coming to the HIV clinic were more often from the south than the north of Italy (17.9+/-49% from the north, 18+/-53% from the center and 9.3+/-83.9% from the south; p<0.001). This a difference disappeared when comparing the women who had had a Pap test in 2001 (28+/-39.6% from the north, 31.6+/-44.2% from the center and 25.6+/-45.7% from the south; p=0.88). Despite the published guidelines in Italy, only 38% of women had ever had a Pap test before coming to the HIV clinic and only 43% had had a Pap test in 2001. Strategies aimed to improve these proportions should be rapidly implemented at all levels of care organization.

Effect of radio-opaque filler on biodegradable stent properties.

The effect of the addition of a radio-opaque filler, barium sulfate (BaSO(4)), on the mechanical properties of a biodegradable amorphous polymer film (poly-lactic-co-glycolic acid, PLGA) was studied, as a function of degradation. With up to about 18% loading (v/v), the modulus of the filled polymer increases; beyond this concentration, agglomerates are formed. The filled systems are also radio-opaque, over a thickness range of 0.07-0.19 mm in stent form (helicoidal). These stents were then immersed in phosphate buffer pH 7.4 at 37(o)C for 2 weeks. The radial strength of stent was measured by using a compression test. It was found that filler-loaded stent (FS) increased in radial strength by about 4 times (14.95 +/- 1.20 N/mm) compared to the unfilled stent (UFS). However, both samples lost radial strength as the polymer degraded in buffer, but FS retained 60% (9.05 +/- 0.07 N/mm) of its strength after 2 weeks whereas only 36% (1.39 +/- 1.04 N/mm) was retained for UFS. Moreover, UFS lost its helical shape after 3 weeks. The findings have implications for optimization of degradable stent formulations.

Development of fibrous biodegradable polymer conduits for guided nerve regeneration.

The technique of microbraiding with modification was employed as a novel method for the fabrication of fibrous tubular scaffolds for nerve tissue engineering purposes. The biodegradable polymers used in this study were poly(L-lactide-co-glycolide) (10:90) and chitosan. The polymeric fibers were microbraided around a Teflon mandrel to make it as a tubular construct. The conduits were then studied for their surface morphology, swelling behaviour and biocompatibility. The surface morphology was analysed by scanning electron microscope, swelling behaviour by weight increase due to water uptake and biocompatibility by in vitro cytotoxicity assessment in terms of cell morphology and cell viability by the MTT assay of polymer extract treated cells. These conduits may also be used for regeneration of tissues, which require tubular scaffolds such as blood vessel, spinal cord, intestine etc.

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

OBJECTIVES: To evaluate the risk factors for lopinavir/ritonavir (LPV/r)-related liver enzyme elevation (LEE) in HIV antiretroviral-experienced patients. METHODS: An open prospective observational study was carried out to analyse the incidence and time of LEE development during LPV/r treatment, and to determine whether LEE development was correlated with epidemiological, clinical and biochemical data, immune and virological profiles, concomitant hepatic diseases, antiretroviral therapy, or histological and ultrasonography liver examination results. A diagnosis of LEE was considered when LEE symptoms occurred after LPV/r introduction and was confirmed by a second control within 2 weeks. RESULTS: A total of 782 HIV-positive outpatients have been enrolled in six different Infectious Diseases Departments in Northern Italy since August 2000. Of these patients, 71 (9.1%) developed LEE within 115+/-85 days (mean+/-standard deviation); 13 of these subjects discontinued LPV/r and four were hospitalized. Of the patients with LEE, 74.6% and 25.4% had grade 2 and > or =3 toxicity, respectively. No correlation between LEE and sex, baseline CD4 cell count, viral load, HIV stage, triglyceride values, histological and ultrasonography liver examination results, nevirapine use, or increase in CD4 cell count was observed. Higher baseline alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) values (P < 0.0001 and P=0.004, respectively), younger age (P=0.008), previous hepatitis B virus (HBV) infection (P=0.012), efavirenz use (P=0.04), and hepatitis C virus (HCV) and/or HBV coinfection (P < 0.0001, relative risk 4.78) were significantly related to LEE. No correlations between LEE and the same risk factors as investigated in the whole study population were found in subgroups of patients with HCV and/or HBV infection. CONCLUSIONS: HCV and HBV testing and measurement of baseline ALT values are essential for screening subjects at risk of LEE before starting LPV/r. Strict monitoring of clinical and biochemical parameters should be performed in these patients.

Nephrolithiasis and hydronephrosis in an HIV-infected man receiving tenofovir.

The use of tenofovir as part of a HAART regimen has been widely used in HIV-multi-experienced-patients because of its favourable resistance profile. Tenofovir is mainly eliminated by the kidneys and renal toxicity should be carefully monitored. We describe here the case of an HIV-infected patient, without a prior history of renal failure who developed nephrolithiasis and hydronephrosis after starting a tenofovir-containing HAART regimen.

Peripheral nerve regeneration by microbraided poly(L-lactide-co-glycolide) biodegradable polymer fibers.

Tiny tubes with fiber architecture were developed by a novel method of fabrication upon introducing some modification to the microbraiding technique, to function as nerve guide conduit and the feasibility of in vivo nerve regeneration was investigated through several of these conduits. Poly(L-lactide-co-glycolide) (10:90) polymer fibers being biocompatible and biodegradable were used for the fabrication of the conduits. The microbraided nerve guide conduits (MNGCs) were characterized using scanning electron microscopy to study the surface morphology and fiber arrangement. Degradation tests were performed and the micrographs of the conduit showed that the degradation of the conduit is by fiber breakage indicating bulk hydrolysis of the polymer. Biological performances of the conduits were examined in the rat sciatic nerve model with a 12-mm gap. After implantation of the MNGC to the right sciatic nerve of the rat, there was no inflammatory response. One week after implantation, a thin tissue capsule was formed on the outer surface of the conduit, indicating good biological response of the conduit. Fibrin matrix cable formation was seen inside the MNGC after 1 week implantation. One month after implantation, 9 of 10 rats showed successful nerve regeneration. None of the implanted tubes showed tube breakage. The MNGCs were flexible, permeable, and showed no swelling apart from its other advantages. Thus, these new poly(L-lactide-co-glycolide) microbraided conduits can be effective aids for nerve regeneration and repair and may lead to clinical applications.

Declining incidence of AIDS and increasing prevalence of AIDS presenters among AIDS patients in Italy.

Presented here are the results of a cohort study conducted on 3,483 consecutive HIV/AIDS patients between January 1993 and December 2000 to determine trends in AIDS incidence and presentation. The incidence of AIDS was calculated in the general population and examined further according to gender, age (< or = or >49 years), and heterosexual behaviour as a risk factor for HIV. Multivariate analysis was used to identify variables associated with AIDS presenters (defined as patients diagnosed with AIDS within 1 month of the first HIV-positive test). The numbers of patients with AIDS classified as (i) AIDS presenters, (ii) known HIV-positive patients on antiretroviral treatment, and (iii) known HIV-positive patients not receiving antiretroviral treatment were calculated. The overall incidence of AIDS decreased over time, mainly due to the lower number of patients on antiretroviral treatment developing AIDS. Factors associated with a higher risk of being an AIDS presenter were male gender and year of HIV diagnosis. Among patients with AIDS, the proportion of AIDS presenters increased from 13.8% prior to 1997 (when protease inhibitors were introduced in Italy) to 32.5% after 1997. Variables predictive of being an AIDS presenter were male gender, age at diagnosis, and AIDS diagnosis in the years 1997-2000. Heterosexuals had a higher risk of being AIDS presenters and a lower risk of being HIV-positive and not receiving antiretroviral treatment than intravenous drug users. In Italy, AIDS occurs mainly in subjects unaware of their HIV status (especially males, the elderly, and those infected heterosexually) or in patients refusing antiretroviral therapy (mainly intravenous drug users who do not refer to specialised centres).

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.