Giovanni Dolci

Aging with HIV vs. HIV seroconversion at older age: a diverse population with distinct comorbidity profiles.

Objective People aging with HIV might have different health conditions compared with people who seroconverted at older ages. The study objective was to assess the prevalence of, and risk factors for, individual co-morbidities and multimorbidity (MM) between HIV-positive patients with a longer duration of HIV infection, and patients who seroconverted at an older age. We compared estimates across both groups to a matched community-based cohort sampled from the general population. Methods We performed a case-control study including antiretroviral therapy (ART)–experienced patients who were HIV seropositive for ≥ 20.6 years (“HIV-Aging”), or who were seropositive for < 11.3 years (“HIV-Aged”) having access in 2013 at the Modena HIV Metabolic Clinic. Patients were matched in a 1:3 ratio with controls from the CINECA ARNO database. MM was defined as the concurrent presence of >2 NICM. Logistic regression models were constructed to evaluate associated predictors of NICM and MM. Results We analysed 404 HIV-Aging and 404 HIV-Aged participants in comparison to 2424 controls. The mean age was 46.7±6.2 years, 28.9% were women. Prevalence of HIV co-morbidities and MM were significantly higher in the HIV-positive groups compared to the general population (p<0.001) and a trend towards higher rates of MM was found in aging vs aged group. This difference turned to be significant in patients above the age of 45 years old (p<0.001). Conclusions People aging with HIV display heterogeneous health conditions. Host factors and duration of HIV infection are associated with increased risk of MM compared to the general population.

The PNPLA3 Genetic Variant rs738409 Influences the Progression to Cirrhosis in HIV/Hepatitis C Virus Coinfected Patients.

Contradictory data about the impact of the rs738409 steatosis-related polymorphism within PNPLA3 gene on liver fibrosis progression in HIV/hepatitis C virus (HIV/HCV)-coinfected patients have been reported. Our objective was to test whether this, and other polymorphisms previously related to fatty liver disease in HIV infection linked to SAMM50 or LPPR4 genes, influence liver fibrosis progression in HIV/HCV-coinfected individuals. Three hundred and thirty two HIV/HCV-coinfected patients who consecutively attended four Spanish university hospitals from November 2011 to July 2013 were included. A liver stiffness cut-off of 14.6 kPa, as determined by transient elastography, was used to diagnose cirrhosis. Liver stiffness progression was studied in 171 individuals who had two available LS determinations without anti-HCV treatment between them. Moreover, 28 HIV/HCV-coinfected patients who underwent liver transplant, as well as 19 non-cirrhotic coinfected individuals used as controls, were included in an additional study. Only rs738409 was associated with cirrhosis: 45 (29.6%) of 152 G allele carriers versus 36 (20.0%) of 180 CC carriers showed cirrhosis (multivariate p = 0.018; adjusted odds ratio = 1.98; 95% confidence interval = 1.12–3.50). Also, 21 (30.4%) of 69 G allele carriers versus 16 (15.7%) of 102 CC patients showed significant liver stiffness progression (adjusted p-value = 0.015; adjusted odds ratio = 2.89; 95% confidence interval = 1.23–6.83). Finally, the proportion of rs738409 G allele carriers was significantly higher in transplanted individuals than in controls (p = 0.044, odds ratio = 3.43; 95% confidence interval = 1.01–11.70). Our results strongly suggest that the rs738409 polymorphism is associated with liver fibrosis progression in HIV/HCV-coinfected patients.

Impact of polypharmacy on antiretroviral prescription in people living with HIV.

Objectives To evaluate the relationship between polypharmacy and ART, delivered as conventional multi-tablet three-drug regimens, single-tablet regimens or less-drug regimens (simplified mono or dual regimens). Methods We conducted a cross-sectional analysis of electronic data from the prospective Modena HIV Metabolic Clinic Cohort Study. We included the last clinical observation for each patient from January 2006 to December 2015. Polypharmacy was defined as the use of five or more medications (excluding ART). Multi-morbidity was classified as the presence of two or more non-infectious comorbidities. Factors associated with different ART regimens were analysed using multivariable multinomial logistic regression analyses with multi-tablet three-drug regimens as the reference. Results A total of 2944 patients (33.7% females) were included in the analysis. Multinomial logistic regression analysis identified polypharmacy to be negatively associated with single-tablet regimens [relative risk reduction (RRR) = 0.48, 95% CI = 0.28–0.81] independently from frailty (RRR = 0.68, 95% CI = 0.59–0.78), after correction for age, gender, HIV infection duration, current and nadir CD4 and calendar year. This association was not found comparing multi-tablet three-drug regimens and less-drug regimens. Conclusions Single-tablet regimens are less likely to be prescribed in patients with polypharmacy. Single-tablet regimens are perceived to be less flexible in patients with multi-morbidity and at higher risk of drug–drug interaction.

Successful Pre- and Posttransplant Sofosbuvir-Based Anti-Hepatitis C Virus Treatment in Persons Living With Human Immunodeficiency Virus Infection

Abstract This retrospective study reports the data of sofosbuvir-based anti-hepatitis C virus treatment in 24 candidates and 24 recipients of liver transplantation coinfected with human immunodeficiency virus. Sustained virologic response was cumulatively 85% (90% and 100% in those treated with optimal schedules pre- and posttransplant, respectively).

Urolithiasis associated with atazanavir may mask a metabolic ‘channelling’ bias

Sir, Chronic kidney disease (CKD) is an emerging clinical issue in HIV, particularly in ageing infected patients. Nephrotoxicity is a major issue and a frequent cause of drug switching owing to glomerular or tubular damage and the fear of progressive CKD.However, the incidence and impact of urolithiasis as an independent contributor to CKD are not known in HIV-infected patients. Historically, antiretroviral-induced urolithiasis has been common inpatientstreatedwith indinavir,probablyduetodrugcrystallization and precipitation in the kidneys. At present, with regards to the risk of urolithiasis, the use of boosted or unboosted atazanavir as preferred protease inhibitor (PI) is of concern. In a large retrospective studyof 1240 HIV-infected individuals, Hamada et al. reported a urolithiasis incidence of 23.7 cases per 1000 patient-years among atazanavir-treated patients. Notably, the authors postulated that atazanavir/ritonavir can promote kidney stones via similar mechanisms to indinavir-induced urolithiasis. This single-centre study, as the authors pointed out, had several limitations owing to its observational and retrospective nature and because of the absence of renal stone composition analyses. In particular, the hypothesized pathogenetic mechanism – atazanavir-supersaturated urine inducing crystalluria – is difficult to test in consideration of the lack of association between serum bilirubin levels, surrogate markers of plasma atazanavir concentration and the risk of kidney stones. By contrast, baseline data showed significantly higher uric acid concentrations in patients treated with atazanavir/ritonavir compared with patients treated with other PIs. Even though uric acid levels did not affect the Cox proportional hazard regression model results, and atazanavir/ritonavir exposure was associated with a 10-fold increased risk for kidney stones, these results may have been distorted by a ‘channelling’ bias. Atazanavir/ritonavir is preferentially prescribed to patients with higher metabolic risk profiles (European AIDS Clinical Society; Version 6.1; November 2012; http:// www.europeanaidsclinicalsociety.org/index.php?option1⁄4com_con tent&view1⁄4article&id1⁄459&Itemid=41). An expanding body of evidence supports the notion that kidney stones are not always a separate entity but in some instances represent an epiphenomenon of a systemic metabolic disorder, being associated with insulin resistance and metabolic syndrome.In keeping with the study by Hamada et al., it is plausible that at least some of the reported effects of atazanavir/ritonavir could be confounded by physician prescription. Interestingly, the prevalence of nephrolithiasis seems higher among HIV-infected individuals than the general population (0.8%). Raheem et al. described 46 cases of nephrolithiasis in a cohort of 436 HIV-positive subjects, corresponding to an overall 11% prevalence: similar to what is expected in the general population. Unfortunately, stone analysis was only available in seven subjects and documented four cases of calcium oxalate monohydrate crystals and only one case each of cystine, uric acid and atazanavir crystals. A similar prevalence of kidney stones was described in the Castle study, the largest randomized clinical trial on atazanavir/ritonavir ever performed in naive patients. Though evidence in HIV-infected individuals is far from being conclusive, the study by Hamada et al. suggests a thorough metabolic evaluation for nephrolithiasis in HIV-infected patients with recurrent episodes of kidneystones, a family historyof nephrolithiasis or evidence of multiple kidney stones at imaging. However, we suggest caution in interpreting the epidemiological data linking atazanavir exposure and kidney stones owing to a potential ‘channelling’ bias. Indeed, an excess number of patients with metabolic disturbance may be prescribed the atazanavir/ritonavir regimen in light of its favourable lipid profile, but these patients are in fact at higher risk for urolithiasis. This situation significantly resembles our observation regarding the spurious association between abacavir and cardiovascular disease, which in fact was mediated by CKD, which was in turn the comorbidity that prompted healthcare workers to prefer abacavir to tenofovir. New observational studies and randomized clinical trials are needed to prove this hypothesis.

Clinical outcome of kidney transplantation in HIV-infected recipients: a retrospective study:

Kidney transplantation is a safe and effective option for HIV-positive (HIV+) patients. We conducted a retrospective study on HIV+ kidney transplant recipients who underwent transplantation from March 2008 to September 2016. Inclusion criteria for transplantation were CD4+ T-cell count ≥200 per mm3 and undetectable HIV load. The current study reports the outcome of 19 HIV+ recipients, mostly of Caucasian origin (79%) with a median age of 50 years (interquartile range [IQR], 42–52), who were followed up for a median period of 2.4 years (IQR, 1.2–4.6) after transplantation. Compared with HIV-negative (HIV−) controls, HIV+ recipients had similar one- and three-year graft and patient survival, but significantly lower five-year patient survival (P = 0.03). The differences in graft outcome became less evident with the analysis of death-censored graft survival rates. Cumulative incidence of allograft rejection at one year was 32.9%. Rates of infections were not particularly elevated and HIV replication remained well controlled in all but one patient. A high prevalence of metabolic and endocrine complications (68%) was reported after transplantation. Further studies are needed to evaluate long-term outcomes of HIV+ recipients who underwent kidney transplantation.