Rosuvastatin decreases serum inflammatory markers and slows atherosclerosis progression rate in treated HIV-infected patients with metabolic syndrome.

OBJECTIVES: Metabolic syndrome (MetS) is usually associated in general population with systemic inflammation and higher cardiovascular risk, but data about the effect of statins in patients with HIV infection and MetS are lacking to date. METHODS: Prospective cohort study of treated HIV-infected patients, aged from 40 to 60 years, with or without MetS, who started rosuvastatin (10 mg daily), and were followed-up for 12 months. The primary endpoint was change in serum levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α). The secondary endpoint was change in the carotid intima-media thickness (IMT). RESULTS: One hundred and twenty-five patients were enrolled: 61 with MetS (MetS group) and 64 without MetS (control group). After 12 months, rosuvastatin produced a significant decrease in mean serum levels of hsCRP (-0.28 mg/dL; p = .037), IL-6 (-2.1 pg/mL; p = .018) and TNF-α (-6.3 pg/mL; p = .004) in patients with MetS. On the contrary, in controls rosuvastatin did not lead to a significant change in mean levels of all biomarkers. After 12 months, the mean IMT increase at the carotid bifurcation was significantly lower in the MetS group than in the control group at the carotid bifurcation (0.017 vs. 0.031 mm; p = .037) and in all other anatomical sites. CONCLUSION: Our findings suggest that rosuvastatin is effective in reducing serum inflammation markers and slowing atherosclerosis progression rate in HIV-infected patients on cART and with MetS, while its effects on serum biomarkers and IMT increase seem to be negligible in those without MetS.

HIV policy in Italy and recommendations across the HIV care continuum.

The HIV epidemic has not yet ended, and there are ever more challenges: the recent Italian National Plan of Interventions against HIV and AIDS (Piano Nazionale di Interventi Contro HIV e AIDS (PNAIDS) 2017-2019) was hailed for its comprehensiveness. Its likelihood of success across the HIV care continuum was therefore assessed. Awareness interventions are sporadic and continue to miss high risk populations; if effectively implemented, the prescriptive detail in PNAIDS may help address this. Combined prevention needs greater focus and investment. However, there has been recent progress: free anonymous testing is available at multiple settings although improvements to provide access to key vulnerable populations are needed. Clinical management is available to a high standard across the country, with some areas for improvement in ensuring equality of access. Long-term management of people living with HIV is often effective, but discrepancies exist across regions and settings of care. It is recommended to enable implementation of PNAIDS as a matter of urgency, develop integrated awareness and testing interventions for STIs and HIV, make condoms free for high-risk populations, and develop a network of multidisciplinary services for long-term holistic care of people living with HIV.

Prevalence of chronic kidney disease among HIV-1-infected patients receiving a combination antiretroviral therapy.

BACKGROUND: Chronic kidney disease (CKD) has become one of the most frequent non-infectious comorbidities in the aging HIV-infected population on long-standing combination antiretroviral therapy (cART). METHODS: We conducted a retrospective, cross-sectional study including HIV-infected adult patients attending our HIV outpatient clinic during the years 2017 and 2018 to assess prevalence and associated risk factors of CKD. Estimated glomerular filtration rate (eGFR) was measured by Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. CKD was diagnosed and classified according to the National Kidney Foundation guidelines. Logistic regression was employed to identify factors associated with CKD. RESULTS: We enrolled 2339 HIV-infected patients (91% were Caucasian) with a mean age of 45.3 years and a mean current CD4 lymphocyte count of 531 cells/mm3. CKD was diagnosed in 311 subjects (13.3%). Overall, 294 (12.6%) patients had albuminuria, 108 (4.6%) had eGFR < 60 mL/min/1.73 m2, and 78 (3.3%) had albuminuria plus eGFR < 60 mL/min/1.73 m2. Stages 4-5 of CKD were documented in 23 (1%) cases. Age greater than 50 years, male gender, hypertension, diabetes mellitus, high triglycerides, nadir CD4 cell count < 200 cells/mm3, current use of tenofovir disoproxyl fumarate (TDF) and of TDF plus a ritonavir-boosted protease inhibitors were independently associated with CKD, while current use of abacavir plus one integrase inhibitor was associated with a reduced risk of CKD. CONCLUSION: There is a significant prevalence of CKD among HIV-infected persons in association with both traditional and HIV-specific risk factors, requiring a careful periodic monitoring of renal function in these patients.

Factors associated with vitamin D deficiency in HIV-1 infected patients on combination antiretroviral therapy: a case-control study.

The aim of our study was to assess risk factors associated with vitamin D deficiency among HIV-1-infected patients on combination antiretroviral therapy (cART). A retrospective, case-control study was conducted to assess risk factors associated with vitamin D deficiency among HIV-1-infected adults on stable cART. Vitamin D deficiency was defined as 25-OH vitamin D concentration <30 ng/mL. A total of 195 patients (77% males, mean age 49.2 years) were enrolled into the study: 98 subjects with vitamin D deficiency (cases) and 97 with normal vitamin D serum concentration (controls). The mean serum concentration + standard deviation (SD) of vitamin D was 18.2+6.7 ng/mL among cases and 39.6+13.4 ng/ mL among controls. Current cART including tenofovir disoproxil fumarate (TDF) (OR 1.65; 95% CI, 1.31 to 1.94), osteoporosis (OR 1.78; 95% CI, 1.25 to 2.09), males who have sex with males (MSM) risk category (OR 1.59; 95% CI, 1.19 to 2.21), chronic hepatitis C (OR 1.44; 95% CI, 1.17 to 1.86), previous or current cancer (OR 1.47; 95% CI, 1.13 to 1.79), metabolic syndrome (OR 2.57; 95% CI, 1.96 to 2.98), and hepatic steatosis (OR 1.59; 95% CI, 1.17 to 2.05) were significant associated with an increased risk of vitamin D deficiency. On the other hand, current CD4+ lymphocyte count >600 cells/mm3 and current HIV RNA <20 copies/mL were significantly associated with a lower risk of vitamin D deficiency. In our case-control study, vitamin D deficiency is associated with TDF exposure, osteoporosis, and metabolic disturbances.

Vitamin D insufficiency is associated with subclinical atherosclerosis in HIV-1-infected patients on combination antiretroviral therapy.

Objectives: Vitamin D insufficiency has been associated with faster progression of atherosclerosis and increased cardiovascular disease risk, but limited data are available in HIV-infected people. So, we examined potential correlation between vitamin D status and atherosclerosis in people living with HIV.Methods: A cross-sectional study was performed including adult HIV-infected patients on stable antiretroviral therapy, aged 40-60 years, and with a recent carotid ultrasonography. Subclinical atherosclerosis was defined as a carotid intima-media thickness (IMT) ≥0.9 mm at any site. Patients with diabetes mellitus or atherosclerotic cardiovascular disease were excluded.Results: On the whole, 188 patients were enrolled: 86.2% were men and the mean age was 49.1 years. The mean CD4 T lymphocyte count was 567 cells/mm3, 176 (93.6%) had plasma HIV RNA <20 copies/mL, 51.1% were smoker, 29.2% had hypertension, 27.7% metabolic syndrome, and 44.7% LDL cholesterol >150 mg/dL. The mean serum concentration of vitamin D was 35.2 ng/mL, and 84 (44.6%) patients had a vitamin D insufficiency (<30 ng/mL). Subclinical atherosclerosis was reported in 105 (55.8%) and the mean vitamin D concentration was significantly lower among patients with subclinical atherosclerosis than among those without (18.2 vs 41.3 ng/mL, p < 0.001). Moreover, the multivariate linear regression analysis adjusted by confounding factors showed an independent association between subclinical atherosclerosis and vitamin D insufficiency, age >50 years, smoking, hypertension, metabolic syndrome, higher BMI, higher LDL cholesterol, longer duration of HIV infection, lower nadir CD4 cell count, and longer exposure to boosted protease inhibitors.Conclusion: In our study, vitamin D insufficiency is significantly associated with subclinical atherosclerosis, so its role in HIV-associated cardiovascular disease should be further evaluated as a possible target for intervention.

Rosuvastatin and atorvastatin preserve renal function in HIV-1-infected patients with chronic kidney disease and hyperlipidaemia.

BACKGROUND: Hyperlipidaemia is a risk factor for the progression of chronic kidney disease (CKD), which is a frequent comorbidity in patients with HIV-1 infection, but the renal effects of statins remain unclear. METHODS: We performed an observational, prospective study of HIV-infected patients on suppressive antiretroviral therapy, with CKD and hyperlipidaemia, and starting a lipid-lowering treatment with rosuvastatin, atorvastatin or omega-3 fatty acids. CKD was defined as an estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73 m2 for >3 months. RESULTS: As a whole, 69 patients (53 men, 58 Caucasian, median age 56.2 years) were enrolled. Overall, 25 patients started rosuvastatin (10 mg daily, group A), 23 patients atorvastatin (20 mg daily, group B), and 21 started omega-3 fatty acids (3 g daily, group C). At baseline, median eGFR was 54.4 mL/min/1.73 m2, and the eGFR ranged between 50 and 60 mL/min/1.73 m2 in 87% of patients. After 12 months, the median eGFR decline was significantly lower in group A (-0.84 mL/min/1.73 m2) and in group B (-0.91 mL/min/1.73 m2) in comparison with the group C (-1.53 mL/min/1.73 m2; p < 0.001 for both comparisons). The median decrease in prevalence of proteinuria and high-sensitivity C-reactive protein was also significantly greater in groups A and B than in group C, while the incidence of treatment discontinuations was comparable across the three groups. CONCLUSION: In our study, rosuvastatin and atorvastatin showed a significant protective effect on the renal function compared to omega-3 fatty acids in HIV-1-infected patients with CKD and dyslipidaemia.

Heel quantitative ultrasound in HIV-infected patients: a cross-sectional study.

PURPOSE: HIV infection has been associated with increased risk of osteoporosis and fragility fractures. Dual-energy X-ray absorptiometry (DXA) is the reference standard to assess bone mineral density (BMD); however, it is not easily accessible in several settings. Heel Quantitative ultrasound (QUS) is a radiation-free, easy-to-perform technique, which may help reducing the need for DXA. METHODS: In this cross-sectional study, we used heel QUS (Hologic Sahara(®)) to assess bone status in a cohort of HIV-infected patients. A QUS stiffness index (QUI) threshold >83 was used to identify patients with a low likelihood of osteoporosis. Moreover, we compared QUS results with those of 36 sex- and age-matched HIV-negative controls. RESULTS: 244 HIV-positive patients were enrolled. Median heel QUI value was 83 (73-96) vs. 93 (IQR 84-104) in the control group (p = 0.04). 110 patients (45 %) had a QUI value ≤83. Risk factors for low QUI values were age (OR 1.04 per year, 95 % CI 1.01-1.07, p = 0.004), current use of protease inhibitors (OR 1.85, CI 1.03-3.35, p = 0.039), current use of tenofovir (OR 2.28, CI 1.22-4.27, p = 0.009) and the number of risk factors for secondary osteoporosis (OR 1.46, CI 1.09-1.95, p = 0.01). Of note, QUI values were significantly correlated with FRAX score (r = -0.22, p = 0.004). According to EACS guidelines, 45 % of patients had risk factors for osteoporosis which make them eligible for DXA. By using QUS, we may avoid DXA in around half of them. CONCLUSIONS: As HIV-positive patients are living longer, the prevalence of osteoporosis is expected to increase over time. Appropriate screening, prevention and treatment are crucial to preserve bone health in this population. The use of screening techniques, such as heel QUS, may help reducing the need for DXA. Further studies are needed to define the diagnostic accuracy of this promising technique in the setting of HIV.

Changes in Serum Markers of Inflammation and Endothelial Activation in HIV-Infected Antiretroviral Naive Patients Starting A Treatment with Abacavir-Lamivudine or Tenofovir-Emtricitabine Plus Efavirenz.

BACKGROUND: The association between abacavir use and increased risk of myocardial infarction has been heavily debated, but cohort studies and randomized trials have provided conflicting results. Aim of our study is to compare the effect of abacavir and tenofovir on the inflammation and endothelial activation markers. METHODS: We performed an observational study of HIV-infected naïve patients starting tenofovir/emtricitabine (group A) or abacavir/lamivudine (group B) plus efavirenz. In the present analysis, we measured serum levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), soluble vascular adhesion molecule-1 (VCAM-1), soluble intercellular adhesion molecule-1 (ICAM-1), E-selectin and P-selectin at baseline and during a 48-week follow-up. RESULTS: As a whole, 118 patients (93 males; mean age ± SD of 42.8 ± 10.1 years) were enrolled: 61 in group A and 57 in group B. In group A at weeks 24 and 48 the mean concentrations of IL-6, TNF-α, ICAM-1, VCAM-1, E-selectin and Pselectin decreased significantly in comparison with respective baseline values. In group B at week 24 a significant increase in mean values of these markers was reported in comparison with group A, but after 48 weeks they significantly decreased in group B too and no significant differences between groups A and B were found. CONCLUSION: In our study, naïve patients starting tenofovir/emtricitabine or abacavir/lamivudine plus efavirenz showed after 48 weeks a significant and comparable decrease in serum concentrations of IL-6, TNF-α, ICAM-1, VCAM-1, Eselectin and P-selectin, while the mean level of hs-CRP did not change significantly in any group.

Prevalence and predictors of low bone mineral density and fragility fractures among HIV-infected patients at one Italian center after universal DXA screening: sensitivity and specificity of current guidelines on bone mineral density management.

Low bone mineral density (BMD) is frequent in HIV infection regardless of the use of antiretroviral therapy (ART). Uncertainties remain, however, as to when in HIV infection BMD screening should be performed. We designed a prospective study to estimate the efficacy of universal BMD screening by dual-energy X-ray absorptiometry (DXA). Since April 2009 through March 2011, HIV patients attending our Center were offered femoral/lumbar DXA to screen BMD. Low BMD for chronological age, that is significant osteopenia, was defined as a Z-score ≤ -2.0 at femur and lumbar spine. Nontraumatic bone fractures (NTBFs) were evaluated. The final sample included 163 patients. A Z-score ≤ -2.0 at any site was observed in 19.6% of cases: among these, 18.8% had no indication to DXA using current Italian HIV guidelines for BMD screening. A lower femoral Z-score was independently associated with lower BMI, AIDS diagnosis, HCV co-infection, antiretroviral treatment, and NTBFs; a lower lumbar Z-score with age, BMI, Nadir CD4 T-cell counts, and NTBFs. Prevalence of NTBFs was 27.0%, predictors being male gender, HCV co-infection, and lower femoral Z-scores. Our results suggest that measuring BMD by DXA in all HIV patients regardless of any further specification may help retrieving one-fifth of patients with early BMD disorders not identified using current criteria for selective screening of BMD.

Antiretroviral molecules and cardiovascular diseases.

Antiretroviral therapy has effectively tackled HIV replication and prevented the development of AIDS-related complications in the majority of HIV-positive patients. This pharmacological approach has dramatically increased the life expectancy of HIV-positive subjects transforming HIV infection into a chronic disease. Notwithstanding this major improvement in HIV disease management, several HIV-positive patients show an earlier and significant onset of aging related chronic conditions such as cardiovascular disease, osteoporosis, diabetes and neoplasias with respect to uninfected individuals. In particular, cardiovascular diseases are associated with both HIV infection and antiretroviral treatment, and represent major clinical complications in HIV-positive patients. Here, we discuss the interaction between antiretroviral therapy and cardiovascular system in HIV-positive patients focusing on the antiretroviral-related mechanisms involved in cardiovascular alterations.

Statin therapy decreases serum levels of high-sensitivity C-reactive protein and tumor necrosis factor-α in HIV-infected patients treated with ritonavir-boosted protease inhibitors.

BACKGROUND: Statins are lipid-lowering drugs that exhibit anti-inflammatory and immune-modulatory properties, leading to a reduction of serum levels of C-reactive protein (CRP) in the general population. OBJECTIVE: Because very limited data are available today, our objective was to assess the lipid-lowering effects of statins and their capacity to decrease selected soluble markers of inflammation in HIV-infected patients. METHODS: Retrospective cohort study of HIV-infected adult patients with hypercholesterolemia who were receiving a stable antiretroviral regimen including a ritonavir-boosted protease inhibitor and who started a lipid-lowering therapy with rosuvastatin (10 mg daily), atorvastatin (10 mg daily), or pravastatin (40 mg daily) and were followed-up for at least 12 months. One hundred and fifty-one patients were enrolled in the study: 51 in the rosuvastatin group, 47 in the atorvastatin group, and 53 in the pravastatin group. The primary observation was change in plasma lipid levels and serum markers of inflammation (high-sensitivity C-reactive protein [hsCRP], interleukin-6 [IL-6], and tumor necrosis factor-α [TNF- α]), while secondary observations include immunovirological parameters and safety profile of statins. RESULTS: One year after starting the statin therapy, patients treated with rosuvastatin had significantly greater decreases in total cholesterol and LDL cholesterol than subjects on atorvastatin or pravastatin. All statins led to a similar, significant reduction in serum levels of hsCRP and TNF-α, without correlation between biomarkers and lipid values, and toxicity rates were similar for all 3 statins. CONCLUSION: Our findings suggest that rosuvastatin has a significantly greater lipid-lowering effect than atorvastatin or pravastatin, but all 3 statins exert a similar effect in lowering markers of inflammation as hsCRP and TNF-α.

Prospective evaluation of bone markers, parathormone and 1,25-(OH)2 vitamin D in HIV-positive patients after the initiation of tenofovir/emtricitabine with atazanavir/ritonavir or efavirenz.

BACKGROUND: Increased risk of fractures and osteoporosis have been associated with the use of antiretroviral drugs. There is a paucity of prospective evaluations of bone markers after the initiation of drugs currently recommended to treat HIV infection and results on the evolution of these markers are conflicting. Lastly, the effect of tenofovir on 1,25-(OH)2 vitamin D is uncertain. METHODS: We performed a prospective study on the evolution of bone markers, parathormone and 1,25-(OH)2 vitamin D before and after standard antiretroviral regimens. This was a sub-study of a trial conducted in antiretroviral-naïve patients randomized to tenofovir + emtricitabine in combination with either atazanavir/ritonavir (ATV/r) or efavirenz (EFV). Follow-up lasted 48 weeks. The following bone markers were analyzed: C-terminal cross-laps (CTx), osteocalcin (OC), osteoprotegerin (OPG), and receptor activator of nuclear factor κB ligand (RANKL). Mixed-factorial analysis of variance with random-coefficient general linear model was used to compare their trends over time and linear multivariable regression was performed with a backward selection method to assess predictors of their variations from baseline to week 48. Trends of parathormone and 1,25-(OH)2 vitamin D were also evaluated. RESULTS: Seventy-five patients were studied: 33 received EFV and 42 ATV/r. Significant increases were found for all markers except for RANKL. There was a significant direct association between CTx and OC increases. Multivariable analysis showed that higher glomerular filtration rate (estimated through cystatin C clearance) predicted greater OPG increase, while older age, higher HIV RNA at baseline and use of ATV/r predicted greater CTx increase. A significant increase of parathormone accompanied the evolution of the study markers. 1,25-(OH)2 vitamin D remained stable, though a seasonality variation was demonstrated. CONCLUSIONS: These data demonstrate CTx increase (bone resorption marker) corresponding to OC increase (bone formation marker) early upon HAART initiation. Moreover, predictors of bone marker increases have been suggested, possibly indicating that a stricter monitoring of bone health and pro-active interventions are needed in older patients, those with higher HIV RNA, prescribed ATV/r rather than EFV, and with decreased renal function at baseline. Further studies are needed to clarify the mechanisms responsible for up-regulation of bone turnover markers, as well as to understand if and what markers are best correlated or predictive of pathological fractures.

Analysis of the effects of HIV-1 Tat on the survival and differentiation of vessel wall-derived mesenchymal stem cells.

HIV infection is an independent risk factor for atherosclerosis development and cardiovascular damage. As vessel wall mesenchymal stem cells (MSCs) are involved in the regulation of vessel structure homeostasis, we investigated the role of Tat, a key factor in HIV replication and pathogenesis, in MSC survival and differentiation. The survival of subconfluent MSCs was impaired when Tat was added at high concentrations (200-1,000 ng/ml), whereas lower Tat concentrations (1-100 ng/ml) did not promote apoptosis. Tat enhanced the differentiation of MSC toward adipogenesis by the transcription and activity upregulation of PPARγ. This Tat-related modulation of adipogenesis was tackled by treatment with antagonists of Tat-specific receptors such as SU5416 and RGD Fc. In contrast, Tat inhibited the differentiation of MSCs to endothelial cells by downregulating the expression of VEGF-induced endothelial markers such as Flt-1, KDR, and vWF. The treatment of MSCs with Tat-derived peptides corresponding to the cysteine-rich, basic, and RGD domains indicated that these Tat regions are involved in the inhibition of endothelial marker expression. The Tat-related impairment of MSC survival and differentiation might play an important role in vessel damage and formation of the atherosclerotic lesions observed in HIV-infected patients.

HIV-1 and recombinant gp120 affect the survival and differentiation of human vessel wall-derived mesenchymal stem cells.

BACKGROUND: HIV infection elicits the onset of a progressive immunodeficiency and also damages several other organs and tissues such as the CNS, kidney, heart, blood vessels, adipose tissue and bone. In particular, HIV infection has been related to an increased incidence of cardiovascular diseases and derangement in the structure of blood vessels in the absence of classical risk factors. The recent characterization of multipotent mesenchymal cells in the vascular wall, involved in regulating cellular homeostasis, suggests that these cells may be considered a target of HIV pathogenesis. This paper investigated the interaction between HIV-1 and vascular wall resident human mesenchymal stem cells (MSCs). RESULTS: MSCs were challenged with classical R5 and X4 HIV-1 laboratory strains demonstrating that these strains are able to enter and integrate their retro-transcribed proviral DNA in the host cell genome. Subsequent experiments indicated that HIV-1 strains and recombinant gp120 elicited a reliable increase in apoptosis in sub-confluent MSCs. Since vascular wall MSCs are multipotent cells that may be differentiated towards several cell lineages, we challenged HIV-1 strains and gp120 on MSCs differentiated to adipogenesis and endotheliogenesis. Our experiments showed that the adipogenesis is increased especially by upregulated PPARγ activity whereas the endothelial differentiation induced by VEGF treatment was impaired with a downregulation of endothelial markers such as vWF, Flt-1 and KDR expression. These viral effects in MSC survival and adipogenic or endothelial differentiation were tackled by CD4 blockade suggesting an important role of CD4/gp120 interaction in this context. CONCLUSIONS: The HIV-related derangement of MSC survival and differentiation may suggest a direct role of HIV infection and gp120 in impaired vessel homeostasis and in genesis of vessel damage observed in HIV-infected patients.

HIV-1 Tat protein enhances RANKL/M-CSF-mediated osteoclast differentiation.

Impaired osteoblast/osteoclast cross-talk and bone structure homeostasis resulting in osteopenia/osteoporosis are often observed in HIV seropositive patients but the causal mechanisms remain unsettled. This study analyzed the biological effects of Tat on peripheral blood monocyte-derived osteoclast differentiation. Tat enhances osteoclast differentiation and activity induced by RANKL plus M-CSF treatment increasing both the mRNA expression of specific osteoclast differentiation markers, such as cathepsin K and calcitonin receptor, and TRAP expression and activity. These Tat-related biological effects may be related, at least in part, to the induction of c-fos expression and AP-1 activity. c-fos up-regulation was triggered by Tat when cell cultures were co-treated with RANKL/M-CSF and an analysis of c-fos promoter with c-fos deletion mutant constructs disclosed specific c-fos promoter domains targeted by Tat. Together, these results show that Tat may be considered a viral factor positively modulating the osteoclastogenesis and then bone resorption activity suggesting a pathogenetic role of this viral protein in the HIV-related osteopenia/osteoporosis.

Analysis of the effects of specific protease inhibitors on OPG/RANKL regulation in an osteoblast-like cell line.

Bone mass loss with the subsequent development of osteopenia and osteoporosis is related to HIV infection and antiretroviral treatment, even though the mechanisms involved have not yet been elucidated. In this report analyzes the early effects of some specific protease inhibitors on OPG/RANKL yielding and cell survival in osteoblast-like HOBIT cell line. None of the compounds, tested at scalar concentrations (C1, C2, C3), affected cell survival except for tipranavir that elicited a reliable induction of apoptosis at the highest concentration (C3). Atazanavir, saquinavir and indinavir did not affect OPG/RANKL in the cell surnatant in our experimental conditions. By contrast, at optimal concentration (C2), fosamprenavir induced a significant increase in OPG associated with a RANKL decrease whereas tipranavir down-regulated both OPG and RANKL (at C2 and C3) and darunavir increased RANKL only at C3 concentration. Together these data (coupled with the analysis of OPG/RANKL ratio) indicate that at early times and at optimal concentrations the PIs did not impair the OPG/RANKL system with the exception of fosamprenavir that showed a relative positive OPG/RANKL ratio regulation. Instead, cell cultures treated by the highest concentrations of tipranavir or darunavir showed a change in cell survival or an increase in RANKL, with a negative effect on the OPG/RANKL balance.

Paradoxical immune reconstitution inflammatory syndrome associated with previous Cryptococcus neoformans infection in an HIV-positive patient requiring neurosurgical intervention.

Immune reconstitution inflammatory syndrome (IRIS) in HIV-1-infected patients is associated with an exaggerated inflammatory response against an opportunistic infection during highly active antiretroviral therapy. The only review on IRIS associated with Criptococcus neoformans reported 21 episodes including lymphadenitis, necrotizing pneumonitis, breast and cutaneous abscess, and cryptococcomas. To our knowledge this is the first report of IRIS associated with previous meningeal criptococcal infection which required neurosurgical intervention with placement of a ventriculo-peritoneal shunt to drain a CSF cyst formed by exclusion of the temporal horn of the right lateral ventricle. We demonstrate that this procedure is possible without complications such as cryptococcal dissemination into the peritoneum.

HIV-1 triggers apoptosis in primary osteoblasts and HOBIT cells through TNFalpha activation.

Several HIV-1 infected patients show bone loss and osteopenia/osteoporosis during the course of disease. The mechanisms underlying this degenerative process are largely unsettled and it has not been determined yet whether bone dysfunction is linked to HIV-1-mediated direct and/or indirect effects on osteoblasts/osteoclasts cross-talk regulation. This study investigated the effects of HIV-1(IIIb) and HIV-1(ADA) strains on osteoblasts using the osteoblast-derived cell line (HOBIT) and primary human osteoblasts as cellular models. The challenge of these cell cultures by both HIV-1 strains triggered a significant apoptosis activation unrelated to viral infection, since proviral HIV-1 DNA and supernatant HIV-1 RNA were not detected by real time PCR or b-DNA assays respectively. Under the experimental conditions, even heat-inactivated HIV-1 or cross-linked recombinant gp120 treatment of HOBIT and osteoblasts induced programmed cell death, suggesting that apoptosis is regulated by the interaction between HIV-1 gp120 and cell membrane. The analysis of cell culture supernatants showed a significant up-regulation of TNFalpha, a pleiotropic protein considered an apoptosis inducer in the osteoblast model. In fact, pretreatment of HOBIT and osteoblast cell cultures with anti-TNFalpha polyclonal antibody tackled effectively HIV-1 related induction of cell apoptosis. As a whole, these results indicate that HIV-1 may impair bone mass structure homeostasis by TNFalpha regulated osteoblast apoptosis.

RANKL/OPG/TRAIL plasma levels and bone mass loss evaluation in antiretroviral naive HIV-1-positive men.

Osteopenia and osteoporosis are common in HIV-1-infected individuals and represent a challenge in clinical and therapeutic management. This report investigated osteopenia/osteoporosis in a group of 31 antiretroviral naive HIV-1-positive men and the role of specific molecules belonging to TNF and the TNF-receptor family in HIV-1-related bone mass loss. Osteoprotegerin (OPG), the receptor activator of NF-kappab-ligand (RANKL), and the TNF-related apoptosis-inducing ligand (TRAIL) were significantly increased in the plasma of antiretroviral naive HIV-1-positive patients compared to a control group of healthy blood donors. In addition, TRAIL and RANKL plasma concentrations were positively correlated to HIV-1-RNA viral load. Measurement of bone mineral density in 20 out of 31 HIV-1-positive subjects disclosed osteopenia/osteoporosis in 40% of these patients. The antiretroviral naive HIV-1-positive subjects with low bone mineral density had a decreased plasma OPG/RANKL ratio and a plasma RANKL concentration >500 pg/ml. Together, these data indicate that plasma concentrations of specific factors involved in bone homeostasis were increased during HIV-1 infection and that RANKL and OPG/RANKL ratio deregulation may be involved in osteopenia/osteoporosis occurring in antiretroviral naive HIV-1 individuals.