Elevated effector cell sensitivity to Treg-cell suppression that is not associated with reduced Th17-cell expression distinguishes HIV+ asymptomatic subjects from progressors.

Suppression mediated by Treg cells is a balance between Treg-cell suppressive potency versus sensitivity of effector cells to Treg-cell suppression. We assessed if this balance, along with Treg-cell number relative to the Treg-cell counter-regulatory cytokine IL-17, differs between asymptomatic HIV(+) subjects versus those who progress onto disease. Cross-over studies comparing Treg-cell potency, measured by effector cell proliferation or IFN-γ expression, from HIV-infected versus control subjects to suppress the proliferation of allogeneic control effector cells demonstrated increased sensitivity of CD4(+) CD25(-) effector cells from asymptomatic HIV(+) subjects to suppression, rather than an increase in the suppressive potential of their CD4(+) CD25(+) Treg cells. In contrast, HIV(+) progressors did not differ from controls in Treg-cell potency or effector cell sensitivity to Treg-cell suppression. Both CD4(+) CD25(+) Foxp3(+) Treg and effector IL-17 absolute cell numbers were significantly lower in all HIV(+) subjects tested and not restored by antiviral therapy. Thus, these novel data suggest that elevated Treg-cell-mediated suppression due to increased sensitivity of effectors to Treg cells may be a natural host response in chronic asymptomatic HIV infection, which is lost as disease progresses and that this feature of CD25(-) effector cells is not inextricably linked to reduced production of the Treg-cell counter-regulatory cytokine IL-17.

Lung infections in the HIV-infected adult.

PURPOSE OF REVIEW: This review describes current epidemiology, diagnosis, treatment and prevention of adult HIV-related lung infections using evidence published within the past 2 years. RECENT FINDINGS: Recent evidence has helped better determine the importance of early initiation of antiretroviral therapy in co-infected individuals with advanced immune suppression. Although this has led to a greatly reduced incidence of opportunistic infections in people with HIV, Pneumocystis pneumonia remains common. Pneumonia due to bacterial pathogens, such as Streptococcus pneumoniae, also causes considerable disease burden, but emerging evidence of the clinical efficacy of pneumococcal vaccination, especially conjugated vaccines, offers considerable promise. As HIV-infected populations become older, more emphasis should be given to the potential benefit of influenza prevention, particularly with vaccination, and encouraging smoking cessation. Co-infection with tuberculosis is still a huge problem worldwide, but the recent development and use of simple clinical algorithms based on symptoms and point-of-care testing for recognizing active disease offers great potential. SUMMARY: The lung remains an important site of disease in HIV-infected individuals. Increasing emphasis should be placed upon prevention of infection and modification of risk factors.

Type 2 diabetes prevalence and its risk factors in HIV: A cross-sectional study.

BACKGROUND: Type 2 diabetes (T2D) has a reported greater prevalence and poorer treatment outcomes in people living with HIV (PLWH) than comparable HIV-uninfected cohorts. We conducted a cross-sectional study to delineate the factors driving T2D in PLWH in an ethnically diverse cohort, and additionally observed how these have changed over time. SETTING: We studied a diverse HIV cohort in London to determine the prevalence and risk factors for T2D, and compared them to a cohort studied 10 years previously. METHODS: Patients were classified as normoglycaemic (fasting glucose <6.0 mmol/l) or dysglycaemic (≥6.0 mmol/l). The relative contribution to dysglycaemia of modifiable and fixed factors, including demographics, anthropometrics, comorbidities, immune status, and HIV therapy, were analysed using univariate and logistic regression analyses. RESULTS: T2D prevalence was 15.1% in 2015 with a relative risk of 2.4 compared to the general population. The prevalence compared to 6.8% ten years earlier. The 2015 versus the 2005 cohort was significantly older (median age 49 (42-57) years versus 41 (IQR 35-47), p<0.001), had a higher BMI (27.4 (23.3-29.9) versus 24.9 (22.4-28.0) kg/m2 respectively, p = 0.019) and hypertensive (37.9% versus 19.6 respectively, p<0.001). The strongest predictors of dysglycaemia in the 2015 cohort were hepatic steatosis and hypertension, odds ratios (OR) and 95% confidence intervals (CI) 6.74 (3.48-13.03) and 2.92 (1.66-5.16) respectively, and also HIV-related factors of weight gain following antiretroviral initiation and longer known duration of HIV infection (OR 1.07 (1.04-1.11) and 1.06 (1.02-1.10) respectively). CONCLUSIONS: The alarmingly high prevalence of T2D in HIV requires improved screening, targeted to older patients and those with a longer duration of exposure to antiretrovirals. Effective diabetes prevention and management strategies are needed urgently to reduce this risk; such interventions should target both conventional risk factors, such as abdominal obesity, and HIV-specific risk factors such as weight gain following initiation of antiretrovirals.

Severe osteoporosis and multiple fractures in an AIDS patient treated with short-term steroids for lymphoma: a need for guidelines.

An HIV-1 infected patient on dual protease inhibitor treatment developed spontaneous vertebral fractures and avascular necrosis of the femoral bone after receiving combined chemotherapy for Burkitt's lymphoma including short-term prednisolone. The factors involved in the pathogenesis of osteopaenia and osteoporosis in this case are discussed and we propose the need for guidelines in order to reduce the incidence of such events in HIV-infected patients in the future.

Dyslipidaemia and cardiovascular risk in HIV infection.

Cardiovascular disease is increasingly recognised as a consequence of human immunodeficiency virus (HIV) infection in the era of highly active antiretroviral therapy (HAART). Dyslipidaemia is also a feature of HIV infection itself and the antiretroviral drugs from the protease inhibitor classes. Increased rates of atherosclerotic disease and diabetes have been associated with lipodystrophy and now from one of the major causes of morbidity in HIV and acquired immunodeficiency syndrome (AIDS).This review, based on a multi-database keyword search, summarises the lipid changes observed in the course of HIV infection and its treatment, and puts them into the context of other risk factors for cardiac disease, and other causes of cardiovascular disease in HIV.

A comparative phase 1 clinical trial to identify anti-infective mechanisms of vitamin D in people with HIV infection.

OBJECTIVES: To determine if there is a biological mechanism that explains the association between HIV disease progression and increased mortality with low circulating vitamin D levels; specifically, to determine if restoring vitamin D levels induced T-cell functional changes important for antiviral immunity. DESIGN: This was a pilot, open-label, three-arm prospective phase 1 study. METHODS: We recruited 28 patients with low plasma vitamin D (<50 nmol/l 25-hydroxyvitamin D3), comprising 17 HIV+ patients (11 on HAART, six treatment-naive) and 11 healthy controls, who received a single dose of 200 000 IU oral cholecalciferol. Advanced T-cell flow cytometry methods measured CD4 T-cell function associated with viral control in blood samples at baseline and 1-month after vitamin D supplementation. RESULTS: One month of vitamin D supplementation restored plasma levels to sufficiency (>75 nmol/l) in 27 of 28 patients, with no safety issues. The most striking change was in HIV+ HAART+ patients, where increased frequencies of antigen-specific T cells expressing macrophage inflammatory protein (MIP)-1ß - an important anti-HIV blocking chemokine - were observed, with a concomitant increase in plasma MIP-1ß, both of which correlated significantly with vitamin D levels. In addition, plasma cathelicidin - a vitamin D response gene with broad antimicrobial activity - was enhanced. CONCLUSION: Vitamin D supplementation modulates disease-relevant T-cell functions in HIV-infected patients, and may represent a useful adjunct to HAART therapy.

Mutations in HIV-1 reverse transcriptase during therapy with abacavir, lamivudine and zidovudine in HIV-1-infected adults with no prior antiretroviral therapy.

OBJECTIVE: To evaluate HIV-1 reverse transcriptase (RT) drug resistance in patients receiving abacavir, lamivudine and zidovudine therapy. METHODS: In a randomized, double-blind study, 173 antiretroviral treatment-naive HIV-1-infected adults received abacavir/lamivudine/zidovudine or lamivudine/zidovudine for up to 48 weeks. After week 16, patients could switch to open-label abacavir/lamivudine/zidovudine, and those with plasma HIV-1 RNA (vRNA) > 400 copies/ml could add other antiretrovirals. From weeks 11 to 48, samples with vRNA > 400 copies/ml were collected for genotyping and phenotyping. RESULTS: At baseline, 90% of isolates were wild-type (WT). At week 16, vRNA was > 400 copies/ml in seven of 72 (10% patients receiving abacavir/lamivudine/zidovudine and in 41 of 66 (62%) receiving lamivudine/ zidovudine. At week 16, the genotypes in isolates from the abacavir/lamivudine/zidovudine group were M184V alone (n = 3 cases), WT (n = 3) and M184V plus thymidine analogue mutations (TAMs) (n = 1). The genotypes in isolates from the lamivudine/zidovudine group were M184V alone (n = 37), WT ( n= 1) and M184V plus TAMs (n = 3). In the four cases where M184V plus TAMs were detected some mutations were present at baseline. Despite detectable M184V in 74% of patients on lamivudine/zidovudine, addition of abacavir with or without another antiretroviral therapy resulted in a reduction in vRNA, with 42 of 65 (65%) patients having week 48 vRNA < 400 copies/ml (intent-to-treat with missing = failure). At week 48, the most common genotype was M184V alone in the abacavir/ lamivudine/zidovudine group (median vRNA 1-2 log,10 below baseline), and M184V with or without TAMs in patients originally assigned to lamivudine/zidovudine. At week 48, phenotypic results were obtained for 11 isolates for patients from both arms, and all had reduced susceptibility to lamivudine but all remained sensitive to stavudine, all protease inhibitors and all non-nucleoside reverse transcriptase inhibitors. Three, three and two isolates had reduced susceptibility to abacavir, didanosine and zidovudine, respectively. CONCLUSIONS: Abacavir retained efficacy against isolates with the M184V genotype alone. TAMs did not develop during 48 weeks of abacavir/lamivudine/zidovudine therapy and were uncommon when abacavir was added after 16 weeks of lamivudine/zidovudine therapy. Limited mutations upon rebound on this triple nucleoside combination allows for several subsequent treatment options.

A cross-sectional randomised study of fracture risk in people with HIV infection in the probono 1 study.

OBJECTIVE: To determine comparative fracture risk in HIV patients compared with uninfected controls. DESIGN: A randomised cross-sectional study assessing bone mineral density (BMD), fracture history and risk factors in the 2 groups. SETTING: Hospital Outpatients. SUBBBJECTS: 222 HIV infected patients and an equal number of age-matched controls. ASSESSMENTS: Fracture risk factors were assessed and biochemical, endocrine and bone markers measured. BMD was assessed at hip and spine. 10-year fracture probability (FRAX) and remaining lifetime fracture probability (RFLP) were calculated. MAIN OUTCOME MEASURES: BMD, and history of fractures. RESULTS: Reported fractures occurred more frequently in HIV than controls, (45 vs. 16; 20.3 vs. 7%; OR=3.27; p=0.0001), and unsurprisingly in this age range, non-fragility fractures in men substantially contributed to this increase. Osteoporosis was more prevalent in patients with HIV (17.6% vs. 3.6%, p<0.0001). BMD was most reduced, and predicted fracture rates most increased, at the spine. Low BMD was associated with antiretroviral therapy (ART), low body mass index and PTH. 10-year FRAX risk was <5% for all groups. RLFP was greater in patients with HIV (OR=1.22; p=0.003) and increased with ART (2.4 vs. 1.50; OR= 1.50; p=0.03). CONCLUSIONS: The increased fracture rate in HIV patients in our relatively youthful population is partly driven by fractures, including non-fragility fractures, in men. Nonetheless, these findings may herald a rise in osteoporotic fractures in HIV patients. An appropriate screening and management response is required to assess these risks and identify associated lifestyle factors that are also associated with other conditions such as cardiovascular disease and diabetes.

The effect of a 12-week course of omega-3 polyunsaturated fatty acids on lipid parameters in hypertriglyceridemic adult HIV-infected patients undergoing HAART: a randomized, placebo-controlled pilot trial.

BACKGROUND: Hypertriglyceridemia is common in patients with HIV treated with highly active antiretroviral therapy (HAART). OBJECTIVE: The goal of this study was to investigate the effect of the polyunsaturated fatty acids (PUFA) docosahexaenoic acid (DHA) 460 mg/eicosapentaenoic acid (EPA) 380 mg on hypertriglyceridemia in HIV-treated patients. METHODS: A double-blind, placebo-controlled, randomized, multicenter pilot study was undertaken in 48 evaluable HIV-infected patients undergoing HAART, with fasting triglyceride levels of 3.39 to 11.3 mmol/L. Patients were allowed fibrate or niacin but not statins and were randomized to PUFA 4 g daily versus placebo for 12 weeks. The primary end point was mean fasting triglyceride levels. RESULTS: The study included 48 patients; 23 in the PUFA group (mean age, 46.1 years) and 25 in the placebo group (mean age, 43.6 years). All except one were male. All patients in the PUFA group were white; in the placebo group, 20 were white, 4 Asian, and 1 black. The PUFA group had a mean body mass index of 24.7 kg/m(2); the placebo group, 24.1 kg/m(2). All patients were receiving concomitant fibrate therapy. Median baseline triglyceride levels were 5.58 (1.76-10.6) mmol/L for the PUFA group and 4.29 (1.81-6.14) mmol/L for the placebo group. PUFA reduced triglycerides by a median of 1.75 mmol/L versus a 0.41 mmol/L increase for the placebo group (baseline-corrected percentage change relative to placebo [95% CI, -69.48% to -6.53%; P = 0.019). No effect was seen on biochemical or virologic safety parameters. No severe treatment-emergent adverse events (TEAEs) occurred. Mild and moderate TEAEs occurred in 20 PUFA-treated patients versus 19 patients receiving placebo. Five were adjudged treatment related, and one was due to cholelithiasis, which led to early discontinuation. Most TEAEs affected the gastrointestinal tract (DHA/EPA, n = 7; placebo, n = 4) and comprised diarrhea, nausea, and flatulence (DHA/EPA vs placebo: 3, 2, and 2 vs 2, 0, and 0, respectively). CONCLUSIONS: PUFA therapy with DHA/EPA reduced triglyceride levels significantly compared with placebo in HIV-infected patients with HAART-associated hypertriglyceridemia.

The assessment of metabolic syndrome in UK patients with HIV using two different definitions: CREATE 2 study.

OBJECTIVE: To determine the prevalence and clinical associations of the metabolic syndrome (M-IRS) in an HIV cohort. METHODS AND DESIGN: Data was collected prospectively on demographics, anthropometry, HIV disease, drug regimens and cardiometabolic risk factors using a two-centre cross-sectional cohort study design. M-IRS was diagnosed by National Cholesterol Education Program (NCEP) and International Diabetes Federation (IDF) criteria. RESULTS: The prevalence of M-IRS in 678 subjects was 14% by NCEP and 10% by IDF. One feature of the M-IRS was present in 68%, while 37% had two or more features. Increased waist circumference was found in 32% by NCEP or by IDF criteria, hypertriglyceridaemia in 32%, reduced HDL-C in 27%, 18% had raised systolic blood pressure and 13% had dysglycaemia. Protease inhibitor (PI) usage was similar in both M-IRS categories (43 vs. 38%; p = 0.38) but increased use of efavirenz was seen in M-IRS (47 vs. 36%; p = 0.07) and nevirapine in the non-M-IRS groups (10 vs. 20%; p = 0.05). Multiple drug therapies were associated with raised triglyceride levels while nevirapine therapy was associated with raised HDL-C and abacavir with dysglycaemia. CONCLUSIONS: The prevalence of M-IRS in this HIV cohort was similar to the general population and independent of current or previous highly active antiretroviral therapy (HAART) or its duration. Given the relationship between individual drugs and features of M-IRS its significance must be interpreted in the light of probable accrual bias in prescribing. Prospective studies are required to ascertain the cardiometabolic risk factors to include in a prognostically useful HIV disease-specific definition of M-IRS.

HIV lipodystrophy and its metabolic consequences: implications for clinical practice.

BACKGROUND: The introduction of highly active antiretroviral therapy (HAART) around 1996 markedly reduced mortality and morbidity from human immunodeficiency virus (HIV) infection. As life expectancy has improved, the chronic complications of HIV and HAART have become increasingly relevant. SCOPE: This article provides an overview of the HIV-associated lipodystrophy, its pathogenesis and its clinical consequences (based on a search strategy in PubMed including literature published to November 2007). FINDINGS: Lipodystrophy syndrome is characterized by abnormal fat distribution syndrome associated with metabolic disturbances and includes insulin resistance, deranged glucose and lipid metabolism. It is associated with increased risks of progression to type 2 diabetes and cardiovascular disease. Robust diagnostic criteria are required for lipodystrophy, and subsequent prospective cohort studies and randomized controlled trials are then required to determine the etiology and prognosis of lipodystrophy, and to evaluate therapeutic interventions for this consequence of HAART. Therapies to improve insulin resistance have been tried but they are frequently ineffective, and are limited by potential toxicity in this population. Hence, current management options for HIV associated lipodystrophy are limited and are mostly based on avoidance of risk factors and switching of antiretroviral drugs. CONCLUSION: As the '3 by 5 strategy' of providing HIV drugs to the developing world is implemented worldwide, the numbers of patients adhering to antiretroviral medicines is dramatically increasing. One must be aware that in reducing the burden of acute retroviral disease, the treatments proposed might lead to significant rates of metabolic complications and further exacerbation of the epidemic of diabetes and cardiovascular disease.

Studies of a prophylactic HIV-1 vaccine candidate based on modified vaccinia virus Ankara (MVA) with and without DNA priming: effects of dosage and route on safety and immunogenicity.

BACKGROUND: Two parallel studies evaluated safety and immunogenicity of a prophylactic HIV-1 vaccine in 192 HIV-seronegative, low-risk volunteers. Modified vaccinia virus Ankara (MVA) and plasmid DNA (pTHr) expressed HIV-1 clade A gag p24 and p17 fused to a string of 25 overlapping CD8+ T cell epitopes (HIVA). METHODS: These studies compared intramuscular, subcutaneous, and intradermal MVA at dosage levels ranging from 5x10(6)-2.5x10(8) pfu. In Study IAVI-010, DNA vaccine was given as a prime at months 0 and 1, followed by MVA as a boost at months 5 and 8. In Study IAVI-011, MVA alone was given at months 0 and 2. Regular safety monitoring was performed. Immunogenicity was measured by the interferon (IFN)-gamma ELISPOT assay on peripheral blood mononuclear cells (PBMC). RESULTS: No serious adverse events were attributed to either vaccine; most adverse events were mild or moderate, although MVA resulted in some severe local reactions. Five vaccine recipients had at least one positive IFN-gamma ELISPOT response, but none were sustained. CONCLUSION: This HIV-1 vaccine candidate was in general safe and well-tolerated. Local reactions were common, but tolerable. Detectable immune responses were infrequent.