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We assessed whether HIV status was associated with white matter hyperintensities (WMH), a neuroimaging correlate of cerebral small vessel disease (CSVD), in men aged ≥50 years. A cross-sectional substudy was nested within a larger cohort study. Virologically suppressed men living with HIV (MLWH) and demographically matched HIV-negative men aged ≥50 underwent magnetic resonance imaging (MRI) at 3 Tesla. Sequences included volumetric three-dimensional (3D) T1-weighted, fluid-attenuated inversion recovery and pseudocontinuous arterial spin labeling. Regional segmentation by automated image processing algorithms was used to extract WMH volume (WMHV) and resting cerebral blood flow (CBF). The association between HIV status and WMHV as a proportion of intracranial volume (ICV; log-transformed) was estimated using a multivariable linear regression model. Thirty-eight MLWH [median age 59 years (interquartile range, IQR 55-64)] and 37 HIV-negative [median 58 years (54-63)] men were analyzed. MLWH had median CD4 + count 570 (470-700) cells/μL and a median time since diagnosis of 20 (14-24) years. Framingham 10-year risk of cardiovascular disease was 6.5% in MLWH and 7.4% in controls. Two (5%) MLWH reported a history of stroke or transient ischemic attack and five (13%) reported coronary heart disease compared with none of the controls. The total WMHV in MLWH was 1,696 μL (IQR 1,229-3,268 μL) or 0.10% of ICV compared with 1,627 μL (IQR 1,032-3,077 μL), also 0.10% of ICV in the HIV-negative group ( p  = .43). In the multivariable model, WMHV/ICV was not associated with HIV status ( p  = .86). There was an age-dependent decline in cortical CBF [-3.9 mL/100 mL/min per decade of life (95% confidence interval 1.1-6.7 mL)] but no association between CBF and HIV status ( p  > .2 in all brain regions analyzed). In conclusion, we found no quantitative MRI evidence of an increased burden of CSVD in MLWH aged 50 years and older.

Context: Therapies to decrease immune activation might be of benefit in slowing HIV disease progression., Objective: To determine whether hydroxychloroquine decreases immune activation and slows CD4 cell decline., Design, Setting, and Patients: Randomized, double-blind, placebo-controlled trial performed at 10 HIV outpatient clinics in the United Kingdom between June 2008 and February 2011. The 83 patients enrolled had asymptomatic HIV infection, were not taking antiretroviral therapy, and had CD4 cell counts greater than 400 cells/μL., Intervention: Hydroxychloroquine, 400 mg, or matching placebo once daily for 48 weeks., Main Outcome Measures: The primary outcome measure was change in the proportion of activated CD8 cells (measured by the expression of CD38 and HLA-DR surface markers), with CD4 cell count and HIV viral load as secondary outcomes. Analysis was by intention to treat using mixed linear models., Results: There was no significant difference in CD8 cell activation between the 2 groups (-4.8% and -4.2% in the hydroxychloroquine and placebo groups, respectively, at week 48; difference, -0.6%; 95% CI, -4.8% to 3.6%; P = .80). Decline in CD4 cell count was greater in the hydroxychloroquine than placebo group (-85 cells/μL vs -23 cells/μL at week 48; difference, -62 cells/μL; 95% CI, -115 to -8; P = .03). Viral load increased in the hydroxychloroquine group compared with placebo (0.61 log10 copies/mL vs 0.23 log10 copies/mL at week 48; difference, 0.38 log10 copies/mL; 95% CI, 0.13 to 0.63; P = .003). Antiretroviral therapy was started in 9 patients in the hydroxychloroquine group and 1 in the placebo group. Trial medication was well tolerated, but more patients reported influenza-like illness in the hydroxychloroquine group compared with the placebo group (29% vs 10%; P = .03)., Conclusion: Among HIV-infected patients not taking antiretroviral therapy, the use of hydroxychloroquine compared with placebo did not reduce CD8 cell activation but did result in a greater decline in CD4 cell count and increased viral replication., Trial Registration: isrctn.org Identifier: ISRCTN30019040.

Background: Randomized control studies have not shown an association between treatment with tenofovir (TDF) and clinically significant kidney toxicity. However, multiple cases of renal tubular toxicity have been described in patients with HIV treated with TDF. It is unclear whether spot urine protein- or albumin-creatinine ratio is a sufficiently sensitive screening test to detect subclinical renal tubular toxicity in patients with HIV., Study Design: Cross-sectional., Setting & Participants: 99 patients with HIV with serum creatinine levels < 1.70 mg/dL and dipstick-negative proteinuria; 19 were antiretroviral treatment (ART) naive, 47 were on a TDF regimen, and 33 were on ART, but with no history of TDF exposure., Predictor or Factor: Exposure to TDF., Outcomes: Spot urine concentrations of retinol-binding protein (RBP; a low-molecular-weight protein normally reabsorbed by the proximal tubule), N-acetyl-beta-D-glucosaminidase (NAG; a proximal tubule lysosomal enzyme), albumin (A; a marker of glomerular disease), and protein (P; a standard clinical screening test for kidney pathological states) expressed as a ratio to creatinine (C; U(RBP/C), U(NAG/C), U(A/C), and U(P/C), respectively)., Results: There were no significant differences in median U(A/C) (ART-naive, 7.3 mg/g [range, 0-245.8 mg/g]; TDF, 9.0 mg/g [range, 0.1-184.1 mg/g]; and non-TDF, 10.5 mg/g [range, 2.6-261.6 mg/g]; P = 0.8). U(RBP/C) excretion was significantly higher in the TDF group (median, 214.2 microg/g [range, 26.8-17,454.5 microg/g]) than in the ART-naive group (92.5 microg/g [range, 21.3-3,969.0 microg/g]; P = 0.03); there was also a trend toward higher values than in the non-TDF group (111.6 microg/g [range, 31.0-6,136.3 microg/g]; P = 0.08). U(NAG/C) excretion was significantly higher in both the TDF (median, 394.7 micromol/h/g [range, 140.5-10,851.3 micromol/h/g]; P = 0.01) and non-TDF (406.8 micromol/h/g [range, 12.4-8,485.8 micromol/h/g]; P = 0.03) groups compared with the ART-naive group (218.6 micromol/h/g [range, 56.5-2,876.1 micromol/h/g]). U(P/C) was significantly higher in the TDF (median, 123.9 mg/g [range, 53.1-566.4 mg/g]) than the non-TDF group (97.3 mg/g [range, 0-451.3 mg/g]; P = 0.03). The proportion of patients with evidence of tubular dysfunction (increased U(RBP/C) and/or U(NAG/C)) was considerably higher than the proportion with an increase in U(A/C) or U(P/C) in all groups: for ART-naive, 52.6% vs 31.6% vs 25.0%; for TDF, 80.9% vs 29.8% vs 52.2%; and for non-TDF, 81.8% vs 39.4% vs 30.0%. The level of agreement among the different urinary test results was low., Limitations: Causality cannot be established from single measurements of urinary markers in a cross-sectional study., Conclusions: Patients with HIV had high rates of subclinical proteinuria, but neither U(P/C) nor U(A/C) is sufficiently sensitive alone to detect many of these cases. Patients using TDF have increased U(RBP/C) and U(P/C); the significance of this will need to be determined from longer-term outcome studies.

Objectives: The aims of the study were to describe the clinical presentation and renal and bone abnormalities in a case series of HIV-infected patients receiving treatment with tenofovir (TDF), and to recommend appropriate screening for toxicity related to TDF., Methods: Patients were identified from referrals to a specialist HIV renal clinic. Patients were included if treatment with TDF was assessed as the primary cause of the renal function impairment and clinical data were available prior to and following discontinuation of TDF treatment. Data were collected from case note review and clinic databases., Results: Twenty-two patients (1.6% of all those who received TDF) were identified with TDF-associated renal toxicity. All had normal serum creatinine prior to TDF therapy. All presented with proteinuria. On stopping TDF, renal function improved. Eight patients had confirmed Fanconi syndrome. Twelve patients presented with bone pain and osteomalacia was confirmed on an isotope bone scan in seven of these patients. The findings (in those patients tested) of tubular proteinuria, reduced tubular transport maximum of phosphate (TmP), and glycosuria were all consistent with the proximal tubule being the site of toxicity., Conclusion: Renal toxicity remains a concern in patients treated with TDF. Clinical presentation may be with renal dysfunction, Fanconi syndrome or osteomalacia. Our investigations suggest proximal tubular toxicity as a common pathogenic mechanism.

Home delivery (HD) of medication is a goal of the Department of Health's Pharmacy in the Future; Implementing the NHS Plan. We evaluated the safety and effectiveness of an HD service for antiretroviral therapy (ART). Patients on ART with stable viral load (VL) <50 were identified. Comparison was made between patients using HD and those using the clinic-based pharmacy (CP). The primary endpoint was HIV virological failure (VF) (HIV VL >400 copies/mL on two consecutive occasions). Secondary endpoints included frequency of outpatient attendances (OPA) and an incidence of adverse events. Cumulative incidences (CulmIn) for each outcome event were calculated. Incidence-rate ratios (IRR) were obtained using Poisson regression. Of 1663 patients identified; 450 received HD and 1213 used CP. CuImIn of VF was =4% in those using HD and =7% in those using CP (IRR [95% confidence intervals, CI] =0.53, 0.32-0.90). HD patients had fewer OPA, less frequent blood test monitoring and less frequent abnormal liver function results (IRR [95% CI]= 0.63 [0.59-0.67] and 0.59 [0.53-0.67], 0.68 [0.65-0.71] and 0.64 [0.53-0.78], respectively). Patients deemed stable enough on social, psychological and medical grounds to receive HD of ART had a lower risk of VF, fewer OPA and no increase in adverse events when compared with patients using CP.

Background: We sought to investigate renal function in previously untreated symptomatic human immunodeficiency virus (HIV)-infected adults with CD4(+) cell counts of <200 cells/mm(3) who were undergoing antiretroviral therapy (ART) in Africa., Methods: The study was an observational analysis within a randomized trial of ART management strategies that included 3316 participants with baseline serum creatinine levels of < or =360 micromol/L. Creatinine levels were measured before ART initiation, at weeks 4 and 12 of therapy, and every 12 weeks thereafter. We calculated estimated glomerular filtration rate (eGFR) using the Cockcroft-Gault formula. We analyzed the incidence of severely decreased eGFR (<30 mL/min/1.73 m(2)) and changes in eGFR to 96 weeks, considering demographic data, type of ART, and baseline biochemical and hematological characteristics as predictors, using random-effects models., Results: Sixty-five percent of the participants were women. Median values at baseline were as follows: age, 37 years; weight, 57 kg; CD4(+) cell count, 86 cells/mm(3); and eGFR, 89 mL/min/1.73 m(2). Of the participants, 1492 (45%) had mild (> or =60 but <90 mL/min/1.73 m(2)) and 237 (7%) had moderate (> or =30 but <60 mL/min/1.73 m(2)) impairments in eGFR. First-line ART regimens included zidovudine-lamivudine plus tenofovir disoproxil fumarate (for 74% of patients), nevirapine (16%), and abacavir (9%) (mostly nonrandomized allocation). After ART initiation, the median eGFR was 89-91 mL/min/1.73 m(2) for the period from week 4 through week 96. Fifty-two participants (1.6%) developed severe reductions in eGFR by week 96; there was no statistically significant difference between these patients and others with respect to first-line ART regimen received (P = .94). Lower baseline eGFR or hemoglobin level, lower body mass index, younger age, higher baseline CD4(+) cell count, and female sex were associated with greater increases in eGFR over baseline, with small but statistically significant differences between regimens (P < .001 for all)., Conclusions: Despite screening, mild-to-moderate baseline renal impairment was relatively common, but these participants had greatest increases in eGFR after starting ART. Severe eGFR impairment was infrequent regardless of ART regimen and was generally related to intercurrent disease. Differences between ART regimens with respect to changes in eGFR through 96 weeks were of marginal clinical relevance, but investigating longer-term nephrotoxicity remains important.

Objective: To evaluate whether the addition of a fourth drug for up to 32 weeks to a standard three-drug antiretroviral combination decreases the risk of virological failure without increasing toxicity in treatment-naive patients., Design: Induction/maintenance (IM) therapy [two nucleoside reverse transcriptase inhibitors (NRTIs) + one non-NRTI (NNRTI) + one protease inhibitor for 24-32 weeks until plasma HIV RNA viral load (VL) < or =50 copies/ml then two NRTIs + NNRTI] was compared with standard therapy (ST) (two NRTIs + NNRTI). The primary endpoint was virological failure: VL >50 copies/ml at 32 (and 24) weeks or subsequent rebound to >400 copies/ml., Results: 122 (62 IM, 60 ST) participants were randomized and followed for a median of 81 weeks (IQR 64-145). 52% were asymptomatic; median CD4+ T-cell count was 160 x 10(6)/l (IQR 92-260) and median VL 98,830 copies/ml (IQR 37,500-241,290). In an intent-to-treat analysis, the proportion of participants with virological failure at or after 32 weeks was higher in the ST arm [26 (43%) versus 11 (18%), P = 0.002]. The mean decrease in VL at 48 weeks was 0.84 95% confidence interval (CI) (0.15, 1.53) log10 copies/ml greater in the IM arm (P = 0.02). There were no significant differences between the two arms in the change in CD4+ T-cell count from baseline to 48 weeks, the number of participants with adverse events or the frequency of progression to AIDS/death. Drug resistance at failure was detected less frequently in the IM arm., Conclusions: Starting antiretroviral therapy with an IM strategy improved virological outcomes compared with a three-drug regimen, without significantly increasing toxicity.

Objectives: The study tests the hypothesis that monocyte derived dendritic cells from HIV-1 infected individuals are normal and can restore impaired CD4 T-cell antigen specific responses., Design: Monocyte derived dendritic cells were isolated from individuals at three different stages of HIV-1 infection with a wide spectrum of viral load and CD4 T-cell counts, and from healthy volunteers. The cell surface phenotype and allogeneic stimulatory potential of these dendritic cells was documented. CD4 T-cell responses to HIV p24, tetanus toxoid and purified protein derivative were measured using either unfractionated peripheral blood mononuclear cells, or purified dendritic cell/T-cell cultures., Results: Dendritic cells from all three HIV-1 infected groups did not differ from each other or from healthy volunteers in terms of cell surface phenotype or allogeneic stimulatory potential using T cells from healthy volunteers. Dendritic cells from immunosuppressed antiretroviral naive individuals enhanced the autologous recall proliferative responses both to HIV-1 p24, and third party antigens tetanus toxoid and purified protein derivative, both in terms of the proportion of responding individuals, and median proliferation., Conclusion: Antigen presentation by dendritic cells partially restores impaired antigen specific CD4 T-cell responses associated with HIV-1 infection. Immunization strategies which target dendritic cells may therefore offer significant advantages in the ability to stimulate HIV-specific protective immune responses.

With the number of people living with HIV infection increasing and the problems of drug resistance and long-term toxicity associated with current antiretroviral agents continuing, there is a growing need for new therapy options. Enfuvirtide is the first fusion inhibitor, a new class of drug, to be licensed for the treatment of HIV infection and is a welcome addition to the arsenal of antiretrovirals. This paper, which is the result of a multidisciplinary discussion meeting, reviews current practice in treating HIV infection, the clinical data available on enfuvirtide and discusses its introduction into clinical practice. Data available to date indicate that enfuvirtide is appropriate for use in patients who have previously taken nucleoside reverse transcriptase inhibitor (NRTI), non-NRTI and protease inhibitor containing regimens and are either intolerant of them or have experienced virological failure. Enfuvirtide should ideally be used while the patient still has other active drug options available to them to combine with enfuvirtide in an effective therapy regimen.

Background/objective: There is concern that use of highly active antiretroviral therapy (HAART) may be linked to increased sexual risk behaviour among homosexual men. We investigated sexual risk behaviour in HIV positive homosexual men and the relation between use of HAART and risk of HIV transmission., Methods: A cross sectional study of 420 HIV positive homosexual men attending a London outpatient clinic. Individual data were collected from computer assisted self interview, STI screening, and clinical and laboratory databases., Results: Among all men, sexual behaviour associated with a high risk of HIV transmission was commonly reported. The most frequently reported type of partnership was casual partners only, and 22% reported unprotected anal intercourse with one or more new partners in the past month. Analysis of crude data showed that men on HAART had fewer sexual partners (median 9 versus 20, p=0.28), less unprotected anal intercourse (for example, 36% versus 27% had insertive unprotected anal intercourse with a new partner in the past year, p=0.03) and fewer acute sexually transmitted infections (33% versus 19%, p=0.004 in the past 12 months) than men not on HAART. Self assessed health status was similar between the two groups: 72% on HAART and 75% not on HAART rated their health as very or fairly good, (p=0.55). In multivariate analysis, differences in sexual risk behaviour between men on HAART and men not on HAART were attenuated by adjustment for age, time since HIV infection. CD4 count and self assessed health status., Conclusion: HIV positive homosexual men attending a London outpatient clinic commonly reported sexual behaviour with a high risk of HIV transmission. However, behavioural and clinical risk factors for HIV transmission were consistently lower in men on HAART than men not on HAART. Although use of HAART by homosexual men with generally good health is not associated with higher risk behaviours, effective risk reduction interventions targeting known HIV positive homosexual men are still urgently needed.

Long-term effects of therapeutic vaccination of human immunodeficiency virus (HIV)-1-infected subjects with HIV-1 p17/p24:Ty virus-like particles (p24-VLP) on progression to AIDS, death, a CD4 cell count

Objective: To determine the frequency of detection of human herpesvirus-8 (HHV-8) in HIV-related oral ulcers., Design: Analysis of archived biopsy material., Methods: Nested polymerase chain reaction of DNA extracts., Results: HHV-8 DNA was detected in six of 10 oral ulcers of HIV-positive patients without oral Kaposi's sarcoma (KS) lesions and five of 11 oral KS lesions. The positive non-KS samples were derived from various oral sites., Conclusions: In HIV-positive people, HHV-8 can infect oral tissues that are not affected by KS.

Objective: Oral ulceration occurs in an estimated 2-4% of patients with HIV infection. This retrospective observational study describes the aetiology and characteristics of 94 HIV-positive patients with either severe and/or recurrent oral ulceration presenting at a dedicated HIV dental unit over a 4-year period., Methods: Case records were reviewed for diagnosis investigations, CD4 count, CDC stage and treatment modality., Results: Of the 94 patients 50% had an AIDS diagnosis. In patients with asymptomatic HIV disease minor recurrent oral ulceration was the commonest diagnosis whilst large non-specific neutropenic ulcers were more frequently seen in patients with symptomatic disease with low CD4 counts. A variety of treatment modalities were used including thalidomide. An algorithm is presented for the management of patients with severe oral ulceration.

A 210-bp DNA segment specific to the human herpesvirus 8 (HHV-8) genome was amplified by nested polymerase chain reaction from 10 of 14 archived oral biopsy samples of HIV-positive patients in London who had no evidence of oral Kaposi's sarcoma (KS). Various oral sites were represented. Oral tissues from 20 general dental patients not known to be HIV-infected were negative. When DNA sequences of these products were compared with sequences derived from 5 oral KS tissues of AIDS patients in London and 10 skin biopsies of Italian patients with Mediterranean KS (total number of positive tissues = 25), 11 were found to be unique. DNA and predicted peptide motifs of these sequences were also different from those in 28 of 36 HHV-8-positive lesions previously reported from American and African patients. HHV-8 is tropic for the oral mucosa of HIV-infected persons, and HHV-8 variants, though diverse, may be geographically restricted.

In studies of the natural history of human immunodeficiency virus type 1 (HIV-1) infection, it has been repeatedly shown that higher-titer antibody responses to the HIV gag p24 protein correlate with less rapid disease progression. In HIV-negative persons, immunization with HIV-1 p17/p24:Ty virus-like particles (p24-VLP) induced humoral and cellular immune responses to p24. This construct was therefore studied as a potential immunotherapeutic agent with the objective of augmenting the immune response to p24 in a double-blind placebo-controlled trial involving 74 p24 antibody-positive, asymptomatic HIV-1-infected subjects with CD4 cell counts > 350/mm3. Immunization with p24-VLP was generally well tolerated. Immunization with p24-VLP did not increase p24 antibody levels and had no effect on CD4 cell counts or virus load. The failure to increase p24 antibody titers cannot entirely be explained by the subjects' immunodeficiency because most generated an antibody response to Ty, a yeast component of the immunogen.

Objective: Dyslipidaemia in HW-seropositive patients treated with highly active antiretroviral therapy (HAART) has been extensively described. The underlying derangement remains unclear. The physiology of the lipid metabolism of individuals treated with HAART was studied measuring lipid absorption, gastrointestinal lipid handling and lipid oxidation. Methods: The following groups were studied: six HIV+ individuais with established (2 years) lipidaemia on treatment with a protease inhibitor (PI); six age-matched healthy HIV-negative controls; seven HW-seropositive prior to treatment (study 1) and after 1 month (study 2) on a PI-containing regimen and again after 3 months (study 3). All patients were given a standard test meal containing 3.7 MJ, 45g lipid and 93g carbohydrate and 1g palmitic acid. Recovery of tracer in the breath as [sup 13]CO[sub 2] was determined hourly for 6 hours after the meal. Results: The rates of lipid absorption and oxidation were not significantly different between the (study 1) patient group and controls. However, the rate of lipid oxidation had increased by study 3 when compared with study 1. This rate was lower than in those who had established dyslipidaemia. Conclusion: Prior to commencing PI lipid metabolism in HIVseropositive males is normal. However, on a PI-containing regimen a progressive abnormality of lipid handling occurs in ali patients with decreased peripheral uptake of lipid and enhanced oxidation. [ABSTRACT FROM AUTHOR]

Objective: To review outcomes of HIV PEP regimens. Background: The recommended regimen of AZT, 3TC and indinavir (IDV) is often poorly tolerated. Mainly for reasons of compliance our policy from 11/97 has been to use D4T, 3TC and nevirapine (NVP). NVP is a potent inhibitor of HIV and intracellular therapeutic levels are rapidly achieved after a single dose. Methods: Retrospective case-note review between 1/97 and 6/99. Results: Eighty patients were considered for PEP. Of 67 who started: 34 followed occupational exposure (20 from known positive 'donors'), of whom 17 (50%) completed a 4-week course of PEP; 33 followed sexual exposure (24 from known positive 'donors'), of whom 22 (67%) completed. 0ne patient tested positive at baseline, one seroconverted by 6 months, having tested negative at 3 months; 46/67 (68.6%) received a NVP-based regimen: 28 (60.9%) completed; 10 (21.3%) reported minor and four (8.7%) major A/Es (ACTG toxicity criteria), one grade 4 hepatitis with a grade 3 rash, three grade 3 hepatitis, 13/67 (19.4%) had an IDVbased regimen: nine (69.2%) completed, seven (53.8%) reported minor A/Es; 7/67 (10.4%) received AZT/3TC, two (28.6%) completed; three (42.9%) reported minor A/Es. Conclusion: Documented completion of PEP regimens was no different between IDV- and NVP-containing regimens. Although a lower proportion experienced any A/Es with NVP, severe A/Es were only reported in those receiving D4T, 3TC and NVP, which is of concern in this population. Data are now being collected prospectively and policy is under review. [ABSTRACT FROM AUTHOR]

Objective: To determine any differences in the demographics of 100 people diagnosed with HIV in 1994 (pre-HAART) compared to 1998 (post-HAART). Method: Data were collected from an established database and supplemented from medical and counselling notes. Results: Mean age was 31 in 1994 and 34 in 1998. Most were male (74%, 78%) and Caucasian (67%, 68%). In 1994 the main risk groups were 62% homosexual and 34% heterosexual compared with 69% and 28% in 1998, 3% in both years were IDU. In 1994 19% had AIDS at the time of diagnosis, in 1998 this was 12%. The mean CD4 in 1994 was 445 (CI 374-516) and in 1998313 (CI 258367). Mean viral load in 1998 was 5.07 log[sub 10]. Most people tested via the Same Day Testing Clinic (73%, 74%). In 1994 34% had been tested previously and in 1998, 33%. In 1994 18% of the 100 were using condoms regularly, in 1998 22%. In 1994 20% had a known HIV+ partner and 19% in 1998. Conelusion: Very few differences were seen in those diagnosed HIV+ in the pre- and post-HAART era. Many people still present with relatively advanced disease at a stage when antivirals would be considered. Mean CD4 at presentation was lower in 1998. New sites and increased availability for testing do not seem to be impacting yet on where and when people present. Most people newly diagnosed in our service were still homosexual men. [ABSTRACT FROM AUTHOR]