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BACKGROUND Cardiovascular disease (CVD) is an important cause of morbidity in people living with HIV (PLWH). We compared the predictive value of HIV-related and traditional CVD risk factors to assess which factors best predict the presence of subclinical coronary atherosclerosis in PLWH. METHODS Cross-sectional study in PLWH over 50 years of age who performed CT coronary artery calcium (CAC) scoring between 2009-2019 at Chelsea and Westminster Hospital. The following outcomes were analyzed: CAC=0 (no calcification), CAC >0 (any calcification), CAC >100 (moderate calcification) and CAC >400 (severe calcification). Univariate and multivariate logistic regression analyses were performed to assess predictors of coronary calcification. RESULTS A total of 744 patients were included (mean age 56 ± 5.7 years, 94.8% male, 84% white). A CAC >0 was found in 392 (52.7%), CAC >100 in 90 (12.1%) and CAC >400 in 42 (5.6%) subjects. CAC >100 was strongly associated with hypertension [odds ratio OR: 2.91, (95% confidence interval CI: 1.93-4.36), P 6 years) to protease inhibitors [1.67 (1.06-2.61), P =0.05] whereas exposure to tenofovir (> 8 years) was negatively associated with CAC >100 [0.54 (0.30-0.98), P =0.05]. Despite the high prevalence of hypertension (45.4%), only 21.5% were on anti-hypertensives whereas only 29.2% of eligible candidates were receiving lipid lowering drugs for primary prevention of CVD. CONCLUSIONS Traditional cardio-metabolic risk factors remain the strongest predictors of coronary atherosclerosis in PLWH as in the general population. These results underscore the importance of optimizing treatment of hypertension and promoting primary prevention strategies that may be underused in PLWH.

Background The safety and immunogenicity profile of COVID-19 vaccines when administered concomitantly with seasonal influenza vaccines have not yet been reported. We therefore aimed to report the results of a substudy within a phase 3 UK trial, by evaluating the safety, immunogenicity, and efficacy of NVX-CoV2373 when co-administered with licensed seasonal influenza vaccines. Methods We did a planned exploratory substudy as part of the randomised, observer-blinded, placebo-controlled, phase 3 trial of the safety and efficacy of the COVID-19 vaccine (NVX-CoV2373) by co-administrating the influenza vaccine at four study hospitals in the UK. Approximately, the first 400 participants meeting the main study entry criteria—with no contraindications to influenza vaccination—were invited to join the substudy. Participants of the main study were randomly assigned (1:1) to receive two intramuscular injections of either NVX-CoV2373 (5 μg) or placebo (normal saline) 21 days apart; participants enrolled into the substudy were co-vaccinated with a single (0·5 mL) intramuscular, age-appropriate (quadrivalent influenza cell-based vaccine [Flucelvax Quadrivalent; Seqirus UK, Maidenhead] for those aged 18–64 years and adjuvanted trivalent influenza vaccine [Fluad; Seqirus UK, Maidenhead] for those ≥65 years), licensed, influenza vaccine on the opposite deltoid to that of the first study vaccine dose or placebo. The influenza vaccine was administered in an open-label manner and at the same time as the first study injection. Reactogenicity was evaluated via an electronic diary for 7 days after vaccination in addition to monitoring for unsolicited adverse events, medically attended adverse events, and serious adverse events. Immunogenicity was assessed with influenza haemagglutination inhibition and SARS-CoV-2 anti-spike protein IgG assays. Vaccine efficacy against PCR-confirmed, symptomatic COVID-19 was assessed in participants who were seronegative at baseline, received both doses of study vaccine or placebo, had no major protocol deviations affecting the primary endpoint, and had no confirmed cases of symptomatic COVID-19 from the first dose until 6 days after the second dose (per-protocol efficacy population). Immunogenicity was assessed in participants who received scheduled two doses of study vaccine, had a baseline sample and at least one post-vaccination sample, and had no major protocol violations before unmasking (per-protocol immunogenicity population). Reactogenicity was analysed in all participants who received at least one dose of NVX-CoV2373 or placebo and had data collected for reactogenicity events. Safety was analysed in all participants who received at least one dose of NVX-CoV2373 or placebo. Comparisons were made between participants of the substudy and the main study (who were not co-vaccinated for influenza). This study is registered with ClinicalTrials.gov, number NCT04583995. Findings Between Sept 28, 2020, and Nov 28, 2020, a total of 15 187 participants were randomised into the main phase 3 trial, of whom 15 139 received treatment (7569 received dose one of NVX-CoV2373 and 7570 received dose one of placebo). 431 participants were co-vaccinated with a seasonal influenza vaccine in the substudy (217 received NVX-CoV2373 plus the influenza vaccine and 214 received placebo plus the influenza vaccine). In general, the substudy participants were younger, more racially diverse, and had fewer comorbid conditions than those in the main study. Reactogenicity events were more common in the co-administration group than in the NVX-CoV2373 alone group: tenderness (113 [64·9%] of 174 vs 592 [53·3%] of 1111) or pain (69 [39·7%] vs 325 [29·3%]) at injection site, fatigue (48 [27·7%] vs 215 [19·4%]), and muscle pain (49 [28·3%] vs 237 [21·4%]). Incidences of unsolicited adverse events, treatment-related medically attended adverse events, and serious adverse events were low and balanced between the co-administration group and the NVX-CoV2373 alone group. No episodes of anaphylaxis or deaths were reported within the substudy. Co-administration resulted in no change to influenza vaccine immune response although a reduction in antibody responses to the NVX-CoV2373 vaccine was noted. NVX-CoV2373 vaccine efficacy in the substudy (ie, participants aged 18 to

Summary: Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19. Methods: A phase I first-in-human dose-ranging trial of a saRNA COVID-19 vaccine candidate LNP-nCoVsaRNA, was conducted at Imperial Clinical Research Facility, and participating centres in London, UK. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0·1-10·0mg, given four weeks apart. An open-label dose escalation was followed by a dose evaluation. Solicited adverse events (AEs) were collected for one week from enrolment, with follow-up at regular intervals (1-8 weeks). The binding and neutralisation capacity of anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, immunoblot, SARS-CoV-2 pseudoneutralisation and wild type neutralisation assays. Findings: 192 healthy individuals with no history or serological evidence of COVID-19, aged 18-45 years were enrolled. The vaccine was well tolerated with no serious adverse events related to vaccination. Seroconversion at week six whether measured by ELISA or immunoblot was related to dose (both p

Excessive weight gain has been reported with integrase strand transfer inhibitors (INSTIs). We evaluated weight changes in virologically suppressed adults with HIV who switched from non-INSTI regimens to raltegravir (RAL)-containing or dolutegravir (DTG)-containing antiretroviral therapy.Retrospective single-centre cohort.Adults who switched to RAL or DTG before or between January 2015 and October 2017 were identified. Virologically suppressed, treatment-experienced (≥2 years) individuals, at least 6 months on INSTI, with weight measurements 2 years or less pre and postswitch were included. Our analysis used a random effects model with linear slope pre and post-INSTI with adjustment for age, sex, ethnicity, preswitch-regimen (protease inhibitor vs. nonprotease inhibitor), and RAL vs. DTG use.A total of 378 individuals, 81.2% male, 70.1% white ethnicity, median age of 49 years, median of four weight measurements per participant, and median weight and BMI at switch of 76.6 kg and 25.3 kg/m, respectively, were included. Weight increased by an average of 0.63 kg/year (95% confidence interval 0.17-1.09) preswitch with no overall change in rate of weight gain postswitch [+0.05 kg/year (-0.61-0.71, P = 0.88)]. In our adjusted model, a transition from minimal weight change to weight gain postswitch was isolated to older individuals though this lacked statistical significance [e.g., +1.59 kg/year (-0.26-3.45) if aged 65 years]. Our findings did not differ by sex, ethnicity, preswitch regimen, or RAL vs. DTG. Similar results were seen for BMI and after adjusting for fixed nucleoside/nucleotide reverse transcriptase inhibitor backbone.We found no clear evidence of an overall increase in rate of weight gain following switch to INSTI in virologically suppressed individuals.

Successful management of HIV infection as a chronic condition has resulted in a demographic shift where the proportion of people living with HIV (PLWH) older than 50 years is steadily increasing. A dedicated clinic to PLWH older than 50 years was established at Chelsea and Westminster Hospital in January 2009 and then extended to HIV services across the directorate. We report the results of a service evaluation reviewing 10 years of activities of this clinic between January 2009 and 2019. We aimed to estimate the prevalence of major noninfectious comorbidities, polypharmacy (≥5 medications), and multimorbidity (≥2 non-HIV-related comorbidities) and describe algorithms devised for use in HIV outpatient clinics across the directorate. A cohort of 744 PLWH older than 50 years attending this service were analyzed (93% male; mean age of 56 ± 5.5 years; 84% white ethnicity); 97.7% were on antiretroviral treatment and 95.9% had undetectable HIV-RNA at the time of evaluation. The most common comorbidities diagnosed were dyslipidemia (50.1%), hypertension (21.5%), mental health disorders (depression and/or anxiety disorders, 15.7%), osteoporosis (12.2%), obesity (11.9%), chronic kidney disease (7.5%), and diabetes (5.8%). Low vitamin D levels were found in 62% of patients [43% with vitamin D deficiency (40 mmol/liter) and 57% with vitamin D insufficiency (40-70 mmol/liter)]. The overall prevalence of polypharmacy and multimorbidity was 46.6% and 69.3%, respectively. This study showed significant rates of non-HIV-related comorbidities and polypharmacy in PLWH older than 50 years, leading on to the implementation of clinical care pathways and new joint HIV/specialty clinics (cardiology, nephrology, neurology, metabolic, menopause, and geriatric) to improve prevention, diagnosis, and management of major comorbidities in people aging with HIV.

OBJECTIVES Current British HIV Association (BHIVA) guidelines recommend the use of FRAX for the routine assessment of bone fracture risk in people living with HIV over 50 years of age every 3 years. Bone mineral density measurement with dual-energy X-ray absorptiometry (DXA) scan is recommended for those with increased fracture risk (FRAX major > 10%). Our objectives were to estimate the prevalence of and risk factors for osteoporosis in a population of PLWH aged > 50 years and assess the utility of FRAX in predicting the presence of DXA-proven osteoporosis in this cohort. METHODS This was a cross-sectional study of a cohort of PLWH aged > 50 years attending the Chelsea and Westminster Hospital and who had a DXA scan between January 2009 and December 2018. FRAX scores were calculated using the Sheffield algorithm. Multiple regression models and Cohen's kappa values were used to assess risk factors for osteoporosis and agreement between FRAX and DXA scan results, respectively. RESULTS In all, 744 patients were included (92.9% male, mean age 56 ± 5 years). The prevalence rates of osteoporosis (at DXA scans) and osteopenia were 12.2% and 63.7%, respectively. FRAX major was > 10% in only two patients, while 90/91 (98.9%) patients with osteoporosis had a normal FRAX score. The presence of osteoporosis was significantly associated with low body mass index and estimated glomerular filtration rate (p

Changes in body weight in people living with HIV vary by regimen components, timing of therapy introduction (naive, switch) and demographic factors. Our objective was to evaluate weight change and factors associated in an ageing cohort of treated subjects with HIV at Chelsea and Westminster Hospital. We found that the prevalence of obesity was similar to general population and was associated with a number of health conditions, which increase metabolic risk.

OBJECTIVES Treatment with bisphosphonates and discontinuation of tenofovir disoproxil fumarate (TDF) are recommended strategies for managing osteoporosis in people living with HIV (PLHIV). This study aimed to compare the effects on bone mineral density (BMD) of TDF discontinuation with and without bisphosphonate therapy in osteoporotic PLHIV. METHODS The present study is a retrospective cohort analysis of dual-energy X-ray absorptiometry scan results of PLHIV attending Chelsea and Westminster Hospital HIV clinic between 2009 and 2020. Osteoporotic (T-score

Studies conducted in people living with HIV (PLHIV) report high rates of sleep disturbance, without a clear explanation as to cause or effect. Therefore, we proposed use of multiple validated questionnaires that would allow a more comprehensive evaluation of sleep quality in PLHIV. We administered eight validated sleep and wellbeing questionnaires, recording different aspects of sleep in order to provide a comprehensive description of sleep quality, quantity, daytime functioning, wakefulness, and general wellbeing. Associations with demographics and clinical data were analyzed by univariable/multivariable analyses. Of 254 subjects 99% were male (98% men who have sex with men), 88% white, mean age 41 (SD ± 9.9) years, HIV duration eight years (SD ± 6.3), 94% were on antiretroviral therapy, mean CD4 cell count was 724 cells/mm3, 81% had HIV RNA

BACKGROUND Cardiovascular disease (CVD) risk assessment remains a critical step in guiding decisions to initiate primary prevention interventions in people living with HIV (PLWH). SETTING We investigated whether coronary artery calcium (CAC) scoring allowed a more accurate selection of patients who may benefit from statin therapy, compared with current risk assessment tools alone. METHODS Cross-sectional analysis of PLWH over 50 years old who underwent CAC scoring between 2009 and 2019. Framingham Risk score (FRS), QRISK2 and D:A:D scores were calculated for each participant at the time of CAC scoring and statin eligibility determined based on current European guidelines on the prevention of CVD in PLWH. RESULTS A total of 739 patients were included (mean age 56 ± 5, 92.8% male, 84% white). Among 417 (56.4%) candidates for statin therapy based on FRS ≥10%, 174 (23.5%) had no detectable calcification (CAC = 0). Conversely, 145 (19.6%) patients with detectable calcification (CAC > 0) were identified as low-risk (FRS < 10%). When compared with FRS, CAC scoring reclassified CVD risk in 43.1% of patients, 145 (19.6%) to a higher risk group that could benefit from statin therapy and 174 (23.5%) statin candidates to a lower risk group. QRISK2 and D:A:D scores performed similarly to FRS, underestimating the presence of significant coronary calcification in 21.1% and 24.9% respectively and overestimating risk in 16.9% and 18.8% patients with CAC = 0. CONCLUSIONS Establishing a decision-model based on the combination of conventional risk tools and CAC scoring improves risk assessment and the selection of PLWH who would benefit from statin therapy.

OBJECTIVE The aim of the current study is to assess the effect of tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) on lipids in patients switching from TDF to TAF and back. METHODS Retrospective data collection on patients who were initially switched from TDF to TAF and switched back to TDF after generics of TDF became available. RESULTS In total, 385 patients were included. Median duration of TDF exposure before switch was 317 weeks (interquartile range 172-494). After switching from TDF to TAF, mean total cholesterol (TC) increased from 186 ± 37 mg/dl at baseline to 206 ± 43 and 204 ± 43 mg/dl at weeks 12 and 24 (P

As a consequence of ageing, the number of prescribed medications for people living with HIV is increasing. Concomitant use of different drugs and their potential interactions may increase anticholinergic exposure and escalate the risk for side effects. We conducted an analysis in our cohort of people living with HIV over 50 years of age to evaluate the overall anticholinergic risk, as it is useful to identify, prevent, and manage increased side effect risks.

ObjectivesIn order to assess whether the BioSure HIV Self-Test could be reliably performed by users at home and to determine whether they were able to perform and correctly interpret the test, we carried out an evaluation study among attendees at a sexual health service.MethodsA prospective observational study of clinic attendees to determine their ability to follow the instructions, complete the test on themselves and correctly interpret the results. The evaluation included interpretation of three dummy (contrived) devices, chosen at random from a sample of 12 devices, to ensure that a sufficient number of all possible test outcomes were included.ResultsTwo hundred participants were recruited. 97.0% (95% CI 93.5 to 98.9) conducted the test so as to achieve a valid result. 99.5% correctly identified the test result. Participants correctly interpreted the result of 94.0% (95% CI 91.4 to 95.9) of 586 contrived devices.ConclusionsThe majority of participants were able to follow the instructions and perform the test in order to get a valid result. Interpretation of the test results was good and the majority of participants were able to correctly read the result of their own and contrived tests. The availability of HIV self-tests will provide another option to increase access to testing particularly for those who may not wish or are unable to access clinical services.

Alcohol misuse has been associated with negative consequences among HIV-positive patients. Data on real prevalence of risky alcohol consumption among the HIV-positive population in the UK are lacking. A cross-sectional questionnaire study using standardised validated instruments among HIV-positive (n = 227) and HIV-negative (n = 69) patients was performed. The prevalence of risky alcohol consumption (AUDIT) and associations with depressive symptoms (PHQ-9), problematic drug use (DUDIT), adherence to ART (CASE Adherence Index), sexual behaviour and demographic characteristics were assessed among both patient groups independently. A quarter (25.1%) of HIV-positive patients and 36.1% of HIV-negative patients reported risky alcohol consumption (AUDIT-score ≥ 8). In the multivariable analysis among HIV-positive patients depressive symptoms (p = 0.03) and problematic drug use (p = 0.007) were associated with risky alcohol consumption. Among HIV-negative patients these associations were not present. Risky alcohol consumption among HIV-positive patients is prevalent, and together with depressive symptoms and problematic drug use, may influence HIV-disease progression and patients’ wellbeing. Electronic supplementary material The online version of this article (10.1007/s10461-019-02714-2) contains supplementary material, which is available to authorized users.

We evaluated associations between history of syphilis infection and both cognitive function and depressive symptoms in people living with HIV (PLHIV) and comparable HIV-negative controls. Syphilis serological tests, cognitive function and depression were assessed in PLHIV and controls participating in the Pharmacokinetic and Clinical Observations in People Over Fifty study. Cognitive test scores were converted to demographically adjusted T-scores (mean = 50, SD = 10) and then averaged to obtain a global T-score. Severity of depressive symptoms was assessed via the Patient Health Questionnaire-9. Associations of syphilis with global T-scores and depression were assessed using median regression. The 623 PLHIV and 246 HIV-negative controls were predominantly male (89.3% and 66.5%) with median age (interquartile range [IQR]) of 57 (53–63) and 58 (53–63) years, respectively. PLHIV had lower global cognitive T-scores (median [IQR] 48.7 [45.1, 52.1] versus 50.5 [47.0, 53.9], p

Background We aimed to measure the effect of raltegravir (RAL) on insulin sensitivity and surrogates of cardiovascular risk in healthy HIV-seronegative volunteers compared to that of lopinavir/r (LPV/r), a positive control. Methods An open-label, two phase crossover study in HIV-negative male subjects randomized 1:1 to receive either 2 weeks of LPV/r followed by a 2-week washout period and 2 weeks of RAL, or RAL initially followed by LPV/r. A hyperinsulinaemic euglycaemic clamp was performed prior to and following each 2-week dosing phase. Fasting samples for lipids, adiponectin, leptin, vascular inflammatory biomarkers and CD36 were also taken. Results A total of 16 subjects completed the study. At the baseline visit the mean insulin-stimulated glucose disposal per unit insulin (M/I) was 7.97 and 8.30 for LPV/r and RAL, respectively. The mean (sem) percentage change from baseline was -16.10% (3.84) after 2 weeks of LPV/r and -0.43% (4.83) after 2 weeks of RAL. Absolute M/I was 25% lower for LPV/r than for RAL ( P=0.001). Triglycerides and total cholesterol rose significantly with LPV/r (+0.5 mmol/l, P=0.002 and +0.4 mmol/l, PConclusions RAL was not associated with measurable change in glycaemic, metabolic or inflammatory effects.

OBJECTIVES: Post-exposure prophylaxis (PEP) for HIV is often poorly tolerated and not completed. Alternative PEP regimens may improve adherence and completion, aiding HIV prevention. We conducted a randomized controlled trial of a maraviroc-based PEP regimen compared with a standard-of-care regimen using ritonavir-boosted lopinavir. METHODS: Patients meeting criteria for PEP were randomized to tenofovir disoproxil/emtricitabine (200/245 mg) once daily plus ritonavir-boosted lopinavir (Kaletra ® 400/100 mg) or maraviroc 300 mg twice daily. The composite primary endpoint was completion of 28 days of the allocated PEP regimen without grade 3 or 4 clinical or laboratory adverse events (AEs) related to the PEP medication. RESULTS: Two hundred and thirteen individuals were randomized (107 to maraviroc; 106 to Kaletra ® arm). Follow-up rates were high in both groups. There was no difference in the primary endpoint; 70 (71%) in the maraviroc and 64 (65%) in the Kaletra ® arm ( P = 0.36) completed PEP without grade 3 or 4 AEs. Discontinuation of PEP was the same (18%) in both groups. There were no grade 3 or 4 clinical AEs in either arm, but more grade 1 or 2 clinical AEs in the Kaletra ® arm (91% versus 70%; P

Antiretroviral therapy during pregnancy is critical to preventing human immunodeficiency virus vertical transmission. Physiological changes during pregnancy can alter drug kinetics. The aim of this study was to assess the pharmacokinetics (PK) of saquinavir (SQV) boosted with ritonavir during pregnancy and postpartum. Fourteen human immunodeficiency virus-positive pregnant women started SQV 500 mg new tablet formulation plus ritonavir at a dose of 1000/100 mg twice a day + 2 nucleoside retrotranscriptase inhibitors during pregnancy. At weeks 24 and 34 of pregnancy and 6 weeks postpartum, a 12-hour PK study was conducted. PK parameters were calculated using Win Nolin software version 4.1. At week 24, the geometric mean values for SQV area under the plasma concentration-time curve from 0-12 hours (AUC₀₋₁₂), the maximum observed plasma concentration (C(max)), trough plasma concentration (C(min)), and the elimination half-life (t(1/2)) were 24.80 mg·h⁻¹·mL⁻¹, 4.66 mg/mL, 0.93 mg/mL, and 4.31 hours, respectively. At week 34, AUC₀₋₁₂, C(max), C(min), and t(1/2) were 12.71 mg·h⁻¹·mL⁻¹, 3.23 mg/mL, 0.26 mg/mL, and 4.06 hours, respectively. Finally, at 6 weeks postpartum, mean values for SQV AUC₀₋₁₂, C(max), C(min), and t(1/2) were 28.94 mg·h⁻¹·mL⁻¹, 3.92 mg/mL, 0.86 mg/mL, and 3.60 hours, respectively. Although PK parameters in week 24 and postpartum were very similar, those for week 34 showed an important reduction: -71.20%, -30.61%, -48.73%, and -5.81% in C(min), C(max), AUC₀₋₁₂, and t(1/2), respectively, compared with week 24, but no statistically significant differences were shown between patients. No vertical transmissions were reported. Therapeutic drug monitoring of SQV during pregnancy should be considered, mainly during the third trimester, to ensure adequate drug exposure throughout the entire pregnancy.

Patients infected with HIV treated with highly active antiretroviral therapy (HAART) frequently develop body physical changes (BPC) that have an important psychosocial burden. The purpose of this study was to determine the prevalence of BPC observed by HIV-infected patients and their attending physicians and to assess the impact BPC had on daily life. In this epidemiologic multicenter study, patients with HIV infection and their treating physicians filled out parallel questionnaires about their perceptions of specific BPC and their impact on daily activities. A total of 965 patient-physician questionnaires were collected across 98 health centers. Patient's mean age was 43.7 +/- 8.5 years and 72.6% were men. Adjusted prevalence of perceived BPC by patients and physicians was 55.1% (95% confidence interval [CI]: 52.0-58.1) and 55.2% (95% CI: 52.1-58.2), respectively (p = 1.000). Overall patient-physician agreement concerning perception of BPC was 83% (p < 0.0005). The most common BPC was lipoatrophy, described by 46.8% (95% CI: 43.7-49.8) of patients and 49.4% (95% CI: 46.3-52.5) of physicians (p = 0.033) followed by lipohypertrophy. No gender differences were observed in the global prevalence of BPC (p = 0.649). However, significantly more women reported lipoatrophy of the lower limbs (p = 0.009) and buttocks (p = 0.007), as well as lipohypertrophy (p = 0.007), than men; 58.2% (95% CI: 54.0-62.4) patients noted that BPC negatively affected their daily activities. This study reflects the high prevalence of patient and physician-perceived BPC in the HIV population, and the adverse impact on daily life. Physicians should be aware of the psychosocial consequences of BPC in HIV patients in order to improve patient well-being.

Background: Mitochondrial damage of HIV and antiretrovirals, especially nucleoside-analogue interference on mitochondrial DNA (mtDNA) replication, is reported to underlay highly active antiretroviral therapy (HAART)-related hyperlactatemia, but scarce approaches have been performed to correlate clinical manifestations and mitochondrial abnormalities. Methods: We obtained lymphocytes and monocytes of 26 HIV-infected and treated patients who developed hyperlactatemia and after recovery, 28 nonhyperlactatemic HIV subjects on HAART, 31 naive individuals, and 20 uninfected controls. Mitochondrial replication and transcription analysis were performed by quantitative real-time PCR, mitochondrial translation quantification by western blot and mitochondrial enzymatic activities by spectrophotometry. Results: Mitochondrial parameters decreased during hyperlactatemia and improved at recovery. Mitochondrial replication and transcription species were reduced (P = 0.16 and P = 0.71), but the most significant decay was observed on mitochondrial protein content (P < 0.05) and mitochondrial complexes III and IV activities (P < 0.01 and P < 0.001). During hyperlactatemia lactate level correlated complexes III and IV function (P < 0.05). After recovery mitochondrial parameters achieved values of nonhyperlactatemic HIV individuals, which were lower than ranges of naive subjects and uninfected controls. Conclusions: HIV and HAART-related hyperlactatemia is associated with a general mitochondrial impairment which reverts after recovery. Mitochondrial biochemistry show a better correlation with lactate levels than mitochondrial genetics suggesting that mitochondrial function could be a better marker of hyperlactatemia development than mtDNA content.

Although two pegylated interferons (Peg-IFN) are available to treat chronic hepatitis C virus (HCV) infection, no head-to-head comparative studies have been published. We aim to compare the efficacy and safety of PEG IFN alfa-2b (PEG 2b) versus PEG IFN alfa-2a (PEG 2a), plus ribavirin (RBV). A prospective, randomized, multi-center, open-label clinical trial including 182 human immunodeficiency virus (HIV)–hepatitis C virus (HCV) patients naive for HCV therapy was performed. Patients were assigned to PEG 2b (80-150 μg/week; n = 96) or PEG 2a (180 μg/week; n = 86), plus RBV (800-1200 mg/day) for 48 weeks. The primary endpoint was sustained virological response (SVR: negative HCV-RNA 24 weeks after completion of treatment). At baseline, both groups were well balanced: 73% male; 63% HCV genotype 1 through 4; 29% had fibrosis index of 3 or greater. The overall SVR was 44% (42% PEG 2b versus 46% PEG 2a, P = 0.65). Among genotypes 1 through 4, SVRs were 28% versus 32% (P = 0.67) and 62% versus 71% (P = 0.6) in genotypes 2 through 3 for PEG 2b and PEG 2a, respectively. Early virological response (EVR; ≥2 log reduction from baseline or negative HCV-RNA at week 12) was 70% in the PEG 2b group and 80% in the PEG 2a group (P = 0.13), reaching a positive predictive value of SVR of 64% and a negative predictive value of 100% in both arms. Side effects were present in 96% of patients but led to treatment discontinuation in 10% of patients (8% on PEG 2b and 13% on PEG 2a, P = 0.47). Conclusion: In patients with HIV, HCV therapy with PEG 2b or PEG 2a plus RBV had no significant differences in efficacy and safety. (HEPATOLOGY 2009;49:22-31.)

Background Since the introduction of highly active antiretroviral therapy (HAART), the incidence of death in HIV-infected patients has dramatically decreased, and causes of death other than those related to HIV infection have increased, although it is unclear how these parameters compare with those in the age-matched general population living in the same geographical region. Methods Consecutive HIV-infected adults who were prescribed HAART in our hospital were prospectively followed from January 1997 to December 2004 or until death, loss to follow-up or discontinuation of HAART. Estimations of the annual incidence and causes of death in the general population of similar age in Catalonia per calendar year in the study period were obtained and compared with those in the HIV-infected cohort. Results There were 235 deaths among the 4471 patients on HAART (5%). The incidence of mortality decreased over time in HIV-infected patients (P

Stavudine is a nucleoside analogue used for the treatment of HIV-1 infection, as part of highly active antiretroviral treatment. In developing countries, stavudine is used widely, owing to low cost and inclusion in generic fixed-dose combinations. In developed countries, stavudine is now rarely used, although it is highly effective. This is because newer drugs show lower rates of mitochondrial toxicities, such as lipoatrophy, peripheral neuropathy and lactic acidosis. In the development of stavudine, there was evidence that a dosage of 20-30 mg b.i.d. was effective, but the 40-mg b.i.d. dose gained regulatory approval. This review analyses the clinical trials conducted before and after the regulatory approval of stavudine, and shows that the dose of 30 mg b.i.d. has equivalent antiviral efficacy (given the caveats of meta-analysis), with some evidence of lower rates of peripheral neuropathy and lipoatrophy. With limited resources for HIV-1 treatment in developing countries, and only 25% of eligible patients receiving highly active antiretroviral treatment, low-cost treatment options such as stavudine still need to be pursued, if safety can be improved by dose optimisation.

Triple-nucleoside therapy with abacavir (ABV)/lamivudine (3TC)/zidovudine (ZDV) combination tablets provides simple, nonfood-dependent, twice-daily, well-tolerated therapy with the potential to improve long-term adherence at a lower cost than other triple-drug regimens. Of all the triple nucleoside reverse transcriptase inhibitor combinations currently available, ABV/3TC/ZDV is most extensively studied. Although ABV/3TC/ZDV is possibly less potent than other treatment options when used alone, other attributes described in this review make it an attractive option for selected patients. This combination spares the use of protease inhibitors and their associated side effects, such as metabolic abnormalities, which may contribute to premature cardiovascular disease. Furthermore, by using only one drug class, it may maintain a greater number of future treatment options. Data from ongoing clinical trials may result in expanding the use of ABV/3TC/ZDV as a component of multidrug, highly active antiretroviral therapy regimens.

Introduction: Integrase inhibitors (INIs) are the latest class of antiretroviral drugs approved for the treatment of HIV infection and are becoming ‘standard’ drugs in the treatment of both naive as well as heavily pretreated individuals with HIV.Areas covered: Data on efficacy, safety, tolerability, pharmacokinetics, drug-drug interactions and resistance are reviewed from the pivotal Phase III clinical trials published in PubMed high-impact medical journals or presented at international meetings.Expert opinion: Due to their outstanding data of efficacy, tolerability, safety – shared by all three drugs (raltegravir, elvitegravir, dolutegravir) currently belonging to this new family of antiretrovirals – INIs have become part of the recommended initial antiretroviral therapy options. Some differences in dosing, drug-drug interactions and robustness/genetic barrier among the three drugs will provide the physician the characteristics to make the best choice.

The chronic infection by the hepatits C virus represents a serious sanitary problem affecting 1-3% of the world-wide population. It is transmitted by sexual route, vertical route and mainly after blood exposure by percutanea route. While HIV shares similar routes of transmission, the co-infection HCV-HIV is very frequent and the chronic hepatopathy and complications associated with its clinical course are an important cause of morbi-mortality in this population. The gold standard of the treatment for the HCV, has been the interferon and later the combination therapy of interferon plus ribavirine. Currently, the combination of ribavirine and a new pegilated formulation of the interferon has become the standard in the treatment reaching rates of sustained viral response around 40-80%.

To investigate the effects of HIV infection on mitochondrial DNA (mtDNA) content and other mitochondrial parameters, we used peripheral blood mononuclear cells (PBMCs) from 25 asymptomatic antiretroviral-naive human immunodeficiency virus (HIV)-infected patients and from 25 healthy control subjects. HIV-infected patients had significant decreases in mtDNA content (decrease, 23%; P

Dyslipidaemia associated with the treatment of HIV infection, particularly with the use of protease inhibitors (PIs), can raise cholesterol and triglyceride (TG) levels to the thresholds indicated for intervention. Recent evidence from epidemiological studies has shown that there are correlations between antiretroviral drug use and increased risks for, and incidences of, cardiovascular disease, including myocardial infarction and coronary heart disease. The primary goals of dyslipidaemia therapy for HIV patients are reductions of both low-density lipoprotein cholesterol (LDL-C) and markedly elevated TG levels. Dietary strategies and exercise programs may be tried, although these have shown inconsistent results. The two options for drug therapy are switching anti-retroviral agents and using lipid-lowering drugs. Each approach is associated with advantages and limitations, and the need to maintain viral suppression must be balanced with the need to treat abnormal lipid levels. Most drug switches replace the PI component with drugs from another antiretroviral class. Selection of drug therapy for lipid lowering depends on the type of dyslipidaemia predominating and the potential for drug interactions. The use of the statins pravastatin and atorvastatin is recommended for the treatment of patients with elevated LDL-C levels and gemfibrozil or fenofibrate for patients with elevated TG concentrations. Development of new PIs with more favourable effects on the lipid profile should be of benefit.

Nevirapine (Viramune, Boehringer Ingelheim Ltd) is the first marketed non-nucleoside reverse transcriptase inhibitor. As with any antiretroviral drug, nevirapine should always be used as part of a fully suppressive regimen. Clinical studies have shown that nevirapine-containing regimens may accomplish durable virological and immunological responses in approximately half of all antiretroviral-naive patients. It can also be successfully used as a component of salvage therapies and as a part of a strategy to simplify protease inhibitor-containing regimens. Nevirapine has a beneficial effect on the lipid profile in both treatment-naive and -experienced patients. Nevirapine also has an important role in preventing mother-to-child transmission of HIV. It is usually well-tolerated with rash and liver toxicity being the most frequently reported adverse events. Nevirapine interacts with cytochrome P450 enzymes both as a substrate and as an inducer. For this reason, therapeutic drug monitoring should be recommended whenever nevirapine is used with protease inhibitors, methadone (Methadose, Rosemont Pharmaceuticals Ltd), oral contraceptives, rifampicin (Rifadin, Aventis Pharma) and other potentially interacting drugs. Nevirapine-resistant mutations are common to the non-nucleoside reverse transcriptase inhibitor family and they include K103N, V106A, Y181C, Y188C and G190A. A better understanding of the nevirapine profile will certainly contribute to ensuring that its clinical application becomes more effective and beneficial.

A standardized questionnaire was used to assess the impact of lipodystrophy (LD) on quality of life (QoL). Eighty-four consecutive asymptomatic human immunodeficiency virus type 1 (HIV-1)-infected outpatients with clinical LD completed a modified version of the Dermatology Life Quality Index (DLQI) survey to measure the impact of body fat changes on their QoL. Body changes influenced dressing for 55 patients (65%), produced feelings of shame for 41 (49%), and disrupted sexual life for 23 (27%). There was a greater impact on the DLQI due to body changes among women, injection drug users, patients with abdominal or breast lipoaccumulation, and patients with a high number of non-LD side effects. Multivariate proportional odds model analysis showed that the severity of non-LD-associated side effects and the presence of breast lipoaccumulation were associated with impaired psychosocial functioning. Specific characteristics of patients, antiretroviral-based side effects, and breast lipoaccumulation exert a greater impact on QoL in HIV-1-infected patients with LD.

Direct evidence confirming the hypothesis that a dysfunction of the mitochondrial respiratory chain (MRC) underlies the pathogenesis of hyperlactatemia associated with highly active antiretroviral therapy (HAART) is scarce. We studied mitochondrial DNA (mtDNA) content and MRC function in the skeletal muscle of an HIV-infected patient during an episode of symptomatic hyperlactatemia. Skeletal muscle biopsy was performed during the episode when the patient was symptomatic and 3 months later when the patient was clinically recovered. Assessment of mitochondria was performed using histological, polarographic, spectrophotometrical, and Southern blot and real time PCR DNA quantification methods. The histological study disclosed extensive mitochondrial impairment in the form of ragged-red fibers or equivalents on oxidative reactions. These findings were associated with an increase in mitochondrial content and a decrease in both mitochondrial respiratory capacity and MRC enzyme activities. Mitochondrial DNA content declined to 53% of control values. Mitochondrial abnormalities had almost disappeared later when the patient became asymptomatic. Our findings support the hypothesis that MRC dysfunction stands at the basis of HAART-related hyperlactatemia.

Background Hypertriglyceridaemia and insulin resistance are common in HIV-infected patients treated with protease inhibitors, particularly in those with lipodystrophy. Whether a therapeutic approach addressed to those metabolic abnormalities may have any impact on body fat is not clear. Methods Patients on stable antiretroviral therapy containing protease inhibitors, with abdominal obesity defined by increased waist-to-hip ratio, and plasma triglycerides >200 mg/dl, were randomized to receive blind medication consisting of metformin 850 mg, gemfibrozil 600 mg or placebo every 12 h for 1 year. Weight, height, waist and hip were measured, and fasting blood analyses, including at least CD4 cell count, plasma HIV-1 RNA, lactate, glucose, insulin, triglycerides, total, HDL and LDL cholesterol were performed at baseline and every 3 months. An oral glucose tolerance test, and assessments of total and regional fat by bioimpedance analysis and sonography, respectively, were also done at baseline, 6 and 12 months. Results One-hundred-and-eight patients were randomized to placebo ( n=36), gemfibrozil ( n=37) or metformin ( n=35). There was absolute loss of total and regional fat in the three arms without significant changes in the waist-to-hip ratio. However, the loss of fat in patients on gemfibrozil was significantly lower than in patients on placebo. No patient discontinued study drugs due to adverse effects. Conclusion In this population of HIV-infected patients, there was a loss of fat along time. The finding of relative preservation of fat associated with gemfibrozil therapy deserves further investigation in the search of potential effective therapies for lipodystrophy in HIV-infected subjects.

Objectives: To assess the incidence and risk factors for hepatotoxicity associated with nevirapine.Design: A prospective cohort study in a teaching and referral hospital involving all consecutive patients who were prescribed a nevirapine-containing antiretroviral regimen between September 1997 and May 2000.Method: Cutaneous and hepatic adverse reactions and clinical hepatitis were assessed. Blood analysis including plasma HIV-1 RNA CD4 cell counts, liver chemistry tests, and serology for hepatitis B and C viruses. Hepatotoxicity was defined as an increase of at least threefold in serum alanine aminotransferase or aspartate aminotransferase levels compared with baseline values.Results: Of a total of 610 patients, 82 (13.4%) were antiretroviral naive when commencing nevirapine, and 46.2 and 8.9% were coinfected with hepatitis C and B viruses, respectively. Median duration of exposure to nevirapine was 8.7 months (interquartile range 3.4-14.3). Hepatotoxicity developed in 76 (12.5%), an incidence of 13.1/100 person-years. Kaplan-Meier estimated incidence of hepatotoxicity at 3, 6 and 12 months was 3.7, 9.7 and 20.1%, respectively, in seven (1.1%) patients, hepatotoxicity was associated with clinical hepatitis, which was reversible upon discontinuation of therapy. Multivariate analysis identified the duration of prior exposure to antiretroviral drugs, hepatitis C virus, and higher baseline levels of alanine aminotransferase as independent risk factors for hepatotoxicity.Conclusions: Hepatotoxicity but not clinical hepatitis was common in HIV-1-infected patients receiving nevirapine-containing regimens and the incidence steadily increased over time. Prolonged exposure to any antiretroviral therapy, coinfection with hepatitis C virus and abnormal baseline levels of alanine aminotransferase identified patients at a higher risk. (C) 2001 Lippincott Williams & Wilkins.

To assess the prevalence, imaging appearance, and clinical significance, of bone marrow MR signal changes in a group of human immunodeficiency virus (HIV)-infected patients with lipodystrophy syndrome.Twenty-eight HIV-infected patients with lipodystrophy syndrome treated with highly active antiretroviral therapy, and 12 HIV-negative controls underwent MRI of the legs. Whole-body MRI, SPECT/CT, and a complete radiographic skeletal survey were obtained in subjects with signal changes in bone marrow. MRI and clinical evaluations were reviewed 6 months after baseline to determine changes after switching from thymidine analogs (TA) to tenofovir-DF (TDF). MRI results correlated with clinical parameters.We observed foci of a serous-like pattern (low signal and no enhancement on T1-weighted, high signal on T2-weighted images) in 4 out of 28 patients (14.3%) and an intermediate signal on T1-weighted images in 4 out of 28 patients (14.3%). Serous-like lesions were located in the lower limbs and scattered in the talus, calcaneus, femurs, and humeral bones; they showed slight uptake on SPECT bone scans and were normal on CT and radiographs. Patients with serous-like lesions had significantly lower peripheral and total fat at baseline than other groups (P0.05). No changes at 6 months were observed on MRI, and the serous-like lesion group showed good peripheral fat recovery after changing drug treatment.A serous-like MRI pattern is observed in the peripheral skeletons of HIV-infected patients with lipodystrophy, which correlates with peripheral lipoatrophy, and should not be misdiagnosed as malignant or infectious diseases. Although the MR lesions did not improve after switching the treatment, there was evidence of lipoatrophy recovery.

The OK04 trial has shown that 48 weeks of lopinavir-ritonavir monotherapy with reintroduction of nucleosides as needed was noninferior to continuation of triple therapy with 2 nucleosides and lopinavir-ritonavir in patients with prior stable suppression. However, it is still uncertain if this experimental strategy can maintain suppression in the long term.Patients entered this noninferiority trial (upper limit 95% confidence interval: +12%) with no history of virological failure while receiving a protease inhibitor and receiving 2 nucleosides plus lopinavir/ritonavir, with HIV RNA50 copies per milliliter for more than 6 months. Primary end point was percent of patients without therapeutic failure, defined as confirmed HIV RNA500 copies per milliliter with exclusion of monotherapy patients who resuppressed to50 copies per milliliter after resuming baseline nucleosides, or loss to follow-up, or change of randomized therapy other than reinduction.Through 96 weeks, percentage of patient without therapeutic failure was 87% (monotherapy, n = 100) vs. 78% (triple therapy, n = 98; 95% confidence interval: -20% to +1.2%). Percentage with HIV RNA50 copies per milliliter (intention to treat, missing = failure, reinduction = failure): 77% (monotherapy) vs. 78% (triple therapy). Low-level viral rebound was more frequent in the monotherapy group. Twelve patients in the monotherapy group (12%) needed reinduction with nucleosides. Discontinuations due to adverse events were significantly more frequent in the triple therapy group (8%) than in the monotherapy group (0%); P = 0.003.At 96-week lopinavir/ritonavir monotherapy with reintroduction of nucleosides as needed was noninferior to continuation of triple therapy. Incidence of adverse events leading to treatment discontinuation was significantly lower with monotherapy. (ClinicalTrials.gov number, NCT00114933).

Background: CD4+ T cell recovery dynamics were analysed during the 'on treatment' periods in structured therapy interruption (STI) as well as the long-term immune reconstitution with highly active antiretroviral therapy (HAART) after finishing STI. Methods: One hundred and twenty HIV-1-infected patients on successful HAART were randomized to receive for 2 years continuous HAART (n = 37) or two different strategies of STI (n = 83). After this period, most patients received continuous HAART for 2 years. Results: During the STI period, the rate of recovery of CD4+ T cells decreased progressively from the first to the last resumption of HAART {median change of increase: +232 [interquartile range (IQR): +126, +318], +116 (IQR: +10, +471), +87 (IQR: -54, +252) and -26 (IQR: -352, +211) cells/mm 3 after the first, second, third and fourth resumption, respectively}. After the STI period and 2 years of continuous HAART, the median CD4+ count remained significantly lower than at baseline in STI arms, both in the virological arm [559 (IQR: 383, 727) versus 771 (IQR: 625, 913) cells/mm 3 , P< 0.0001] and the immunological arm [619 (IQR: 501, 789) versus 787 (IQR: 657, 954) cells/mm 3 , P

Occult hepatitis B virus (HBV) infection is diagnosed when HBc antibodies (HBcAb) and HBV DNA are detectable in serum while hepatitis B surface antigen (HBsAg) is not. This situation has been frequently described in patients with chronic hepatitis C virus (HCV) infection. The objective of this study was to evaluate the prevalence of occult hepatitis B in HIV-HCV-coinfected patients and its clinical relevance in liver histology and viral response after interferon therapy for HCV. A total of 238 HIV-HCV-infected patients,negative for HBsAg, were included. Serum samples were analyzed for the presence of HBV DNA and HBcAb.HBV DNA quantification was determined with the Cobas TaqMan HBV Test (detection limit 6 IU/ml). Data from liver biopsy and laboratory tests were also analyzed. HBcAb resulted in 142 (60%) patients, being the independent associated factors: male gender, previous history of intravenous drug use, age, CD4 count,and HAV antibody presence. Among 90 HBcAb patients that we could analyze, HBV DNA was positive in 15 (16.7% of occult hepatitis B infection in this group, and 6.3% in the whole HIV-HCV cohort studied). No baseline factors, liver histology, or HCV therapy response were related to the presence of HBV DNA. We found that occult hepatitis B is a frequent condition present in at least 6.3% of our HCV-HIV patients and in more than 16% of those with HBcAb. Despite the high prevalence, this phenomenon does not seem to affect the clinical evolution of chronic hepatitis C or modify the viral response to interferon-based HCV therapies

Several serum markers reflecting extracellular matrix status have been correlated with liver fibrosis in non-HIV-infected patients with chronic hepatitis C infection. These indexes have been less examined in HIV/HCV-coinfected individuals.We aimed to evaluate the predictive value of serum markers for liver fibrosis in HIV-infected patients with chronic hepatitis C virus (HVC).Serum levels of metalloproteinases 1 and 2 (MMP-1 and -2), tissue inhibitors of matrix metalloproteinases (TIMP-1), procollagen type III N-terminal peptide (PIIINP), and hyaluronic acid (HA) were measured in HIV-infected patients with chronic hepatitis C at the time of obtaining a liver biopsy and before the consideration of anti-hepatitis C therapy.One hundred and nineteen consecutive HIV-HVC coinfected patients were included. TIMP-1 (r = 0.6; P0.001), TIMP-1/MMP-1 ratio (r = 0.5; P0.001), TIMP-1/MMP-2 ratio (r = 0.3; P0.001), MMP-2 (r = 0.2; P = 0.044), PIIINP (r = 0.4; P0.001), and HA (r = 0.5; P0.001) were positively and significantly correlated with the fibrosis stage. In the multivariate analysis, TIMP-1 (odds ratio [OR] = 1.004, 95% confidence interval [CI]: 1.002 to 1.006, P = 0.001) and HA95 microg/dL (OR = 6.041, 95% CI: 1.184 to 30.816, P = 0.031) were independently associated with liver fibrosis. The area under the curve of score to discriminate mild (F0-F1) from significant (F2-F4) fibrosis in the received-operating analysis using the variables TIMP-1 and HA was 0.84, with a sensitivity of 72.9% and a specificity of 83.1%.TIMP-1 and HA were quite sensitive and specific for predicting the degree of liver fibrosis in HIV-infected patients with chronic hepatitis C. These parameters may become a noninvasive alternative to liver biopsy when the degree of liver fibrosis needs to be estimated.

BACKGROUND As a result of adverse events, a moderate rate of virologic response, and high costs associated with hepatitis C virus (HCV) therapy, finding early markers of sustained treatment response is a clinical priority. In the HCV-monoinfected population, a reduction >or=2 log in plasma HCV RNA at week 12 of therapy (early virologic response [EVR]) predicts a sustained virologic response (SVR). Few data are available in HIV/HCV-coinfected patients, however. METHODS A subanalysis of data from HIV/HCV-coinfected patients treated with pegylated interferon-alpha-2b (PEG, 100-150 mug/wk) or interferon-alpha-2b (IFN, 3 MIU 3 times per week) plus ribavirin (RBV, 800-1200 mg/d) was conducted in a randomized single-center clinical trial. The duration of treatment was 48 weeks (only 24 weeks for HCV genotype 2 or 3 with a baseline HCV RNA level

Background: the prevalence of risky alcohol consumption, associated factors and its impact on the brain is not well established in clinically stable HIV-patients. Materials and methods: Within the PIVOT neurocognitive sub-study, effectively suppressed HIV-infected adults on either standard cART or ritonavir-boosted PI monotherapy completed the Alcohol Use Disorders Identification Test (AUDIT) designed to detect risky alcohol consumption. They also completed a brief neuropsychological assessment (NPZ 5) composed by five measures. For this cross-sectional analysis, we calculated rates of hazardous (AUDIT=8-15) or harmful (AUDIT=16-19) consumption and likely dependence (AUDIT>20). We explored the association between risky alcohol intakes (AUDIT>8) and clinical/demographical variables, conducting logistic regressions when significant association was found (p

In recent years, lipodystrophy and its related complications have changed from an anecdotal issue into a major problem for HIV-infected patients on antiretroviral therapy. Despite great efforts to achieve a consensus in defining this problem, a simple, readily available definition is still lacking. More comprehensive knowledge of the underlying molecular basis and the natural history of body fat changes and metabolic abnormalities is needed to make progress. Also, an objective assessment of body fat is still to be incorporated in clinical practice, so interventions to prevent or treat body fat changes cannot be adequately monitored. Several objective techniques have been used, and all of them have limitations and advantages. There seems to be a good correlation between different techniques for measuring fat, but that is not the case for detecting fat changes. A huge amount of data have been generated on how to manage lipodystrophy. Nevertheless, there is no clinically proven treatment for any feature of lipodystrophy. The only intervention that has been shown to reverse lipoatrophy is the discontinuation of thymidine analogues, but the results obtained are partial or modest at most. Structured therapy interruptions have become an increasingly popular strategy aimed at preventing or reducing antiretroviral drug toxicity, but little objective data exist on their impact on body composition of HIV-infected patients. The issue of body composition has become extremely important for the adequate management of HIV-infected patients.

Summary The rise in didanosine concentrations in plasma when given with tenofovir raises concern for a high risk of toxic effects. Recommendations to reduce didanosine dose have been issued, but only for adults weighing more than 60 kg. We reviewed cases of pancreatitis in patients receiving didanosine plus tenofovir, didanosine alone, and tenofovir alone to assess the incidence of and risk factors for pancreatitis. Between Aug 1, 2001, and Nov 30, 2003, five of 185 (2·7%) patients receiving didanosine plus tenofovir, one of 182 (0·5%) on didanosine without tenofovir, and none of 208 on tenofovir without didanosine developed pancreatitis (p=0·016). Co-administration of both drugs versus each of them individually was an independent risk factor for pancreatitis (crude hazard ratio 10·666, 95% CI 1·246–91·294, p=0·031). These results suggest that the risk of pancreatitis is heightened when didanosine and tenofovir are given together.

Background The prevalence, risk factors, and potential hormonal abnormalities associated with gynecomastia in a cohort of HIV-infected men are poorly understood. Methods Breast enlargement was assessed in consecutively evaluated HIV-infected men, and gynecomastia was subsequently confirmed with sonography. For each patient with breast enlargement, a randomly selected control subject without breast enlargement was studied. Clinical data were obtained, including age, body mass index, clinically evident lipodystrophy, prior symptomatic hyperlactatemia, current antiretroviral therapy and duration of exposure to each antiretroviral drug, history of injection drug use, and serological status regarding hepatitis B and hepatitis C. Laboratory parameters, including plasma HIV-1 RNA load, CD4 cell count, free testosterone index, and levels of fasting triglycerides, cholesterol, prolactin, total testosterone, sex hormone-binding globulin, 17-beta-estradiol, follicle-stimulating hormone, luteinizing hormone, and thyroid-stimulating hormone, were measured. Results There were 44 of 2275 patients with breast enlargement, of whom 40 (1.8%) had gynecomastia. The mean free testosterone index (+/-SD) was significantly lower among the 40 patients with gynecomastia (42.6%+/-24.0%) than among the 44 control subjects (58.0%+/-25.3%) (P=.006). Although the proportion of patients who were receiving treatment with zidovudine, stavudine, and/or efavirenz at the time of the present study was significantly different between case patients and control subjects, the duration of exposure to each individual antiretroviral drug was not. Lipoatrophy (adjusted odds ratio [OR], 5.6; 95% confidence interval [CI], 1.7-18.6; P=.005), hepatitis C (adjusted OR, 6.1; 95% CI, 1.8-20.6; P=.003), and hypogonadism (adjusted OR, 7.6; 95% CI, 1.8-32.2; P=.003) were independent factors associated with gynecomastia. Conclusions The data suggest that gynecomastia among HIV-infected patients is related to hypogonadism, rather than to an adverse effect of antiretroviral drugs.

Background A decrease in the mitochondrial (mt) DNA to nuclear DNA ratio has gained acceptance as a marker of mitochondrial toxicity in treated HIV-infected patients, but the functional meaning of this alteration is unclear. Methods We assessed mtDNA content, mitochondrial content and function in peripheral blood mononuclear cells (PBMCs) of consecutive asymptomatic HIV-infected patients. Patients selected had been receiving a first-line highly active antiretroviral therapy (HAART) regimen for at least 6 months, consisting of zidovudine plus lamivudine or stavudine plus didanosine plus either nelfinavir or nevirapine, or were antiretroviral-naive. The mtDNA content was assessed by quantitative real-time PCR, mitochondrial content by citrate synthase activity, enzyme activity of complexes III and IV (both partially encoded by mtDNA) of the electron transport chain by spectrophotometry, oxygen consumption by polarography, and oxidative damage in cell membranes by monitoring cis-parinaric acid fluorescence. Results Mitochondrial content was significantly lower in all treated groups. Patients receiving stavudine plus didanosine had mtDNA depletion and a decrease in complex IV activity. However, oxygen consumption capacity and lipid peroxidation were unaffected in all groups. Conclusion Long-term HAART may induce mitochondrial abnormalities in PBMC mitochondria, which do not necessarily translate into functional abnormalities, at least in asymptomatic patients. This study was presented in the 4th International Workshop on Adverse Drug Reactions & Lipodystrophy in HIV (San Diego, Calif., USA, September 2002) and in ‘Late Breakers & Hot Topics’ session in the 6th International Congress on Drug Therapy in HIV Infection (Glasgow, UK, November 2002).

The evolution of fasting glucose, triglyceride, and total and high-density lipoprotein (HDL) cholesterol level and the factors associated with development of clinically significant abnormalities in these metabolic parameters at 6 months were assessed in 353 consecutive human immunodeficiency virus (HIV)-infected patients who were receiving antiretroviral therapy containing lopinavir-ritonavir. Although glucose and HDL cholesterol levels did not change, triglyceride and total cholesterol levels significantly increased (P.0001 for each), as did the proportion of patients with a triglyceride level of400 mg/dL and a total cholesterol level of240 mg/dL (P=.002). A baseline triglyceride level of400 mg/dL and a baseline total cholesterol level of240 mg/dL were identified as independent factors predicting clinically significant hypertriglyceridemia and hypercholesterolemia, respectively, at 6 months. These findings may have clinical implications when the therapeutic option of lopinavir-ritonavir is considered.

Introduction Lipodystrophy (LD) represents an important problem for HIV-1-infected patients receiving highly active antiretroviral therapy (HAART), although its impact on quality of life (QoL) has not been properly studied. Design Cross-sectional, nonrandomized, observational study performed on consecutive, clinically stable outpatients taking HAART for more than 1 year. Methods Data on patients' characteristics, HIV-1 infection, treatment adherence and adverse effects, overall QoL measured by the Profil der Lebensqualitat Chronischkranker (PLC), and the presence of LD defined by clinical criteria were assessed. Results Eighty-four (56%) of 150 interviewed patients fulfilled criteria for LD. Patients with LD were older, had been taking antiretroviral treatment longer, and reported a poorer physical status than patients without LD. Surprisingly, LD itself was not found to influence overall QoL. However, homosexual patients, unemployed patients, and those patients undergoing current psychiatric treatment showed greater impairment on some of the QoL subscales related to psychological well-being if they suffered from LD. Conclusion The impact of HIV-related LD on QoL depends on certain patient characteristics, rather than on the presence of LD itself.