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IMPORTANCE: Cardiovascular disease (CVD) is increased in people with HIV (PWH) and is characterized by premature noncalcified coronary plaque. In the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE), pitavastatin reduced major adverse cardiovascular events (MACE) by 35% over a median of 5.1 years. OBJECTIVE: To investigate the effects of pitavastatin on noncalcified coronary artery plaque by coronary computed tomography angiography (CTA) and on inflammatory biomarkers as potential mechanisms for MACE prevention. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, placebo-controlled randomized clinical trial enrolled participants from April 2015 to February 2018 at 31 US clinical research sites.PWH without known CVD who were taking antiretroviral therapy and had low to moderate 10-year CVD risk were included. Data were analyzed from April to November 2023. INTERVENTION: Oral pitavastatin calcium, 4 mg per day. MAIN OUTCOMES AND MEASURES: Coronary CTA and inflammatory biomarkers at baseline and 24 months. The primary outcomes were change in noncalcified coronary plaque volume and progression of noncalcified plaque. RESULTS: Of 804 enrolled persons, 774 had at least 1 evaluable CTA. Plaque changes were assessed in 611 who completed both CT scans. Of 611 analyzed participants, 513 (84.0%) were male, the mean (SD) age was 51 (6) years, and the median (IQR) 10-year CVD risk was 4.5% (2.6-7.0). A total of 302 were included in the pitavastatin arm and 309 in the placebo arm. The mean noncalcified plaque volume decreased with pitavastatin compared with placebo (mean [SD] change, −1.7 [25.2] mm3 vs 2.6 [27.1] mm3; baseline adjusted difference, −4.3 mm3; 95% CI, −8.6 to −0.1; P = .04; 7% [95% CI, 1-12] greater reduction relative to placebo). A larger effect size was seen among the subgroup with plaque at baseline (−8.8 mm3 [95% CI, −17.9 to 0.4]). Progression of noncalcified plaque was 33% less likely with pitavastatin compared with placebo (relative risk, 0.67; 95% CI, 0.52-0.88; P = .003). Compared with placebo, the mean low-density lipoprotein cholesterol decreased with pitavastatin (mean change: pitavastatin, −28.5 mg/dL; 95% CI, −31.9 to −25.1; placebo, −0.8; 95% CI, −3.8 to 2.2). The pitavastatin arm had a reduction in both oxidized low-density lipoprotein (−29% [95% CI, −32 to −26] vs −13% [95% CI, −17 to −9]; P < .001) and lipoprotein-associated phospholipase A2 (−7% [95% CI, −11 to −4] vs 14% [95% CI, 10-18]; P < .001) compared with placebo at 24 months. CONCLUSIONS AND RELEVANCE: In PWH at low to moderate CVD risk, 24 months of pitavastatin reduced noncalcified plaque volume and progression as well as markers of lipid oxidation and arterial inflammation. These changes may contribute to the observed MACE reduction in REPRIEVE. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02344290

Drugs taken during pregnancy can affect maternal and child health outcomes, but few studies have compared the safety and virological efficacy of different antiretroviral therapy (ART) regimens. We report the primary safety outcomes from enrolment up to 50 weeks post partum and a secondary virological efficacy outcome at 50 weeks post partum of three commonly used ART regimens for HIV-1.

Background: Patients infected with HIV who experience increases in CD4(super +) cell counts are at reduced risk for opportunistic infections. However, the safety of discontinuing prophylaxis against Mycobacterium avium complex has been uncertain. Objective: To compare the rate of M. avium complex infection in patients with increased CD4(super +) cell counts who receive azithromycin and those receiving placebo. Design: Randomized, double-blind, placebo-controlled trial. Setting: 29 university-based clinical centers in the United States. Participants: 643 HIV-l-infected patients with a previous CD4(super +) cell count less than 0.05 x 10(super 9) cells/L and a sustained increase to greater than 0.10 x 10(super 9) cells/L during antiretroviral therapy. Intervention: Azithromycin, 1200 mg once weekly (n = 321), or matching placebo (n = 322). Measurements: Mycobacterium avium complex cultures, CD4(super +) cell counts, and clinical evaluations for AIDS-defining illnesses and bacterial infections were done every 8 weeks. Plasma HIV-1 RNA levels were measured at 16-week intervals. Results: During follow-up (median, 16 months), 2 cases of M. avium complex infection were reported among the 321 patients assigned to placebo (incidence rate, 0.5 event per 100 person-years [95% CI, 0.06 to 1.83 events per 100 person-years]) compared with no cases among the 322 patients assigned to azithromycin (CI, 0 to 0.92 events per 100 person-years), resulting in a treatment difference of 0.5 event per 100 person-years (CI, -0.20 to 1.21 events per 100 person-years) for placebo versus azithmmycin. Both cases were atypical in that M. avium complex was localized to the vertebral spine. Patients receiving azithromycin were more likely than those receiving placebo to discontinue treatment with the study drug permanently because of adverse events (8% vs. 2%; hazard ratio, 0.24 [CI, 0.10 to 0.57]). Conclusions: Prophylaxis against Mycobacterium avium complex can safely be withdrawn or withheld in adults with HIV infection who experience increases in CD4(super +) cell count while receiving antiretroviral therapy.

Azithromycin, clarithromycin, and rifabutin are all FDA-approved for prophylaxis against Mycobacterium avium complex (MAC) in patients with advanced HIV infection. Recently, results of two large, randomized, controlled trials were reported that may alter the way these compounds are used in preventing MAC. Results have shown that both azithromycin (1,200 mg once weekly) and clarithromycin (500 mg twice daily) are more efficacious than rifabutin in preventing MAC. Combination prophylaxis with a macrolide and rifabutin improves the efficacy of azithromycin but not that of clarithromycin. Additionally, combination therapy has been associated with increased toxicity, resulting in more adverse events. While both azithromycin and clarithromycin are very effective, the once-weekly administration and fewer drug interactions offer an advantage to azithromycin prophylaxis over clarithromycin in most settings. Am J Med. 1997;102(5C):28-31. [C] 1997 by Excerpta Medica, Inc.

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As early and effective antiretroviral therapy has become more widespread, HIV has transitioned from a progressive, fatal disease to a chronic, manageable disease marked by elevated risk of chronic comorbid diseases, including cardiovascular diseases (CVDs). Rates of myocardial infarction, heart failure, stroke, and other CVD manifestations, including pulmonary hypertension and sudden cardiac death, are significantly higher for people living with HIV than for uninfected control subjects, even in the setting of HIV viral suppression with effective antiretroviral therapy. These elevated risks generally persist after demographic and clinical risk factors are accounted for and may be partly attributed to chronic inflammation and immune dysregulation. Data on long-term CVD outcomes in HIV are limited by the relatively recent epidemiological transition of HIV to a chronic disease. Therefore, our understanding of CVD pathogenesis, prevention, and treatment in HIV relies on large observational studies, randomized controlled trials of HIV therapies that are underpowered to detect CVD end points, and small interventional studies examining surrogate CVD end points. The purpose of this document is to provide a thorough review of the existing evidence on HIV-associated CVD, in particular atherosclerotic CVD (including myocardial infarction and stroke) and heart failure, as well as pragmatic recommendations on how to approach CVD prevention and treatment in HIV in the absence of large-scale randomized controlled trial data. This statement is intended for clinicians caring for people with HIV, individuals living with HIV, and clinical and translational researchers interested in HIV-associated CVD.

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Objective The contribution of hepatitis C virus (HCV) infection to the risk of heart failure in human immunodeficiency virus (HIV)-coinfected persons is unknown. The objective was to characterize cardiac function and morphology in HIV-treated coinfected persons.Methods In a cross-sectional study, HIV-infected patients virologically suppressed on antiretroviral therapy without known cardiovascular disease or diabetes mellitus underwent cardiac magnetic resonance imaging and spectroscopy for measures of cardiac function, myocardial fibrosis, and steatosis.Results The study included 18 male patients with a median age of 44 years. Of these, 10 had untreated HCV coinfection and eight had HIV monoinfection. Global systolic and diastolic function in the cohort were normal, and median myocardial fat content was 0.48% (interquartile range 0.35–1.54). Left ventricular (LV) mass index and LV mass/volume ratio were significantly greater in the HIV/HCV-coinfected group compared with the HIV-monoinfected group. In the HIV-monoinfected group, there was more myocardial fibrosis as measured by extracellular volume fraction.Conclusions There were differences between HIV/HCV-coinfected and HIV-monoinfected patients in cardiac structure and morphology. Larger studies are needed to examine whether HIV and HCV independently contribute to mechanisms of heart failure.

Background We examined whether waist circumference (WC) and self-reported abdominal size changes can estimate visceral adipose tissue (VAT) changes for those initiating antiretroviral therapy (ART).Methods Prospectively collected data from ACTG A5257 and its metabolic substudy, A5260s, were used for this analysis. ART-naive HIV-infected participants were randomized to one of three contemporary ART regimens. Changes in abdominal CT-measured VAT and total adipose tissue (TAT) and DXA-measured trunk fat were tested for association with WC changes (by Pearson correlation) and categories of self-reported abdominal size changes (by ANOVA) between entry and week 96. Linear models compared WC and self-reported changes.Results The study population (n=328) was predominantly male (90%) and White non-Hispanic (44%) with a baseline median age of 36 years and body mass index of 25 kg/m2. At week 96, median WC change was +2.8 cm. Of those reporting at week 96, 53% indicated ‘no change/lost’, 39% ‘gained some/somewhat larger’ and 8% ‘gained a lot/much larger’ as their self-reported changes. Trunk fat, VAT and TAT changes differed across self-reported groups (ANOVA P<0.0001 for all), and the group ordering was as expected. WC changes were strongly correlated with CT and DXA changes (trunk fat: ?=0.72, p<0.0001; VAT: ?=0.52, p<0.0001; TAT: ?=0.62, p<0.0001). While WC changes explained a greater proportion of VAT, TAT and trunk fat variation, self-reported changes remained a significant predictor after controlling for WC (p<0.05).Conclusions WC and self-reported abdominal changes each correlated directly with imaging-derived abdominal fat measures, and can be used as reliable, affordable tools for central adiposity assessment.

Background The role of oxidized lipoproteins (high-density [HDLox] and low-density [LDLox]) and total lipoprotein particle (Lp) number and size in HIV-related cardiovascular disease (CVD) is unclear. The goal of this study was to evaluate changes of these biomarkers and their associations with rate of carotid intima media thickness progression over 3 years (?CIMT) in chronic HIV infection.Methods Prospective study of 234 HIV-infected anti-retroviral treatment-naive participants without CVD who were randomized to receive tenofovir-emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir or raltegravir (RAL) and achieved plasma HIV-1 RNA <50 copies/ml by week 24 and thereafter. Biomarker changes over 24, 48 or 96 weeks from baseline and pairwise treatment group comparisons were examined. Associations of these bio-markers with dCIMT were analysed with mixed effects linear regression.Results HDLp number increased with both protease inhibitors (PIs) over 48 weeks, while LDLp number declined with RAL; Lp size did not change. Over 96 weeks, normalized HDLox declined with both PIs; LDLox increased in all groups. Few treatment group differences were observed across all biomarkers. Associations between ?CIMT and oxidized lipoproteins at all time points were not apparent (P=0.10). There was some evidence of slower ?CIMT for higher HDLp number (P=0.06) and for lower LDLp number (P=0.08) measured at baseline.Conclusions Unexpectedly, LDLox increased modestly in all treatment groups after ART initiation. Associations of plasma HDLox and LDLox with ?CIMT were not apparent. While plasma levels of abnormal lipoproteins have been shown to be associated with CVD outcomes, clear associations with sub-clinical atherosclerosis progression were not apparent in our study.

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(Abstracted from N Engl J Med2018;378:1593–1603)Three-drug antiretroviral therapy (ART) during pregnancy has reduced the risk of perinatal transmission of HIV to less than 1% and has become the global standard of care. The Promoting Maternal and Infant Survival Everywhere (PROMISE) trial recently found that pregnant women in multiple sites of sub-Saharan Africa and India receiving tenofovir, disoproxil fumarate, emtricitabine, and ritonavir-boosted lopinavir (TDF-FTC-LPV/r) were more than twice as likely to deliver very prematurely (<34 weeks of gestation), at very low birth weight (<1500 g), and were significantly more likely to have infants that died within 14 days after delivery compared with those assigned to receive zidovudine, lamivudine, and ritonavir-boosted lopinavir (ZDV-3TC-LPV/r).

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies (mAbs) are among the treatments recommended for high-risk ambulatory persons with coronavirus 2019 (COVID-19). Here, we study viral culture dynamics post-treatment in a subset of participants receiving the mAb bamlanivimab in the ACTIV-2 trial (ClinicalTrials.gov: NCT04518410). Viral load by qPCR and viral culture are performed from anterior nasal swabs collected on study days 0 (day of treatment), 1, 2, 3, and 7. Treatment with mAbs results in rapid clearance of culturable virus. One day after treatment, 0 of 28 (0%) participants receiving mAbs and 16 of 39 (41%) receiving placebo still have culturable virus (p < 0.0001). Recrudescence of culturable virus is detected in three participants with emerging mAb resistance and viral RNA rebound. While further studies are necessary to fully define the relationship between shed culturable virus and transmission, these results raise the possibility that mAbs may offer immediate (household) and public-health benefits by reducing onward transmission.

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To explore factors associated with short and long-term hepatitis B virus (HBV) DNA suppression in a multinational cohort of HIV–HBV co-infected patients receiving HBV-active antiretrovirals.

Background HIV is associated with atherosclerosis and low high-density lipoprotein (HDL). With inflammation, HDL becomes dysfunctional. We previously showed that proinflammatory HDL has high HDL redox activity (HRA). In this study, we compare HRA in HIV-infected versus non-HIV-infected subjects and relate HRA to indices of macrophage activation and cardiovascular disease risk.Methods 102 HIV-infected subjects and 41 matched non-HIV controls without clinical cardiovascular disease underwent coronary CT angiography (CTA) and testing for immune/inflammatory biomarkers. The effect of purified HDL from each study subject on the oxidation rate of dihydrorhodamine-123 (DOR) was normalized to the DOR of pooled HDL from healthy subjects. The normalized ratio DOR subject/DOR pooled was used as a measure of HRA, with higher HRA suggesting dysfunctional HDL.Results HRA was higher in HIV-infected versus non-HIV subjects (1.4 ±0.01 versus 1.3 ±0.01, P=0.03). In multivariate modelling for HRA among all subjects, HIV status remained positively related to HRA (P=0.02), even after controlling for traditional cardiovascular risk factors, comorbid conditions and immune activation. Among HIV-infected subjects, HRA correlated inversely with HDL (rho=-0.32, P=0.002) and log adiponectin (r=-0.28, P=0.006), and correlated positively with log sCD163 (r=0.24, P=0.02) – a monocyte/macrophage activation marker – and with the percentage of non-calcified coronary atherosclerotic plaque (r=0.29, P=0.03). sCD163 remained significantly associated with HRA in multivariate modelling among HIV-infected subjects (P=0.03).Conclusions These data demonstrate increased HRA among HIV-infected subjects versus matched non-HIV subjects with comparable HDL levels. In HIV-infected subjects, HRA relates to macrophage activation and to non-calcified coronary atherosclerotic plaque, which may be rupture-prone. Further studies are needed in HIV-infected patients to elucidate the interplay between immune activation, HDL function and CVD risk. Clinical trial registration number: NCT 00455793.

(Abstracted from N Engl J Med2016;375:1726–1737)Antiretroviral regimens used for the prevention of mother-to-child transmission of the human immunodeficiency virus (HIV) have evolved over the years. Combination antiretroviral therapy (ART) is currently used for prevention of mother-to-child transmission of HIV but has shown more adverse effects compared with regimens containing fewer antiretroviral agents.

The pathogenesis of atherosclerosis in human immunodeficiency virus (HIV)-infected individuals is incompletely understood and appears to be multifactorial. Proatherogenic changes in blood and tissue lipids are associated with an increased risk of cardiovascular disease among HIV-infected subjects, and these changes may be both quantitative (dyslipidemia) and qualitative. In view of the pivotal role of dyslipidemia in the process of atherosclerosis, the increased incidence of dyslipidemia in HIV-infected individuals, and the emerging role of lipid abnormalities in systemic pathophysiologic processes such as immune activation, we review the contributions of dyslipidemia to cardiovascular risk in HIV infection.

To evaluate associations between traditional cardiovascular disease (CVD) risk factors, inflammatory markers and markers of HIV disease activity with ultrasonographic measures of CVD risk in patients with HIV who are not receiving antiretroviral therapy (ART).

To understand the HIV–hepatitis B virus (HBV) epidemic from a global perspective by clinically and virologically characterizing these viruses at the time of antiretroviral therapy (ART) initiation in a multinational cohort.

The Gender, Race, and Clinical Experience (GRACE) study was designed to assess sex-based differences in darunavir/ ritonavir-based therapy and to enroll a female population representative of the racial demographics of women with human immunodeficiency virus (HIV)/AIDS in the United States. Here, we report week 48 results, stratified by race. GRACE was a multicenter, open-label, phase 3b study. Patients received 600 mg of darunavir and 100 mg of ritonavir twice daily plus an investigator-selected optimized background regimen. Virologic response (HIV-1 RNA <50 copies/ mL) and safety were assessed over 48 weeks. Post hoc multivariate analyses were performed to investigate factors associated with response. Of 429 patients enrolled, 61.5% were black, 22.4% were Hispanic, and 15.2% were white.

To estimate nevirapine (NVP) pharmacokinetics and examine its association with rash andor hepatotoxicity in women starting antiretroviral treatment in the AIDS Clinical Trials Group A5208OCTANE study in Africa.

Most current assays of HDL functional properties are cell-based. We have developed a fluorometric biochemical assay based on the oxidation of dihydrorhodamine 123 (DHR) by HDL. This cell-free assay assesses the intrinsic ability of HDL to be oxidized by measuring increasing fluorescence due to DHR oxidation over time. The assay distinguishes the oxidative potential of HDL taken from different persons, and the results are reproducible. Direct comparison of this measurement correlated well with results obtained using a validated cell-based assay (r2= 0.62, P < 0.001). The assay can be scaled from a 96-well format to a 384-well format and, therefore, is suitable for high-throughput implementation. This new fluorometric method offers an inexpensive, accurate, and rapid means for determining the oxidative properties of HDL that is applicable to large-scale clinical studies.

ABSTRACTHIV-1 protease inhibitors (PIs) have antimalarial activity in vitroand in murine models. The potential beneficial effect of HIV-1 PIs on malaria has not been studied in clinical settings. We used data from Adult AIDS Clinical Trials Group A5208 sites where malaria is endemic to compare the incidence of clinically diagnosed malaria among HIV-infected adult women randomized to either lopinavir/ritonavir (LPV/r)-based antiretroviral therapy (ART) or to nevirapine (NVP)-based ART. We calculated hazard ratios and 95% confidence intervals. We conducted a recurrent events analysis that included both first and second clinical malarial episodes and also conducted analyses to assess the sensitivity of results to outcome misclassification. Among the 445 women in this analysis, 137 (31%) received a clinical diagnosis of malaria at least once during follow-up. Of these 137, 72 (53%) were randomized to LPV/r-based ART. Assignment to the LPV/r treatment group (n= 226) was not consistent with a large decrease in the hazard of first clinical malarial episode (hazard ratio = 1.11 [0.79 to 1.56]). The results were similar in the recurrent events analysis. Sensitivity analyses indicated the results were robust to reasonable levels of outcome misclassification. In this study, the treatment with LPV/r compared to NVP had no apparent beneficial effect on the incidence of clinical malaria among HIV-infected adult women. Additional research concerning the effects of PI-based therapy on the incidence of malaria diagnosed by more specific criteria and among groups at a higher risk for severe disease is warranted.

Background Information is lacking on outcomes in HIV-infected Brazilian women with CD4+T-cell counts>200 cells/mm3who initiate HAART for the prevention of mother-to-child transmission, and discontinue after delivery.Methods Clinical event rates after postpartum HAART discontinuation were calculated for all WHO stage 2–3 events, as well as for HIV progression warranting HAART re-initiation, defined by a WHO stage 4 event and/or CD4+T-cell decrease to=200 cells/mm3. Predictors of the WHO stage 2–3 events and HIV progression outcomes were evaluated with Cox's proportional hazards models.Results A total of 120 women were followed for a mean of 1.5 years after delivery. Overall, 26 women had 30 events as follows: 20 developed WHO stage 2–3 events, yielding an incidence rate of 13/100 person-years (PY; 95% CI 8–20); 10 developed HIV progression requiring HAART re-initiation (incidence ratio 6/100 PY, 95% CI 3–11). Among progressors, a single woman developed a WHO stage 4 clinical event and the remainder had CD4+T-cell decreases. Women who had baseline CD4+T-cell counts between 200–500 cells/mm3had a hazard ratio for WHO stage 2–3 events of 2.5 compared to women with baseline=500 cells/mm3(95% CI 1.0–6.3; P=0.05). The only significant predictor of HIV progression was baseline CD4+T-cell count (hazard ratio 0.99, 95% CI 0.98–0.99; P=0.02).Conclusions In this observational study, a baseline CD4+T-cell count<500 cells/mm3was associated with an increased risk of postpartum WHO stage 2–3 clinical events and HIV disease progression. Randomized studies are needed to further evaluate the effect of postpartum treatment discontinuation on maternal health.

Two well-recognized patterns of calcification occur in large- and medium-sized arteries, intimal calcification associated with atherosclerosis and medial calcification described by Mönckeberg. Calcification limited to the internal elastic lamina is a third pattern of calcification not previously reported in coronary arteries. Here we describe 19 cases of coronary artery internal elastic lamina calcification. We serially sectioned and examined the coronary arteries of 66 patients with advanced AIDS and 27 HIV− controls with other chronic illnesses. We observed calcification of the internal elastic lamina in 10 HIV+ patients and 9 controls. HIV− patients with internal elastic lamina calcification were significantly older than HIV− patients without it (P=0.008) and HIV+ patients with it (P=0.006). Occasionally, calcification encroached on adjacent intimal or medial tissue with mild fibrosis. There was frequent disruption of the internal elastic lamina but no evidence of inflammation. Calcification was the dominant histologic feature in all cases. Von Kossa, Alizarin red, and trichrome/elastic stains confirmed these findings. Patients with internal elastic lamina calcification often had extensive medical histories but did not suffer from chronic renal failure or other conditions known to cause calcium dysregulation. We describe coronary internal elastic lamina calcification in HIV+ patients and older HIV− adults. The clinical significance of this finding is unknown. It could lead to arterial stiffening and increased pulse pressure and could be mistaken for intimal calcification on coronary imaging. Internal elastic lamina calcification may result from premature aging due to HIV disease and chronic illness or from metabolic disorders in HIV+ patients.

Antiretroviral (ARV) medications have been in clinical use for 20 years in the treatment of HIV and our knowledge about the safety of these medicines continues to grow. The potential side effects of ARVs can be either short term, such as hypersensitivity reactions, drug-induced hepatitis, anemia and lactic acidosis, or long term, including dyslipidemia, cardiovascular disease, lipoatrophy, lipohypertrophy and diabetes. In general, the safety profile of ARVs is improving as new combinations of medicines and newer medicines are introduced into clinical practice. However, it is crucial that vigilance be maintained in monitoring for side effects, particularly in resource-limited settings.

Worldwide, the rate of new HIV infections continues to increase among women. Over the past 5 years there has been a growing focus on the clinical aspects of HIV infection among women. Historically, the majority of subjects enrolled in HIV clinical trials were male patients. Consequently, most knowledge about antiretroviral efficacy and toxicity has been derived from studies of predominately male subjects. More recently, results from clinical trials, especially those that have focused on HIV-infected female subjects, suggest that there may be clinically important gender-related differences in several aspects of HIV disease. These include, but are not limited to, differences in natural history, efficacy and safety of drug treatment. This chapter reviews current data on gender differences in antiretroviral pharmacokinetics and toxicity.

Background Although adherence clearly influences response to antiretroviral therapy (ART), accurate assessment of adherence is problematic. The objective of this analysis was to assess the independent predictive value of protease inhibitor (PI) concentrations as a supplement to self-report as markers of medication adherence.Methods This retrospective analysis was conducted from a prospective clinical trial designed to compare the outcomes of frequent versus infrequent HIV RNA measurement used to manage antiretroviral therapy. For 131 patients, self-reported medication adherence, HIV RNA levels, CD4 counts and PI concentrations (unannounced, random samples) were measured at baseline (when patients changed to a new regimen) and every 2 months thereafter. The change in HIV RNA from baseline to month 6 (area-based measure) was used to evaluate overall response. The proportion of measured PI concentrations below the detection limit was used as an alternative marker of adherence. An undetectable concentration would be expected after missing a single dose.Results The mean baseline CD4 count was 125 cells/mm3and the mean HIV RNA level was 4.7 log10copies/ml. The mean change in log10HIV RNA was -0.73 copies/ml. The mean percentage of self-reported adherence was 91% (range: 15–100%) and the mean proportion of undetectable PI concentrations was 27% (range: 0–100%, mean 2.5 samples/patient). The correlation between the two measures was -0.23 (P=0.009). In a multivariate model, percentage of visits with undetectable PI concentrations (P=0.02), percentage of medication adherence (P=0.02), baseline HIV RNA level (P=0.005), prior PI use (P=0.0004), prior lamivudine (3TC) use (P=0.0009) and randomization to the frequent HIV RNA measurement group (P<0.0001) were all related to change in HIV RNA. After accounting for adherence, patients who always had detectable PI concentrations had an average of 0.4 log10additional HIV RNA reduction compared with those who had no detectable concentrations.Conclusions Repeated, random PI concentration values are independently predictive of virological response and may add to self-report of adherence in understanding the response to ART.

Objectives (1) To determine the efficacy and safety of nelfinavir versus placebo and abacavir versus other approved nucleoside reverse transcriptase inhibitors (NRTIs), in combination with efavirenz and adefovir dipovoxil, in subjects experiencing virological failure on an indinavir-containing regimen. (2) To determine the relationship of baseline viral drug resistance genotype and phenotype to virological outcome.Design and methods A prospective, randomized, controlled, multicentre study in non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive subjects conducted by the Adult AIDS Clinical Trials Group (ACTG 372B) and an open-label, single-arm, multicentre study in NNRTI-experienced subjects (ACTG 372D). Ninety-four subjects were randomized in ACTG 372B, which used a factorial design. All subjects received efavirenz and adefovir dipivoxil, and were randomly assigned to nelfinavir versus nelfinavir placebo and abacavir versus previously FDA-approved NRTIs. Twenty subjects received abacavir, efavirenz, adefovir dipivoxil and nelfinavir in ACTG 372D. Primary analysis time-point was at 16 weeks with follow-up through 48 weeks. Measures of efficacy were plasma HIV-1 RNA levels and CD4 cell counts. Adverse events were recorded according to ACTG criteria. Baseline reverse transcriptase and protease genotype, and drug susceptibility phenotype were determined. Resistance analyses were combined for ACTG 372B and D.Results At 16 weeks in ACTG 372B, 67% of subjects reached a primary study treatment failure end-point. In factorial analyses, nelfinavir was superior to nelfinavir placebo in rate of this failure end-point (56 vs 78%, P=0.02), but abacavir was not different from other NRTIs. No differences by nelfinavir or abacavir factor were noted at week 48. The failure end-point rate was significantly lower in those with baseline RNA levels=15000 copies/ml versus those with >15000 copies/ml (42 vs 79%, P<0.001). Higher genotypic and phenotypic sensitivity scores were significantly correlated with better virological responses (P=0.003 and 0.030, respectively). Conclusions: (1) Treatment responses were low in this trial of nelfinavir, abacavir, efavirenz and adefovir dipivoxil for subjects experiencing virological failure on an indinavir-containing regimen. (2) Subjects with plasma HIV-1 RNA levels=15000 copies/ml had a significantly better virological response than those with >15000 copies/ml at baseline. Switching at lower, rather than higher, viral load levels improved response rates in treatment-experienced subjects. (3) Summary measures of regimen sensitivity (such as, genotypic and phenotypic sensitivity scores) are useful in the evaluation of multidrug combination regimens.

ABSTRACTThis multicenter, randomized, dose-ranging study was performed to determine the safety and efficacy of two different doses of azithromycin for treating disseminated Mycobacterium aviumcomplex (MAC) in patients with AIDS. Eighty-eight AIDS patients with symptoms and blood cultures consistent with disseminated MAC were treated with 600 or 1,200 mg of azithromycin daily for 6 weeks; 62 patients completed the entire 6 weeks of study. Of note, this study was done prior to the time when combination antiretroviral or anti-MAC regimens were the standard of care. Over the 6-week study period, symptomatic improvement was noted in both dose groups. Microbiological responses were comparable, with mean decreases of 1.5 and 2.0 log CFU/ml in the high- and low-dose groups, respectively. Sterilization of blood cultures occurred in 54% of samples; patients with lower baseline colony counts were more likely to achieve culture negativity. Resistance developed in one patient. Gastrointestinal symptoms were the most common side effects and were more frequent in patients receiving 1,200 mg. Azithromycin is a useful alternative treatment for disseminated MAC infection in AIDS patients. Symptomatic improvement correlates with measurable decreases in mycobacterial load.

To assess the health values of patients infected with human immunodeficiency virus (HIV) and examine the relationships between their health values and health status at two points in time, the authors sought to determine whether patients' physical and mental health statuses were good predictors of how they valued their current state of health.

AbstractObjectives:To assess postoperative exposure to parenteral antibiotics and coded discharge diagnoses of infection as markers of nosocomial infection, postoperative morbidity, and potentially inappropriate antibiotic use after cesarean section.Design:Retrospective cohort study to compare automated markers with the criterion of record review.Setting:Tertiary care hospital.Patients:Women admitted to a large teaching hospital after April 15, 1987, and discharged before October 1, 1989, who underwent a nonrepeat, nonelective cesarean section and had received prophylaxis with a cephalosporin.Methods:Antibiotic exposure and discharge diagnosis codes were obtained from a large electronic hospital data base. A sample of charts was reviewed to determine the presence of infection, other postoperative complications, and postoperative antibiotic exposure.Results:A total of 2,197 women who had undergone a nonrepeat nonelective cesarean section were included in the study cohort. These women were assigned to 6 subgroups based on postoperative antibiotic exposure status and discharge codes suggesting endometritis, other postoperative infection, or no infection. Review of 457 records indicated that the overall infection rate was 9%. Eight percent of all the patients had a coded diagnosis for infection, and 16% received some parenteral antibiotics after the first postoperative day. Exposure to at least 2 days of parenteral postoperative antibiotics was the best marker by which to discriminate between infected and uninfected patients, with a sensitivity of 81 %, a specificity of 95%, and a positive predictive value of 61% for detecting infection. The corresponding figures for coded diagnoses for infection had rates of 65%, 97%, and 74%, respectively. The combination of discharge codes and exposure to parenteral postoperative antibiotics resulted in a more accurate but less sensitive marker for nosocomial infections, with a positive predictive value of 94% and a sensitivity of 59%. The groups with discordant parenteral postoperative antibiotics exposure and discharge codes for infection were enriched for errors in coding, noninfectious morbidity, and unexplained antibiotic use. Less than 1% of the entire cohort had ≥ 2 days of parenteral postoperative antibiotics without any reason apparent in the medical record.Conclusions:Parenteral postoperative antibiotic exposure determined from automated pharmacy records correlated with the results of the more labor-intensive manual review of medical records for the identification of nosocomial infection. In addition, information on antibiotic exposure combined with coded discharge diagnoses provided a rapid screen to identify subgroups of patients with higher rates of infectious and noninfectious morbidity, unexplained antibiotic use, and errors in discharge coding. Information derived from electronic data bases created for administrative purposes may be useful as a marker for infectious complications, inappropriate antibiotic prescribing, and other issues related to total quality hospital monitoring.

The patterns of use of perioperative antimicrobial prophylaxis were assessed in a randomly selected sample of short-stay hospitals in middle Tennessee. Overall, 438 procedures (48%) were associated with antimicrobial prophylaxis. Prophylaxis was more common in hospitals with more than 400 beds than in smaller hospitals. Moreover, prophylactic antibiotics were given more often for procedures with a proven indication for prophylaxis than for those without a proven indication (60% vs. 41%, P< .05); this relationship remained constant regardless of hospital size (common odds ratio, 2.09). However, prophylaxis for procedures with a proven indication was more likely to be given in teaching hospitals than in nonteaching hospitals (odds ratios, 5.41 vs. 1.94). The duration of prophylaxis was <2 days for 89% of procedures. A wide variety of agents were used. This study suggests that while improvements have been made over the past decade in decisions about the duration of prophylaxis, considerable variation remains in the selection of the procedures in which such treatment is administered and of the antimicrobial agents used.