Sleep disturbances in HIV-infected patients associated with depression and high risk of obstructive sleep apnea.

OBJECTIVE: To evaluate sleep disturbances in a diverse, contemporary HIV-positive patient cohort and to identify demographic, clinical, and immune correlates. METHODS: A convenience sample of 176 patients from a racially and ethnically diverse HIV-positive patient cohort in an urban population. This was a cross-sectional, epidemiologic study. We surveyed participants using multiple standardized instruments to assess depression, sleep quality, and risk for sleep apnea. We analyzed demographic, behavioral, and clinical correlates. RESULTS: A total of 56% of participants were female, 75% Black and 64% had heterosexual HIV risk. The median age was 49 years. Poor sleep quality (Pittsburgh Sleep Quality Index > 5) was reported by 73% of patients and 52% met insomnia diagnosis criteria. A single question about self-reported sleep problems predicted a Pittsburgh Sleep Quality Index > 5 with a sensitivity and specificity of 82% and 81%, respectively. Female sex was significantly associated with higher risk of poor sleep quality, depression, and insomnia, whereas higher risk of obstructive sleep apnea was significantly associated with older age, male sex, obesity (body mass index ⩾ 30 kg/m2), and metabolic comorbidities. High risk for obstructive sleep apnea, high rate of depression, and poor sleep hygiene represent treatment targets for sleep problems in HIV patients. CONCLUSION: Sleep disturbances were common in this patient cohort, although largely undiagnosed and untreated. Sleep problems are linked to worse disease progression and increased cardiovascular mortality. Screening for sleep problems with a single question had high sensitivity and specificity. In those patients with self-reported sleep problems, screening for obstructive sleep apnea, depression, and sleep hygiene habits should be part of routine HIV care.

Time spent with HIV viral load above 1500 copies/ml among patients in HIV care, 2000-2014.

OBJECTIVE: Sexual HIV transmission is more likely to occur when plasma HIV RNA level (viral load) exceeds 1500 copies/ml. We assessed the percentage of person-time spent with viral load above 1500 copies/ml (pPT >1500) among adults with HIV in care. DESIGN: Observational cohort in eight United States HIV clinics. METHODS: Participants had at least one HIV Outpatient Study (HOPS) clinic visit and at least two viral loads during 2000-2014. We assessed pPT above 1500 in time intervals between consecutive viral load pairs, overall and by ART status. Trends in pPT above 1500 and associations between pPT above 1500 and chosen baseline demographics and clinical characteristics were analyzed using generalized estimating equations. RESULTS: There were 5873 patients contributing 37 794 person-years; 86.0% person-years had prescribed ART, with increasing coverage over time. Over 2000-2014 pPT above 1500 was 24.2%, decreasing from 38.3% in 2000-2002 to 11.3% in 2012-2014. During observation time with ART prescribed, pPT above 1500 was 16.4% overall, decreasing from 29.9% in 2000-2002 to 8.0% in 2012-2014. pPT above 1500 was higher in patients less than 35 vs. at least 50 years old (31.5 vs. 15.6%), women vs. men (30.8 vs. 22.3%), and black vs. white and Latino/Hispanic patients (32.7 vs. 19.9 and 23.7%, respectively). Multivariable correlates of higher pPT above 1500 included no prescribed ART, being younger, non-Hispanic black vs. white, baseline viral load above 1500 copies/ml or lower CD4 count, and baseline public vs. private insurance. CONCLUSION: pPT above 1500 declined during 2000-2014. Results support decreasing HIV transmission risk from persons in HIV care over the last decade, and the need to focus interventions on patient groups more consistently viremic.

HIV-associated neurocognitive disorders: the relationship of HIV infection with physical and social comorbidities.

The prevalence of HIV (human immunodeficiency virus) associated neurocognitive disorders (HAND) will undoubtedly increase with the improved longevity of HIV-infected persons. HIV infection, itself, as well as multiple physiologic and psychosocial factors can contribute to cognitive impairment and neurologic complications. These comorbidities confound the diagnosis, assessment, and interventions for neurocognitive disorders. In this review, we discuss the role of several key comorbid factors that may contribute significantly to the development and progression of HIV-related neurocognitive impairment, as well as the current status of diagnostic strategies aimed at identifying HIV-infected individuals with impaired cognition and future research priorities and challenges.

Cardiovascular disease in patients with chronic human immunodeficiency virus infection.

In 2012, the United Nations estimated that globally, 34 million people were living with human immunodeficiency virus (HIV) infection at the end of 2011. About 6.5% of AIDS-related mortality is attributable to cardiovascular disease. HIV related cardiovascular disease is diverse. In this review we explore the different disease states associated with HIV such as cardiomyopathy, coronary artery disease, dyslipidemia, electrocardiographic abnormalities, prolonged QT interval and sudden death. The pathophysiology of these numerous diseases is complex and multifactorial. Current management of these patients is challenging due to multiple drug-drug interactions and side effects. However, the approach to prevention is quite familiar, taking on the same rules that apply for any patient to minimize cardiovascular disease risk. The challenges are many, therefore for HIV patients who present after a cardiovascular event, or for prevention of cardiovascular disease, the concept of a heart team is essential, where cardiovascular specialists and the HIV care team work side by side to ensure safety of medications (avoid drug interactions) and to institute a goal directed prevention plan of care.

Retention in care within 1 year of initial HIV care visit in a multisite US cohort: who's in and who's out?

Biannual attendance at medical visits is an established measure of retention in HIV care. We examined factors associated with attending at least 2 clinic visits at least 90 days apart among HIV-infected, antiretroviral therapy (ART)-naive HIV Outpatient Study participants entering care during 2000 to 2011. Of 1441 patients, 85% were retained in care during the first year of observation. Starting ART during the year was the strongest correlate of retention (adjusted odds ratio [aOR] 6.4, 95% confidence interval [CI] 4.4-9.4). After adjusting for starting ART, publicly insured patients (aOR 0.6, 95% CI 0.4-1.0), and patients with baseline CD4 counts <200 cells/mm(3) (aOR 0.5, 95% CI 0.3-0.9) or missing CD4 counts (aOR 0.3, 95% CI 0.2-0.6) were less likely to be retained in care. Although most patients had recommended biannual care visits, some ART-naive individuals may require additional interventions to remain in care. Promptly initiating ART may facilitate engagement in care.

Sadness in the SUN: using computerized screening to analyze correlates of depression and adherence in HIV-infected adults in the United States.

We used a standardized screening tool to examine frequency of depression and its relation to antiretroviral medication adherence among HIV-infected persons on highly active antiretroviral therapy (HAART) in the Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy (SUN Study). This is a prospective observational cohort of 700 HIV-infected patients enrolled between March 2004 and June 2006 in four U.S. cities, who completed a confidential audio computer-assisted self-interview [ACASI] with behavioral risk and health-related questions at baseline and 6-month follow-up visits, including the nine-question PRIME-MD depression screener and a validated 3-day antiretroviral adherence question. Among 539 eligible participants receiving HAART, 14% had depression at baseline (22% women, 12% men). In multivariable analysis using generalized estimating equations (GEE) to account for repeated measurements through 24 months of follow-up, persons who reported depression on a given ACASI were twice as likely to report nonadherence to antiretrovirals on the same ACASI (Odds ratio [OR] 2.02, 95% CI: 1.15, 3.57] for mild/moderate depression versus none); such persons were also less likely to have HIV viral load<400 copies/mL. Self-administered computerized standardized screening tools can identify at-risk individuals with depression who may benefit from interventions to improve antiretroviral adherence.

HIV and hepatitis in an urban penetrating trauma population: unrecognized and untreated.

BACKGROUND: Despite limited prospective data, it is commonly believed that human immunodeficiency virus (HIV) and hepatitis infections are widespread in the penetrating trauma population, placing healthcare workers at risk for occupational exposure. Our primary study objective was to measure the prevalence of HIV (anti-HIV), hepatitis B (HB surface antigen [HBsAg]), and hepatitis C virus (anti-HCV) in our penetrating trauma population. METHODS: We prospectively analyzed penetrating trauma patients admitted to Temple University Hospital between August 2008 and February 2010. Patients (n = 341) were tested with an oral swab for anti-HIV and serum evaluated for HBsAg and anti-HCV. Positives were confirmed with western blot, neutralization immunoassay, and reverse transcription polymerase chain reaction, respectively. Demographics, risk factors, and clinical characteristics were analyzed. RESULTS: Of 341 patients, 4 patients (1.2%) tested positive for anti-HIV and 2 had a positive HBsAg (0.6%). Hepatitis C was the most prevalent measured infection as anti-HCV was detected in 26 (7.6%) patients. Overall, 32 (9.4%) patients were tested positive for anti-HIV, HBsAg, or anti-HCV. Twenty-eight (75%) of these patients who tested positive were undiagnosed before study enrollment. When potential risk factors were analyzed, age (odds ratio, 1.07, p = 0.031) and intravenous drug use (odds ratio 14.4, p < 0.001) independently increased the likelihood of anti-HIV, HBsAg, or anti-HCV-positive markers. CONCLUSIONS: Greater than 9% of our penetrating trauma study population tested positive for anti-HIV, HBsAg, or anti-HCV although patients were infrequently aware of their seropositive status. As penetrating trauma victims frequently require expedient, invasive procedures, universal precautions are essential. The prevalence of undiagnosed HIV and hepatitis in penetrating trauma victims provides an important opportunity for education, screening, and earlier treatment of this high-risk population.

Increased mortality among publicly insured participants in the HIV Outpatient Study despite HAART treatment.

OBJECTIVE: Understanding mortality differences among HIV-infected patients can focus efforts to improve survival. DESIGN: We evaluated death rates, causes, and associated factors among treated patients in the HIV Outpatient Study (HOPS), a large, prospective, multicenter observational cohort of HIV-infected persons seen at a diverse set of US sites of care. METHODS: Among 3754 HOPS participants seen during 1996-2007 with at least 6 months of follow-up after initiating HAART and receiving HAART at least 75% of time under observation ('substantially treated'), we calculated hazard ratios for death using proportional hazards regression models. We also examined death causes and comorbidities among decedents. RESULTS: Substantially treated participants, followed a median 4.7 years (interquartile range, 2.2-8.5), experienced 331 deaths. In multivariable analyses, higher mortality was associated with an index CD4 cell count less than 200 cells/µl [adjusted hazard ratio (aHR), 2.86; 95% confidence interval (CI) 1.95-4.21], older age (aHR, 1.50 per 10 years; 95% CI 1.33-1.70), log(10)HIV RNA (aHR, 1.67 per log(10); 95% CI 1.51-1.85), but not race/ethnicity (aHR, 0.99 for blacks vs. whites, P = 0.92). Mortality was increased among publicly insured (PUB) vs. privately insured participants (PRV) when index CD4 cell count was at least 200 cells/µl (aHR, 2.03; 95% CI 1.32-3.14) but not when index CD4 cell count was less than 200 cells/µl (aHR, 1.3, P = 0.13). By death cause, PUB had significantly more cardiovascular events and hepatic disorders than PRV. Comorbidities more frequent among PUB vs. PRV decedents included cardiovascular disease, renal impairment, and chronic hepatitis. CONCLUSION: Among HAART-treated participants with CD4 cell counts at least 200 cells/µl, PUB experienced higher death rates than PRV. Non-AIDS death and disease causes predominated among publicly insured decedents, suggesting that treatable comorbidities contributed to survival disparities.

Emerging therapies for hepatitis C and HIV in drug abusers: drugs and strategies.

New drug therapies to treat hepatitis C (HCV) and HIV infection are being developed with improved understanding of the molecular structures of the viruses themselves, the pathogenesis of infection and the specific immune responses needed to eradicate or control these infections. Interferon and ribavirin based therapies will continue to be a component of HCV therapy for the near future combined with other novel compounds directed at targets of viral replication, immunomodulation or cell entry. The goals of anti-HCV therapy are viral eradication for differing genotypes and prevention of hepatic morbidity such as hepatocellular carcinoma and cirrhosis. Future antiretroviral therapies for HIV will include agents that focus on new classes of inhibitors of viral replication and cell binding. The new treatment choices in HIV will need to ensure effective and durable viral suppression especially against highly resistant virus strains, regimen tolerability and improved toxicity.

Ezetimibe combined with low-dose statin effectively lowers LDL in protease inhibitor treated patients.

Ezetimibe (EZB) lowers cholesterol by blocking cholesterol absorption in the intestine. Data with EZB are limited in HIV-infected patients. We enrolled HIV-infected adults in this prospective, noncontrolled, single-center pilot study if their low-density lipoprotein (LDL) was not at goal despite therapy with a statin. Stable protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) and a low-dose statin were required for inclusion. The primary endpoint was LDL reduction at 18 weeks. In a subgroup of patients on lopinavir/ritonavir (LPV/r), trough concentrations were obtained before and after addition of EZB. Twenty patients were enrolled; 12 (60%) men, 18 (90%) African American. HAART included ritonavir (RTV)-boosted PIs in 17 (85%) patients; 3 (15%) were on nelfinavir. Mean percent changes from baseline in LDL were -10.9%, -12.2%, and -12.4% at weeks 6, 12, and 18, respectively (p < 0.05 for each time period vs. baseline). Mean percent changes from baseline in total cholesterol (TC) were -11.1%, -9.6%, and 9.1% at weeks 6, 12, and 18, respectively (p < 0.05 at each time period vs. baseline). No significant changes in triglycerides, high-density lipoprotein, and LPV/r concentrations were seen. One patient experienced elevated creatine phosphokinase possibly related to study medication; no other adverse effects were seen. Addition of EZB to low-dose statin effectively lowers LDL and TC and appears to be safe and well tolerated.

CD163/CD16 coexpression by circulating monocytes/macrophages in HIV: potential biomarkers for HIV infection and AIDS progression.

Monocytes and macrophages play a prominent role in the establishment of HIV-1 infection, virus dissemination, and development of viral reservoirs. Like T cells, macrophages display immune polarization that can promote or impair adaptive immunity. We hypothesize that dysregulation of monocyte/macrophage activation and differentiation may promote immune dysfunction and contribute to AIDS pathogenesis. Using flow cytometry, we analyzed the frequency of monocyte subsets in human immunodeficiency virus type 1 (HIV-1) infection relative to seronegative controls, focusing on the CD163(+)/CD16(+) monocyte as a likely precursor of the "alternatively activated" macrophage. Individuals with detectable HIV-1 infection showed an increase in the frequency of CD163(+)/CD16(+) monocytes (CD14(+)) when compared to seronegative or HIV-1-infected persons with undetectable viral loads. A positive correlation between increased CD163(+)/CD16(+) monocyte frequency and viral load was revealed that was not seen between viral load and the number of CD4(+) T cells or frequency of CD16(+) monocytes (without CD163 subtyping). We also found a strong inverse correlations between CD16(+) monocytes (r = -0.71, r(2) = 0.5041, p = 0.0097) or CD163(+)/CD16(+) monocytes (r = -0.86, r(2) = 0.7396, p = 0.0003) and number of CD4(+) T cells below 450 cells/microl. An inverse relationship between CD163(+)/CD16(+) and CD163(+)/CD16() monocytes suggests the expanded CD163(+)/CD16(+) population is derived exclusively from within the "alternatively activated" (MPhi-2) subset. These data suggest a potential role for CD163(+)/CD16(+) monocytes in virus production and disease progression. CD163(+)/CD16(+) monocytes may be a useful biomarker for HIV-1 infection and AIDS progression and a possible target for therapeutic intervention.

Ethnicity, race, and gender. Differences in serious adverse events among participants in an antiretroviral initiation trial: results of CPCRA 058 (FIRST Study).

BACKGROUND: Differences in adverse events by gender and race/ethnicity have not been described extensively in randomized clinical trials of HIV antiretroviral therapy (ART). METHODS: Antiretroviral-naive HIV-infected participants enrolled in a long-term randomized clinical trial of 3 different initial ART strategies -- protease inhibitor (PI), nonnucleoside reverse transcriptase inhibitor (NNRTI), or PI plus NNRTI-based combinations -- with a median follow-up of 5 years, were compared by gender and race for 14 categories of grade 4 adverse events, discontinuation of initial antiretroviral regimen, and all-cause mortality. Multivariate analysis was used to identify predictors of events and death. RESULTS: Among 1301 participants with complete data, there were 701 blacks, 225 Latinos, and 263 women. Several baseline characteristics differed by gender and race, including age, HIV transmission risk, hepatitis B or C coinfection, viral load, diagnosis of AIDS, body mass index, and baseline hypertension. Grade 4 events occurred in 409 participants (rate: 8.9/100 person-years). There were 176 deaths (rate: 3.0/100 person-years) and 523 discontinuations of regimen for any toxicity (rate: 13/100 person-years). In the fully adjusted regressions, blacks had greater risk for cardiovascular (hazard ratio [HR] = 2.64, 95% confidence interval [CI]: 1.04 to 6.67) and renal (HR = 3.83, 95% CI: 1.28 to 11.5) events. Black men had more psychiatric events (HR = 2.45, 95% CI: 1.13 to 5.30). Women had a higher risk for anemia (HR = 2.34, 95% CI: 1.09 to 4.99). CONCLUSION: Among HIV-infected participants initiating ART, there were significant risk-adjusted differences for specific adverse events by gender and race but not in the overall adverse event rates, all-cause mortality, or rates of toxicity-related treatment discontinuations.

Increased body mass index does not alter response to initial highly active antiretroviral therapy in HIV-1-infected patients.

BACKGROUND: Body mass index (BMI) can influence drug metabolism, thus affecting efficacy and risk for toxicities. Hypothesizing that persons with an increased BMI and larger volumes of distribution may experience a suboptimal response to highly active antiretroviral therapy (HAART), we evaluated the effect of BMI on virologic and immunologic response in previously ART-naive patients initiating therapy. METHODS: Using data from the HIV Outpatient Study, we analyzed the statistical association of BMI and other selected demographic variables with achieving an undetectable viral load and experiencing a CD4 cell count increase of more than 100 cell/microL after 3 to 9 months of therapy among antiretroviral-naive patients initiating HAART. RESULTS: Among 711 patients included in analysis, 43% had a BMI of more than 25 (overweight-obese). Higher BMI was associated with being female, having black or Hispanic race/ethnicity, being heterosexual, and using injection drugs (all P<0.001). The patients in BMI groups did not differ significantly by baseline CD4 cell count or the duration of the initial HAART regimen. Although median baseline viral loads were significantly lower in obese participants (P=0.008), overweight or obese BMI did not significantly alter the likelihood of achieving an undetectable viral load and a CD4 cell count increase of more than 100 cells/microL compared with normal weight persons. CONCLUSION: A substantial proportion of HIV-infected outpatients in this cohort were overweight or obese. Increased BMI was not associated with decreased virologic and immunologic responses to initial HAART. Responses were equivalent and within expected ranges between normal weight patients, overweight patients, and obese patients at 3 to 9 months of observation.

New drug targets for HIV and hepatitis C virus coinfection.

Current interferon (IFN)-based therapies for hepatitis C in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) may be limited by incomplete virological response, lack of adherence, and poor tolerability. Newer therapies for hepatitis C will target viral replication (e.g., HCV serine protease inhibitors, helicase inhibitors, RNA interference, or an HCV polymerase inhibitor). Other treatments will focus on viral translation (e.g., antisense molecules). Additions to IFN therapy that can modulate the immune response (e.g., thymosin, isatorbine, or injectable histamine) may improve tolerability of treatment. There need to be targets that minimize the inflammatory response by the liver (e.g., IFN-gamma). There are some therapeutic vaccines in early development. Drugs to replace or enhance ribavirin are being studied with IFN-based treatments. Strategic treatment trials that address sequencing of HCV and HIV therapy with current and future therapeutic agents and combination therapy need to be undertaken.

Hepatitis A and B vaccination practices for ambulatory patients infected with HIV.

Few studies exist of adherence to guidelines for vaccination of persons infected with human immunodeficiency virus (HIV), especially in the era of highly active antiretroviral therapy (HAART). In a retrospective, cross-sectional analysis in the HIV Outpatient Study sites, 198 (32.4%) of 612 patients eligible for hepatitis B vaccine received at least 1 dose. In multivariate analysis, hepatitis B vaccination was associated with HIV risk category, education level, and number of visits to the HIV clinic per year. Among 716 patients eligible for hepatitis A vaccine, 167 (23.3%) received > or =1 dose. Response to hepatitis B vaccination was associated with higher nadir CD4+ cell counts (P=.008) and HIV RNA levels less than the level of detection (P=.04), although some response was documented at all CD4+ levels. Although there were low rates of complete hepatitis vaccination in this cohort of ambulatory patients, prompt efforts to vaccinate patients entering care, receipt of antiretroviral therapy, and practice reminder systems may enhance vaccination practices.

Grade 4 events are as important as AIDS events in the era of HAART.

OBJECTIVE: To estimate incidence and predictors of serious or life-threatening events that are not AIDS defining, AIDS events, and death among patients treated with highly active antiretroviral therapy (HAART) in the setting of 5 large multicenter randomized treatment trials conducted in the United States. METHODS: Data were analyzed from 2,947 patients enrolled from December 1996 through December 2001. All patients were to receive antiretrovirals throughout follow-up. Data collection was uniform for all main outcome measures: serious or life-threatening (grade 4) events, AIDS, and death. RESULTS: During follow-up, 675 patients experienced a grade 4 event (11.4 per 100 person-years); 332 developed an AIDS event (5.6 per 100 person-years); and 272 died (4.6 per 100 person-years). The most common grade 4 events were liver related (148 patients, 2.6 per 100 person-years). Cardiovascular events were associated with the greatest risk of death (hazard ratio = 8.64; 95% CI: 5.1 to 14.5). The first grade 4 event and the first AIDS event were associated with similar risks of death, 5.68 and 6.95, respectively. CONCLUSIONS: Grade 4 events are as important as AIDS events in the era of HAART. To adequately evaluate the impact of HAART on morbidity, comorbidities and other key factors must be carefully assessed.

Prevalence and characteristics of hepatitis C virus coinfection in a human immunodeficiency virus clinical trials group: the Terry Beirn Community Programs for Clinical Research on AIDS.

The baseline prevalence of hepatitis C virus (HCV) and human immunodeficiency virus (HIV) coinfection among 2705 patients enrolled in HIV clinical trials in the Community Programs for Clinical Research on AIDS (CPCRA) was 16.6%. For men, multivariate logistic regression showed that the baseline prevalence of HIV-HCV coinfection was positively associated with history of injection drug use, older age, antiretroviral therapy naive status, African American or Latino ethnicity, and no history of having sex with men. No association was found with baseline CD4+ cell count or HIV RNA level. The prevalence of HCV coinfection in a diverse HIV clinical trials cohort provides additional information about risk behaviors and demographic factors that can be used in the analysis of clinical and virologic outcomes.

Influence of coinfection with hepatitis C virus on morbidity and mortality due to human immunodeficiency virus infection in the era of highly active antiretroviral therapy.

To ascertain the impact of hepatitis C virus (HCV) infection on human immunodeficiency virus (HIV) disease progression and associated death in the era of highly active antiretroviral therapy (HAART), we examined mortality rates, the presence of other diseases, and antiretroviral use in an observational cohort of 823 HIV-infected patients with and without HCV coinfection during the period of January 1996 through June 2001. Analyses were used to compare patient characteristics, comorbid conditions, and survival durations in HIV-infected and HIV-HCV-coinfected patients. HIV-HCV-coinfected persons did not have a statistically greater rate of acquired immunodeficiency syndrome or of renal or cardiovascular disease, but they did have more cases of cirrhosis and transaminase elevations. There were proportionately more deaths in the HIV-HCV-coinfected group. Age, baseline CD4+ cell count, and duration of HAART were significantly associated with survival, but HCV infection was not. HAART use was a strong predictor of increased duration of survival, suggesting that treatment is more important to survival than is HCV coinfection status.