Prevalence, Incidence, and Clearance of Human Papillomavirus Types Covered by Current Vaccines in Men With Human Immunodeficiency Virus in the SUN Study.

BACKGROUND: High-risk anal human papillomavirus (HPV) infection is prevalent among men living with human immunodeficiency virus (HIV); the association between 9-valent (9v) high-risk HPV (HR-HPV) vaccine types and abnormal cytology has not been well characterized. METHODS: We followed a prospective cohort study of persons with HIV at 7 HIV clinics in 4 US cities from March 2004 through June 2012. Annually, providers collected separate anal swabs for HPV detection and cytopathologic examination. Among men, we examined prevalence, incidence, and clearance of 9v HR-HPV vaccine types, compared with other HR types, and associations with abnormal cytology to assess potential vaccine impact. RESULTS: Baseline prevalence of any anal 9v HR-HPV type among men who have sex with men (MSM) and men who have sex with women (MSW) was 74% and 25% (P < .001), respectively. Among 299 MSM, abnormal cytology was detected in 161 (54%) MSM and was associated with the presence of any 9v HR-HPV (relative risk [RR], 1.8 [95% confidence interval {CI}, 1.3-2.6]; P < .001). Among 61 MSW, abnormal anal cytology was detected in 12 (20%) and was associated with the presence of any 9v HR-HPV (RR, 4.3 [95% CI, 1.6-11.5]; P < .001). CONCLUSIONS: Among men with HIV, the prevalence of the 7 HR-HPV types in the 9v vaccine was high and was associated with abnormal cytology. These findings indicate that men with HIV could benefit from prophylactic administration of the 9v HPV vaccine.

The Effect of Interrupted/Deferred Antiretroviral Therapy on Disease Risk: A SMART and START Combined Analysis.

Background: Pooled data from the SMART and START trials were used to compare deferred/intermittent versus immediate/continuous antiretroviral therapy (ART) on disease risk. Methods: Endpoints assessed were AIDS, serious non-AIDS (SNA), cardiovascular disease (CVD), cancer, and death. Pooled (stratified by study) hazard ratios (HRs) from Cox models were obtained for deferred/intermittent ART versus immediate/continuous ART; analyses were conducted to assess consistency of HRs across baseline-defined subgroups. Results: Among 10156 participants, there were 124 AIDS, 247 SNA, 117 cancers, 103 CVD, and 120 deaths. Interventions in each trial led to similar differences in CD4 count and viral suppression. Pooled HRs (95% confidence interval) of deferred/intermittent ART versus immediate/continuous ART were for AIDS 3.63 (2.37-5.56); SNA 1.62 (1.25-2.09); CVD 1.59 (1.07-2.37); cancer 1.93 (1.32-2.83); and death 1.80 (1.24-2.61). Underlying risk was greater in SMART than START. Given the similar HRs for each trial, absolute risk differences between treatment groups were greater in SMART than START. Pooled HRs were similar across subgroups. Conclusions: Treatment group differences in CD4 count and viral suppression were similar in SMART and START. Likely as a consequence, relative differences in risk of AIDS and SNA between immediate/continuous ART and deferred/intermittent ART were similar. Clinical Trials Registration: NCT00027352 and NCT00867048.

HIV Protease-Generated Casp8p41, When Bound and Inactivated by Bcl2, Is Degraded by the Proteasome.

HIV protease is known to cause cell death, which is dependent upon cleavage of procaspase 8. HIV protease cleavage of procaspase 8 generates Casp8p41, which directly binds Bak with nanomolar affinity, causing Bak activation and consequent cell death. Casp8p41 can also bind Bcl2 with nanomolar affinity, in which case cell death is averted. Central memory CD4 T cells express high levels of Bcl2, possibly explaining why those cells do not die when they reactivate HIV. Here, we determine that the Casp8p41-Bcl2 complex is polyubiquitinated and degraded by the proteasome. Ixazomib, a proteasome inhibitor in clinical use, blocks this pathway, increasing the abundance of Casp8p41 and causing more cells to die in a Casp8p41-dependent manner.IMPORTANCE The Casp8p41 pathway of cell death is unique to HIV-infected cells yet is blocked by Bcl2. Once bound by Bcl2, Casp8p41 is polyubiquitinated and degraded by the proteasome. Proteasome inhibition blocks degradation of Casp8p41, increasing Casp8p41 levels and causing more HIV-infected cells to die.

Prevalence and Incidence of Anal and Cervical High-Risk Human Papillomavirus (HPV) Types Covered by Current HPV Vaccines Among HIV-Infected Women in the SUN Study.

Background: Nonavalent (9v) human papilloma virus vaccine targets high-risk human papillomavirus (HR-HPV) types 16, 18, 31, 33, 45, 52, 58, and low-risk 6, 11. We examined prevalence, incidence, and clearance of anal and cervical HR-HPV in HIV-infected women. Methods: The SUN Study enrolled 167 US women in 2004-2006. Anal and cervical specimens were collected annually for cytology and identification of 37 HPV types: 14 HR included: 9v 16, 18, 31, 33, 45, 52, 58; non-9v 35, 39, 51, 56, 59, 66, 68. Results: Baseline characteristics of 126 women included: median age 38 years; 57% non-Hispanic black; 67% HIV RNA < 400 copies/mL; 90% CD4 counts ≥200 cells/mm3. HPV prevalence at anus and cervix was 90% and 83%; for 9v HR-HPV types, 67% and 51%; non-9v HR-HPV, 54% and 29%, respectively. The 9v and non-9v HR-HPV incidence rates/100 person-years were similar (10.4 vs 9.5; 8.5 vs 8.3, respectively); 9v clearance rates were 42% and 61%; non-9v 46% and 59%, in anus and cervix, respectively. Conclusions: Anal HR-HPV prevalence was higher than cervical, with lower clearance; incidence was similar. Although prevalence of non-9v HR-HPV was substantial, 9v HR-HPV types were generally more prevalent. These findings support use of nonavalent vaccine in HIV-infected women.

Prevalence, Incidence, and Clearance of Anal High-Risk Human Papillomavirus Infection Among HIV-Infected Men in the SUN Study.

Background: The natural history of anal human papilloma virus (HPV) infection among human immunodeficiency virus (HIV)-infected men is unknown. Methods: Annually, from 2004 to 2012, we examined baseline prevalence, incidence, and clearance of anal HPV infection at 48 months, and associated factors among HIV-infected men. Results: We examined 403 men who have sex with men (MSM) and 96 men who have sex with women (MSW) (median age 42 years for both, 78% versus 81% prescribed cART, median CD4+ T-lymphocyte cell count 454 versus 379 cells/mm3, and 74% versus 75% had undetectable viral load, respectively). Type 16 prevalence among MSM and MSW was 38% versus 14% (P < .001), and incidence 24% versus 7% (P = .001). Type 18 prevalence was 24% versus 8% (P < .001), and incidence 13% versus 4% (P = .027). Among MSM and MSW, clearance of prevalent HPV 16 and HPV 18 was 31% and 60% (P = .392), and 47% and 25% (P = .297), respectively. Among MSM, receptive anal sex (with or without a condom) was associated with persistent HPV 16 (OR 2.24, P < .001). Conclusions: MSM had higher prevalence and incidence of HPV than MSW, but similar clearance. Receptive anal sex may predict cancer risk among HIV-infected MSM.

Immediate Antiretroviral Therapy Reduces Risk of Infection-Related Cancer During Early HIV Infection.

BACKGROUND: In the Strategic Timing of Antiretroviral Treatment (START) study, immediate combination antiretroviral therapy (cART) initiation reduced cancer risk by 64%. We hypothesized that risk reduction was higher for infection-related cancer and determined by differences in CD4 cell counts and human immunodeficiency virus (HIV) RNA between the study arms. METHODS: Incident malignancies in START were categorized into infection-related and infection-unrelated cancer. We used Cox models to assess factors associated with both cancer categories. We used sequential adjustment for baseline covariates, cancer risk factors, and HIV-specific variables to investigate potential mediators of cancer risk reduction with immediate cART. RESULTS: There were 14 cancers among persons randomized to immediate cART (6 infection-related and 8 infection-unrelated) and 39 cancers in the deferred arm (23 infection-related and 16 infection-unrelated); hazard ratios of immediate vs deferred cART initiation were 0.26 (95% confidence interval [CI], .11-.64) for infection-related and 0.49 (95% CI, .21-1.15) for infection-unrelated cancer. Independent predictors of infection-related cancer were older age, higher body mass index, low- to middle-income region, HIV RNA, and baseline CD8 cell count. Older age and baseline CD8 cell count were independent predictors of infection-unrelated cancer. Adjustment for latest HIV RNA level had little impact on the protective effect of immediate cART on infection-related cancer. Adjustment for latest HIV RNA level, but not for CD4 cell count or cancer risk factors, attenuated the effect of immediate cART on infection-unrelated cancer. CONCLUSIONS: Immediate cART initiation significantly reduces risk of cancer. Although limited by small sample size, this benefit does not appear to be solely attributable to HIV RNA suppression and may be also mediated by other mechanisms.

High Prevalence of Low Bone Mineral Density and Substantial Bone Loss over 4 Years Among HIV-Infected Persons in the Era of Modern Antiretroviral Therapy.

HIV-infected persons are living longer on combination antiretroviral therapy (cART) but experiencing more comorbidities including low bone mineral density (BMD). Using data from the Study to Understand the Natural History of HIV and AIDS in the Era of Effective Therapy (SUN Study), we determined the prevalence of low BMD (T-score below one standard deviation of the reference mean) and compared it with matched controls from the National Health and Nutrition Examination Survey (NHANES). We also assessed 4-year longitudinal BMD changes among participants virologically suppressed on cART. Of 653 participants included in this analysis (77% male, 29% black, median age 41 years, median CD4(+) cell count 464 cells/mm(3), 89% with HIV RNA <400 copies/ml), 51% and 10% had baseline osteopenia and osteoporosis, respectively. Low BMD at the femoral neck was significantly more prevalent than for the NHANES controls (47% versus 29%, p<0.001). Lower body mass index, nonwhite race, longer tenofovir exposure, older age, being unemployed or retired, and lower apolipoprotein E were independently associated with baseline osteoporosis. Among 170 participants virologically suppressed on cART and with longitudinal BMD data, 31% experienced substantial bone loss (≥5% BMD decline from baseline) over 4 years. Female sex, current smoking, and longer stavudine use were more common among participants who had substantial bone loss, although these variables failed to reach statistical significance. Low BMD was highly prevalent among HIV-infected persons. One-third of participants experienced substantial bone loss despite cART, suggesting the need for monitoring and potential clinical interventions.

Incidence and Predictors of Abnormal Anal Cytology Findings Among HIV-Infected Adults Receiving Contemporary Antiretroviral Therapy.

BACKGROUND: Anal cancer rates are higher for human immunodeficiency virus (HIV)-infected adults than for uninfected adults. Limited published data exist characterizing the incidence of precursor lesions detected by anal cytology. METHODS: The Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy was a prospective cohort of 700 HIV-infected participants in 4 US cities. At baseline and annually thereafter, each participant completed a behavioral questionnaire, and healthcare professionals collected anorectal swabs for cytologic examination and human papillomavirus (HPV) detection and genotyping. RESULTS: Among 243 participants with negative baseline results of anal cytology, 37% developed abnormal cytology findings (incidence rate, 13.9 cases/100 person-years of follow-up; 95% confidence interval [CI], 11.3-16.9) over a median follow-up duration of 2.1 years. Rates among men having sex with men, among women, and among men having sex with women were 17.9 cases/person-years of follow-up (95% CI, 13.9-22.7), 9.4 cases/person-years of follow-up (95% CI, 5.6-14.9), and 8.9 cases/person-years of follow-up (95% CI, 4.8-15.6), respectively. In multivariable analysis, the number of persistent high-risk HPV types (adjusted hazard ratio [aHR], 1.17; 95% CI, 1.01-1.36), persistent high-risk HPV types except 16 or 18 (aHR, 2.46; 95% CI, 1.31-4.60), and persistent types 16 or 18 (aHR, 3.90; 95% CI, 1.78-8.54) remained associated with incident abnormalities. CONCLUSIONS: The incidence of abnormal anal cytology findings was high and more likely to develop among persons with persistent high-risk HPV.

Switching to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of non-nucleoside reverse transcriptase inhibitor with emtricitabine and tenofovir in virologically suppressed adults with HIV (STRATEGY-NNRTI): 48 week results of a randomised, open-label, phase 3b non-inferiority trial.

BACKGROUND: Coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (tenofovir) might be a safe and efficacious switch option for virologically suppressed patients with HIV who have neuropsychiatric side-effects on a non-nucleoside reverse transcriptase inhibitor (NNRTI) or who are on a multitablet NNRTI-containing regimen and want a regimen simplification. We assessed the non-inferiority of such a switch compared with continuation of an NNRTI-containing regimen. METHODS: STRATEGY-NNRTI is a 96 week, international, multicentre, randomised, open-label, phase 3b, non-inferiority trial enrolling adults (≥18 years) with HIV-1 and plasma HIV RNA viral load below 50 copies per mL for at least 6 months on an NNRTI plus emtricitabine and tenofovir regimen. With a computer-generated randomisation sequence, we randomly allocated participants (2:1; blocks of six, stratified by efavirenz use at screening) to switch to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir (switch group) or continue the NNRTI plus emtricitabine and tenofovir regimen (no-switch group). Key eligibility criteria included no history of virological failure and an estimated glomerular filtration rate of 70 mL per min or greater. The primary endpoint was the proportion of participants with plasma viral loads below 50 copies per mL at week 48 based on a snapshot algorithm with a non-inferiority margin of 12% (assessed by modified intention to treat). This trial is ongoing and is registered at ClinicalTrials.gov, number NCT01495702. FINDINGS: Between Dec 29, 2011, and Dec 13, 2012, we randomly allocated 439 participants to treatment: 290 participants in the switch group and 143 participants in the no-switch group received treatment and were included in the modified intention-to-treat population. At week 48, 271 (93%) of 290 participants in the switch group and 126 (88%) of 143 participants in the no-switch group maintained plasma viral loads below 50 copies per mL (difference 5·3%, 95% CI -0·5 to 12·0; p=0·066). We detected no treatment-emergent resistance in either group. Safety events leading to discontinuation were uncommon in both groups: six (2%) of 291 participants in the switch group and one (1%) of 143 in the no-switch group. INTERPRETATION: Coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir seems to be efficacious and well tolerated in virologically suppressed adults with HIV and might be a suitable alternative for patients on an NNRTI with emtricitabine and tenofovir regimen considering a regimen modification or simplification. FUNDING: Gilead Sciences.

Disparities in prevalence of key chronic diseases by gender and race/ethnicity among antiretroviral-treated HIV-infected adults in the US.

BACKGROUND: Certain sociodemographic subgroups of HIV-infected patients may experience more chronic disease than others due to behavioural risk factors, advanced HIV disease or complications from extended use of combination antiretroviral therapy (cART), but recent comparative data are limited. METHODS: We studied HIV-infected adult patients in care during 2006-2010 who had been prescribed ≥ 6 months of cART. We analysed the prevalence of selected key chronic conditions and polymorbidity (having 2 or more out of 10 key conditions) by gender and race/ethnicity. RESULTS: Of the 3,166 HIV-infected patients (median age 47 years, CD4⁺ T-cell count 496 cells/mm³, duration of cART use 6.8 years), 21% were female, 57% were non-Hispanic White and over half were current or former tobacco smokers. The five most frequent conditions among women (median age 45 years) were dyslipidaemia (67.3%), hypertension (57.4%), obesity (31.7%), viral hepatitis B or C coinfection (29.0%) and low high-density lipoprotein cholesterol (HDLc; 27.3%). The five most frequent conditions in men (median age 47 years) were dyslipidaemia (81.2%), hypertension (54.4%), low HDLc (41.1%), elevated triglycerides (32.3%) and elevated non-HDLc (26.8%). In multivariable analyses, Hispanic patients had higher prevalence of obesity and diabetes than White patients; Black patients had higher prevalence of obesity and hypertension but lower rates of lipid abnormalities. Of all patients, 73.7% of women and 66.8% of men had polymorbidity, with no evidence of disparities by race/ethnicity. CONCLUSIONS: Among contemporary cART-treated HIV-infected adults, chronic conditions and polymorbidity were common, underscoring the importance of chronic disease prevention and management among ageing HIV-infected patients.

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.

Routine brief risk-reduction counseling with biannual STD testing reduces STD incidence among HIV-infected men who have sex with men in care.

BACKGROUND: We evaluated whether routine biannual sexually transmitted disease (STD) testing coupled with brief risk-reduction counseling reduces STD incidence and high-risk behaviors. METHODS: The SUN study is a prospective observational HIV cohort study conducted in 4 US cities. At enrollment and every 6 months thereafter, participants completed a behavioral survey and were screened for STDs, and if diagnosed, were treated. Medical providers conducted brief risk-reduction counseling with all patients. Among men who have sex with men (MSM), we examined trends in STD incidence and rates of self-reported risk behaviors before and after exposure to the risk-reduction intervention. The "preintervention" visit was the study visit that was at least 6 months after enrollment STD screening and treatment and at which the participant was first exposed to the intervention. The "postintervention" visit was 12 months later. RESULTS: Among 216 MSM with complete STD and behavioral data, median age was 44.5 years; 77% were non-Hispanic white; 83% were on highly active antiretroviral treatment; 84% had an HIV RNA level <400 copies/mL and the median CD4 (cluster of differentiation 4) count was 511 cells/mm. Twelve months after first exposure to the risk-reduction intervention, STD incidence declined from 8.8% to 4.2% (P = 0.041). Rates of unprotected receptive or insertive anal intercourse with HIV-positive partners increased (19% to 25%, P = 0.024), but did not change with HIV-negative partners or partners of unknown HIV status (24% to 22%, P = 0.590). CONCLUSIONS: STD incidence declined significantly among HIV-infected MSM after implementing frequent, routine STD testing coupled with risk-reduction counseling. These findings support adoption of routine STD screening and risk-reduction counseling for HIV-infected MSM.

Prevalence and risk factors associated with herpes simplex virus-2 infection in a contemporary cohort of HIV-infected persons in the United States.

BACKGROUND: We compared the herpes simplex virus type 2 (HSV-2) seroprevalence in a contemporary HIV cohort with the general US population and determined risk factors for HSV-2 infection among HIV-infected persons. METHODS: The Study to Understand the Natural History of HIV and AIDS in the Era of Effective Therapy (SUN) Study is a prospective observational cohort of 700 HIV-infected adults enrolled in 4 U.S. cities between 2004 and 2006. At baseline, participants completed a behavioral risk questionnaire and provided specimens for HSV-2 serology. We calculated HSV-2 seroprevalence, standardized by age, gender, and race among HIV-infected persons compared with the general US adult population, using data from the National Health and Nutrition Examination Survey from 2003 to 2006. We examined risk factors associated with HSV-2 infection among HIV-infected persons using multivariate logistic regression. RESULTS: Among 660 (94%) SUN participants with adequate specimens for HSV-2 serologic testing, 548 (83%) were 20 to 49 years old (median age, 39 years; 77% male; 59% non-Hispanic white; median CD4 count, 470 cells/mm; 74% with HIV RNA viral loads <400 copies/mL). HSV-2 seroprevalence was significantly higher among HIV-infected adults (59.7%, 95% confidence interval: 55.8-63.6) compared with the general US population (19.2%, 95% confidence interval: 17.5-21.1). In multivariate analysis, we found that older age, female gender, black non-Hispanic race/ethnicity, being currently unemployed, high-risk anal HPV infection, and longer duration since HIV diagnosis were associated with significantly higher odds of HSV-2 infection. CONCLUSION: HSV-2 seroprevalence is 3 times as high among HIV-infected adults as in the general U.S. population. Clinicians should be aware that increased risk for HSV-2 infection was distributed broadly among HIV-infected persons and not limited to those with high-risk sexual behaviors.

Cystatin C and baseline renal function among HIV-infected persons in the SUN Study.

In the combination antiretroviral therapy (cART) era, renal dysfunction remains common. The Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy (SUN) (ClinicalTrials.gov number, NCT00146419) is a prospective observational cohort study of HIV-infected adults. At baseline, comprehensive data were collected, including cystatin C and measures of renal function. Univariate and multivariate regression analyses were performed to identify factors associated with baseline renal dysfunction [estimated glomerular filtration rate (eGFR) < 90 ml/min/1.73 m(2) calculated using the simplified Modification of Diet in Renal Disease equation] and elevated cystatin C (>1.0 mg/liter) in a cross-sectional analysis. Among 670 subjects with complete data (mean age 41 years, mean CD4 cell count 530 cells/mm(3), 79% prescribed cART), the mean eGFR was 96.8 ml/min/1.73 m(2). Forty percent of subjects had renal dysfunction; 3.3% had chronic kidney disease (eGFR < 60 ml/min/1.73 m(2)). Elevated cystatin C was present in 18% of subjects. In multivariate analysis, renal dysfunction was associated with older age, non-Hispanic white race/ethnicity, higher body mass index (BMI), hypertension, higher cystatin C levels, and current prescription of ritonavir. Factors associated with elevated cystatin C included hepatitis C coinfection, hypertension, current smoking, older age, current tenofovir use, detectable plasma HIV RNA, and elevated microalbuminuria. The prevalence of chronic kidney disease (CKD) was low in this contemporary HIV cohort. However, mild to moderate renal dysfunction was common despite the widespread use of cART.

High Prevalence of Echocardiographic Abnormalities among HIV-infected Persons in the Era of Highly Active Antiretroviral Therapy.

BACKGROUND: in the era of highly active antiretroviral therapy (HAART), human immunodeficiency virus (HIV)-infected persons have higher cardiovascular disease risk. Little is known about asymptomatic abnormalities in cardiac structure and function in this population. METHODS: the Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy (SUN Study) is a prospective, observational, multi-site cohort of 656 HIV-infected participants who underwent baseline echocardiography during 2004-2006. We examined prevalence of and factors associated with left ventricular systolic dysfunction (LVSD), diastolic dysfunction (DD), pulmonary hypertension (PHTN), left ventricular hypertrophy (LVH), and left atrial enlargement (LAE). RESULTS: participant characteristics were as follows: median age, 41 years; 24% women; 29% non-Hispanic black; 73% receiving HAART; and median CD4+ cell count, 462 cells/µL. Among evaluable participants, 18% had LVSD, 26% had DD, 57% had PHTN (right ventricular pressure >30 mm Hg), 6.5% had LVH, and 40% had LAE. In multivariate analyses, significant factors (P < .05) associated with LVSD were history of MI, elevated highly sensitive C-reactive protein (hsCRP) level, and current tobacco smoking; for DD, elevated hsCRP level and hypertension; for PHTN, current use of ritonavir; for LVH, hypertension, diabetes, non-white race, female sex with elevated body mass index, calculated as the weight in kilograms divided by the square of height in meters, of ≥ 25, elevated hsCRP level, and current use of abacavir; for LAE, hypertension and recent marijuana use. CONCLUSIONS: in this large contemporary HIV cohort, the prevalence of subclinical functional and structural cardiac abnormalities was greater than expected for age. Abnormalities were mostly associated with expected and often modifiable risks. Lifestyle modification should become a greater priority in the management of chronic HIV disease.

Human papillomavirus infection and cytologic abnormalities of the anus and cervix among HIV-infected women in the study to understand the natural history of HIV/AIDS in the era of effective therapy (the SUN study).

BACKGROUND: Human papillomavirus (HPV) infection of the cervix and related abnormal cervical cytology in HIV-infected women has been well described. Little is known about anal HPV infection in HIV-infected women. METHODS: The SUN Study is a prospective cohort study of 700 HIV-infected patients including 167 women. At baseline, patients completed a behavioral questionnaire and provided, among other samples, cervical and anal swabs for HPV detection and genotyping and for cytologic examination. Here, we present the available baseline data on the 167 women in the SUN study. RESULTS: Baseline results were available for 120 women (median age: 38 years, 57% non-Hispanic black, median CD4 cell count 444.5 cells/mm3), of whom, 77% were taking antiretroviral therapy. The prevalences in the anus and cervix of any HPV were 90% and 83%, respectively (P = 0.039), and of high-risk (HR) types 85% and 70%, respectively, (P = 0.001). There was no significant difference in the prevalences of abnormal cytology between the anus and cervix: 38% and 33%, respectively (P = 0.217). Although the presence of abnormal cervical cytology was associated with the presence of abnormal anal cytology (relative risk: 1.7, P = 0.024), its sensitivity (52.5%) and positive predictive value positive (45.6%) for identifying women with abnormal anal cytology were poor. A history of anal sex was not associated with anal HPV infection or abnormal anal cytology. CONCLUSIONS: In this cohort of HIV-infected women, anal HPV infection was more prevalent and diverse than cervical HPV infection. Anal cytologic abnormalities were as prevalent as cervical cytologic abnormalities, and although abnormal cervical cytology was predictive of abnormal anal cytology, results were not highly concordant. These data support the need for studies of anal cytologic screening of HIV-infected women.

High-density lipoprotein particles and markers of inflammation and thrombotic activity in patients with untreated HIV infection.

BACKGROUND: Untreated human immunodeficiency virus (HIV) infection is associated with changes in blood lipids, inflammation, thrombotic activity, and increased risk for cardiovascular disease. METHODS: We studied high-density lipoprotein particle (HDLp) concentrations and inflammatory (high-sensitivity C-reactive protein [hsCRP] and interleukin [IL] 6), endothelial activation (E-selectin and soluble intercellular adhesion molecule-1 [sICAM-1]), and thrombotic (fibrinogen and D-dimer) biomarkers in a group of 32 untreated HIV-infected and 29 uninfected persons. Differences in the levels of blood lipids and biomarkers by HIV status were examined before and after adjustment for age, sex, race/ethnicity, smoking status, body mass index, and the presence of hepatitis C. RESULTS: HIV-infected participants, compared with uninfected participants, had lower HDL cholesterol (HDLc) levels (-26%) and HDLp numbers (-21%), with reductions in large (-50%) and small (-20%) HDLp, specifically (P < or = .01 for all). A trend was present for higher total cholesterol (P = .15 and triglyceride levels (P = .11) among individuals with HIV infection. Levels of IL-6, sICAM-1, and D-dimer were 65%-70% higher in HIV-infected participants (P < or = .02 for all). Covariate adjustment did not diminish these associations. For HIV-infected participants, total and small HDLp (respectively) tended to correlate inversely with levels of IL-6 (P = .08 and P = .02), sICAM-1 (P < .01 for both) and D-dimer (P = .03 and p < .01). CONCLUSIONS: Persons with untreated HIV infection have lower HDLp (primarily large and small HDLp) and higher IL-6, sICAM-1, and D-dimer levels, and the relationship of these markers to HIV-mediated atherosclerotic risk requires further study.

Untreated HIV infection and large and small artery elasticity.

BACKGROUND: Untreated HIV infection may increase risk for cardiovascular disease, and arterial elasticity is a marker of cardiovascular risk and early disease. METHODS: HIV-infected participants not taking antiretroviral therapy (n=32) were compared with HIV-negative controls (n=30). Large and small artery elasticity (LAE and SAE) were estimated via analysis of radial pulse waveforms. Differences in LAE and SAE by HIV status were compared using analysis of covariance, with and without adjustment for Framingham risk (model 1); covariates that differed between groups [smoking, injection drug use, hepatitis C, and high-density lipoprotein cholesterol (HDLc); model 2]; or age, sex, race/ethnicity, smoking, injection frug use, hepatitis C, HDLc, and non-HDLc (model 3). RESULTS: HIV infection was associated with impaired LAE (-2.55 mL/mm Hg x 10; P=0.02) and SAE (-1.50 mL/mm Hg x 100; P=0.02). Associations with traditional risk factors were often stronger for SAE than LAE, including with Framingham score (per 1% higher; SAE -0.18, P=0.01; LAE -0.19, P=0.13). Fasting lipid levels were not significantly associated with LAE and SAE. After adjustment, differences between HIV-infected and HIV-uninfected participants were similar in model 1 (-2.36 for LAE, P=0.04; -1.31 for SAE, P=0.04), model 2 (-2.67 for LAE, P=0.02; -1.13 for SAE, P=0.07) and model 3 (-2.91 for LAE, P=0.02; -1.34 for SAE, P=0.03). CD4 count and HIV RNA level were not associated with LAE and SAE among HIV-infected participants. CONCLUSIONS: Untreated HIV infection is associated with impaired arterial elasticity, of both the large and small vasculature, after controlling for additional risk factors. Pulse waveform analysis is a noninvasive technique to assess cardiovascular disease risk that should be evaluated in larger studies of HIV-infected persons.

Internal medicine/primary care reminder: what are the standards of care for HIV-positive patients aged 50 years and older?

The demographics of HIV-positive persons in the United States signal a steady shift toward an older population. The relationship between aging and HIV infection suggests that there is an additive and possibly synergistic effect increasing the risk for numerous common medical conditions, including heart disease, cancer, osteoporosis, frailty, depression, and dementia. Given the current crisis in the US health care system regarding universal access to quality primary and geriatric care, the aging of the HIV-positive population will pose numerous challenges to providers and policy makers. This review summarizes key areas of knowledge and concern regarding the care of HIV-positive persons aged 50 years and older.

Poor initial CD4+ recovery with antiretroviral therapy prolongs immune depletion and increases risk for AIDS and non-AIDS diseases.

BACKGROUND: Low CD4+ increases risk for both AIDS- and non-AIDS-related morbidity and mortality. The magnitude of CD4+ recovery early after initial antiretroviral therapy (ART) is important in the ultimate duration of immune depletion. METHODS: We examined CD4+ recovery among 850 participants in the Community Program for Clinical Research on AIDS Flexible Initial Retrovirus Suppressive Therapies study with virologic suppression (ie, achieved an HIV RNA level <400 copies/mL) with 8 months of initial ART and determined subsequent risk for AIDS, non-AIDS diseases (non-AIDS cancers and cardiovascular, end-stage renal, and liver diseases), or death using Cox regression during a median 5-year follow-up. RESULTS: Mean pretreatment CD4+ was 221 cells/microL; 18% (n = 149) had a poor CD4+ recovery (<50 cells/microL) after 8 months of effective ART, resulting in lower CD4+ over 5 years. Older age (hazard ratio 1.34/10 yrs, P = 0.003) and lower screening HIV RNA (hazard ratio 0.65 per log10 copies/mL higher, P = 0.001), but not screening CD4+, were associated with a poor CD4+ recovery. After 8 months of effective ART, 30 patients experienced the composite outcome of AIDS, non-AIDS, or death among participants with a poor CD4+ recovery (rate = 5.8/100 person-years) and 74 patients among those with an adequate recovery (>or=50 cells/muL; rate = 2.7/100 person-years) (adjusted hazard ratio = 2.24, P < 0.001). The risk of this composite outcome associated with a poor CD4+ recovery declined when ART was initiated at higher CD4+ counts (P < 0.01). CONCLUSIONS: Impaired immune recovery, despite effective ART, results in longer time spent at low CD4+, thereby increasing risk for a broad category of HIV-related morbidity and mortality conditions.