Ellen Tedaldi

Low CD4+ T Cell Count Is a Risk Factor for Cardiovascular Disease Events in the HIV Outpatient Study

BACKGROUND Traditional cardiovascular disease (CVD) risk factors, human immunodeficiency virus (HIV) infection, and antiretroviral (ARV) agents have been associated with CVD events in HIV-infected patients. We investigated the association of low CD4(+) T lymphocyte cell count with incident CVD in a cohort of outpatients treated in 10 HIV specialty clinics in the United States. METHODS We studied patients who were under observation from 1 January 2002 (baseline), categorized them according to National Cholesterol Education Program guidelines into 10-year cardiovascular risk score (10-y CVR) groups , and observed them until CVD event, death, last HIV Outpatient Study contact, or 30 September 2009. We calculated rates of incident CVD events and identified associated baseline risk factors using Cox proportional hazard models. We also performed a nested case-control study to examine the association of latest CD4(+) cell count with CVD events. RESULTS Among 2005 patients, 148 experienced incident CVD events. CVD incidence increased steadily from 0.4 to 3.0 events per 100 person-years from lowest to highest 10-y CVR group (P < .001). In multivariable Cox analyses adjusted for 10-y CVR, CD4(+) cell count <350 cells/mm(3) was associated with incident CVD events (hazard ratio, 1.58 [95% confidence interval, 1.09-2.30], compared with >500 cells/mm(3)), suggesting an attributable risk of approximately 20%. In the multivariable case-control analyses, traditional CVD risk factors and latest CD4(+) cell count <500 cells/mm(3), but not cumulative use of ARV class or individual drugs, were associated with higher odds of experiencing CVD events. CONCLUSION CD4(+) count <500 cells/mm(3) is an independent risk factor for incident CVD, comparable in attributable risk to several traditional CVD risk factors in the HIV Outpatient Study cohort.

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.

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 2947 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.

Elimination of HIV-1 Genomes from Human T-lymphoid Cells by CRISPR/Cas9 Gene Editing

We employed an RNA-guided CRISPR/Cas9 DNA editing system to precisely remove the entire HIV-1 genome spanning between 5′ and 3′ LTRs of integrated HIV-1 proviral DNA copies from latently infected human CD4+ T-cells. Comprehensive assessment of whole-genome sequencing of HIV-1 eradicated cells ruled out any off-target effects by our CRISPR/Cas9 technology that might compromise the integrity of the host genome and further showed no effect on several cell health indices including viability, cell cycle and apoptosis. Persistent co-expression of Cas9 and the specific targeting guide RNAs in HIV-1-eradicated T-cells protected them against new infection by HIV-1. Lentivirus-delivered CRISPR/Cas9 significantly diminished HIV-1 replication in infected primary CD4+ T-cell cultures and drastically reduced viral load in ex vivo culture of CD4+ T-cells obtained from HIV-1 infected patients. Thus, gene editing using CRISPR/Cas9 may provide a new therapeutic path for eliminating HIV-1 DNA from CD4+ T-cells and potentially serve as a novel and effective platform toward curing AIDS.

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.

Virologic and immunologic response to HAART, by age and regimen class

Objective:To determine the impact of age and initial HAART regimen class on virologic and immunologic response within 24 months after initiation. Design:Pooled analysis of data from 19 prospective cohort studies in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). Methods:Twelve thousand, one hundred and ninety-six antiretroviral-naive adults who initiated HAART between 1998 and 2008 using a boosted protease inhibitor-based regimen or a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen were included in our study. Discrete time-to-event models estimated adjusted hazard odds ratios (aHOR) and 95% confidence intervals (CIs) for suppressed viral load (≤500 copies/ml) and, separately, at least 100 cells/μl increase in CD4 cell count. Truncated, stabilized inverse probability weights accounted for selection biases from discontinuation of initial regimen class. Results:Among 12 196 eligible participants (mean age = 42 years), 50% changed regimen classes after initiation (57 and 48% of whom initiated protease inhibitor and NNRTI-based regimens, respectively). Mean CD4 cell count at initiation was similar by age. Virologic response to treatment was less likely in those initiating using a boosted protease inhibitor [aHOR = 0.77 (0.73, 0.82)], regardless of age. Immunologic response decreased with increasing age [18–<30: ref; 30–<40: aHOR = 0.92 (0.85, 1.00); 40–<50: aHOR = 0.85 (0.78, 0.92); 50–<60: aHOR = 0.82 (0.74, 0.90); ≥60: aHOR = 0.74 (0.65, 0.85)], regardless of initial regimen. Conclusion:We found no evidence of an interaction between age and initial antiretroviral regimen on virologic or immunologic response to HAART; however, decreased immunologic response with increasing age may have implications for age-specific when-to-start guidelines.

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.

Opportunistic Disease and Mortality in Patients Coinfected with Hepatitis B or C Virus in the Strategic Management of Antiretroviral Therapy (SMART) Study

BACKGROUND In the Strategic Management of Antiretroviral Therapy (SMART) study, the risk of opportunistic disease (OD) and/or death due to any cause was elevated in the drug conservation (i.e., interrupt antiretroviral therapy until the CD4(+) cell count is <250 cells/microL) group, compared with the viral suppression (continued use of antiretroviral therapy) group. We assessed whether participants with concurrent hepatitis had an increased risk of the end points evaluated in the SMART study. METHODS Participants were classified as being positive for hepatitis B virus (HBV) if they had positive hepatitis B surface antigen results for >6 months and positive for HCV if they tested HCV antibody positive. The rate and hazard ratio (HR) of OD and/or death and its 2 components were compared by hepatitis status and drug conservation versus the viral suppression group. RESULTS Among 5472 participants enrolled from 8 January 2002 through 11 January 2006, 930 (17%) were HBV positive and/or HCV positive. The relative risk of non-OD death in participants randomized to the drug conservation group versus the viral suppression group was comparable regardless of hepatitis status (HR for coinfected and HIV-monoinfected participants, respectively, 1.9 [95% confidence interval {CI}, 1.0-3.9 and 1.8 [95% CI, 0.9-3.4]). The rate of OD or death was 3.9 events per 100 person-years in the coinfected group and 2.0 per 100 person-years in the HIV-monoinfected group. This excess risk was due to a higher risk of non-OD death among the coinfected participants (HR, 3.6; 95% CI, 2.3-5.6), whereas the risk of OD was comparable (HR, 1.1; 95% CI, 0.7-1.8). The 3 leading causes of non-OD death in coinfected participants were unknown cause, substance abuse, and non-acquired immunodeficiency disease cancer. CONCLUSIONS Interruption of antiretroviral therapy is particularly unsafe in persons with hepatitis virus coinfection. Although HCV- and/or HBV-coinfected participants constituted 17% of participants in the SMART study, almost one-half of all non-OD deaths occurred in this population. Viral hepatitis was an unlikely cause of this excess risk.

Frequent hepatitis B virus rebound among HIV-hepatitis B virus-coinfected patients following antiretroviral therapy interruption.

Background:The impact of antiretroviral therapy (ART) interruption in HIV–hepatitis B virus (HBV)-coinfected patients was examined in the Strategic Management of AntiRetroviral Therapy (SMART) study. Methods:Plasma HBV DNA was measured in all hepatitis B surface antigen-positive (HBV-positive) participants at baseline, and at months 1, 2, 4, 6, 8, 10, and 12. Results:Among HBV-positive participants in the ART interruption (drug conservation) (n = 72) and ART continuation (virological suppression) (n = 62) arms, HBV DNA rebound of more than 1 log from baseline at months 1–4 was seen in 31–33% (P = 0.003) and 3–4% (P = 0.017), respectively. Thirteen HBV-positive participants had HBV DNA rebound of more than 3 log, including 12 in the drug conservation arm, of which eight were on tenofovir-containing regimens. Factors independently associated with a HBV DNA rebound were drug conservation arm (P = 0.0002), nondetectable HBV DNA at baseline (P = 0.007), and black race (P = 0.03). Time to ART reinitiation was shorter (7.5, 15.6, and 17.8 months; P < 0.0001) and proportion reinitiating greater (62.5, 46.5, and 39.7%; P = 0.0002) among HBV-positive participants as compared with hepatitis C virus-positive and non-HBV/hepatitis C virus participants in the drug conservation arm. No hepatic decompensation events occurred among HBV-positive participants in either arm. Conclusion:HBV DNA rebound following ART interruption is common and may be associated with accelerated immune deficiency in HIV–HBV-coinfected patients.

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.