Marcus D. Durham

Immune reconstitution inflammatory syndrome: incidence and implications for mortality

Objective:To describe incidence of immune reconstitution inflammatory syndrome (IRIS) and its association with mortality in a large multisite US HIV-infected cohort applying an objective, comprehensive definition. Design:We studied 2 610 patients seen during 1996–2007 who initiated or resumed highly active combination antiretroviral therapy (cART) and, during the next 6 months, demonstrated a decline in plasma HIV-RNA viral load of at least 0.5 log10 copies/ml or an increase of at least 50% in CD4 cell count per microliter. We defined IRIS as the diagnosis of a type B or C condition [as per the Centers for Disease Control and Prevention (CDC) 1993 AIDS case definition] or any new mucocutaneous disorder during this same 6-month period. Methods:We assessed the incidence of IRIS and evaluated risk factors for IRIS using conditional logistic regression and for all-cause mortality using proportional hazards models. Results:We identified 370 cases of IRIS (in 276 patients). Median and nadir CD4 cell counts at cART initiation were 90 and 43 cells/&mgr;l, respectively; median viral load was 2.7 log10 copies/ml. The most common IRIS-defining diagnoses were candidiasis (all forms), cytomegalovirus infection, disseminated Mycobacterium avium intracellulare, Pneumocystis pneumonia, varicella zoster, Kaposis sarcoma and non-Hodgkin lymphoma. Only one case of Mycobacterium tuberculosis was observed. IRIS was independently associated with CD4 cell count less than 50 cells/&mgr;l vs. at least 200 cells/&mgr;l [odds ratio (OR) 5.0] and a viral load of at least 5.0 log10 copies vs. less than 4.0 log10 copies (OR 2.3). IRIS with a type B-defining or type C-defining diagnosis approximately doubled the risk for all-cause mortality. Conclusion:In this large US-based HIV-infected cohort, IRIS occurred in 10.6% of patients who responded to effective ART and contributed to increased mortality.

CD4 Cell Counts at HIV Diagnosis among HIV Outpatient Study Participants, 2000–2009

Background. It is unclear if CD4 cell counts at HIV diagnosis have improved over a 10-year period of expanded HIV testing in the USA. Methods. We studied HOPS participants diagnosed with HIV infection ≤6 months prior to entry into care during 2000–2009. We assessed the correlates of CD4 count <200 cells/mm3 at HIV diagnosis (late HIV diagnosis) by logistic regression. Results. Of 1,203 eligible patients, 936 (78%) had a CD4 count within 3 months after HIV diagnosis. Median CD4 count at HIV diagnosis was 299 cells/mm3 and did not significantly improve over time (P = 0.13). Comparing periods 2000-2001 versus 2008-2009, respectively, 39% and 35% of patients had a late HIV diagnosis (P = 0.34). Independent correlates of late HIV diagnosis were having an HIV risk other than being MSM, age ≥35 years at diagnosis, and being of nonwhite race/ethnicity. Conclusions. There is need for routine universal HIV testing to reduce the frequency of late HIV diagnosis and increase opportunity for patient- and potentially population-level benefits associated with early antiretroviral treatment.

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/&mgr;l [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), log10HIV RNA (aHR, 1.67 per log10; 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/&mgr;l (aHR, 2.03; 95% CI 1.32–3.14) but not when index CD4 cell count was less than 200 cells/&mgr;l (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/&mgr;l, 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.

Treatment of hepatitis C virus (HCV) infection in patients coinfected with HIV in the HIV Outpatient Study (HOPS), 1999-2007.

Summary.  Liver disease due to hepatitis C virus (HCV) infection is a leading cause of non‐AIDS‐related morbidity and mortality in patients infected with HIV. We assessed the frequency of and predictors for initiation of treatment for HCV infection among patients coinfected with HCV/HIV enrolled in the HIV Outpatient Study (HOPS) during 1999–2007. We included patients with confirmed HCV infection, at least 1 year of subsequent follow‐up, and no evidence of prior HCV treatment. We assessed predictors of HCV treatment initiation using Cox proportional hazards analyses. During 1999–2007, 103 (20%) HOPS patients coinfected with HCV/HIV initiated HCV treatment during a median of 4.3 years of follow‐up (interquartile range: 2.7, 6.7). In multivariable analysis, non‐Hispanic black race/ethnicity (hazard ratio HR] 0.3; 95% confidence interval [CI] = 0.2, 0.6) was independently associated with a lower likelihood of HCV treatment. Elevated alanine aminotransferase (ALT; HR 3.5; 95% CI = 2.2, 5.6) and CD4+ cell count ≥500 cells/mm3 (HR 1.8; 95% CI = 1.2, 2.8) at the start of observation were independently associated with higher likelihood of HCV treatment. For patients starting observation in 1999–2001, 2002–2004 and 2005–2007, 5%, 11% and 21% of patients initiated treatment during the first year of follow‐up, respectively. Between 1999 and 2007, despite a stable low fraction of patients coinfected with HCV/HIV initiating treatment for HCV infection, an increasing proportion initiated treatment within the first year after the infection was confirmed. Treatment of HCV infection in patients coinfected with HCV/HIV should be considered a priority, given the increased risk of accelerated end‐stage liver disease.

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.

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/mm3 (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.

Rates and correlates of influenza vaccination among HIV-infected adults in the HIV Outpatient Study (HOPS), USA, 1999–2008

BACKGROUND We sought to describe rates of vaccination among HIV-infected adults in care and identify factors associated with vaccination. METHODS Using data abstracted from medical records of participants in the HIV Outpatient Study (HOPS) during 8 influenza seasons (1999-2008) and negative binomial models with generalized estimating equation methods, we examined factors associated with increased prevalence of annual influenza vaccination. RESULTS Among active patients, 25.8% to 43.3% were vaccinated for influenza each year (annual mean=35%, test for trend p=0.71). Vaccination rates peaked in October and November of each season and decreased sharply thereafter. In multivariable analysis, patients who were male (67.2%), non-Hispanic white (70%) or Hispanic (66%), had lower HIV viral loads (73.5%), were prescribed antiretroviral treatment (72.7%), or had a greater number of clinical encounters per year (86.7%) were more likely to receive influenza vaccination. DISCUSSION The decreased likelihood of vaccination among women and non-Hispanic black patients suggests the need for focused efforts to reduce disparities. Increasing patient and clinician education on the importance of universal vaccination, and ensuring that vaccination activities continue in HIV clinics during the later months of the influenza season may improve influenza vaccine coverage.

Trends in use of genotypic resistance testing and frequency of major drug resistance among antiretroviral-naive persons in the HIV Outpatient Study, 1999–2011

BACKGROUND Monitoring antiretroviral drug resistance can inform treatment recommendations; however, there are few such data from US patients before they initiate ART. METHODS We analysed data from HIV Outpatient Study (HOPS) participants from nine US HIV clinics who were diagnosed with HIV infection during 1999-2011. Using the IAS-USA December 2010 guidelines, we assessed the frequency of major drug resistance mutations (mDRMs) related to antiretroviral agents in viral isolates from patients who underwent commercial genotypic testing (GT) for resistance before initiating ART. We employed general linear regression models to assess factors associated with having undergone GT, and then factors associated with having mDRM. RESULTS Among 1531 eligible patients, 758 (49.5%) underwent GT before first ART, increasing from 15.5% in 1999-2002 to 75.9% in 2009-11 (P < 0.001). GT was carried out a median of 1.2 months after the diagnosis of HIV. In adjusted regression analyses, patients with pre-ART CD4+ T lymphocyte counts ≥200 cells/mm(3) or with HIV RNA levels >5.0 log10 copies/mL and those with a first HOPS visit in 2006 or later were significantly (P < 0.05) more likely to have undergone GT. Of the 758 patients, 114 (15.0%) had mDRMs; mutations relating to NRTIs, NNRTIs and PIs were present in 8.0%, 7.1% and 2.6%, respectively. There was no temporal change in the frequency of mDRM, and mDRMs were associated with an HIV RNA level <4.0 log10 copies/mL. CONCLUSIONS During 1999-2011, GT use among antiretroviral-naive patients became more common, but a quarter of patients in recent years remained untested. The frequency of mDRMs remained stable over time at about 15%.

CD4 cell count at initiation of ART, long-term likelihood of achieving CD4 >750 cells/mm3 and mortality risk

OBJECTIVES We sought to evaluate associations between CD4 at ART initiation (AI), achieving CD4 >750 cells/mm(3) (CD4 >750), long-term immunological recovery and survival. METHODS This was a prospective observational cohort study. We analysed data from ART-naive patients seen in 1996-2012 and followed ≥3 years after AI. We used Kaplan-Meier (KM) methods and log-rank tests to compare time to achieving CD4 >750 by CD4 at AI (CD4-AI); and Cox regression models and generalized estimating equations to identify factors associated with achieving CD4 >750 and mortality risk. RESULTS Of 1327 patients, followed for a median of 7.9 years, >85% received ART for ≥75% of follow-up time; 64 died. KM estimates evaluating likelihood of CD4 >750 during 5 years of follow-up, stratified by CD4-AI <50, 50-199, 200-349, 350-499 and 500-750, were 20%, 25%, 56%, 80% and 87%, respectively (log-rank P < 0.001). In adjusted models, CD4-AI ≥200 (versus CD4-AI <200) was associated with achievement of CD4 >750 [adjusted HR (aHR) = 4.77]. Blacks were less likely than whites to achieve CD4 >750 (33% versus 49%, aHR = 0.77). Mortality rates decreased with increasing CD4-AI (P = 0.004 across CD4 strata for AIDS causes and P = 0.009 for non-AIDS death causes). Among decedents with CD4-AI ≥50, 56% of deaths were due to non-AIDS causes. CONCLUSIONS Higher CD4-AI resulted in greater long-term CD4 gains, likelihood of achieving CD4 >750, longer survival and decreased mortality regardless of cause. Over 80% of persons with CD4-AI ≥350 achieved CD4 >750 by 4 years while 75% of persons with CD4-AI <200 did not. These data confirm the hazards of delayed AI and support early AI.

Predictors of Willingness of Participate in HIV Vaccine Trials among African Americans

African Americans in the United States (U.S.) are disproportionately affected by HIV. Developing an HIV vaccine is an important part of the HIV prevention and treatment toolkit and may help contribute to ending the HIV epidemic. To date, HIV vaccine trials have not engaged representative numbers of African Americans. We evaluated the willingness of African Americans to participate in HIV vaccine trials and identified correlates of willingness to participate (WTP) by surveying African Americans at low- and high-risk of HIV infection in a multi-site, cross-sectional study. We enrolled 1,452 participants; 59% heterosexual women; 21% heterosexual men; 20% men who have sex with men (MSM). Over half of participants (58%) expressed some level of WTP in HIV vaccine trials. Multivariable analyses revealed several variables were positively related to WTP: HIV risk behavior, knowing someone with HIV/AIDS, social support for trial participation, high perception of risk, perceived protection if in a trial, altruism, and greater tolerance for the ambiguous nature of trials (p<0.01). Emphasis on contextual factors related to personal HIV experiences, including knowledge of someone with HIV, and community support for research, may provide effective strategies for engaging African Americans in future HIV vaccine trials.