Jacqueline Astemborski

Sex differences in HIV-1 viral load and progression to AIDS

BACKGROUND Plasma HIV-1 RNA measurements are used for initiation of antiretroviral treatments. Whether the viral-load association with prognosis is similar in women and men is unknown. METHODS We studied 812 specimens from 650 injection-drug users (IDUs) participating in a continuous observational study of patients based in a community clinic. HIV-1 load was measured by branched-chain DNA on samples from 527 IDUs from the baseline visit, and by reverse-transcriptase PCR and quantitative microculture on samples from 285 IDUs at a follow-up visit 3 years later. FNDINGS: Women had lower median viral-load measurements than men by branched-chain DNA (3365 vs 8907 copies/mL; p=0.001), reverse-transcriptase PCR (45416 vs 93130 copies/mL; p=0.02), and quantitative microculture (5 vs 8 infectious units per million peripheral blood mononuclear cells; p=0.015). This association remained even after adjustment for CD4 cell count, race, and drug use within the previous 6 months. Time to AIDS was statistically similar for men and women in a univariate proportional-hazards model and in a model adjusting for CD4 cell count. Proportional-hazards models showed that women with the same viral load as men had a 1.6-fold higher risk of AIDS (95% CI 1.10-2.32); or, equivalently, that women with half the viral load of men had a similar time to AIDS as men. INTERPRETATION Although a biological mechanism remains unclear, these data suggest that current recommendations for HIV-1 viral-load thresholds to initiate antiretroviral therapy should be revised downwards for women.

High-Programmed Death-1 Levels on Hepatitis C Virus-Specific T Cells during Acute Infection Are Associated with Viral Persistence and Require Preservation of Cognate Antigen during Chronic Infection

Hepatitis C virus (HCV) is an important human pathogen that represents a model for chronic infection given that the majority of infected individuals fail to clear the infection despite generation of virus-specific T cell responses during the period of acute infection. Although viral sequence evolution at targeted MHC class I-restricted epitopes represents one mechanism for immune escape in HCV, many targeted epitopes remain intact under circumstances of viral persistence. To explore alternative mechanisms of HCV immune evasion, we analyzed patterns of expression of a major inhibitory receptor on T cells, programmed death-1 (PD-1), from the time of initial infection and correlated these with HCV RNA levels, outcome of infection, and sequence escape within the targeted epitope. We show that the level of PD-1 expression in early HCV infection is significantly higher on HCV-specific T cells from subjects who progress to chronic HCV infection than from those who clear infection. This correlation is independent of HCV RNA levels, compatible with the notion that high PD-1 expression on HCV-specific CD8 T cells during acute infection inhibits viral clearance. Viral escape during persistent infection is associated with reduction in PD-1 levels on the surface of HCV-specific T cells, supporting the necessity of ongoing antigenic stimulation of T cells for maintenance of PD-1 expression. These results support the idea that PD-1 expression on T cells specific for nonescaped epitopes contributes to viral persistence and suggest that PD-1 blockade may alter the outcome of HCV infection.

Changes in Blood-borne Infection Risk Among Injection Drug Users

BACKGROUND Population-level hepatitis C virus (HCV) infection incidence is a surrogate for community drug-related risk. METHODS We characterized trends in human immunodeficiency virus (HIV) and HCV infection incidence and HCV infection prevalence among injection drug users (IDUs) recruited over 4 periods: 1988-1989, 1994-1995, 1998, and 2005-2008. We calculated HIV and HCV infection incidence within the first year of follow-up among IDUs whose test results were negative for these viruses at baseline (n = 2061 and n = 373, respectively). We used Poisson regression to compare trends across groups. RESULTS HIV infection incidence declined significantly from 5.5 cases/100 person-years (py) in the 1988-1989 group to 2.0 cases/100 py in the 1994-1995 group to 0 cases/100 py in the 1998 and 2005-2008 groups. Concurrently, HCV infection incidence declined but remained robust (22.0 cases/100 py in the 1988-1989 cohort to 17.2 cases/100 py in the 1994-1995 cohort, 17.9 cases/100 py in the 1998 cohort, and 7.8 cases/100 py in the 2005-2008 cohort; P = .07). Likewise, HCV infection prevalence declined, but chiefly in younger IDUs. For persons aged <39 years, relative to the 1988-1989 cohort, all groups exhibited significant declines (adjusted prevalence ratio [PR] for the 2005-08 cohort, .73; 95% confidence interval [CI], .65-.81). However, for persons aged ≥ 39 years, only the 2005-2008 cohort exhibited declining prevalence compared with the 1988-1989 cohort (adjusted PR, .87; 95% CI, .77-.99). CONCLUSIONS Although efforts to reduce blood-borne infection incidence have had impact, this work will need to be intensified for the most transmissible viruses, such as HCV.

Prospective study of infective endocarditis among injection drug users

To determine the effect of human immunodeficiency virus (HIV) infection and other factors on infective endocarditis (IE) among injection drug users (IDUs), the incidence of IE was determined according to HIV status in a cohort of IDUs. A nested case-control study assessed IE risk factors. IE incidence (117 cases) was higher among HIV-seropositive than HIV-seronegative IDUs (13.8 vs. 3.3 cases/1000 person-years) during 1988-1998. Multivariate analysis of HIV-infected case patients revealed an inverse association between IE and CD4 lymphocyte count (odds ratio [OR] for 200-499 cells/mm(3), 2.01; OR for <200 cells/mm(3), 3.61) and with alcohol intake (OR for 1-21 drinks/week, 0.43; OR for >21 drinks/week, 0.32). Women had an increased risk of IE (OR, 3.26), as did persons with increasing injection drug use frequency (OR for less than daily use, 3.15; OR for at least daily use, 6.07). This study confirms that IE is more common among IDUs with advanced HIV immunosuppression even after accounting for injection drug use behaviors.

Correlates of non-medical prescription drug use among a cohort of injection drug users in Baltimore City

Despite reports of increasing non-medical prescription drug use, relatively few studies have systematically evaluated the prevalence and correlates of non-medical prescription drug use, particularly in populations that might be especially vulnerable (e.g., injection drug users [IDUs]). We examined factors associated with non-medical prescription drug use among a community-based cohort of current and former IDUs in Baltimore (The ALIVE Study). We conducted a cross-sectional analysis of data from cohort participants that responded to a survey that included questions on non-medical prescription drug use between 2005-06 (n=1320). Non-medical prescription drug use was considered to be use of any of the following: Opiates (Oxycontin, Percocet), Benzodiazepines or Clonidine, purchased on the street and taken orally within the last six months. Data on other covariates of interest (e.g., demographics, substance use, general health) was obtained through a standardized interview. The median age was 46 years; 66% were male, 85% were African-American. Twenty one percent reported any non-medical prescription drug use; 12% reported using more than one drug. Non-medical use of opiates was most common (17%). In multivariate analysis, non-medical prescription drug use was significantly associated with Caucasian race (prevalence ratio [PR]: 1.79), self-reported bodily pain (PR: 1.58), hazardous alcohol use (PR: 1.47), marijuana use (PR: 1.65), non-injection cocaine/heroin use (PR: 1.70), diverted use of buprenorphine (PR: 1.51) or methadone (PR: 2.51), and active injection drug use (PR: 3.50; p<0.05 for all). The association between bodily pain and non-medical prescription drug use was stronger among persons that were not using substances (marijuana, injecting drugs, snorting/smoking heroin, cocaine, using crack) as compared to those using these substances. The high prevalence of non-medical prescription drug use among this population warrants further research and action. Information on the risks of nonmedical prescription drug use especially overdose, should be incorporated into interventions targeted at IDUs.

Comparison of clinical manifestations of HIV infection between male and female injecting drug users

ObjectiveTo compare occurrence of clinical symptoms, physical examination findings and hematologic variables in male and female HIV-seropositive injecting drug users (IDU) with similar CD4+ lymphocyte counts. MethodWe interviewed and examined 118 female and 444 male AIDS-free HIV-seropositive IDU for clinical signs and symptoms. HIV serology and T-lymphocyte subset evaluations were performed. Comparisons were analyzed by Mantel-Haenszel procedures. ResultsIn this population, median age for men was 35 years versus 33 years for women; median CD4 cell count was 490 × 106/l for men versus 480 × 106/l for women. The overall frequency of oral candidiasis increased as CD4 cell count decreased, but did not vary by sex. Recent history of genital herpes was more frequent (P < 0.05) in women than men, but this difference was not significant on physical examination. Symptoms of diarrhea, fatigue, weight loss, shortness of breath, presence of enlarged posterior cervical lymph nodes did not vary by CD4 cell count or sex, and no strong interactions were evident. Although absolute values of hematocrit were higher (P < 0.001) and platelet count lower (P < 0.001) in HIV-seropositive men than women, distributions of hematocrit and platelet count by sex were similar for HIV-seropositive participants and HIV-seronegative controls. ConclusionOur data on IDU prior to a diagnosis of AIDS suggest that constitutional signs and symptoms are generally similar among men and women early in HIV infection. Additional follow-up is needed to determine whether differential rates of signs and symptoms by sex appear with progression of HIV infection.

Factors Associated with Initiation of Zidovudine in a Cohort of Injection Drug Users

To estimate the prevalence of zidovudine (ZVD) use among human immunodeficiency virus (HIV) seropositive injection drug users (IDU), and to identify predisposing factors that predicted initiation of ZVD use. Participants from an ongoing prospective cohort study who met Public Health Service (PHS) criteria for zidovudine, with a CD4 cell count of less than ≤200/μL prior to December 1990 or a CD4 count of ≤500μL, after December, 1990 and had at least one clinic visit after determination of these cell counts were included. Eligibility criteria was met for 412 individuals for ZVD use; 173 (42% used ZVD at any period. Variables significantly associated with ZVD use included CD4 cell counts less than ≤200μL (OR=3.30); two or more HIV related symptoms (OR=2.07); a child living in the participants home (OR=1.59), and, in the six months prior to eligibility for ZVD, any outpatient visit (OR=2.28) or any inpatient admission (OR=1.85). This study suggests that utilization of ZVD among IDUs remains low.