Bryan Lau

Effect of Early versus Deferred Antiretroviral Therapy for HIV on Survival

BACKGROUND The optimal time for the initiation of antiretroviral therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection is uncertain. METHODS We conducted two parallel analyses involving a total of 17,517 asymptomatic patients with HIV infection in the United States and Canada who received medical care during the period from 1996 through 2005. None of the patients had undergone previous antiretroviral therapy. In each group, we stratified the patients according to the CD4+ count (351 to 500 cells per cubic millimeter or >500 cells per cubic millimeter) at the initiation of antiretroviral therapy. In each group, we compared the relative risk of death for patients who initiated therapy when the CD4+ count was above each of the two thresholds of interest (early-therapy group) with that of patients who deferred therapy until the CD4+ count fell below these thresholds (deferred-therapy group). RESULTS In the first analysis, which involved 8362 patients, 2084 (25%) initiated therapy at a CD4+ count of 351 to 500 cells per cubic millimeter, and 6278 (75%) deferred therapy. After adjustment for calendar year, cohort of patients, and demographic and clinical characteristics, among patients in the deferred-therapy group there was an increase in the risk of death of 69%, as compared with that in the early-therapy group (relative risk in the deferred-therapy group, 1.69; 95% confidence interval [CI], 1.26 to 2.26; P<0.001). In the second analysis involving 9155 patients, 2220 (24%) initiated therapy at a CD4+ count of more than 500 cells per cubic millimeter and 6935 (76%) deferred therapy. Among patients in the deferred-therapy group, there was an increase in the risk of death of 94% (relative risk, 1.94; 95% CI, 1.37 to 2.79; P<0.001). CONCLUSIONS The early initiation of antiretroviral therapy before the CD4+ count fell below two prespecified thresholds significantly improved survival, as compared with deferred therapy.

Competing Risk Regression Models for Epidemiologic Data

Competing events can preclude the event of interest from occurring in epidemiologic data and can be analyzed by using extensions of survival analysis methods. In this paper, the authors outline 3 regression approaches for estimating 2 key quantities in competing risks analysis: the cause-specific relative hazard ((cs)RH) and the subdistribution relative hazard ((sd)RH). They compare and contrast the structure of the risk sets and the interpretation of parameters obtained with these methods. They also demonstrate the use of these methods with data from the Womens Interagency HIV Study established in 1993, treating time to initiation of highly active antiretroviral therapy or to clinical disease progression as competing events. In our example, women with an injection drug use history were less likely than those without a history of injection drug use to initiate therapy prior to progression to acquired immunodeficiency syndrome or death by both measures of association ((cs)RH = 0.67, 95% confidence interval: 0.57, 0.80 and (sd)RH = 0.60, 95% confidence interval: 0.50, 0.71). Moreover, the relative hazards for disease progression prior to treatment were elevated ((cs)RH = 1.71, 95% confidence interval: 1.37, 2.13 and (sd)RH = 2.01, 95% confidence interval: 1.62, 2.51). Methods for competing risks should be used by epidemiologists, with the choice of method guided by the scientific question.

Risk of Anal Cancer in HIV-Infected and HIV-Uninfected Individuals in North America

BACKGROUND Anal cancer is one of the most common cancers affecting individuals infected with human immunodeficiency virus (HIV), although few have evaluated rates separately for men who have sex with men (MSM), other men, and women. There are also conflicting data regarding calendar trends. METHODS In a study involving 13 cohorts from North America with follow-up between 1996 and 2007, we compared anal cancer incidence rates among 34 189 HIV-infected (55% MSM, 19% other men, 26% women) and 114 260 HIV-uninfected individuals (90% men). RESULTS Among men, the unadjusted anal cancer incidence rates per 100 000 person-years were 131 for HIV-infected MSM, 46 for other HIV-infected men, and 2 for HIV-uninfected men, corresponding to demographically adjusted rate ratios (RRs) of 80.3 (95% confidence interval [CI], 42.7-151.1) for HIV-infected MSM and 26.7 (95% CI, 11.5-61.7) for other HIV-infected men compared with HIV-uninfected men. HIV-infected women had an anal cancer rate of 30/100 000 person-years, and no cases were observed for HIV-uninfected women. In a multivariable Poisson regression model, among HIV-infected individuals, the risk was higher for MSM compared with other men (RR, 3.3; 95% CI, 1.8-6.0), but no difference was observed comparing women with other men (RR, 1.0; 95% CI, 0.5-2.2). In comparison with the period 2000-2003, HIV-infected individuals had an adjusted RR of 0.5 (95% CI, .3-.9) in 1996-1999 and 0.9 (95% CI, .6-1.2) in 2004-2007. CONCLUSIONS Anal cancer rates were substantially higher for HIV-infected MSM, other men, and women compared with HIV-uninfected individuals, suggesting a need for universal prevention efforts. Rates increased after the early antiretroviral therapy era and then plateaued.

Hazardous alcohol use: a risk factor for non-adherence and lack of suppression in HIV infection.

Objective:We examined the independent effect of alcohol and combined effects of drug and alcohol use on antiretroviral (ART) utilization, adherence, and viral suppression in an urban cohort of HIV-infected individuals. Methods:In an observational clinical cohort, alcohol use, active drug use, and adherence were prospectively assessed at 6-month intervals. We classified hazardous alcohol use as >7 drinks/week or >3 drinks/occasion in women, and >14 drinks/week or >4 drinks/occasion in men and active drug use as any use in the previous 6 months. Our outcomes included ART utilization, 2-week adherence, and viral suppression. We used generalized estimating equations to analyze the association between independent variables and outcomes. Analyses were adjusted for age, sex, race, years on ART, and clinic enrollment time. Results:Between 1998 and 2003, 1711 individuals participated in 5028 interviews. 1433 of these individuals received ART accounting for 3761 interviews. The prevalence of any alcohol use at the first interview was 45%, with 10% classified as hazardous drinkers. One-third of the sample used illicit drugs. In multivariate analyses adjusting for age, sex, race, active drug use, years on ART, and clinic enrollment time, hazardous alcohol use was independently associated with decreased ART utilization (AOR, 0.65; 95% CI: 0.51 to 0.82), 2-week adherence (AOR, 0.46; 95% CI: 0.34 to 0.63), and viral suppression (AOR, 0.76; 95% CI: 0.57 to 0.99) compared to no alcohol use. Concurrent injection drug use (IDU) exacerbated this negative effect on ART use, adherence, and suppression. Conclusions:Hazardous alcohol use alone and combined with IDU was associated with decreased ART uptake, adherence, and viral suppression. Interventions targeting alcohol use may improve HIV outcomes in individuals with hazardous alcohol use.

Chronic Kidney Disease Incidence, and Progression to End-Stage Renal Disease, in HIV-Infected Individuals: A Tale of Two Races

BACKGROUND Little is known about the racial differences in the incidence and progression of HIV-related chronic kidney disease (CKD) that underlie African American-white disparities in HIV-related end-stage renal disease (ESRD). METHODS In a cohort in Baltimore, Maryland, we measured CKD incidence, glomerular filtration rate (GFR) slope, and progression to ESRD in 3332 African American and 927 white HIV-infected subjects. RESULTS A total of 284 subjects developed CKD, 100 (35%) of whom subsequently developed ESRD. African American subjects were at slightly increased risk for incident CKD, compared with white subjects (hazard ratio [HR], 1.9 [95% confidence interval {CI}, 1.2-2.8]). However, once CKD had commenced, the African American subjects developed ESRD markedly faster than did the white subjects (HR, 17.7 [95% CI, 2.5-127.0]), and, correspondingly, their GFR decline after diagnosis of CKD was 6-fold more rapid (P < .001). In the subset of African American subjects for whom kidney-biopsy data were available, progression to ESRD was significantly faster than that in white subjects with CKD, irrespective of the presence of HIV-associated nephropathy. CONCLUSIONS The results of this study suggest that African American-white disparities in HIV-related ESRD are explained predominantly by a more aggressive natural disease history in African Americans and less by racial differences in CKD incidence.

Association of race and gender with HIV-1 RNA levels and immunologic progression

Context: HIV‐1 RNA and lymphocyte subset levels are the principal indications for antiretroviral treatment. Past reports have differed with regard to the effect of gender and race on these measures and in measures of disease progression. Objective: To assess racial and gender differences in HIV‐1 RNA levels and CD4+ lymphocyte decline. Design: A longitudinal study based in the two largest HIV natural history cohort studies conducted in 7 metropolitan areas of the United States. Results: In all, 1256 adult women and 1603 adult men for whom multiple data points were available prior to initiation of antiretroviral therapy were included. Women were more likely to be nonwhite, to have a history of injection drug use, and to have HIV‐associated symptoms. After adjustment for differences in measurement method, baseline CD4+ cell count, age, and clinical symptoms, HIV‐1 RNA levels were 32% to 50% lower in women than in men at CD4+ counts >200 cells/mm3 (p < .001) but not at CD4+ cell counts <200 cells/mm3. HIV‐1 RNA levels were also 41% lower in nonwhites than in whites (p < .001) and 21% lower in persons reporting a prior history of injection drug use (p < .001). Women had more rapid declines in CD4+ cell counts over time than men (difference in slope of 46 cells/year) and nonwhite individuals had slower decline in CD4 cell counts than whites (difference of 39 cells/year). Conclusions: Both race and gender influence the values of HIV‐1 RNA and the rate of HIV‐1 disease progression as indicated by decline in CD4 cell counts over time. These effects could provide clues regarding the factors that influence HIV‐disease progression and may indicate that guidelines for therapy should be adjusted for demographic characteristics.

Risk of Non-aids-related Mortality May Exceed Risk of Aids-related Mortality Among Individuals Enrolling Into Care With Cd4+ Counts Greater Than 200 Cells/mm3

Objective:To quantify cause-specific mortality risk attributable to non-AIDS-related and AIDS-related causes before and after the advent of highly active antiretroviral therapy (HAART). Methods:Competing-risk methods were used to determine the cumulative AIDS-related and non-AIDS-related risk of mortality between 1990 and the end of 2003 in the Johns Hopkins HIV Clinical Cohort, a prospective cohort study. Results:Beginning in 1997 with the introduction of HAART, all-cause mortality declined and has remained stable at approximately 39 deaths per 1000 person-years. AIDS-related mortality continued to decline in this period (P = 0.008), whereas non-AIDS-related mortality increased (P < 0.001). Using competing-risk methods, the risk of dying attributable to AIDS-related causes remains significantly higher than the risk of dying attributable to non-AIDS-related causes for patients with a CD4+ count ≤200 cells/mm3 in the HAART era. For those with a CD4+ count >200 cells/mm3, however, non-AIDS-related mortality was greater than AIDS-related mortality, particularly among injection drug users. Other transmission categories had similar AIDS-related and non-AIDS-related cumulative mortalities. Conclusions:HAART has reduced mortality rates among HIV-infected individuals, but further efforts to reduce mortality in this population require increased attention to conditions that have not traditionally been considered to be HIV related.

Risk factors for chronic kidney disease in a large cohort of HIV-1 infected individuals initiating antiretroviral therapy in routine care

Objective:To examine long-term effects of antiretroviral therapy (ART) on kidney function, we evaluated the incidence and risk factors for chronic kidney disease (CKD) among ART-naive, HIV-infected adults and compared changes in estimated glomerular filtration rates (eGFR) before and after starting ART. Methods:Multicenter observational cohort study of patients with at least one serum creatinine measurement before and after initiating ART. Cox proportional hazard models, and marginal structure models examined CKD risk factors; mixed-effects linear models examined eGFR slopes. Results:Three thousand, three hundred and twenty-nine patients met entry criteria, contributing 10 099 person-years of observation on ART. ART was associated with a significantly slower rate of eGFR decline (from −2.18 to −1.37 ml/min per 1.73 m2 per year; P = 0.02). The incidence of CKD defined by eGFR thresholds of 60, 45 and 30 ml/min per 1.73 m2 was 10.5, 3.4 and 1.6 per 1000 person-years, respectively. In adjusted analyses black race, hepatitis C coinfection, lower time-varying CD4 cell count and higher time-varying viral load on ART were associated with higher CKD risk, and the magnitude of these risks increased with more severe CKD. Tenofovir and a ritonavir-boosted protease inhibitor (rPI) was also associated with higher CKD risk [hazard odds ratio for an eGFR threshold <60 ml/min per 1.73 m2: 3.35 (95% confidence interval (CI) = 1.40–8.02)], which developed in 5.7% of patients after 4 years of exposure to this regimen-type. Conclusion:ART was associated with reduced CKD risk in association with CD4 cell restoration and plasma viral load suppression, despite an increased CKD risk that was associated with initial regimens that included tenofovir and rPI.

Importance of Age of Onset in Pancreatic Cancer Kindreds

Background Young-onset cancer is a hallmark of many familial cancer syndromes, yet the implications of young-onset disease in predicting risk of pancreatic cancer among familial pancreatic cancer (FPC) kindred members remain unclear. Methods To understand the relationship between age at onset of pancreatic cancer and risk of pancreatic cancer in kindred members, we compared the observed incidence of pancreatic cancer in 9040 individuals from 1718 kindreds enrolled in the National Familial Pancreas Tumor Registry with that observed in the general US population (Surveillance, Epidemiology, and End Results). Standardized incidence ratios (SIRs) were calculated for data stratified by familial vs sporadic cancer kindred membership, number of affected relatives, youngest age of onset among relatives, and smoking status. Competing risk survival analyses were performed to examine the risk of pancreatic cancer and risk of death from other causes according to youngest age of onset of pancreatic cancer in the family and the number of affected relatives. Results Risk of pancreatic cancer was elevated in both FPC kindred members (SIR = 6.79, 95% confidence interval [CI] = 4.54 to 9.75, P < .001) and sporadic pancreatic cancer (SPC) kindred members (SIR = 2.41, 95% CI = 1.04 to 4.74, P = .04) compared with the general population. The presence of a young-onset patient (<50 years) in the family did not alter the risk for SPC kindred members (SIR = 2.74, 95% CI = 0.05 to 15.30, P = .59) compared with those without a young-onset case in the kindred (SIR = 2.36, 95% CI = 0.95 to 4.88, P = .06). However, risk was higher among members of FPC kindreds with a young-onset case in the kindred (SIR = 9.31, 95% CI = 3.42 to 20.28, P < .001) than those without a young-onset case in the kindred (SIR = 6.34, 95% CI = 4.02 to 9.51, P < .001). Competing risk survival analyses indicated that the lifetime risk of pancreatic cancer in FPC kindreds increased with decreasing age of onset in the kindred (hazard ratio = 1.55, 95% CI = 1.19 to 2.03 per year). However, youngest age of onset for pancreatic cancer in the kindred did not affect the risk among SPC kindred members. Conclusions Individuals with a family history of pancreatic cancer are at a statistically significantly increased risk of developing pancreatic cancer. Having a member of the family with a young-onset pancreatic cancer confers an added risk in FPC kindreds.

Viremia Copy-Years Predicts Mortality Among Treatment-Naive HIV-Infected Patients Initiating Antiretroviral Therapy

BACKGROUND Cross-sectional plasma human immunodeficiency virus (HIV) viral load (VL) measures have proven invaluable for clinical and research purposes. However, cross-sectional VL measures fail to capture cumulative plasma HIV burden longitudinally. We evaluated the cumulative effect of exposure to HIV replication on mortality following initiation of combination antiretroviral therapy (ART). METHODS We included treatment-naive HIV-infected patients starting ART from 2000 to 2008 at 8 Center for AIDS Research Network of Integrated Clinical Systems sites. Viremia copy-years, a time-varying measure of cumulative plasma HIV exposure, were determined for each patient using the area under the VL curve. Multivariable Cox models were used to evaluate the independent association of viremia copy-years for all-cause mortality. RESULTS Among 2027 patients contributing 6579 person-years of follow-up, the median viremia copy-years was 5.3 log₁₀ copy × y/mL (interquartile range: 4.9-6.3 log₁₀ copy × y/mL), and 85 patients (4.2%) died. When evaluated separately, viremia copy-years (hazard ratio [HR] = 1.81 per log₁₀ copy × y/mL; 95% confidence interval [CI], 1.51-2.18 per log(10) copy × y/mL), 24-week VL (1.74 per log₁₀ copies/mL; 95% CI, 1.48-2.04 per log₁₀ copies/mL), and most recent VL (HR = 1.89 per log₁₀ copies/mL; 95% CI: 1.63-2.20 per log₁₀ copies/mL) were associated with increased mortality. When simultaneously evaluating VL measures and controlling for other covariates, viremia copy-years increased mortality risk (HR = 1.44 per log₁₀ copy × y/mL; 95% CI, 1.07-1.94 per log₁₀ copy × y/mL), whereas no cross-sectional VL measure was independently associated with mortality. CONCLUSIONS Viremia copy-years predicted all-cause mortality independent of traditional, cross-sectional VL measures and time-updated CD4+ T-lymphocyte count in ART-treated patients, suggesting cumulative HIV replication causes harm independent of its effect on the degree of immunodeficiency.