When to start antiretroviral therapy: as soon as possible

BACKGROUND: The debate regarding ‘When to Start’ antiretroviral therapy has raged since the introduction of zidovudine in 1987. Based on the entry criteria for the original Burroughs Wellcome 002 study, the field has been anchored to CD4 cell counts as the prime metric to indicate treatment initiation for asymptomatic individuals infected with Human Immunodeficiency Virus. The pendulum has swung back and forth based mostly on the relative efficacy, toxicity and convenience of available regimens. DISCUSSION: In today’s world, several factors have converged that compel us to initiate therapy as soon as possible: 1) The biology of viral replication (1 to 10 billion viruses per day) strongly suggests that we should be starting early. 2) Resultant inflammation from unchecked replication is associated with earlier onset of multiple co-morbid conditions. 3) The medications available today are more efficacious and less toxic than years past. 4) Clinical trials have demonstrated benefits for all but the highest CD4 strata (>500 cells/μl). 5) Some cohort studies have demonstrated the clear benefit of antiretroviral therapy at any CD4 count and no cohort studies have demonstrated that early therapy is more detrimental than late therapy at the population level. 6) In addition to the demonstrated and inferred benefits to the individual patient, we now have evidence of a Public Health benefit from earlier intervention: treatment is prevention. SUMMARY: From a practical, common sense perspective we are talking about life-long therapy. Whether we start at a CD4 count of 732 cells/μl or 493 cells/μl, the patient will be on therapy for over 40 to 50 years. There does not seem to be much benefit in waiting and there likely is significant long-term harm. Do not wait. Treat early. The counter-argument to this debate topic can be freely accessed here: http://www.biomedcentral.com/1741-7015/11/148

Integrated safety studies of the urate reabsorption inhibitor lesinurad in treatment of gout.

ObjectiveLesinurad (LESU) is a selective urate reabsorption inhibitor approved at 200 mg daily for use with a xanthine oxidase inhibitor (XOI) to treat hyperuricaemia in gout patients failing to achieve target serum urate on XOI. The aim of the study was to investigate the long-term safety of LESU + XOI therapy.MethodsSafety data were pooled from three 12-month phase III (core) trials evaluating LESU 200 and 400 mg/day combined with an XOI (LESU200+XOI and LESU400+XOI), and two 12-month extension studies using descriptive statistics. To adjust for treatment duration, treatment-emergent adverse events (TEAEs) were expressed as exposure-adjusted incidence rates (patients with events per 100 person-years).ResultsIn the core studies, exposure-adjusted incidence rates for total and total renal-related TEAEs were comparable for XOI alone and LESU200+XOI but higher with LESU400+XOI. Exposure-adjusted incidence rates for serum creatinine (sCr) elevations ⩾1.5×baseline were 2.9, 7.3 and 18.7, respectively. Resolution (sCr ⩽1.2×baseline) occurred in 75-90% of all events, with 66-75% occurring without any study medication interruption. Major adverse cardiovascular events were 3, 4 and 9 with XOI, LESU200+XOI and LESU400+XOI, respectively. Longer exposure in core+extension studies did not increase rates for any safety signals.ConclusionAt the approved dose of 200 mg once-daily combined with an XOI, LESU did not increase renal, cardiovascular or other adverse events compared with XOI alone, except for sCr elevations. With extended exposure in the core+extension studies, the safety profile was consistent with that observed in the core studies, and no new safety concerns were identified

Health-Related Quality of Life in the Gender, Race, And Clinical Experience Trial

Background. We report health-related QoL (HRQoL) from GRACE (Gender, Race, And Clinical Experience) study by sex and race over 48 weeks. Methods. 429 treatment-experienced adults (HIV-1 RNA ≥ 1000 copies/mL) received darunavir/ritonavir 600/100 mg twice daily plus an appropriate background regimen. QoL was measured by the Functional Assessment of HIV Infection (FAHI) questionnaire. Results. 67% women and 77% men, including 67.4% black, 76.0% Hispanic, and 73.8% white patients, completed the trial. Baseline total FAHI scores were similar between sexes and races. Total FAHI of the entire population improved by Week 4 (P < .05); near-maximum changes obtained by Week 12 were maintained through Week 48. Women and black patients demonstrated larger improvements in total FAHI versus men, and Hispanic and white patients, respectively. Conclusion. HRQoL improved in all sex and racial/ethnic groups. Sex-based and race-based differences in improvements in FAHI subscales may provide insight into subtle differences of HIV-1 and treatment on HRQoL in different populations

Clinical inertia in the management of low-density lipoprotein abnormalities in an HIV clinic

A retrospective cohort study evaluating the frequency of and factors related to clinical inertia in low-density lipoprotein (LDL) management was performed. Subjects were 90 patients that were not meeting National Cholesterol Education Program Adult Treatment Panel III LDL goals at the University of Alabama at Birmingham 1917 HIV/AIDS Clinic between 1 August 2004 and 1 August 2005. Clinical inertia was observed in 44% of cases. Patients with higher baseline LDL levels were less likely to experience inertia, whereas women and those in the highest coronary heart disease risk category were more likely to be affected

Nucleoside reverse-transcriptase inhibitor dosing errors in an outpatient HIV clinic in the electronic medical record era

Information on antiretroviral dosing errors among health care providers for outpatient human immunodeficiency virus (HIV)-infected patients is lacking. We evaluated factors associated with nucleoside reverse-transcriptase inhibitor dosing errors in a university-based HIV clinic using an electronic medical record. Overall, older age, minority race or ethnicity, and didanosine use were related to such errors. Impaired renal function was more common in older patients and racial or ethnic minorities and, in conjunction with fixed-dose combination drugs, contributed to the higher rates of errors in nucleoside reverse-transcriptase inhibitor dosing. Understanding the factors related to nucleoside reverse-transcriptase inhibitor dosing errors is an important step in the building of preventive tools

Association Between Chronic Hepatitis C Virus Infection and Myocardial Infarction Among People Living With HIV in the United States.

Hepatitis C virus (HCV) infection is common among people living with human immunodeficiency virus (PLWH). Extrahepatic manifestations of HCV, including myocardial infarction (MI), are a topic of active research. MI is classified into types, predominantly atheroembolic type 1 MI (T1MI) and supply-demand mismatch type 2 MI (T2MI). We examined the association between HCV and MI among patients in the Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems, a US multicenter clinical cohort of PLWH. MIs were centrally adjudicated and categorized by type using the Third Universal Definition of Myocardial Infarction. We estimated the association between chronic HCV (RNA+) and time to MI while adjusting for demographic characteristics, cardiovascular risk factors, clinical characteristics, and history of injecting drug use. Among 23,407 PLWH aged ≥18 years, there were 336 T1MIs and 330 T2MIs during a median of 4.7 years of follow-up between 1998 and 2016. HCV was associated with a 46% greater risk of T2MI (adjusted hazard ratio (aHR)&nbsp;=&nbsp;1.46, 95% confidence interval (CI): 1.09, 1.97) but not T1MI (aHR&nbsp;=&nbsp;0.87, 95% CI: 0.58, 1.29). In an exploratory cause-specific analysis of T2MI, HCV was associated with a 2-fold greater risk of T2MI attributed to sepsis (aHR&nbsp;=&nbsp;2.01, 95% CI: 1.25, 3.24). Extrahepatic manifestations of HCV in this high-risk population are an important area for continued research

Comparative efficacy versus effectiveness of initial antiretroviral therapy in clinical trials versus routine care

BACKGROUND: The applicability of clinical trial findings (efficacy) to the routine care setting (effectiveness) may be limited because of study eligibility criteria and volunteer bias. Although well-chronicled in many conditions, the efficacy versus effectiveness of antiretroviral therapy (ART) remains understudied. METHODS: A retrospective study of the University of Alabama at Birmingham 1917 Clinic Cohort evaluated ART-naive patients who started ART from 1 January 2000 through 31 December 2006. Patients received ART through clinical trials or routine care. Multivariable logistic and linear regression models were fit to evaluate factors associated with virological failure (virological failure was defined as a viral load \u3e50 copies/mL) and change from baseline CD4+ cell count 6 and 12 months after ART initiation. Sensitivity analyses evaluated the impact of missing data on outcomes. RESULTS: Among 570 patients starting ART during the study period, 121 (21%) enrolled in clinical trials, and 449 (79%) received ART via routine care. ART receipt through routine care was not associated with viral failure at either 6 months (odds ratio [OR], 1.00; 95% confidence interval [CI], 0.54-1.86) or 12 months (OR, 1.56; 95% CI, 0.80-3.05) in primary analyses. No statistically significant differences in CD4+ cell count responses at 6 and 12 months were observed. CONCLUSIONS: Although marked differences in efficacy versus effectiveness have been observed in the therapeutic outcomes of other conditions, our analyses found no evidence of such divergence among our patients who initiated antiretroviral therapy for human immunodeficiency virus infection

Failure to establish HIV care: characterizing the no show phenomenon

It is estimated that up to one-third of persons with known human immunodeficiency virus (HIV) infection in the United States are not engaged in care. We evaluated factors associated with patients\u27 failure to establish outpatient HIV care at our clinic and found that females, racial minorities, and patients lacking private health insurance were more likely to be no shows. At the clinic level, longer waiting time from the call to schedule a new patient visit to the appointment date was associated with failure to establish care. Because increased numbers of patients will be in need of outpatient HIV care as a result of recent Centers for Disease Control and Prevention guidelines advocating routine HIV testing, it is imperative that strategies to improve access are developed to overcome the no show phenomenon