The Antiretroviral Pregnancy Registry: Three decades of prospective monitoring for birth defects.

Purpose: Antiretrovirals (ARVs) are life-saving drugs used for the treatment and prevention of HIV infection and antiviral drugs (AVs) for the treatment of chronic HBV infection. ARVs have proven highly effective in reducing perinatal HIV transmission, however the risk of birth defects from prenatal exposure to ARVs/AVs is an ongoing concern. The Antiretroviral Pregnancy Registry (APR), an international, prospective exposure-registration cohort study, monitors ARV and AV use in pregnancy for early signals of teratogenicity.

Overview of Causality Assessment for Drug-Induced Liver Injury (DILI) in Clinical Trials.

Causality assessment for suspected drug-induced liver injury (DILI) during drug development and following approval is challenging. The IQ DILI Causality Working Group (CWG), in collaboration with academic and regulatory subject matter experts (SMEs), developed this manuscript with the following objectives: (1) understand and describe current practices; (2) evaluate the utility of new tools/methods/practice guidelines; (3) propose a minimal data set needed to assess causality; (4) define best practices; and (5) promote a more structured and universal approach to DILI causality assessment for clinical development. To better understand current practices, the CWG performed a literature review, took a survey of member companies, and collaborated with SMEs.

Consensus Guidelines: Best Practices for Detection, Assessment and Management of Suspected Acute Drug-Induced Liver Injury During Clinical Trials in Adults with Chronic Viral Hepatitis and Adults with Cirrhosis Secondary to Hepatitis B, C and Nonalcoholic Steatohepatitis.

With the widespread development of new drugs to treat chronic liver diseases (CLDs), including viral hepatitis and nonalcoholic steatohepatitis (NASH), more patients are entering trials with abnormal baseline liver tests and with advanced liver injury, including cirrhosis. The current regulatory guidelines addressing the monitoring, diagnosis, and management of suspected drug-induced liver injury (DILI) during clinical trials primarily address individuals entering with normal baseline liver tests. Using the same laboratory criteria cited as signals of potential DILI in studies involving patients with no underlying liver disease and normal baseline liver tests may result in premature and unnecessary cessation of a study drug in a clinical trial population whose abnormal and fluctuating liver tests are actually due to their underlying CLD.

Consensus guidelines: best practices for detection, assessment and management of suspected acute drug-induced liver injury occurring during clinical trials in adults with chronic cholestatic liver disease.

Background: Improved knowledge of the molecular pathophysiology and immunopathogenesis of cholestatic liver diseases in recent years has led to an increased interest in developing novel therapies. Patients with cholestatic liver disease often require different approaches to assessment and management of suspected drug-induced liver injury (DILI) compared to those with healthy livers and those with parenchymal liver diseases. At present, there are no regulatory guidelines or society position papers, that systematically address best practices pertaining to detection of DILI in these patients.

Consensus: guidelines: best practices for detection, assessment and management of suspected acute drug-induced liver injury during clinical trials in patients with nonalcoholic steatohepatitis.

Background: The last decade has seen a rapid growth in the number of clinical trials enrolling patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). Due to the underlying chronic liver disease, patients with NASH often require different approaches to the assessment and management of suspected drug-induced liver injury (DILI) compared to patients with healthy livers. However, currently no regulatory guidelines or position papers systematically address best practices pertaining to DILI in NASH clinical trials.

The Impact of State AIDS Drug Assistance Policies on Clinical and Economic Outcomes of People With HIV.

We investigated the effect of changes to state AIDS Drug Assistance Programs (ADAP) policies, which govern access to antiretroviral therapy (ART), on clinical and economic outcomes among low-income people living with HIV/AIDS. Retrospective analyses of ART access were conducted on state ADAP policies, using data from ADAP Monitoring Reports and Kaiser Family Foundation from 2006 to 2010. We found stricter eligibility requirements reduce the number of HIV-positive individuals with ART access through ADAP, and decreased ART use increases mortality by 2.

Efavirenz Capsule Sprinkle and Liquid Formulations With Didanosine and Emtricitabine in HIV-1-infected Infants and Children 3 Months to 6 Years of Age: Study AI266-922.

Background: AI266-922 was an open-label, dose-ranging study that assessed the pharmacokinetics, safety and efficacy of efavirenz (EFV) in children (3 months to 6 years).

Methods: Antiretroviral-naïve and antiretroviral-experienced HIV-1-infected children received once-daily EFV as oral solution or capsule sprinkle plus didanosine and emtricitabine (FTC). Pharmacokinetic analyses were undertaken at week 2 and repeated at weeks 10 and 18 after an EFV dose change or switch from oral solution to capsule sprinkle.

Comparative value of four measures of retention in expert care in predicting clinical outcomes and health care utilization in HIV patients.

This study compared the ability of four measures of patient retention in HIV expert care to predict clinical outcomes. This retrospective study examined Veterans Health Administration (VHA) beneficiaries with HIV (ICD-9-CM codes 042 or V08) receiving expert care (defined as HIV-1 RNA viral load and CD4 cell count tests occurring within one week of each other) at VHA facilities from October 1, 2006, to September 30, 2008. Patients were ≥18 years old and continuous VHA users for at least 24 months after entry into expert care.

Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial.

Background: Nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons.

Objective: To evaluate 3 nonnucleoside reverse transcriptase inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability.

Design: A phase 3, open-label study randomized in a 1:1:1 ratio with follow-up for at least 96 weeks.

The prospect of a generation free of HIV may be within reach if the right policy decisions are made.

Scientific advances have transformed HIV treatment and prevention, leading to the adoption of an approach that emphasizes broad testing and antiretroviral treatment at earlier stages in the disease, called "test and treat." In addition to clinical benefits, early treatment generates considerable social and economic value. These changes raise the prospect that for the first time since the 1980s, an entire generation might be free of HIV.

Nearly 60,000 uninsured and low-income people with HIV/AIDS live in states that are not expanding Medicaid.

Health insurance gives people living with HIV/AIDS access to medical care, including antiretroviral therapy, which in turn can dramatically improve health and reduce the risk of HIV transmission. Yet many people living with HIV/AIDS remain uninsured. The Affordable Care Act (ACA) seeks to decrease the number of uninsured Americans in part by extending Medicaid coverage to individuals with incomes of up to 138 percent of the federal poverty level.

Early HIV treatment led to life expectancy gains valued at $80 billion for people infected in 1996-2009.

In late 2009 US guidelines for HIV treatment were revised to recommend the initiation of combination antiretroviral therapy (cART) earlier in the course of the disease. We analyzed the life expectancy gains of people infected with HIV between the introduction of cART in 1996 and the 2009 guideline revisions. Compared to people who initiated cART late (defined as having a CD4 cell count of less than 350 per cubic millimeter of blood), those who initiated treatment early (with a CD4 count of 350-500) could expect to live 6.

Early HIV treatment in the United States prevented nearly 13,500 infections per year during 1996-2009.

In recent years, guidelines for HIV treatment have recommended initiation of combination antiretroviral therapy (cART) earlier in the course of the disease than was previously the case. These recommendations stem in part from growing evidence that treatment reduces the risk of sexual transmission. We used an epidemiological model of disease transmission and progression to assess HIV prevention through early treatment-that is, initiation of cART when CD4 white blood cell counts are in excess of 350 cells per cubic millimeter.

Impact of health care payer type on HIV stage of illness at time of initiation of antiretroviral therapy in the USA.

There is evidence that earlier initiation of HIV antiretroviral therapy (ART) is associated with better outcomes, including lower morbidity and mortality. Based on recent studies indicating that Medicaid enrollees are more likely to have suboptimal access to medical care, we hypothesized that HIV severity at time of ART initiation is worse for Medicaid patients than patients with other health care coverage. We conducted a US retrospective analysis of GE Centricity Outpatient Electronic Medical Records spanning 1 January 1997 through 30 September 2009.

Patterns and correlates of linkage to appropriate HIV care after HIV diagnosis in the US Medicaid population.

Background: Timely linkage to appropriate care after human immunodeficiency virus (HIV) diagnosis is critical to optimizing patient outcomes. Medicaid is the largest source of health care coverage for patients with HIV in the United States, yet no studies of linkage to appropriate HIV care have focused solely on the Medicaid population.

Methods: This is a retrospective study using Medicaid claims data from 15 states.

Association between prescription cost sharing and adherence to initial combination antiretroviral therapy in commercially insured antiretroviral-naïve patients with HIV.

Background: In treatment of human immunodeficiency virus (HIV), high levels of adherence to combination antiretroviral therapy (cART) are required to prevent failure of virologic suppression, development of drug resistance, and permanent loss of therapeutic options. No published research has assessed the association between cART prescription cost sharing and adherence to cART.

Objective: To analyze the association between cART prescription cost sharing and adherence to initial cART in commercially insured antiretroviral (ARV)-naïve patients with HIV.

Virologic failures on initial boosted-PI regimen infrequently possess low-level variants with major PI resistance mutations by ultra-deep sequencing.

Background: It is unknown whether HIV-positive patients experiencing virologic failure (VF) on boosted-PI (PI/r) regimens without drug resistant mutations (DRM) by standard genotyping harbor low-level PI resistant variants. CASTLE compared the efficacy of atazanavir/ritonavir (ATV/r) with lopinavir/ritonavir (LPV/r), each in combination with TVD in ARV-naïve subjects.

Objective: To determine if VF on an initial PI/r-based regimen possess low-level resistant variants that may affect a subsequent PI-containing regimen.

Prevalence and clinical significance of HIV drug resistance mutations by ultra-deep sequencing in antiretroviral-naïve subjects in the CASTLE study.

Background: CASTLE compared the efficacy of atazanavir/ritonavir with lopinavir/ritonavir, each in combination with tenofovir-emtricitabine in ARV-naïve subjects from 5 continents.

Objectives: Determine the baseline rate and clinical significance of TDR mutations using ultra-deep sequencing (UDS) in ARV-naïve subjects in CASTLE.

Methods: A case control study was performed on baseline samples for all 53 subjects with virologic failures (VF) at Week 48 and 95 subjects with virologic successes (VS) randomly selected and matched by CD4 count and viral load.

Switch from protease inhibitor- to efavirenz-based antiretroviral therapy improves quality of life, treatment satisfaction and adherence with low rates of virological failure in virologically suppressed patients.

Regimen selection in antiretroviral therapy can impact treatment adherence, quality of life (QoL) and treatment satisfaction, and may influence clinical outcome. We evaluated the effect of regimen switching on virological, safety and patient-reported outcomes. In this 48-week, open-label, randomized, non-inferiority study, 262 HIV-1-infected adult patients with a viral load <50 copies/mL on protease inhibitor (PI)-based regimens were switched to either once-daily efavirenz, lamivudine and enteric-coated didanosine (efavirenz-A [QD]) or once-daily efavirenz plus continuation of current nucleoside reverse transcriptase inhibitors (efavirenz-B).

Virologic suppression, treatment adherence, and improved quality of life on a once-daily efavirenz-based regimen in treatment-Naïve HIV-1-infected patients over 96 weeks.

Purpose: This study evaluated the long-term efficacy, safety, adherence, and quality of life (QoL) of a once-daily efavirenz-based antiretroviral regimen in two 96-week prospective open-label single-arm studies of treatment-naïve HIV-1-infected patients.

Methods: Patients received once-daily efavirenz 600 mg and lamivudine 300 mg with either enteric-coated didanosine 400 mg (Daily Antiretroviral Therapy trial [DART] I) or extended-release stavudine 100 mg (DART II). The primary efficacy outcome measure was HIV RNA <400 copies/mL at Week 48.

Simplification of antiretroviral therapy to a single-tablet regimen consisting of efavirenz, emtricitabine, and tenofovir disoproxil fumarate versus unmodified antiretroviral therapy in virologically suppressed HIV-1-infected patients.

Objective: To evaluate a simplification strategy for HIV-1-infected patients virologically suppressed on antiretroviral therapy (ART) by switching to a single-tablet regimen consisting of efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF).

Design: : Prospective, randomized, controlled, open-label, multicenter study.

Methods: Patients on stable ART with HIV-1 RNA <200 copies per milliliter for > or = 3 months were stratified by prior nonnucleoside reverse transcriptase inhibitor-based or protease inhibitor-based therapy and randomized (2:1) to simplify treatment to EFV/FTC/TDF or to stay on their baseline regimen (SBR).