A Qualitative Assessment of Clinical Practice Guidelines and Patterns for Congenital Cytomegalovirus in the United States.

Cytomegalovirus (CMV) infection during pregnancy may result in long-term health problems for children with congenital CMV (cCMV). Currently, no prevention or treatment interventions are approved by the Food and Drug Administration for a cCMV indication. Healthcare provider and public awareness is low, and formal clinical practice guidelines and local practice patterns vary. A pilot study of eight cCMV experts was performed using qualitative semi-structured interviews to better understand clinical practice guidelines and patterns in the United States. Results from participant interviews highlighted the need for better prenatal diagnostic techniques, broader neonatal screening opportunities, and more robust evidence supporting intervention strategies. Healthcare provider and public partnerships are essential for advancing cCMV guidelines and improving care delivery. Our results provide a preliminary knowledge base and framework for developing a consensus cCMV research agenda to address evidence gaps that limit the revision of clinical practice guidelines. The changes in clinical practice patterns that may arise as a result of further research have the potential to reduce risk during pregnancy and improve care for children with cCMV infection.

Cross-sectional comparison of age- and gender-related comorbidities in people living with HIV in Canada.

Because antiretroviral therapy (ART) is allowing people living with human immunodeficiency virus (PLWH) to survive longer, they are developing more age-related comorbidities. We evaluated the effects of age and gender on the burden of age-related comorbidities among PLWH. In this retrospective real-world study, de-identified data were extracted from the medical charts of 2000 HIV-positive adults on ART across 10 sites in Canada. The prevalence of age-related comorbidities was determined in 6 age subgroups (<30, 30-39, 40-49, 50-59, 60-69, and ≥70 years). The effects of gender on these comorbidities were also examined. Risks of cardiovascular disease and chronic kidney disease (CKD) were calculated using the Framingham and D:A:D equations. Most persons were White (68%), male (87%), and virologically suppressed (94%). The mean age was 50.3 years (57% aged ≥50 years), and mean CD4+ T-cell count was 616 cells/mm3. The most common comorbidities were neuropsychiatric symptoms (61%), overweight/obesity (43%), liver disease (37%), and dyslipidemia (37%). The mean number of comorbidities increased across age subgroups (P < .001). Across all age subgroups, the prevalence of hypertension (P = .04), dyslipidemia (P = .04), CKD (P = .03), bone fragility (P = .03), and depression (P = .02) differed between males and females. Both age (P < .001) and gender (P < .001) impacted cardiovascular disease and CKD risk. Age and gender influenced the burden, types, and risks of age-related comorbidities in PLWH in this Canadian cohort. These comorbidities should be diagnosed and treated in routine clinical practice.

Healthcare resource utilization and costs associated with renal, bone and cardiovascular comorbidities among persons living with HIV compared to the general population in Quebec, Canada.

There is limited understanding on healthcare utilization and costs of age-related comorbidities such as cardiovascular, bone and renal disease/disorder in people living with human immunodeficiency virus, so we compared comorbidity prevalence and associated healthcare utilization and costs. Through the Quebec health insurance database, people living with human immunodeficiency virus on antiretroviral therapy for ≥6 months from January 2006 to June 2012 were categorized by their comorbidity status using International Classification of Diseases (ICD)-9 codes, and controls without human immunodeficiency virus diagnosis or antiretroviral therapy use were age and gender matched. We compared healthcare utilization and costs. A total of 3,905 people living with human immunodeficiency virus and 11,715 control individuals were included. The mean age of people living with human immunodeficiency virus was 45.3 years and 77.3% were men. Prevalence of comorbidities was higher and occurred earlier in people living with human immunodeficiency virus and increased with older age regardless of human immunodeficiency virus status. Interestingly, bone comorbidity was high (37%) and 5-fold greater in people living with human immunodeficiency virus <20 years than the controls. Polypharmacy and comorbidity scores were greater in people living with human immunodeficiency virus than controls (p<0.01), as were cardiovascular, bone and renal comorbidities (40.3%, 26.0% and 5.5%, respectively; p<0.01). People living with human immunodeficiency virus had higher healthcare utilization and costs than controls largely due to longer hospital stays and prescriptions. Mean total healthcare cost/person/year for people living with human immunodeficiency virus was CAD$6,248 and was highest for those with renal disease (CAD$19,617). Comorbidities in people living with human immunodeficiency virus are more prevalent, occur earlier and incur a higher burden on the healthcare system; earlier screening and improved preventative and management strategies may reduce the burden to people living with human immunodeficiency virus and to the healthcare system.

A Randomized Trial of Time-Limited Antiretroviral Therapy in Acute/Early HIV Infection.

BACKGROUND: It has been proposed that initiation of antiretroviral treatment (ART) very soon after establishment of HIV infection may be beneficial by improving host control of HIV replication and delaying disease progression. METHODS: People with documented HIV infection of less than 12 months' duration in Baltimore MD and seven Canadian sites were randomized to either a) observation and deferred ART, or b) immediate treatment with ART for 12 months. All subjects not receiving ART were followed quarterly and permanent ART was initiated according to contemporaneous treatment guidelines. The endpoint of the trial was total ART-free time from study entry until initiation of permanent ART. RESULTS: One hundred thirteen people were randomized, 56 to the observation arm and 57 to the immediate treatment arm. Twenty-three had acute (<2 months) infection and 90 early (2-12 months) infection. Of those randomized to the immediate treatment arm, 37 completed 12 months of ART according to protocol, 9 declined to stop ART after 12 months, and 11 were nonadherent to the protocol or lost to follow-up. Comparing those in the observation arm to either those who completed 12 months of ART or all 56 who were randomized to immediate ART, there was no significant difference between the arms in treatment-free interval after study entry, which was about 18 months in both arms. CONCLUSIONS: This study did not find a benefit from administration of a brief, time-limited (12-month) course of ART in acute or early HIV infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT00106171.

A pilot, prospective, open-label simplification study to evaluate the safety, efficacy, and pharmacokinetics of once-daily lopinavir-ritonavir monotherapy in HIV-HCV coinfected patients: the MONOCO study.

BACKGROUND: A safe, effective, easy-to-dose antiretroviral therapy that minimizes hepatic complication risk is essential in optimizing HIV-HCV treatment. Nucleoside-sparing boosted protease inhibitor monotherapy may achieve this goal. METHODS: A prospective, open-label pilot simplification study of once-daily lopinavir/ritonavir (LPV/r) monotherapy in HIV-HCV coinfected patients was conducted in patients on HAART with undetectable HIV RNA for ≥6 months. The primary outcome was maintenance of HIV RNA<50 copies/mL through week 48. HIV RNA, immune measures, metabolic markers, and pharmacokinetics were assessed. RESULTS: Twenty participants received once-daily LPV/r monotherapy. Mean baseline age was 46.9 years and CD4 467 cells/L. By per protocol analysis, 71.4% (95% CI, 45.4-88.3) remained on once-daily LPV/r monotherapy with virologic suppression at week 48. Virologic breakthrough (HIV RNA>50 copies/mL on 2 consecutive measures) occurred in 7 patients (mean standard error [SE] time to breakthrough, 38.3 [4.8] weeks). Resuppression occurred with improved adherence in 2 participants and improved adherence plus addition of nucleosides in 2 others. LPV C min was <1 mg/L in 8 patients and was associated with virologic breakthrough in 2 cases but with no development of resistance. No clinically significant changes in CD4, lipids, or glucose were noted. Three participants developed transient≥5-fold liver enzyme elevations. None of 9 severe adverse events were LPV/r- or liver-related. Six discontinued participation for withdrawal of consent (n=1), poor adherence (n=3), or drug intolerance (n=2). CONCLUSIONS: Once-daily LPV/r monotherapy in HIV-HCV coinfected individuals offers a safe and effective approach to the management of the HIV infection, with a predictable pharmacokinetic profile.

Comprehensive Approaches to the Diagnosis and Treatment of HIV Infection in the Community: Can "Seek and Treat" Really Deliver?

For every two people starting on combination antiretroviral therapy (cART), five become infected with HIV. Current prevention strategies are inadequate, and it has been hypothesized that cART itself could be used as a tool for prevention, in combination with enhanced testing and access to treatment-the "seek and treat" approach. Ecologic and modeling data support this strategy, but many questions remain: how to optimize HIV testing, cART uptake and adherence, how to deal with treatment failure and toxicity, and how to implement integrated prevention strategies and deal with key comorbidities. Pilot studies (eg, HIV Prevention Trials Network 065) are underway to validate the approach under controlled circumstances before it is integrated into public health policy. As we redefine the potential benefits of cART on a broader scale, let us not sacrifice the gains that have been made until we are more certain of the potential benefits of the "seek and treat" strategy.

Primary drug resistance in antiretroviral-naïve injection drug users.

OBJECTIVES: We evaluated the prevalence of primary HIV drug resistance in a population of 128 injection drug users (48 female) prior to initiating antiretroviral therapy. METHODS: Genotypic and phenotypic profiles were obtained retrospectively for the period June 1996 to February 2007. Genotypic drug resistance was defined as the presence of a major mutation (IAS-USA table, 2007 revision), adding revertants at reverse transcriptase (RT) codon 215. Phenotypic drug resistance was defined as the fold change associated with >or=80% loss of the wild type virologic response due to viral resistance based on virtual phenotype analysis. RESULTS: Genotypic drug resistance was uncommon, and was only identified in six (4.7%) cases, all in the RT gene (L100I, K103N, Y181C, M184V, Y188L, and T215D). There were no cases of multi-class or protease inhibitor (PI) resistance. However, polymorphisms in the protease and RT genes were extremely common. Phenotypic drug resistance was also identified in six (4.7%) patients, four in the RT gene (in patients with mutations K103N, Y181C, M184V and Y188L) and two the protease gene (in two patients with minor PI mutations). In addition, 25 (19.5%) of the patients had reduced susceptibility to PIs, defined as resistance>20% but <80% of the wild type virologic response, with no primary PI mutations detected in all these patients. CONCLUSION: The prevalence of primary HIV drug resistance was low in this population of injection drug users.

Methadone dosing strategies in HIV-infected injection drug users enrolled in a directly observed therapy program.

OBJECTIVES: We have measured methadone dose adjustments and treatment responses after nevirapine (NVP)-, efavirenz (EFV)-, ritonavir-boosted lopinavir (LPV/r), or atazanavir (ATV; with or without ritonavir)-based highly active antiretroviral therapy (HAART) was initiated in injection drug users (IDUs). METHODS: We identified 120 IDUs receiving HAART and methadone within a directly observed therapy (DOT) program. Follow-up was according to clinical standards, with changes in methadone dose being made as required to achieve clinical stabilization within the first 3 months of HAART. RESULTS: The observed median methadone dose changes from baseline were 20 mg/d (P<0.001) in patients on NVP, with 32 (86%) of 37 patients requiring daily dose increases, and 7.5 mg/d (P=0.004) in patients on EFV, with 11 (61%) of 18 patients requiring daily dose increases. Conversely, median changes were 0 mg/d for patients on LPV/r (P=0.56) or ATV (P=0.95). Virologic suppression (HIV RNA<400 copies/mL) was achieved in 26 (70%) of 37, 12 (67%) of 18, 25 (76%) of 33, and 24 (75%) of 32 patients receiving NVP-, EFV-, LPV/r-, and ATV-based regimens, respectively (P=0.89). CONCLUSIONS: Although methadone-based DOT can be a successful tool for the coadministration of HAART, careful monitoring is required to ensure that methadone withdrawal does not adversely affect the goals of treatment, particularly when nonnucleoside reverse transcriptase inhibitors are used.

The impact of ongoing illicit drug use on methadone adherence in illicit drug users receiving treatment for HIV in a directly observed therapy program.

INTRODUCTION: Studies evaluating the effectiveness of opioid agonist therapy programs typically evaluate drug abstinence or treatment retention as their primary outcomes. However, in many circumstances (e.g. directly observed therapy (DOT) programs within methadone maintenance programs), methadone adherence is an extremely relevant clinical outcome. We sought to evaluate the impact of ongoing illicit drug use on methadone adherence within a DOT program for the treatment of HIV-infection. METHODS: Patients were enrolled in a DOT program, where methadone and HIV medication are co-administered by a community pharmacist. Drug use (amphetamines, benzodiazepines, cocaine, and opiates) was assessed by repeated urinalysis results. Methadone adherence was calculated as the fraction of days methadone was administered. RESULTS: Ongoing drug use, and poly-substance use was common, with only 4 of 60 patients abstaining from all illicit drug use. Overall methadone adherence was 84.5%. Amphetamine use (without benzodiazepine and cocaine use), benzodiazepine use (without amphetamines) and higher methadone doses were associated with higher methadone adherence. When patients used benzodiazepines or cocaine, any positive effect associated with amphetamine use was negated. In addition, opiate use was associated with decreased methadone adherence. DISCUSSION: The effect of many illicit drugs on methadone adherence may differ from reports using other treatment outcomes.

Clinical implications of mutations at reverse transcriptase codon 135 on response to NNRTI-based therapy.

To evaluate the impact of mutations at reverse transcriptase codon 135 on treatment outcomes in patients receiving NNRTI-based antiretroviral therapy, a total of 68 patients (30 with and 38 without baseline mutations at codon 135) were evaluated. Median increases in CD4 counts were 135 and 90 cells/mm(3) (p=0.32), virologic suppression (HIV RNA < 400 copies/mL) was achieved in 16 (53%) and 16 (42%) patients (p=0.50), while NNRTI resistance was detected in 10/14 (71%) and 16/22 (73%) in patients with and without mutations at codon 135, respectively. Patients who experienced a virologic breakthrough and had a baseline mutation at codon 135 were more likely to evolve a single NNRTI resistance mutation (8/14 vs 4/22, p=0.029) but less likely to evolve multiple NNRTI resistance mutations (2/14 vs 12/22, p = 0.033). Mutations at codon 135 do not affect response rates, but affect the pattern of development of NNRTI resistance mutations. This has important implications for the subsequent use of newer NNRTIs such as etravirine in salvage therapy.

A systematic approach to the treatment of HIV and hepatitis C virus infection in the inner city: a Canadian perspective.

The treatment of injection drug users (IDUs) coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) presents multiple challenges, many of which could be addressed by the development of directly observed therapy programs. This is made all the more feasible by the validation of once-daily treatment regimens for HIV. We have demonstrated that virological suppression can be achieved and maintained in as many as 80% of active IDUs who have received highly active antiretroviral therapy for 48 months. This approach has now been validated in first- and second-line therapy, as well as for the treatment of bacterial infections in this population, achieving therapeutic results similar to those reported in the general population. The model is now being applied to the treatment of HCV infection, focusing on patients with infection due to HCV genotype 2 or 3, in whom the likelihood of response may exceed 80%. Our ultimate goal is to ensure that, even in treating IDUs in the inner city, no patient is left behind.