Systematic review of renal and bone safety of the antiretroviral regimen efavirenz,emtricitabine, and tenofovir disoproxil fumarate in patients with HIV infection

Background: Tenofovir disoproxil fumarate (TDF) is a component of many combinations of antiretroviral treatment (ART) regimens. Although potent and generally well tolerated, TDF may cause renal and bone toxicity. The magnitude of off-target side effects is proposed to be related to tenofovir plasma concentrations, which are affected by food and drug–drug interactions with concomitant antiretrovirals.

Objective: To perform a systematic literature review and qualitatively report on renal and bone safety outcomes associated with efavirenz (EFV), emtricitabine (FTC), and TDF (EFV+FTC+TDF) ART.

Methods: Embase and PubMed databases were searched for randomized clinical trials and observational cohort studies reporting on HIV treatment with EFV+FTC+TDF. Relevant articles were hand-searched for renal (Grade 3–4 serum creatinine/estimated glomerular filtration rate elevations, renal adverse events [AEs], discontinuation due to renal AEs, and urinary biomarkers) and bone outcomes (bone mineral density [BMD] reductions, bone turnover markers, and fracture), and results compiled qualitatively.

Results: Of 337 retrieved articles, 29 reporting renal and 11 reporting bone outcomes met the review criteria. EFV+FTC+TDF was associated with a low frequency of renal AEs and treatment discontinuations due to renal AEs. Renal AEs were more frequent when TDF was taken with protease inhibitor (PI)- or cobicistat-containing ART. EFV+FTC+TDF was associated with reduced BMD and increased bone turnover markers, but BMD reductions were less than with PI-containing ART. No treatment-related bone fractures were identified.

Conclusions: EFV+FTC+TDF appeared to have a more favorable renal safety profile than TDF administered with a PI or cobicistat. BMD decreased with EFV+FTC+TDF, but no treatment-related fractures were identified.     

Simplification to single-tablet regimen of elvitegravir,cobicistat, emtricitabine,tenofovir DF from multi-tablet ritonavir-boosted protease inhibitor plus coformulated emtricitabine and tenofovir DF regimens: week 96 results of STRATEGY-PI

Background: Antiretroviral therapy (ART) simplification to a single-tablet regimen can benefit HIV-1-infected, virologically suppressed, individuals on ART composed of multiple pills.

Objective: We assessed long-term efficacy and safety of switching to co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (E/C/F/TDF) from multi-tablet ritonavir-boosted protease inhibitor (PI + RTV) plus F/TDF (TVD) regimens.

Methods: STRATEGY-PI was a 96-week, phase 3b, randomized (2:1), open-label, non-inferiority study examining the efficacy, safety, and tolerability of switching to E/C/F/TDF from PI + RTV + TVD regimens in virologically suppressed individuals (HIV-1 RNA <50 copies/mL). Participants were randomized to switch to E/C/F/TDF (switch group) or to continue their PI + RTV + TVD regimens (no-switch group). Eligibility criteria included no resistance to F/TDF or history of virologic failure, and estimated creatinine clearance ≥70 mL/min.

Results: At week 96, 87% (252/290) of switch and 70% (97/139) of no-switch participants maintained HIV-1 RNA <50 copies/mL (difference: 17%, 95% CI 8.7–26.0%, p < 0.001). Superiority of the switch to E/C/F/TDF vs. no-switch was due to a smaller proportion of both virologic failures (switch, 1% [3/290]; no-switch, 6% [8/139]) and discontinuations for non-virologic reasons (switch, 11% [31/290]; no-switch, 24% [33/139]). No treatment-emergent resistance was observed in switch subjects with virologic failure. Discontinuation rates from adverse events were 3% in both groups (9/293, switch; 4/140, no-switch). Switching from PI + RTV + TVD to E/C/F/TDF was associated with significant improvements in patient-reported outcomes related to gastrointestinal symptoms (nausea and bloating).

Conclusion: E/C/F/TDF is a safe, effective long-term alternative to multi-tablet PI + RTV + TVD-based regimens in virologically suppressed, HIV-1-infected adults, and improves patient-reported gastrointestinal symptoms.     

Efficacy and safety of “unboosting” atazanavir in a randomized controlled trial among HIV-infected patients receiving tenofovir DF

Objectives: To assess safety and efficacy of a switch to unboosted atazanavir (ATV) among HIV-infected adults receiving ATV/ritonavir (r) and tenofovir disoproxil fumarate (TDF).

Methods: HIV-infected adults with viral load (VL) <40 copies/mL at screening and <150 copies/mL consistently for ≥3 months while receiving a regimen including ATV/r and TDF were randomized to continue ATV/r 300/100 mg daily (control) or change to ATV 400 mg daily (switch), while maintaining their TDF backbone. The primary outcome was proportion of subjects without treatment failure (regimen switch or VL > 200 copies/mL twice consecutively) at 48 weeks.

Results: Fifty participants (46 male, median age 47 years) were randomized, 25 to each arm. At week 48, treatment success occurred in 76% in the control arm and 92% in the switch arm (ITT, p = 0.25). ATV trough levels at week 9 were higher in controls (median 438 ng/mL) than in the switch arm (median 124 ng/mL) (p = 0.003), as was total bilirubin at week 48 (median 38 μmol/L and 28 μmol/L, respectively; p = 0.02). Estimated glomerular filtration rate (eGFR) decreased in the control arm (p = 0.007), but did not change in the switch arm. At week 48, eGFR was higher in the switch arm (median 96 mL/min) than in the control arm (median 85 mL/min) (p = 0.035), but the arms were similar with respect to fasting glucose, C-reactive protein, and lipid parameters.

Conclusions: Switching from ATV/r to unboosted ATV appears to be safe and effective in selected virologically suppressed patients receiving TDF-containing regimens, and may have favorable effects on bilirubin and renal function.     

Short-term cost and efficiency analysis of raltegravir versus atazanavir/ritonavir or darunavir/ritonavir for treatment-naive adults with HIV-1 infection in Spain

Introduction: The AIDS Clinical Trial Group (ACTG) 5257 clinical trial showed that raltegravir (RAL) was superior to atazanavir/ritonavir (ATV/r) and darunavir/ritonavir (DRV/r), when used in combination with emtricitabine/tenofovir DF (FTC/TDF), in a 96-week composite endpoint combining virologic efficacy and tolerability for treatment-naive adults with HIV-1 infection. This study aimed to estimate the efficiency associated with these three regimens in Spain.

Methods: An economic model was developed to estimate costs for antiretroviral drugs, adverse event management, and HIV care for individuals initiating first-line therapy. Antiretroviral drug costs were based on hospital costs with mandatory discounts applied. Adverse event management costs and HIV care costs were obtained from published sources and inflated to 2015 euros. Head-to-head efficacy and safety data (discontinuation rates, mean CD4 cell-count changes, adverse event incidence) up to 96 weeks for each regimen were obtained from the clinical trial. The efficiency of each regimen, as measured by the cost per successfully treated patient (i.e. on first-line therapy for 96 weeks), was estimated and examined in sensitivity analyses. All cost outcomes were discounted at 3.0% annually.

Results: Total costs per successfully treated patient were €22,377 for RAL, €26,629 for ATV/r, and €23,928 for DRV/r. These results were found to be robust in sensitivity analyses.

Discussion: RAL has the lowest cost per successfully treated patient when compared with DRV/r and ATV/r, each used in combination with FTC/TDF, for treatment-naive adults with HIV-1 infection in Spain. This economic evidence complements the clinical benefits of RAL reported in the ACTG 5257 clinical trial.     

Deep genealogical analysis of a large cohort of participants in the CARTaGENE project (Quebec,Canada)

Background: Genealogical analysis helps to better understand the genetic structure of populations. The population of Quebec (Canada) often serves as a model for this type of analysis, having one of the world’s most complete genealogical databases.

Aim: The main objective of this study was to reconstruct, analyse and compare the ascending genealogies of participants to CARTaGENE, a project that aims at building a database on various aspects of public health.

Subjects and methods: In total, 5110 genealogies from four Quebec regions were reconstructed. Distribution of ancestors, completeness and depth of the genealogies, characteristics of immigrant ancestors and kinship and inbreeding coefficients were analysed.

Results: Most genealogies go back to the 17th century, with a mean genealogical depth of 10 generations. Origins of immigrant ancestors are more diverse in the Montreal region, resulting in lower inbreeding and kinship among the participants from this region. Inbreeding and kinship values are mainly explained by remote genealogical links (from 6 to 11 generations).

Conclusion: Deep genealogies allowed for a precise measurement of the geographic origins of the participants’ immigrant ancestors, as well as inbreeding and kinship ties in the population, which may be crucial for studies aiming to identify genetic variations associated with Mendelian or complex diseases.     

Development and psychometric evaluation of a condom use self-efficacy measure in Spanish and English

Background: Condom self-efficacy is an important construct for HIV/STI prevention and intervention. A psychometrically sound measure of the self-efficacy for using condoms that has been designed for Hispanic women to respond in Spanish or English is needed.

Objectives: The goal of this study was to develop and evaluate a brief self-report measure of condom use self-efficacy.

Methods: We developed a 15-item measure of condom use self-efficacy based on expert knowledge of measurement and HIV/STI prevention with Hispanic women using a translation-back translation approach. Participants were 320 Hispanic women from the Southeastern US.

Results: Internal consistency of the full measure was 92. A short form of the instrument with a subset of five items also had acceptable internal consistency, alpha = .80, and was significantly correlated with the full scale, r_s = .93, p < .001. A single latent factor explained 9–48% of the variation in these items. Evidence of construct validity of the short form was provided by correlations of the scale with two self-report measures of condom use: r_s = .34** with condom use, r_s = .37** with condom use during vaginal sex.

Conclusions: Either the full measure or the five-item measure could be used in studies where condom use is an important behavioral outcome, such as evaluating prevention interventions, with Hispanic women. Future studies should examine the performance of this measure with other groups, including Hispanic men and members of other ethnic and language groups.     

Long-Term Efficacy,Tolerability, and Renal Safety of Atazanavir/Ritonavir-based Antiretroviral Therapy in a Cohort of Treatment-Naïve Patients with HIV-1 Infection: the REMAIN Study

Background: Boosted protease inhibitors (PIs), including ritonavir-boosted atazanavir (ATV/r), are a recommended option for the initial treatment of HIV-1 infection based upon clinical trial data; however, long-term real-life clinical data are limited.

Objective: We evaluated the long-term use of ATV/r as a component of antiretroviral combination therapy in the real-life setting in the REMAIN study.

Methods: This was an observational cohort study conducted at sites across Germany, Portugal, and Spain. Retrospective historical and prospective longitudinal follow-up data were extracted every six months from medical records of HIV-infected treatment-naïve patients aged ≥ 18 years initiating a first-line ATV/r-containing regimen.

Results: Eligible patients (n = 517) were followed up for a median of 3.4 years. The proportion remaining on ATV/r at 5 years was 51.5% with an estimated Kaplan-Meier median time to treatment discontinuation of 4.9 years. Principal reasons for discontinuation were adverse events (15.9%; 8.9% due to hyperbilirubinemia) and virologic failure (6.8%). The Kaplan-Meier probability of not having virologic failure (HIV-1 RNA < 50 copies/mL) was 0.79 (95% CI: 0.75, 0.83) at five years. No treatment-emergent major PI resistance occurred. ATV/r was generally well tolerated during long-term treatment with no significant changes in estimated glomerular filtration rate over five years.

Conclusions: In a real-life clinical setting over five years, treatment-naïve patients with HIV-1 infection initiating an ATV/r-based regimen showed sustained virologic suppression, an overall treatment persistence rate of 51.5%, an absence of treatment-emergent major PI resistance mutations at virologic failure, a long-term safety profile consistent with that observed in clinical trials, and no significant decline in renal function.     

Maximizing participant retention in a phase 2B HIV prevention trial in Kampala,Uganda: The MTN-003 (VOICE) Study

Background: The success of longitudinal trials depends greatly on using effective strategies to retain participants and ensure internal validity, maintain sufficient statistical power, and provide for the generalizability of study results.

Objective: This paper describes the challenges and specific strategies used to retain participants in a Phase 2B safety and effectiveness study of daily oral and vaginal tenofovir formulations for the prevention of HIV-1 infection in the MTN-003 (VOICE) trial in Kampala, Uganda.

Methods: Once enrolled, participants were seen every 28 days at the research site and their study product was re-filled. Challenges to retention included a mobile population, non-disclosure of study participation to spouse/family, and economic constraints. Strategies used to maintain high participation rates included the use of detailed locator information, a participant tracking database, regular HIV/STI testing, and the formation of close bonds between staff and subjects.

Results: We enrolled 322 women out of the 637 screened. The overall retention rate was 95% over a 3 year follow up period. Only 179 (3%) out of the 6124 expected visits were missed throughout study implementation. Reasons for missed visits included: participants thinking that they did not need frequent visits due to their HIV negative status, time constraints due to commercial sex work, and migration for better employment.

Conclusions: With the implementation of multi-faceted comprehensive follow-up and retention strategies, we achieved very high retention rates in the MTN-003 study. This paper provides a blueprint for effective participant retention strategies for other longitudinal HIV prevention studies in resource-limited settings in Sub-Saharan Africa.     

Topical immunotherapy with diphencyprone (DPCP) for in-transit and unresectable cutaneous melanoma lesions: an inaugural Canadian series

Background: Diphencycprone (DPCP) is an immune contact sensitizer applied to melanoma lesions. Early studies show favorable efficacy. We present the first North-American series of patients treated with DPCP.

Methods: A single center retrospective study of patients with in-transit or unresectable melanoma lesions treated with DPCP from December 1,2014 to December 31,2015 was completed. Primary objectives were response rate and toxicity. Secondary objective was health-related quality of life assessment with the Functional Assessment of Cancer Therapy-Melanoma (FACT-M) questionnaire.

Results: Fifteen consecutive patients were identified with median age of 78 (range 43–92). 73% of patients had prior treatment. Two patients (13%) had a complete response after 25 and 32 weeks, respectively. Four patients (27%) had a partial response with a mean treatment time of 30 weeks (range 6–51 weeks). Six (40%) had stable disease. Six patients stopped DPCP – three from systemic progression and three from toxicity. The most common toxicity was blisters; one patient had significant skin ulceration that resolved on stopping DPCP. Median FACT-M score was 142.95 (possible total 172). Mean overall follow-up time was 22.7 weeks.

Conclusion: DPCP is a feasible option for in-transit and other melanoma cutaneous lesions ineligible/refractory to surgery and may delay need for systemic therapy.     

Identification of specific antibodies against the Ag85C-MPT51-HspX fusion protein (CMX) for serological screening of tuberculosis in endemic area

Objectives: Development of new tools for rapid and accurate diagnosis of tuberculosis (TB) is considered a strategy for controlling the disease. The recombinant CMX fusion protein is composed of immunodominant epitopes of the Ag85C (Rv0129c), MPT51 (Rv3803c) and the entire HspX (Rv2031c) proteins from Mycobacterium tuberculosis H37Rv (Mtb). The aim of this study was to evaluate the applicability of a test using the CMX protein in individuals suspected of TB.

Methods: Indirect ELISA was used to measure serum anti-CMX IgM and IgG in individuals with pulmonary TB.

Results: Patients with pulmonary TB had higher titers of IgM (OD = 0.502 ± 0.281) than healthy controls (OD = 0.200 ± 0.125). The cutoff for IgM-ELISA was determined using ROC curve analyzes (AUC = 0.868) with a sensitivity of 80.1% and a specificity of 78.2%. Patients with pulmonary TB also had higher titers of IgG (OD = 0.525 ± 0.391) than healthy controls (OD = 0.215 ± 0.077). The cutoff for IgG-ELISA was determined using ROC curve analyzes (AUC = 0.864) with a sensitivity of 81.7% and a specificity of 74.7%.

Conclusion: The results suggest that the recombinant protein CMX can be used in a serological test to complement the screening of individuals suspected of having active pulmonary TB.     

Immune Profiling of T Cells Infiltrating Vitreous Humor in Tubercular Uveitis

Purpose: To assess cellular composition and local cytokine response in vitreous humor of tubercular uveitis.

Methods: Cells were collected from vitreous cassettes and peripheral blood of 8 tubercular uveitis and 5 control subjects, undergoing vitrectomy and analyzed by flow cytometry for cellular composition, activation status, proinflammatory cytokine expression, and uptake of TLR9 ligand, CpG ODN 2216.

Results: CD3 + T cells with equal proportion of CD4+ and CD8 + T cells formed major fraction of infiltrating cells. The vitreous humor showed higher expression of recent activation marker, CD69, and proinflammatory cytokines, IFN-γ and IL-17A, in CD4 + T cells as compared to peripheral blood. Lastly, intraocular CD4 + T cells showed reduced uptake of ODN 2216 than peripheral blood.

Conclusions: Our results indicate that local antigenic stimuli trigger T cell infiltration and activation of CD4 + T cells that are hyporesponsive to TLR9 stimulation. These infiltrating T cells might be responsible in further aggravating ocular inflammation.     

Rheumatoid arthritis: A single-center Egyptian experience

Objective: Demonstration of rheumatoid arthritis (RA) characteristics in a large cohort of Egyptian patients.

Methods: Retrospective analysis of data of 3219 RA patients attending the Rheumatology outpatient clinic, Kasr Alainy Hospital, Cairo University; from January 1995 till December 2015.

Results: Mean age at disease onset was 36.1 ±13.4 years; 2774 (84%) were females and mean disease duration was 12.9 ±7.9 years. Regarding number of joint affected at disease onset; polyarticular pattern was found in 77.1%, pattern of joint involvement; combined small and large joints involvement was in 83.2%, subcutaneous nodules in 14.2%, interstitial lung disease in 0.3%, secondary Sjogren’s syndrome in 10.5%, hand bony erosions at diagnosis in 20.6%. Rheumatoid factor was positive in 52%.

There was annual increase in the newly diagnosed cases (P = 0.017) reflecting increase in patients’ awareness and improvement of medical service, also annual increase in: mean age of onset (P < 0.001) reflecting changes in health measures, also in cases with monoarticular or oligoarticular patterns at disease onset (P = 0.02, 0.01 respectively) reflecting earlier diagnosis of patients and in patients with small joint involvement (P = 0.001) with a significant decline in: polyarticular pattern (P = 0.001), combined small and large joint affection (P < 0.001), and number of cases with hand bony erosions (P = 0.01) denoting earlier diagnosis, tight disease control.

Conclusion: We found a female predominance, younger age at disease onset, lower frequency of extra articular manifestations, more frequent polyarticular pattern at disease onset and less erosive disease, denoting changing referral patterns, earlier diagnosis, improved disease control in Egyptian RA patients over 2 decades.

Abbreviations: SNs: Subcutaneous nodules; 2ry SS: 2ry Sjogren’s syndrome; ILD: Interstitial lung disease; ACPA: Anti-cyclic citrullinated peptide antibodies; DMARDs: Disease modifying anti-rheumatic drugs.     

3D-printed poly(lactic acid) scaffolds for trabecular bone repair and regeneration: scaffold and native bone characterization

Purpose: Study objectives were set to (i) fabricate 3D-printed scaffolds/grafts with varying pore sizes, (ii) characterize surface and mechanical properties of scaffolds, (iii) characterize biomechanical properties of bovine trabecular bone, and (iv) evaluate attachment and proliferation of human bone marrow mesenchymal stem cells on 3D-printed scaffolds.

Materials and Methods: Poly(lactic acid) scaffolds were fabricated using 3D-printing technology, and characterized in terms of their surface as well as compressive mechanical properties. Trabecular bone specimens were obtained from bovine and characterized biomechanically under compression. Human bone marrow mesenchymal stem cells were seeded on the scaffolds, and their attachment capacity and proliferation were evaluated.

Results: Contact angles and compressive moduli of scaffolds decreased with increasing pore dimensions of 0.5 mm, 1.0 mm, and 1.25 mm. Biomechanical characterization of trabecular bone yielded higher modulus values as compared to scaffolds with all pore sizes studied. Human bone marrow mesenchymal stem cells attached to the surfaces of all scaffolds yet proliferated more on scaffolds with 1.25 mm pore size.

Conclusions: Collectively, given the similarity between 3D-printed scaffolds and native bone in terms of pore size, porosity, and appropriate mechanical properties of scaffolds, the 3D-printed poly(lactic acid) (PLA) scaffolds of this study appear as candidate substitutes for bone repair and regeneration.     

An observational study on the incidence of tuberculosis among a cohort of HIV infected adults in a setting with low prevalence of tuberculosis

Background: Tuberculosis (TB) remains a main cause of morbidity and mortality among individuals infected with HIV. We investigated the incidence of TB among a cohort of HIV infected patients attending a setting with low TB burden where screening for latent TB infection is not routinely carried out.

Methods: an observational cohort study on HIV-infected adults attending the HIV clinic at Queen Elizabeth Hospital Birmingham, UK between 1 January 2011 and 30 September 2015. Patients with culture-proven TB after HIV diagnosis, or those treated for clinical diagnosis of the infection, were classified as having “active TB”.

Results: 1824 patients were included in the study (5347 patient years of follow up), of whom 21 patients developed TB (16 microbiology confirmed). Of the 666 new HIV diagnoses, six patients developed TB within one month, giving a TB prevalence at the time of HIV diagnosis of 0.9%. The total TB incidence for the remaining 1818 patients was 2.81 cases per 1000 patient years (95% CI: 1.63–4.53). TB incidence was significantly more common among patients with CD4 ≤ 200 cells/mm³ compared to those with CD4 > 500 cells/mm³ (28.2 vs. 1.22 per 1000 patient years, p < 0.001), and in patients with VL ≥ 40 copies/mL compared to <40 copies/mL (8.30 vs. 1.42, p < 0.001).

Conclusion: In settings with low TB prevalence, early start of combined antiretroviral therapy and intensified TB case finding protocols may significantly reduce the incidence of TB.