Protease Inhibitor-containing Regimens Research Articles

Effect of SLCO1B1 c.521T>C polymorphism on the lipid response to statins in people living with HIV on a boosted protease inhibitor-containing regimen.

We previously observed that some individuals on HIV boosted protease inhibitor-containing regimen do not achieve their lipid targets despite elevated statin concentrations. This study evaluated whether the common single polymorphism c.521T>C in SLCO1B1, associated with reduced statin uptake in the liver, could explain this observation. People living with HIV in the Swiss HIV Cohort Study were eligible if they were on a boosted protease inhibitor concomitantly with a statin for at least 6 months and if their SLCO1B1 genotype was available. Furthermore, their lipids had to be documented before and after the introduction of the statin. The statin efficacy was defined as % change in total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and triglycerides levels after statin initiation compared to pretreatment levels. Lipid response was adjusted for differences in potency and dose between statins. In total, 88 people living with HIV were included, of whom 58, 28 and 2 carried the SLCO1B1 TT, TC and CC genotypes, respectively. The change in lipid levels after statin initiation tended to be lower in carriers of the polymorphism although the difference was not statistically significant (TT vs. TC/CC: total cholesterol: -11.7 vs. -4.8%; low-density lipoprotein- cholesterol: -20.6 vs. -7.4%; high-density lipoprotein-cholesterol: 1.6 vs. 0%; triglycerides: -11.5 vs. -7.9%). In the multiple linear regression, change in total cholesterol was inversely correlated with the total cholesterol level prestatin treatment (coefficient -6.60, 95% confidence interval: -9.63 to -3.56, P < .001). The lipid-lowering effect of statins tended to be attenuated by SLCO1B1 polymorphism and progressively declined as total cholesterol under the boosted protease inhibitor treatment decreased.

Real-World Experience of Chronic Hepatitis C-Related Compensated Liver Cirrhosis Treated with Glecaprevir/Pibrentasvir: A Multicenter Retrospective Study.

Background: Glecaprevir/pibrentasvir is a protease inhibitor-containing pangenotypic direct-acting antiviral regimen that has been approved for the treatment of chronic hepatitis C. The present study aimed to evaluate the safety and efficacy of glecaprevir/pibrentasvir in patients with compensated cirrhosis in a real-world setting. Methods: We evaluated the real-world safety and efficacy of glecaprevir/pibrentasvir in patients with compensated cirrhosis from five hospitals in the Changhua Christian Care System, who underwent treatment between August 2018 and October 2020. The primary endpoint was a sustained virological response observed 12 weeks after completion of the treatment. Results: Ninety patients, including 70 patients who received the 12-week therapy and 20 patients who received the 8-week therapy, were enrolled. The mean age of the patients was 65 years, and 57.8% of the patients were males. Sixteen (17.8%) patients had end-stage renal disease, and 15 (16.7%) had co-existing hepatoma. The hepatitis C virus genotypes 1 (40%) and 2 (35.6%) were most common. The common side effects included anorexia (12.2%), pruritus (7.8%), abdominal discomfort (7.8%), and malaise (7.8%). Laboratory adverse grade ≥3 events included anemia (6.3%), thrombocytopenia (5.1%), and jaundice (2.2%). The overall sustained virological response rates were 94.4% and 97.7% in the intention-to-treat and per-protocol analyses, respectively. Conclusions: the glecaprevir/pibrentasvir treatment regimen was highly effective and well tolerated among patients with compensated cirrhosis in the real-world setting.

Association between frailty phenotype, quantification of plasma HIV-1 RNA, CD4 cell count and HAART in HIV-positive subjects: a systematic review and meta-analysis of observational studies

ABSTRACT HIV infection causes a constant activation of the immune system and contributes to an enhanced systemic pro-inflammatory cytokine milieu, which has been associated with premature aging and frailty. We performed a systematic review and meta-analysis to analyze whether the HIV-1 RNA load, CD4+ T-lymphocyte counts and exposure to HAART in HIV-positive subjects are associated with frailty phenotype. Searches were performed in PubMed, SCOPUS, Lilacs, Web of Science, Google Scholar, and OpenThesis databases. We used the odds ratio as a measure of the association. We used either a fixed or random-effects model to pool the results of individual studies depending on the presence of heterogeneity. Eleven studies were included in the review. Data from 8035 HIV-positive subjects were analyzed; 2413 of the subjects had viral load detectable, 981 had a CD4T-cell count <350 cells/μL, and 1342 had HAART exposure information. We found an association between frailty and CD4T-cell count <350 cells/μL (OR 2.68, CI 95% 1.68–4.26, I2 = 46%), HIV-1 RNA load detectable (OR 1.71, CI 95% 1.38–2.12, I2 = 0%), and protease inhibitor-containing HAART regimen (OR 2.21, CI 95% 1.26–3.89, I2 = 0%). Further studies are necessary to evaluate the effects of other factors on the development of clinical features related to frailty.

Virological outcome and frequency of low-level viremia in patients receiving generic dolutegravir-containing regimen at a large tertiary care clinic in Western India.

Background:Dolutegravir (DTG) is widely used for the management of naïve and treatment-experienced HIV-infected patients. Low-level viremia (LLV) is common in patients receiving nonnucleoside reverse transcriptase inhibitor- and protease inhibitor-containing regimens. However, the incidence of LLV associated with DTG-containing regimen is not well known.Objective:The objective of this study was to assess the virological response associated with DTG-containing regimens and explored frequencies of LLV and risk factors for the same.Methods:We performed a retrospective cohort study of HIV-infected patients receiving generic DTG-containing regimen from February 2017 to July 2019. All adult patients (≥18 years), who completed at least the first follow-up after initiating treatment, were included in this study. LLV was defined as plasma viral load between 20 and 200 copies/ml.Results:A total of 597 patients started DTG-containing regimen during the study period, of which 522 patients met the inclusion criteria. The study patients were categorized into five groups: naïve (n = 86), first-line failure (n = 32), second-line failure (n = 53), switch (n = 325), and HIV-2 (n = 26). Complete virological suppression at 6, 12, and 18 months was achieved in 78.5%, 81.1%, and 70.9% of the patients, respectively. Furthermore, 17.9%, 12.9%, and 23.3% of the patients had LLV at 6, 12, and 18 months, respectively. Persistent LLV was found in 2.9% of the patients. Overall, DTG was well tolerated and was discontinued in only three patients due to neuropsychiatric side effects.Conclusion:DTG is well tolerated and effective in suppressing HIV across all antiretroviral treatment categories. The rate of persistent LLV is low in DTG-containing therapy.

993. Risk Factors for Periconception Non-Suppression Among Women Living with HIV in Kisumu, Kenya

BackgroundPregnant and postpartum women living with HIV (WLHIV) are a priority population for virologic monitoring and efforts to ensure viral suppression to reduce the risk for vertical-transmission and poor maternal health outcomes. Few studies have examined the role of parity on viral suppression during periconception in WLHIV.MethodsWe present data from the ongoing Opt4Mamas study which enrolled pregnant women with HIV on antiretroviral therapy between March and November 2019 attending antenatal care in five public health facilities in Kisumu County, Kenya. We evaluated associations between various sociodemographic and psychosocial factors and periconception viral suppression (< 40 copies/mL) within 12 months of study enrollment. We conducted univariate and multivariate logistic regressions, calculating odds ratios (OR) and 95% confidence intervals (CI).ResultsAmong 497 women enrolled, mean age 29.9 years, 301 (61%) had viral load results available within 12 months of study enrollment. Viral loads were available a median of 18 days from conception (interquartile range 71 days before to 90 days after conception), and 237 women (79%) were virally suppressed. The majority (90%) of women were on a non-nucleoside reverse transcriptase inhibitor and 23 (9%) were on a protease inhibitor-containing regimen. In univariate analysis, women younger than 25 and primigravida women were less likely to be virally suppressed (OR 0.31, 95% CI [0.16 - 0.60] and OR 0.25, 95% CI [0.11 - 0.61] respectively; Table 1). The relationship between primigravida and periconception viral suppression is modified by age and duration on ART. Primigravida women who were younger than 25 years or who had less than 1 year of ART had significantly reduced odds of achieving viral suppression in the past year compared to primigravida women who were older or who had more experience taking ART (OR 0.09, 95%CI [0.03-0.31] and OR 0.09, 95%CI [0.02-0.48] respectively; Table 2).Table 1: Comparison of Pregnant Women with HIV by Periconception Viral Suppression Table 2: Interaction Effects with Primigravida Status ConclusionRisk factors for non-suppression around the time of conception in WLHIV include primigravida status, which is modified by age and duration on ART. Interventions targeting viral suppression among WLHIV leading up to their first pregnancy are needed, particularly among those who are newly initiated onto ART or younger age.Disclosures All Authors: No reported disclosures

Combination Antiretroviral Therapy and Hypertensive Disorders of Pregnancy.

To compare the incidence of hypertensive disorders of pregnancy among women living with human immunodeficiency virus (HIV) on combination antiretroviral therapy (ART) to women without HIV, and to evaluate the association of hypertensive disorders of pregnancy with ART regimens or timing of ART initiation. We conducted a retrospective cohort study among two overlapping pregnancy cohorts using preexisting databases at a single tertiary care hospital: all pregnant women who delivered during years 2016-2018 (cohort 1) and all women living with HIV who delivered during years 2011-2018 (cohort 2). The primary outcome for both cohorts was any hypertensive disorder of pregnancy; gestational hypertension and preeclampsia were also examined separately. The primary exposure variables were HIV status for cohort 1 and ART regimen (integrase strand transfer inhibitor-containing, protease inhibitor-containing, or non-nucleoside reverse transcriptase inhibitor-containing) for cohort 2. For estimation of risk ratios (RRs), we used a modified Poisson regression with robust error variances. Multivariate models among the women living with HIV in cohort 2 were tested for a statistical interaction between ART regimen and timing of initiation. In cohort 1, among 80 women living with HIV compared with 3,464 women without HIV, there was no difference in the risk of hypertensive disorders of pregnancy (29% in women living with HIV vs 30% in women without HIV, adjusted RR 0.9, 95% CI 0.6-1.3). In cohort 2, among 265 women living with HIV, integrase strand transfer inhibitor-containing regimens were associated with an increased risk for any hypertensive disorder of pregnancy (25% among integrase strand transfer inhibitor vs 10% among protease inhibitor, adjusted RR 2.8, 95% CI 1.5-5.1) and gestational hypertension (20% among integrase strand transfer inhibitor vs 8% among protease inhibitor, adjusted RR 2.8, 95% CI 1.3-5.9) compared with protease inhibitor-containing regimens. Timing of ART initiation was not associated with hypertensive disorders of pregnancy, nor did it significantly alter the associations between ART regimen and hypertensive disorders of pregnancy outcomes. Overall the risk of hypertensive disorders of pregnancy was similar among women living with HIV on ART and women without HIV. With greater integrase strand transfer inhibitor use, the greater frequency of hypertensive disorders of pregnancy with these regimens compared with protease inhibitor-containing regimens warrants future evaluation using cohorts with greater sample size.

Bictegravir.

In this review, we will highlight and discuss the recent efficacy and safety data of bictegravir (BIC), a novel second-generation integrase strand transfer inhibitor (INSTI) that has been recently approved, in coformulation with emtricitabine and tenofovir alafenamide (B/F/TAF), for the treatment of HIV-1 infection in antiretroviral naïve subjects and in those with suppressed viremia. Preclinical data showed that BIC has a genetic barrier that is higher than that of raltegravir and elvitegravir but is similar to that of dolutegravir (DTG), with retained activity in vitro against isolates containing substitutions associated with resistance against other INSTIs. Its pharmacokinetic interaction risks appear to be low. Results of the phase 3 GS-US-380-1489 and GS-US-380-1490 clinical trials showed that the coformulation B/F/TAF is not inferior to the recommended DTG-containing regimens in naïve subjects. Moreover, B/F/TAF exhibited excellent tolerability, and no treatment-emergent resistance to any component of the coformulation was observed. In addition, preliminary data support switching from DTG and emtricitabine/tenofovir alafenamide or boosted protease inhibitor-containing regimens to B/F/TAF in subjects with undetectable viremia. The coformulation bictegravir/emtricitabine/tenofovir alafenamide is set to become a new option in the management of patients who are antiretroviral naïve and in those with suppressed viremia.

Human Immunodeficiency Virus-1 Drug Resistance Patterns Among Adult Patients Failing Second-Line Protease Inhibitor-Containing Regimens in Namibia, 2010-2015.

Three hundred sixty-six adult patients in Namibia with second-line virologic failures were evaluated for human immunodeficiency virus drug-resistant (HIVDR) mutations. Less than half (41.5%) harbored ≥1 HIVDR mutations to standardized second-line antiretroviral therapy (ART) regimen. Optimizing adherence, viral load monitoring, and genotyping are critical to prevent emergence of resistance, as well as unnecessary switching to costly third-line ART regimens.

Do protease inhibitor-containing combination antiretroviral therapy regimens increase risk of spontaneous preterm birth in pregnant HIV-Positive women?

1) To determine if the use of any antiretroviral therapy (ART) during pregnancy was related to an increased risk of preterm birth (PTB), compared no ART use, in a population-based cohort of HIV-positive pregnant women. 2) To determine if there were any differences in the risk for PTB when comparing different combination ART (cART) regimens (NNRTI, PI, and boosted PI (bPI) based cART). 3) To characterize additional clinical and demographic characteristics associated with PTB in this population.

Brief Report: Prolonged Viral Suppression Over a 12-Year Follow-up of HIV-Infected Patients: The Persistent Impact of Adherence at 4 Months After Initiation of Combined Antiretroviral Therapy in the ANRS CO8 APROCO-COPILOTE Cohort.

The effect of early adherence on long-term viral suppression was assessed among 1281 patients with HIV starting a protease inhibitor-containing regimen in 1997-1999, followed up to 12 years. Association between 4-month adherence (3-level score) and prolonged viral suppression was evaluated using a multivariate mixed logistic model in 891 eligible patients. High 4-months adherence [odds ratio (95% confidence interval): 3.72 (1.98 to 6.98)] was associated with long-term prolonged viral suppression, irrespective of maintenance adherence. This unexpected long-term virological impact of early adherence reinforces the message that, when starting antiretrovirals, all means should be mobilized to ensure optimum early adherence to achieve prolonged antiretroviral success.

Effect of antiretroviral therapy on malaria incidence in HIV-infected Ugandan adults.

Introduction:Using the data of a trial on cotrimoxazole (CTX) cessation, we investigated the effect of different antiretroviral therapy (ART) regimens on the incidence of clinical malaria.Methods:During the cotrimoxazole cessation trial (ISRCTN44723643), HIV-infected Ugandan adults with CD4+ at least 250 cells/μl were randomized to receive either CTX prophylaxis or placebo and were followed for a median of 2.5 years. Blood slides for malaria microscopy were examined at scheduled visits and at unscheduled visits when the participant felt unwell. CD4+ cell counts were done 6-monthly. Malaria was defined as fever with a positive blood slide. ART regimens were categorized as nucleoside reverse transcriptase inhibitor (NRTI) only, non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing or protease inhibitor containing. Malaria incidence was calculated using random effects Poisson regression to account for clustering of events.Results:Malaria incidence in the three ART regimen groups was 9.9 (3.6-27.4), 9.3 (8.3-10.4), and 3.5 (1.6-7.6) per 100 person-years, respectively. Incidence on protease inhibitors was lower than that on the other regimens with the results just reaching significance (adjusted rate ratio 0.4, 95% confidence interval = 0.2–1.0, comparing with NNRTI regimens). Stratification by CTX/placebo use gave similar results, without evidence of an interaction between the effects of CTX/placebo use and ART regimen. There was no evidence of an interaction between ART regimen and CD4+ cell count.Conclusion:There was some evidence that protease inhibitor-containing ART regimens may be associated with a lower clinical malaria incidence compared with other regimens. This effect was not modified by CTX use or CD4+ cell count. The antimalarial properties of protease inhibitors may have clinical and public health importance.

Clinical and Emotional Factors Related to Erectile Dysfunction in HIV-Infected Men.

The prevalence and associated factors of erectile dysfunction (ED) in Human Immunodeficiency Virus (HIV)–infected men remain controversial. The authors evaluated ED, clinical, and emotional variables in a group of 501 HIV-infected men in a cross-sectional 4-month observational study. ED was assessed using the International Index of Erectile Function–5 and emotional status using the Hospital Anxiety and Depression (HAD) questionnaire. Median age (interquartile range) was 42 (35, 48) years. Time since HIV diagnosis was 6.3 (2.6, 17.1) years, 92% were taking antiretroviral treatment and 81.8% had an HIV-RNA viral load <50 copies. The prevalence of ED was 58.5%. ED was mild in 30.1%, mild to moderate in 19.5%, moderate in 6.1%, and severe in 2.5%. ED medications were used by 19% of men. In the univariate analysis, the variables associated with all degrees of ED were older age, longer time since HIV diagnosis, higher scores in HAD, not taking efavirenz, taking etravirine, taking ritonavir, HIV/Hepatitis C Virus coinfection, and taking a protease inhibitor-containing regimen. For mild to moderate, moderate, and severe ED, the same variables were significant, as were lower nadir CD4 cell count, lower social support, taking atazanavir, concomitant conditions, and concomitant treatments. The variables that remained significant in the multivariate analyses, considering all degrees of ED or excluding mild ED were the following: older age and higher scores in HAD total. In summary, ED affected more than half of this cohort of well controlled HIV-infected men. Age and emotional status seemed to play a fundamental role in its presence.

The long-term outcomes of antiretroviral treatment initiated with mono or dual nucleoside reverse transcriptase inhibitors in HIV-1-infected children: an Asian observational study

After a median of 115.9 months of follow-up, 90% of 206 HIV-1-infected children in a cohort in Asia who initiated antiretroviral treatment (ART) with mono or dual nucleoside reverse transcriptase inhibitors were alive and had comparable immunological and virological outcomes as compared to the 1,915 children who had started with highly active antiretroviral regimens. However, these children had higher rates of treatment-related adverse events, opportunistic infections, and cumulative mortality, and were more likely to require protease inhibitor-containing regimens or other more novel ART-based regimens.

364 An Integrated Safety, Efficacy, and Virology Analysis of >500 Patients With Compensated Cirrhosis Treated With Ledipasvir/Sofosbuvir With or Without Ribavirin

Background: Patients with HCV and cirrhosis represent a population in most need of treatment; however, with interferon and ribavirin (RBV)-based therapy, such patients had been more difficult to treat and cure and are often underrepresented in clinical trials. Ledipasvir/sofosbuvir (LDV/SOF) phase 2 and 3 studies included >500 patients with compensated cirrhosis. We analyzed the overall efficacy and safety, and further evaluated the impact of baseline HCV NS5A resistance associated variants (RAVs) on sustained virologic response in a population of HCV infected patients with cirrhosis. Methods: Treatment-naive or treatment-experienced patients with chronic HCV genotype 1 (GT1) infection and compensated cirrhosis who had participated in phase 2 or 3 studies and had received LDV/SOF +/RBV for 12 or 24 weeks were included in this pooled analysis. Results: Five hundred thirteen subjects with compensated cirrhosis were identified. The majority (91%) of patients had cirrhosis diagnosed by biopsy or fibroscan (>12.5 kPa). Of the 292 patients on whom a fibroscan was performed, 137/292 (47%) had a value >20 kPa. The majority were treatmentexperienced (353, 69%), male (342, 67%), GT1a (306, 60%), and IL28B non-CC (405, 79%). Two hundred forty patients (68% of the treatment- experienced patients) had previously received a protease inhibitor-containing regimen. One hundred thirteen (22%) initiated therapy with a baseline platelet count of <100,000 cells/μL. Sixty-three (12%) initiated therapy with a baseline albumin <3.5 g/dL. The patients received one of four regimens: 12 weeks of LDV/SOF (118, 23%), or LDV/SOF+RBV (204, 40%), or 24 weeks of LDV/SOF (133, 26%) or LDV/SOF+RBV (58, 11%). Overall, 96% (493/513) achieved SVR12. Among treatment-experienced patients, 12 weeks of LDV/SOF resulted in a 90% SVR rate, while adding RBV or extending treatment duration increased this rate to ≥96%. With a 1% cutoff, 94/511 (18%) cirrhotic patients were identified as having BL NS5A RAVs. SVR results by regimen and patient group and the effect of baseline NS5A RAVs on SVR will be presented. Safety in patients with cirrhosis was similar to that previously reported in patients without cirrhosis. Adverse events including anemia were more frequent in patients who received RBV. No other trends in adverse events or serious adverse events were noted. Conclusions: Based on these results, LDV/SOF is effective, safe, and well-tolerated for the treatment of HCV GT1 infection in patients with compensated cirrhosis. LDV/SOF regimens for 12 and 24 weeks were efficacious in treatment-naive cirrhotic patients with baseline HCV NS5A RAVs. High SVR rates were also achieved among treatment-experienced patients with cirrhosis when RBV was added to 12 weeks of LDV/SOF or when treatment was extended to 24 weeks.

Viremia copy-years as a predictive marker of all-cause mortality in HIV-1-infected patients initiating a protease inhibitor-containing antiretroviral treatment.

Viremia copy-years (VCY) has been reported as a short-term predictor of mortality. We evaluated the association of this parameter with 10-year outcome within the APROCO-COPILOTE cohort. Prospective data from 1281 HIV-1-infected patients who started a first protease inhibitor-containing regimen in 1997-1999 were analyzed. Patients with baseline plasma viral load (pVL) > 500 copies per milliliter and at least 2 pVL measures from the eighth month of follow-up were selected. VCY was calculated individually over the follow-up as the area under the pVL curve. Multivariate Cox models analyzed the relation between all-cause mortality and the following variables: age, sex, geographical origin, transmission group, HIV infection duration, ART-naive, pVL at baseline, time-dependent CD4 count, and VCY. Nine hundred seventy-nine patients were followed up for a median of 10 years (interquartile range: 5-11.5). At baseline, median (interquartile range) values for duration of HIV infection, pVL, and CD4 cell count were 43 (4-95) months, 4.6 (3.9-5.2) log10 copies per milliliter, and 278 (125-416) cells per cubic millimeter, respectively. At censoring date, 77 patients (8%) had died. VCY >1.4 log10 copies × yrs/mL was an independent predictor of death (hazard ratio: 2.0; 95% confidence interval: 1.2 to 3.5), which was no longer the case after adjustment for the latest pVL value [risk ratio (RR): 1.2 for 1 additional log10 copies per milliliter; 95% confidence interval: 1.1 to 1.4]. VCY was associated with mortality in HIV-infected patients under combined antiretroviral therapy but did not overweigh the predictive value of the latest pVL. VCY might be more useful as a marker of persistent viral replication than for routine clinical care.

Echocardiography and carotid intima-media thickness among asymptomatic HIV-infected adolescents in Thailand.

To evaluate the carotid intima-media thickness (cIMT) in perinatally HIV-infected adolescents and factors associated with cardiovascular abnormalities. A cross-sectional study was conducted in perinatally HIV-infected adolescents who had no known cardiovascular condition and healthy controls. Transthoracic echocardiogram and cIMT measurements were taken by pediatric cardiologists. Serum lipid profiles, high-sensitivity C-reactive protein and N-terminal pro-brain natriuretic peptide were measured. Hundred HIV-infected and 50 healthy adolescents were enrolled. Echocardiograms revealed overall normal systolic function (median left-ventricular ejection fraction 66 vs. 66%; P = 0.825). The mean overall cIMTs of common carotid arteries and internal carotid arteries were not different between the groups (0.373 vs. 0.371; P = 0.744). Among the HIV-infected adolescents, those who had been receiving protease inhibitor-containing regimens had an increased cIMT (0.364 vs. 0.381 mm; P = 0.009). Hypertriglyceridemia was found in 52% of those who had received protease inhibitors for more than 6 months, but only in 21% of those who had never received protease inhibitors (odds ratio 4.0, 95% confidence interval 1.6-9.7, P = 0.002). Current HIV-RNA, CD4, BMI, sex, cholesterol and low-density lipoprotein-cholesterol were not associated with increased cIMT. Serum high-sensitivity C-reactive protein and N-terminal pro-brain natriuretic peptide were not different between the groups and not associated with cardiac abnormalities. Perinatally HIV-infected adolescents had comparable myocardial function and similar cIMT measurements to healthy adolescents. However, hypertriglyceridemia and increased cIMT were found in HIV-infected adolescents receiving protease inhibitor-based regimens. Longer-term follow-up is needed to evaluate HIV-associated cardiovascular disease risk in this population.

Predictors and correlates of adherence to combination antiretroviral therapy (ART) for chronic HIV infection: a meta-analysis

BackgroundAdherence to combination antiretroviral therapy (ART) is a key predictor of the success of human immunodeficiency virus (HIV) treatment, and is potentially amenable to intervention. Insight into predictors or correlates of non-adherence to ART may help guide targets for the development of adherence-enhancing interventions. Our objective was to review evidence on predictors/correlates of adherence to ART, and to aggregate findings into quantitative estimates of their impact on adherence.MethodsWe searched PubMed for original English-language papers, published between 1996 and June 2014, and the reference lists of all relevant articles found. Studies reporting on predictors/correlates of adherence of adults prescribed ART for chronic HIV infection were included without restriction to adherence assessment method, study design or geographical location. Two researchers independently extracted the data from the same papers. Random effects models with inverse variance weights were used to aggregate findings into pooled effects estimates with 95% confidence intervals. The standardized mean difference (SMD) was used as the common effect size. The impact of study design features (adherence assessment method, study design, and the United Nations Human Development Index (HDI) of the country in which the study was set) was investigated using categorical mixed effects meta-regression.ResultsIn total, 207 studies were included. The following predictors/correlates were most strongly associated with adherence: adherence self-efficacy (SMD = 0.603, P = 0.001), current substance use (SMD = -0.395, P = 0.001), concerns about ART (SMD = -0.388, P = 0.001), beliefs about the necessity/utility of ART (SMD = 0.357, P = 0.001), trust/satisfaction with the HIV care provider (SMD = 0.377, P = 0.001), depressive symptoms (SMD = -0.305, P = 0.001), stigma about HIV (SMD = -0.282, P = 0.001), and social support (SMD = 0.237, P = 0.001). Smaller but significant associations were observed for the following being prescribed a protease inhibitor-containing regimen (SMD = -0.196, P = 0.001), daily dosing frequency (SMD = -0.193, P = 0.001), financial constraints (SMD -0.187, P = 0.001) and pill burden (SMD = -0.124, P = 0.001). Higher trust/satisfaction with the HIV care provider, a lower daily dosing frequency, and fewer depressive symptoms were more strongly related with higher adherence in low and medium HDI countries than in high HDI countries.ConclusionsThese findings suggest that adherence-enhancing interventions should particularly target psychological factors such as self-efficacy and concerns/beliefs about the efficacy and safety of ART. Moreover, these findings suggest that simplification of regimens might have smaller but significant effects.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-014-0142-1) contains supplementary material, which is available to authorized users.

The current state and future prospects of chronic hepatitis C virus infection treatment.

Hepatitis C virus (HCV) infection is a significant cause of chronic liver disease with substantial long-term sequelae. Until very recently, therapies to cure HCV were hindered by high nonresponse rates and severe side effects. The first-generation protease inhibitor-containing regimens provided superior cure rates for many HCV-infected patients, although their side-effect profile proved to be quite burdensome. We are now witnessing the emergence of therapies with superior cure rates, limited side effects, and broad genotypic activity. Two therapies, sofosbuvir (an NS5b polymerase inhibitor) and simeprevir (a second-generation NS3/4A protease inhibitor), were approved by the Food and Drug Administration in late 2013 for use in a number of HCV populations. This review focuses primarily upon these therapies and the key studies that support their use in practice. Furthermore, representative novel antiviral therapies, in advanced stages of testing, are also reviewed.

Reversible bone lesions induced by tenofovir disoproxil fumarate

Metabolic bone disease is increasingly common in HIV-infected patients on antiretroviral therapy (ART) [1]. Manifestations of ART-induced bone disease include low bone mineral density, increased bone turnover, osteopenia, osteoporosis, and increased fracture risk [2–4]. To our knowledge, reversible tenofovir disoproxil fumarate (TDF)-induced bone lesions have not been described. We describe a patient who developed diffuse foci of increased bone turnover on a TDF-containing regimen and which resolved upon discontinuation of TDF. A 33-year-old Caucasian woman with HIV had multiple risk factors for metabolic bone disease including low BMI, Caucasian race, and tobacco use. A protease inhibitor-containing regimen was initiated and eventually included TDF, which continued unabated for 74 months. Severe lower-extremity pain began approximately 36 months after TDF was added, occurred with movement, and limited activities of daily living (ADL). Eventually, generalized pain extended to the wrists, upper arms, and thorax, and fluctuated in intensity for several months. At 74 months, pain was reported to be excruciating with significant overall impairment of ADL. Chemistries and serum markers for bone disease including vitamin D, parathyroid hormone, and calcium were within normal limits, with the exception of alkaline phosphatase and liver transaminases, each of which was greater than two and three times the upper limit of normal, respectively. Serum creatinine and blood urea nitrogen were normal. All antiretrovirals were discontinued due to severe bone pain. A technetium bone scan revealed multiple foci of increased activity in distal tibiae, bilateral calcaneus bones, multiple costovertebral junctions and ribs, sternum, sacroiliac joints, and right iliac and superior pubic ramus (Fig. 1). Shortly after these findings, the same protease inhibitor-containing regimen, without TDF, was resumed. The patient reported significant improvement in pain and function 3 months later, and a bone scan 11 months after stopping TDF was normal. Additionally, alkaline phosphatase declined shortly after TDF was discontinued and normalized 12 months later.Fig. 1: Technetium bone scan.In conclusion, reversible bone lesions detected by technetium bone scan present a unique finding and a likely manifestation of TDF-induced metabolic bone disease. In our patient, imaging abnormalities occurred after greater than 6 years of continued TDF use, and resolved after 11 months of TDF-sparing ART, whereas other risk factors for bone disease, including protease inhibitor use, remained constant. A bone scan may be useful for discriminating pain caused by metabolic bone disease on long-term TDF from other types of chronic pain. Acknowledgements Conflicts of interest Financial support: No financial support was received for the manuscript. Disclaimers: There are no conflicts of interest for Staci M. Lockhart or Douglas A. Drevets.

Predictors and correlates of adherence to combination antiretroviral therapy (ART) for chronic HIV infection: a meta-analysis.

Adherence to combination antiretroviral therapy (ART) is a key predictor of the success of human immunodeficiency virus (HIV) treatment, and is potentially amenable to intervention. Insight into predictors or correlates of non-adherence to ART may help guide targets for the development of adherence-enhancing interventions. Our objective was to review evidence on predictors/correlates of adherence to ART, and to aggregate findings into quantitative estimates of their impact on adherence. We searched PubMed for original English-language papers, published between 1996 and June 2014, and the reference lists of all relevant articles found. Studies reporting on predictors/correlates of adherence of adults prescribed ART for chronic HIV infection were included without restriction to adherence assessment method, study design or geographical location. Two researchers independently extracted the data from the same papers. Random effects models with inverse variance weights were used to aggregate findings into pooled effects estimates with 95% confidence intervals. The standardized mean difference (SMD) was used as the common effect size. The impact of study design features (adherence assessment method, study design, and the United Nations Human Development Index (HDI) of the country in which the study was set) was investigated using categorical mixed effects meta-regression. In total, 207 studies were included. The following predictors/correlates were most strongly associated with adherence: adherence self-efficacy (SMD = 0.603, P = 0.001), current substance use (SMD = -0.395, P = 0.001), concerns about ART (SMD = -0.388, P = 0.001), beliefs about the necessity/utility of ART (SMD = 0.357, P = 0.001), trust/satisfaction with the HIV care provider (SMD = 0.377, P = 0.001), depressive symptoms (SMD = -0.305, P = 0.001), stigma about HIV (SMD = -0.282, P = 0.001), and social support (SMD = 0.237, P = 0.001). Smaller but significant associations were observed for the following being prescribed a protease inhibitor-containing regimen (SMD = -0.196, P = 0.001), daily dosing frequency (SMD = -0.193, P = 0.001), financial constraints (SMD -0.187, P = 0.001) and pill burden (SMD = -0.124, P = 0.001). Higher trust/satisfaction with the HIV care provider, a lower daily dosing frequency, and fewer depressive symptoms were more strongly related with higher adherence in low and medium HDI countries than in high HDI countries. These findings suggest that adherence-enhancing interventions should particularly target psychological factors such as self-efficacy and concerns/beliefs about the efficacy and safety of ART. Moreover, these findings suggest that simplification of regimens might have smaller but significant effects.