Treatment-naive HIV-infected Patients Research Articles

Macromolecule Translocation across the Intestinal Mucosa of HIV-Infected Patients by Transcytosis and through Apoptotic Leaks.

Based on indirect evidence, increased mucosal translocation of gut-derived microbial macromolecules has been proposed as an important pathomechanism in HIV infection. Here, we quantified macromolecule translocation across intestinal mucosa from treatment-naive HIV-infected patients, HIV-infected patients treated by combination antiretroviral therapy, and HIV-negative controls and analyzed the translocation pathways involved. Macromolecule permeability was quantified by FITC-Dextran 4000 (FD4) and horseradish peroxidase (HRP) flux measurements. Translocation pathways were addressed using cold inhibition experiments. Tight junction proteins were characterized by immunoblotting. Epithelial apoptosis was quantified and translocation pathways were further characterized by flux studies in T84 cell monolayers using inducers and inhibitors of apoptosis and endocytosis. In duodenal mucosa of untreated but not treated HIV-infected patients, FD4 and HRP permeabilities were more than a 4-fold increase compared to the HIV-negative controls. Duodenal macromolecule permeability was partially temperature-dependent and associated with epithelial apoptosis without altered expression of the analyzed tight junction proteins. In T84 monolayers, apoptosis induction increased, and both apoptosis and endocytosis inhibitors reduced macromolecule permeability. Using quantitative analysis, we demonstrate the increased macromolecule permeability of the intestinal mucosa in untreated HIV-infected patients. Combining structural and mechanistic studies, we identified two pathways of increased macromolecule translocation in HIV infection: transcytosis and passage through apoptotic leaks.

Cost-effectiveness of dolutegravir vs. efavirenz-based combined antiretroviral therapies in HIV-infected treatment-naive patients in a Nigerian treatment centre.

Dolutegravir (DTG) based antiretroviral therapy (ART) has largely replaced Efavirenz (EFV) based therapy as the preferred first-line regimen in the treatment of adults with HIV. This study was carried out to evaluate the comparative cost-effectiveness of DTG and EFV-based ART in HIV-infected treatment-naïve patients in a treatment centre in Nigeria. This was a retrospective case-control study of patients initiated on DTG vs. EFV-based regimens from January 2018 to December 2019 at the APIN/HAVARD clinic of Nigeria's Jos University Teaching Hospital. The current viral load result was used to determine treatment effectiveness using a benchmark of ≤200 copies/mL. Sensitivity analysis was carried out to ensure the robustness of the benchmark. The total cost of treatment was obtained by summing up the relevant cost components. Appropriate descriptive and inferential statistics were employed in data analysis using Statistical Product and Services Solutions (SPSS) V.25. The incremental cost-effectiveness ratio of DTG compared to EFV was presented as cost/effectiveness. Treatment was effective in 42(51.9%) and 58(71.6%) patients initiated on DTG and EFV-based regimen, respectively. The incremental cost-effective ratio (ICER) of patients on DTG compared to those on EFV was $10.5076 per effectiveness, which was less than 1% of the Nigerian 2019 per capita Gross Domestic Product. Sensitivity analysis showed the robustness of the result. Efavirenz based regimen had higher treatment effectiveness than DTG-based regimen in treatment-naive patients after initiating treatment in a short term. Compared to EFV, DTG-based regimen is cost-effective in the management of treatment naïve HIV patients.

Prevalence of Cytopenia and its Correlation with Immunosuppression in Naïve HIV-1 Infected Patients Initiating First-Line Antiretroviral Therapy: A Pilot Study.

Cytopenias serve as common indicators and crucial predictive tools for evaluating disease progression and therapeutic outcomes in individuals with human immunodeficiency virus (HIV) infection. This study aimed to assess the prevalence of cytopenias and their correlation with the level of immunosuppression in treatment-naive HIV-infected participants after initiating highly active combined antiretroviral drug therapy (cART24). This prospective study focused on evaluating cytopenia in 44 treatment-naive HIV-infected patients who consented to initiate cART and were consecutively enrolled. The research was conducted at the Nasara HIV Treatment & Care Centre of Ahmadu Bello University Teaching Hospital (ABUTH), Zaria, Nigeria, spanning from December 2016 to January 2018. Cytopenias, including anemia, leucopenia, lymphocytopenia, and thrombocytopenia, were defined and assessed according to World Health Organization guidelines. A combination of cross-sectional and longitudinal mixed-design two-step analysis was employed to validate our findings. The median time from enrollment to cART initiation was 7 days, following the universal test and treat protocol. The prevalence of cytopenia was 75% at the baseline before treatment and increased to 84% after cART24 administration. There were no statistically significant differences in the median values of immuno-hematological parameters between baseline and after cART24 initiation (P >0.05). In terms of longitudinal assessment, the prevalence of anemia, leucopenia, lymphopenia, and thrombocytopenia at baseline were 66%, 23%, 0%, and 11%, respectively, and after cART24, the rates were 66%, 29%, 5%, and 20%. Notably, the prevalence of cytopenia correlated with declining CD4+ T cell counts. Among instances of unicytopenia, 58% exhibited isolated anemia, 6% had lone leucopenia, and 6% had solitary thrombocytopenia. Additionally, 27% demonstrated bi-cytopenia, and 3% exhibited pancytopenia. Interestingly, none of the study participants presented with lymphopenia. The most common combination was anemia and thrombocytopenia. Both longitudinal and cross-sectional analytical findings were consistent. In treatment-naive HIV-infected individuals, the prevalence of cytopenias, particularly anemia and thrombocytopenia, was substantial and correlated with the degree of immunosuppression as indicated by CD4+ T cell counts. These cytopenias persisted despite initiation of cART24, highlighting the complexity of hematological manifestations in HIV infection. Our study underscores the significant hematopathological impact of HIV and antiretroviral therapy, highlighting the necessity for preventive strategies to mitigate these adverse effects.

Histopathological Pattern of Kidney Diseases Among HIV-Infected Treatment-Naïve Patients in Kano, Nigeria.

IntroductionKidney biopsy in patients with HIV-associated kidney diseases allows for histopathologic diagnosis and institution of appropriate treatment as well as proper prognostication. There is a paucity of data on the histopathological pattern of HIV-associated kidney diseases in most sub-Saharan African countries. This study was aimed at evaluating the histopathologic patterns of kidney diseases seen among HIV-infected treatment-naive patients in our center as this will allow for proper diagnosis and institution of appropriate treatment.MethodsIn this cross-sectional study, consecutive patients who satisfied inclusion criteria and consented to participate were recruited. Percutaneous kidney biopsies were carried out as day procedures under real-time ultrasound guidance using an automatic spring-loaded biopsy gun as per our unit protocols. Baseline investigations including urea, creatinine, electrolytes, CD4 count, complete blood count, and glomerular filtration rate (eGFR) calculations, urinalysis and urine protein creatinine ratios were done on all the participants.ResultsFifty-five patients who satisfied the inclusion criteria were studied. The mean age of the study population was 38.34± 9.26 years, with 32% females. Mean serum creatinine was 249.6±164.6 μmol/L, and mean CD4 count was 238 ±210 cells/mL. The commonest histological type was FSGS seen in 20 patients (37.7%), followed by HIVAN seen in 17 (32.1%) patients; chronic interstitial nephritis in 7 patients (13.2%) and 6 (11%) had no significant pathological finding. Compared to non-HIVAN, HIVAN patients tended to have higher systolic BP (p= 0.05); higher serum creatinine levels (p= 0.05); lower eGFR (0.03) and higher urine protein to creatinine ratio [uPCR; p= 0.02].ConclusionKidney involvement is still a form of presentation among HIV-infected treatment-naïve patients and though a wide range of glomerular and tubulointerstitial lesions may be seen, FSGS and HIVAN are still the most common. We recommend assessment of kidney function, including urinalysis, as part of the routine evaluation of newly diagnosed HIV patients and biopsy where indicated to prognosticate and institute appropriate early treatment.

Prevalence of transmitted drug resistance in HIV-infected treatment-naive patients in Chile

Transmitted drug resistance (TDR) occurs in patients with HIV infection who are not exposed to antiretroviral drugs but who are infected with a virus with mutations associated with resistance. To determine the prevalence of TDR and characterize HIV reverse transcriptase and protease mutation patterns. HIV infected antiretroviral treatment-naive patients treated in three centers between 2014 and 2018 were studied. A genotyping study was carried out. The HIVdb Program (Stanford University) and the World Health Organization (WHO) TDR surveillance mutation list were used to register resistance-associated mutations. We enrolled 220 patients aged a median of 29 (interquartile range (IQR) 24-34) years, 99% men. Median CD4 count was 365 cells/μL (IQR 250-499 cells/μL) and median viral load was 39.150 copies/mL (IQR 9,270 -120,000). The overall prevalence of RTD was 10.45% (95% CI 6.7-15.2, N = 23/220). The higher frequency of TDR was against non-nucleoside reverse transcriptase inhibitors, reaching 9.0% (95% CI 5.6-13.6), followed by nucleoside reverse transcriptase inhibitors reaching 1.8% (95% CI 0.49-4.5) and protease inhibitors reaching 0.45% (95% CI 0.01-2.5). The mutations in reverse transcriptase were M41L, L210W, D67N, K70E, M184V, K103N (6.36%, 95% CI 3.5-10.4), G190A, E138A, K101E, and I84V in protease. These results should prompt a change in recommendations for starting antiretoviral therapy, especially in first-line regimens that include non-nucleoside reverse transcriptase inhibitors.

Lipids, biomarkers, and subclinical atherosclerosis in treatment-naive HIV patients starting or not starting antiretroviral therapy: Comparison with a healthy control group in a 2-year prospective study.

ObjectiveTo assess the effect of HIV infection and combined antiretroviral therapy (c-ART) on various proatherogenic biomarkers and lipids and to investigate their relationship with subclinical atherosclerosis in a cohort of treatment-naive HIV-infected patients.MethodsWe performed a prospective, comparative, multicenter study of 2 groups of treatment-naive HIV-infected patients (group A, CD4>500 cells/μL, not starting c-ART; and group B, CD4<500 cells/μL, starting c-ART at baseline) and a healthy control group. Laboratory analyses and carotid ultrasound were performed at baseline and at months 12 and 24. The parameters measured were low-density lipoprotein (LDL) particle phenotype, lipoprotein-associated phospholipase A2 (Lp-PLA2), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), sCD14, sCD163, monocyte chemoattractant protein-1(MCP-1), and asymmetric dimethylarginine (ADMA). A linear mixed model based on patient clusters was used to assess differences in biomarkers between the study groups and over time.ResultsThe study population comprised 62 HIV-infected patients (group A, n = 31; group B, n = 31) and 22 controls. Age was 37 (30–43) years, and 81% were men. At baseline, the HIV-infected patients had a worse LDL particle phenotype and higher plasma concentration of sCD14, sCD163, hs-CRP, and LDL-Lp-PLA2 than the controls. At month 12, there was an increase in total cholesterol (p = 0.002), HDL-c (p = 0.003), and Apo A-I (p = 0.049) and a decrease in sCD14 (p = <0.001) and sCD163 (p<0.001), although only in group B. LDL particle size increased in group B at month 24 (p = 0.038). No changes were observed in group A or in the healthy controls. Common carotid intima-media thickness increased in HIV-infected patients at month 24 (Group A p = 0.053; group B p = 0.048). Plasma levels of sCD14, sCD163, and hs-CRP correlated with lipid values.ConclusionsIn treatment-naive HIV-infected patients, initiation of c-ART was associated with an improvement in LDL particle phenotype and inflammatory/immune biomarkers, reaching values similar to those of the controls. HIV infection was associated with progression of carotid intima-media thickness.

Cost of Human Immunodeficiency Virus (HIV) and Determinants of Healthcare Costs in HIV-Infected Treatment-Naive Patients Initiated on Antiretroviral Therapy in Germany: Experiences of the PROPHET Study

The purpose of the prospective clinical and pharmacoeconomic outcomes study of different first-line antiretroviral treatment strategies (PROPHET) was to examine the healthcare costs of human immunodeficiency virus (HIV)-infected persons in Germany treated with different antiretroviral therapy (ART) strategies and to identify variables associated with high costs. The setting was a 24-month prospective multicenter observational cohort study in a German HIV-specialized care setting from 2014 to 2017. A microcosting approach was used for the estimation of healthcare costs. Data were obtained via electronic case report forms. The costs were calculated from both the societal and the statutory health insurance perspective. Regression models were performed that took into consideration the impact of several independent variables. Four hundred thirty-four patients from 24 centers throughout Germany were included. Average annual healthcare costs were €20 118 (standard deviation [SD] €6451) per patient from the societal perspective (n= 336) and €17 306 (SD €4106) from the statutory health insurance perspective (n= 292). Expenditures for the ART medication had the highest impact. Total costs declined in the second year of therapy. There was a significant association between the amount of total cost and clinical or therapeutic variables from both perspectives; a diagnosis of acquired immune deficiency syndrome (AIDS) led to higher costs as well as the chosen ART strategy. Age also increased cost from the statutory health insurance perspective. The main cost driver of the healthcare costs for HIV-positive patients was antiretroviral drug expenses. Further variables that influenced the costs were identified. The results provide a detailed overview of the resource use of patients in the PROPHET cohort.

Pharmacogenomics and pharmacokinetics of efavirenz 400or 600mg in 184 treatment-naive HIV-infected patients in China.

Background: The pharmacogenomics and pharmacokinetics/pharmacodynamics of 400mg efavirenz have rarely been reported. Materials & methods: A total of 184 treatment-naive HIV-infected patients were randomly assigned (1:1) to receive a lower dose (tenofovir disoproxil 200mg, efavirenz 400mg andlamivudine) or a standard dose regimen. Relationships between pharmacogenomics and efavirenz pharmacokinetics/pharmacodynamics were explored at 48weeks. Results: There was no relationship between pharmacogenomics and adverse reactions of the central nervous system and antiretoviral efficacy. CYP2B6 516G>T, 785A>G, 18492C>T and ABCB1 3435C>T T/C were associated with higher efavirenz plasma levels in the standard but not the lower dose group. No relationship was found between pharmacogenomics and antiretoviral efficacy. Patients who were<60kg had higher efavirenz concentration compared with those with weight ≥60kg when using 600 mgefavirenz, this was not observed with400mg efavirenz. Conclusion: The effect of pharmacogenomics and body weight on the efavirenz concentration was significant in the 600 mggroupbut not in the 400mg group.

Prevalence and predictors of low bone mineral density in treatment-naive HIV-infected patients and its correlation with CD4 cell counts.

Objective:HIV virtually affects every organ system of the body. The skeletal system is no exception, and antiretroviral therapy (ART) has been implicated in bone diseases. However, not many studies have been done to evaluate bone disease in treatment (ART) naive HIV-infected patients, and hence, the present study was executed.Materials and Methods:One hundred and twenty HIV-infected ART-naive patients and 80 age- and sex-matched healthy controls were recruited for this study. A thorough history and physical examination was done followed by laboratory investigations after an overnight fasting. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry scan at the level of lumbar spine, femur, and forearm.Results:Of 120 ART-naive HIV-infected cases, the prevalence of osteoporosis and osteopenia was 13% and 41%, respectively, as compared to 0% and 17.5% in controls (P < 0.001). The mean BMD in cases was 0.842 g/cm2 which was approximately 25% lesser than that in controls. Hypovitaminosis-D was seen in 100% of cases as compared to 65% of controls (P < 0.01). A significant association of low BMD was seen with HIV-infection per se (P < 0.001), low CD4 cell counts (P < 0.001), low Vitamin D levels (P < 0.001), long duration of disease (P < 0.04), history of opportunistic infections (P < 0.03), and history of tuberculosis in the past (P < 0.05).Conclusion:Bone diseases such as osteoporosis and osteopenia characterized by low BMD are very common in HIV-infected patients. Virus per se, along with low CD4 cell counts and low Vitamin D levels are major predictors of pathological fractures in these individuals.

Antiretroviral therapy adherence among treatment-naive HIV-infected patients.

To determine the incidence of antiretroviral therapy (ART) adherence among treatment-naive HIV-infected patients and to evaluate the impact of single-tablet regimen (STR) on ART adherence among this population. Retrospective cohort study. We used a nationally representative sample of IQVIA LRx Lifelink individual level pharmacy claims database during 2011-2016, and defined adult patients with index date (first complete ART regimen prescription fill date) after 30 June 2011 as treatment naïve. We estimated ART adherence, measured as the proportion of days covered during 1 year following the index date. We conducted multivariable analysis to identify the factors associated with optimum adherence (≥90% proportion of days covered). We also compared adherence between patients prescribed STR and multiple-tablet regimens among those prescribed integrase strand transfer inhibitor-based or nonnucleoside reverse transcriptase inhibitor-based regimens. Overall 42.9% of the patients were optimally adherent. Adherence was significantly lower among blacks, Hispanics and patients in low-income communities. Adjusting for the covariates, patients on STR had higher incidence of optimum adherence compared with those on multiple-tablet regimens among patients on integrase strand transfer inhibitor-based regimens [49 vs. 24%, relative risk, 2.16 (95% confidence interval: 1.96-2.26)], but no significant difference was observed among those on nonnucleoside reverse transcriptase inhibitor-based regimen [45 vs. 45%, relative risk, 1.12 (95% confidence interval: 0.99-1.26)]. Low ART adherence observed among treatment-naive patients in this nationally representative study suggests the need for public health interventions to improve adherence among this population.

Relationship between CD4 cell count and left ventricular dimension and function in treatment-naïve human immunodeficiency virus-infected patients

Introduction: Echo studies have documented obvious changes in the left ventricular (LV) dimension and function of human immunodeficiency virus (HIV)-infected patients. Previous studies had suggested that patients with very low CD4 cell counts (≤200/μl) were more likely to be at risk of cardiac complications. The aim of the present study was to evaluate and correlate the LV dimension and function of treatment-naive HIV-positive patients with their CD4 cell count. Methodology: A total of 100 consenting treatment-naive HIV-infected patients and fifty healthy controls were recruited for this study. The data were analyzed using the Statistical Package for the Social Science version 20.0. The data were subjected to appropriate statistical tests. The statistically significant P value was set at 0.05. Results: Fifty-eight HIV-infected patients had CD4 cell count of >200/μl, whereas 42 had CD4 cell count of ≤200/μl. A higher proportion of treatment-naive HIV-infected patients had larger LV dimension compared to their healthy seronegative counterparts (P = 0.01). The HIV-infected patients were more likely to have asymptomatic systolic and diastolic dysfunctions compared to the healthy seronegative adults (P = 0.01). Thirty-three HIV patients had LV systolic dysfunction consisting of 26 (61.9%) with CD4 cell count 200/μl. Thirty-four of the patients had LV diastolic dysfunction consisting of 20 (47.6%) with CD4 cell count 200/μl. The LV cavity diameter and LV mass index did not show any significant correlation with CD4 cell count ([r] = −0.018; P = 0.863 and [r] =0.012; P = 0.902, respectively). LV systolic function showed significant positive correlation with CD4 cell count, (r = 0.384; P = 0.001). Conclusion: Treatment-naive HIV-infected patients had larger LV dimension and were more likely to have LV systolic and diastolic dysfunction compared to HIV-negative healthy individuals. Some of these findings were more prevalent in HIV-infected patients with very low CD4 cell count of ≤200/μl.

Human immunodeficiency virus infection and older adults: A retrospective single-site cohort study from Johannesburg, South Africa.

IntroductionHIV-infected adults aged over 50 years in South Africa are increasing. This study explored differences between baseline characteristics and 12-month outcomes of younger and older HIV-infected adults initiated on antiretroviral therapy (ART). Additionally, associations with outcomes within the older group were sought.MethodsWe retrospectively reviewed treatment-naive HIV-infected adult patients at ART initiation. Patients aged 18.0–39.9 years were compared to patients aged over 50 years using log-binomial regression for baseline characteristics and 12-month outcomes. Within the older group, outcome associations were found using multivariate regression.ResultsThe older cohort (n = 1635) compared to the younger cohort (n = 10726) comprised more males (47.2% vs. 35.4%, PR 1.52, p < 0.05), smokers (12.9% vs. 9.7%, PR 1.32, p < 0.05) and overweight patients (26.0% vs. 20.0%, PR 1.32, p < 0.05). Fewer older patients had tuberculosis (10.2% vs. 15.3%, PR 0.67, p < 0.05), other opportunistic infections (16.9% vs. 23.3%, PR 0.70, p < 0.05), World Health Organization stage 3/4 disease (39.9% vs. 43.2%, PR 0.89, p < 0.05), anaemia (22.8% vs. 28.4%, PR 0.77, p < 0.05), liver dysfunction (17.1% vs. 21.3%, PR 0.83, p < 0.05) or low CD4+ count < 100 cells/mm3 (56.3% vs. 59.9%, PR 0.71, p < 0.05).Mortality was higher in the older cohort (11.3% vs. 7.5%, PR 1.48, p < 0.05). Virological suppression was greater in the older cohort (89.5% vs. 86.5%, PR 1.28, p < 0.05) but CD4+ restitution was lower (62.8% vs. 75.0%, PR 0.61, p < 0.05). There was no difference in treatment complications between the groups.Within the older cohort, associations with death were as follows: age > 55 years (PR 1.47, p < 0.05), an AIDS-defining condition (PR 2.28, p < 0.05), raised ALT (PR 1.53, p < 0.05) and CD4+ < 100 cells/mm3 (PR 2.15, p < 0.05). Associations with favourable treatment response at 12 months were unemployment (PR 1.18, p < 0.05) and raised ALT (PR 1.19, p < 0.05). Associations with a treatment complication at 12 months were unemployment (PR 1.12, p < 0.05), smoking (PR 1.20, p < 0.05) and nevirapine use (PR 1.36, p < 0.05) but secondary education was protective (PR 0.87, p < 0.05).ConclusionHIV-infected South African adults aged over 50 years differ in characteristics and outcomes compared to their younger counterparts and justify specialised management within HIV treatment facilities.

Analysis of drug-drug interactions among patients receiving antiretroviral regimens using data from a large open-source prescription database.

Results of a study of contraindicated concomitant medication use among recipients of preferred antiretroviral therapy (ART) regimens are reported. A retrospective study was conducted to evaluate concomitant medication use in a cohort of previously treatment-naive, human immunodeficiency virus (HIV)-infected U.S. patients prescribed preferred ART regimens during the period April 2014-March 2015. Data were obtained from a proprietary longitudinal prescription database; elements retrieved included age, sex, and prescription data. The outcome of interest was the frequency of drug-drug interactions (DDIs) associated with concomitant use of contraindicated medications. Data on 25,919 unique treatment-naive patients who used a preferred ART regimen were collected. Overall, there were 384 instances in which a contraindicated medication was dispensed for concurrent use with a recommended ART regimen. Rates of contraindicated concomitant medication use differed significantly by ART regimen; the highest rate (3.2%) was for darunavir plus ritonavir plus emtricitabine-tenofovir disoproxil fumarate (DRV plus RTV plus FTC/TDF), followed by elvitegravir-cobicistat-emtricitabine-tenofovir disoproxil fumarate (EVG/c/FTC/TDF)(2.8%). The highest frequencies of DDIs were associated with ART regimens that included a pharmacoenhancing agent: DRV plus RTV plus FTC/TDF (3.2%) and EVG/c/FTC/TDF (2.8%). In a large population of treatment-naive HIV-infected patients, ART regimens that contained a pharmacoenhancing agent were involved most frequently in contraindicated medication-related DDIs. All of the DDIs could have been avoided by using therapeutic alternatives within the same class not associated with a DDI.

Dolutegravir, Second Generation Integrase Inhibitor: A New Hope for HIV Patient

Undeterred efforts are reported and still continue in future to achieve the goals of virologic suppression in HIV-infected individuals. Dolutegravir is the result of all the efforts made in this direction. It is a recent integrase inhibitor drug approved by the US FDA (Food and Drug Administration) for use in the treatment-naive and treatment-experienced HIV-infected patients. This article has reviewed all the aspects of the drug, including the structural and functional analyses, in vitro activity, pharmacokinetics, drug-drug interactions, MOA, metabolism, excretion, dosing/adverse effects and resistance profile. Dolutegravir is a potent and well tolerated antiretroviral agent that can play an important role in the treating patients harboring resistance to other antiretrovirals. Some new combinations of drug with other antiretrovirals are also in the pipeline that can increase the immunologic response of the HIV patients.

Cardiovascular outcomes among HIV-infected veterans receiving atazanavir.

Objective:Patients with HIV infection have an increased risk of cardiovascular disease compared with uninfected individuals. Antiretroviral therapy with atazanavir (ATV) delays progression of atherosclerosis markers; whether this reduces cardiovascular disease event risk compared with other antiretroviral regimens is currently unknown.Design:Population-based, noninterventional, historical cohort study conducted from 1 July 2003 through 31 December 2015.Setting:Veterans Health Administration hospitals and clinics throughout the United States.Participants:Treatment-naive patients with HIV infection (N = 9500).Antiretroviral exposures:Initiating antiretroviral regimens containing ATV, other protease inhibitors, nonnucleoside reverse transcriptase inhibitors (NNRTIs), or integrase strand transfer inhibitors (INSTIs).Main outcome/effect size measures:Incidence rates of myocardial infarction (MI), stroke, and all-cause mortality within each regimen. ATV versus other protease inhibitor, NNRTI, or INSTI covariate-adjusted hazard ratios by using Cox proportional hazards models and inverse probability of treatment weighting.Results:Incidence rates for MI, stroke, and all-cause mortality with ATV-containing regimens (5.2, 10.4, and 16.0 per 1000 patient-years, respectively) were lower than with regimens containing other protease inhibitors (10.2, 21.9, and 23.3 per 1000 patient-years), NNRTIs (7.5, 15.9, and 17.5 per 1000 patient-years), or INSTIs (13.0, 33.1, and 21.5 per 1000 patient-years). After inverse probability of treatment weighting, adjusted hazard ratios (95% confidence intervals) for MI, stroke, and all-cause mortality with ATV-containing regimens versus all non-ATV-containing regimens were 0.59 (0.41–0.84), 0.64 (0.50–0.81), and 0.90 (0.73–1.11), respectively.Conclusion:Among treatment-naive HIV-infected patients in the Veterans Health Administration initiating ATV-containing regimens, risk of both MI and stroke were significantly lower than in those initiating regimens containing other protease inhibitors, NNRTIs, or INSTIs.

Ultradeep sequencing of B and non-B HIV-1 subtypes: Viral diversity and drug resistance mutations before and after one month of antiretroviral therapy in naive patients

BackgroundUltradeep pyrosequencing technologies permit an assessment of the genetic diversity and the presence and frequency of minority variants in a viral population. The effect of these parameters on the outcome of highly active antiretroviral therapy (HAART) in HIV-infected patients is poorly understood. ObjectivesThe present study used the pyrosequencing Roche 454 prototype assay to determine whether antiretroviral efficacy is correlated with viral diversity and minority drug resistance mutations in HIV-infected treatment-naive patients and to compare assay performance in B and non-B subtypes. Study designThe study included 30 HIV-1 infected naive patients (20 with subtype non-B and 10 with subtype B). Ultradeep pyrosequencing of protease and reverse transcriptase genes was performed at baseline and 1 month after HAART initiation. Plasma HIV VL was measured at 0 and after 1, 3, and 6 months of HAART. ResultsPre-HAART minority drug resistance mutations were observed to NRTI in 4 patients, to NNRTI in 6 patients, and to PI in 1 patient; there was no difference in HAART-induced VL decay between patients. Pre-HAART diversity was significantly correlated with the time elapsed since HIV-1 infection diagnosis, but not with the subtype, VL, or CD4 count. Patients with an undetectable VL after 3 months of HAART had a higher pre-HAART diversity. Pre- and post-HAART diversities were not statistically different. There was no difference in assay performance between subtype B and non-B. ConclusionsA high pre-HAART viral diversity might have a positive effect on the outcome of HAART. Pre-therapeutic minority drug resistance mutations are uncommon in naive patients.

Immune Activation by Mycobacterium tuberculosis in HIV-Infected and -Uninfected Subjects.

This study investigates the influence of Mycobacterium tuberculosis infection on immune activation biomarkers, both in HIV-infected and -uninfected subjects. Forty-eight treatment-naive HIV-infected patients and 74 HIV-uninfected subjects were recruited and divided into groups according to their M. tuberculosis infection status: latent tuberculosis infection (LTBI), active tuberculosis (TB), and no evidence of M. tuberculosis infection. The expression of cellular markers CD38 and HLA-DR on circulating CD8 T lymphocytes and the plasmatic levels of soluble markers interleukin-6, sCD14, and D-Dimer were measured and compared between groups. The HIV-infected patients with no evidence of M. tuberculosis or with LTBI who initiated antiretroviral treatment were tested again for these biomarkers once viral suppression was reached. In both HIV-infected and -uninfected groups, patients with TB had higher levels of immune activation markers than subjects with LTBI and with no evidence of M. tuberculosis. Among the HIV-uninfected subjects, no significant difference in biomarker level was found between those presenting LTBI and those with no evidence of M. tuberculosis. The effect of LTBI on activation biomarkers in the HIV-infected groups was inconclusive because of the small number of individuals in the HIV+/LTBI group. sCD14 and D-Dimer levels were significantly higher in the TB-only group than in the HIV-only group. Although TB is associated with an increase in biomarkers of immune activation, the effect of LTBI is less evident. Further investigation is warranted, and according to our results, soluble markers may offer greater sensitivity for the evaluation of M. tuberculosis-associated immune activation than cellular markers.

Immune activation is associated with decreased thymic function in asymptomatic, untreated HIV-infected individuals.

BackgroundReduced thymic function causes poor immunological reconstitution in human immunodeficiency virus (HIV)-positive patients on combined antiretroviral therapy (cART). The association between immune activation and thymic function in asymptomatic HIV-positive treatment-naive individuals has thus far not been investigated.Aims and objectivesTo optimise a five-colour flow cytometric assay for measurement of thymic function by measuring recent thymic emigrants (RTEs) in treatment-naive HIV-infected patients and healthy controls and correlate results with levels of immune activation, CD4 counts and viral load.MethodsBlood obtained from 53 consenting HIV-positive individuals and 32 controls recruited from HIV prevention and testing clinic in Cape Town, South Africa. RTEs were measured (CD3+/CD4+/CD45RA+/CD31+/CD62L+) and levels were correlated with CD4 counts of HIV-infected individuals, log viral load and levels of immune activation (CD8+/CD38+ T-cells).ResultsHIV-infected individuals had reduced frequencies of RTEs when compared to controls (p = 0.0035). Levels of immune activation were inversely correlated with thymic function (p = 0.0403), and the thymic function in HIV-infected individuals showed no significant correlation with CD4 counts (p = 0.31559) and viral load (p = 0.20628).ConclusionsThere was impaired thymic function in HIV-infected individuals, which was associated with increased levels of immune activation. The thymic dysfunction was not associated with CD4 counts and viral load. Immune activation may result in inflammatory damage to the thymus and subsequent thymic dysfunction, and CD4 counts and viral load may not necessarily reflect thymic dysfunction in HIV.

Unanticipated Effects of New Drug Availability on Antiretroviral Durability: Implications for Comparative Effectiveness Research.

Background. Durability of antiretroviral (ARV) therapy is associated with improved human immunodeficiency virus (HIV) outcomes. Data on ARV regimen durability in recent years and clinical settings are lacking.Methods. This retrospective follow-up study included treatment-naive HIV-infected patients initiating ARV therapy between January 2007 and December 2012 in a university-affiliated HIV clinic in the Southeastern United States. Outcome of interest was durability (time to discontinuation) of the initial regimen. Durability was evaluated using Kaplan-Meier survival analyses. Cox proportional hazard analyses was used to evaluate the association among durability and sociodemographic, clinical, and regimen-level factors.Results. Overall, 546 patients were analyzed. Median durability of all regimens was 39.5 months (95% confidence interval, 34.1–44.4). Commonly prescribed regimens were emtricitabine and tenofovir with efavirenz (51%; median duration = 40.1 months) and with raltegravir (14%; 47.8 months). Overall, 67% of patients had an undetectable viral load at the time of regimen cessation. Discontinuation was less likely with an integrase strand transfer inhibitor (adjusted hazards ratio [aHR] = 0.35, P = .001) or protease inhibitor-based regimen (aHR = 0.45, P = .006) and more likely with a higher pill burden (aHR = 2.25, P = .003) and a later treatment era (aHR = 1.64, P < .001).Conclusions. Initial ARV regimen longevity declined in recent years contemporaneous with the availability of several new ARV drugs and combinations. Reduced durability mostly results from a preference for newly approved regimens rather than indicating failing therapy, as indicated by viral suppression observed in a majority of patients (67%) prior to regimen cessation. Durability is influenced by extrinsic factors including new drug availability and provider preference. Medication durability must be interpreted carefully in the context of a dynamic treatment landscape.

Rare emergence of drug resistance in HIV-1 treatment -naïve patients after 48 weeks of treatment with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide

Tenofovir alafenamide (TAF), a novel prodrug of the NtRTI tenofovir (TFV), delivers TFV-diphosphate (TFV-DP) to target cells more efficiently than the current prodrug, tenofovir disoproxil fumarate (TDF), with a 90% reduction in TFV plasma exposure. TAF, within the fixed dose combination of elvitegravir /cobicistat / emtricitabine (FTC)/TAF (E/C/F/TAF), has been evaluated in one Phase 2 and two Phase 3 randomized, double-blinded studies in HIV-infected treatment-naive patients, comparing E/C/F/TAF to E/C/F/TDF. In these studies, the TAF-containing group demonstrated non-inferior efficacy to the TDF-containing comparator group with 91.9% of E/C/F/TAF patients having <50 copies/mL of HIV-1 RNA at week 48. An integrated resistance analysis across these three studies was conducted, including HIV-1 genotypic analysis at screening, and genotypic/phenotypic analysis for patients with HIV-1 RNA >400 copies/mL at virologic failure. Pre-existing primary resistance-associated mutations (RAMs) were observed at screening among the 1903 randomized and treated patients: 7.5% had NRTI-RAMs, 18.2% had NNRTI-RAMs, and 3.4% had primary PI-RAMs. Pre-treatment RAMs did not influence treatment response at Week 48. In the E/C/F/TAF group, resistance development was rare; seven patients (0.7%, 7/978) developed NRTI-RAMs, five of whom (0.5%, 5/978) also developed primary INSTI-RAMs. In the E/C/F/TDF group, resistance development was also rare; seven patients (0.8%, 7/925) developed NRTI-RAMs, four of whom (0.4%, 4/925) also developed primary INSTI-RAMs. An additional analysis by deep sequencing in virologic failures revealed minimal differences compared to population sequencing. Overall, resistance development was rare in E/C/F/TAF-treated patients, and the pattern of emergent mutations was similar to E/C/F/TDF.