Continuous Antiretroviral Treatment Research Articles

Frailty and prefrailty in people living with HIV, with focus on women living with HIV.

With the increasing lifespan of people living with HIV (PLWH), frailty and prefrailty are becoming topics which require more attention. The reciprocal interactions between chronic inflammation, comorbidities and frailty demonstrate the complex pathophysiology of frailty and its consequences. Female sex, HIV infection without antiretroviral treatment, reduced CD4 cell count, depression and cardiovascular disease are some of the risk factors for frailty among PLWH. Frailty predisposes to falls and can therefore lead to more frequent fractures, hospitalization and death, especially in women with osteoporosis. Continuous antiretroviral treatment, prevention of comorbidities such as depression and diagnosis of prefrailty are crucial interventions to slow the development of frailty. This review summarizes the literature on frailty in people living with HIV and discusses frailty management strategies in order to improve the health outcomes in women living with HIV.

The Determinants Perception Of Male Sex With Man (Msm) Concerning The Utilization Of VCT (Voluntary Counselling And Testing) HIV / AIDS In Dili Municipality, Timor-Leste

Background and objectives: The spread of HIV / AIDS is still a major worrying problem at this time, not a single country in the world is free from HIV / AIDS. WHO has set a target of 90-90-90 which is expected that by 2020, 90% of people living with HIV will know their status, 90% of all people diagnosed with HIV will receive continuous antiretroviral treatment and 90% of all people who receive antiretroviral treatment obtains HIV viral suppression. The Government of Timor-Leste in its efforts to tackle HIV / AIDS in the future by improving coordination between related sectors in the context of implementing AIDS prevention programs with the hope of achieving targets, namely zero new infection, zero AIDS related death and zero discrimination. This study aims to determine the determinants of the perception of MSM in the use of VCT.
 
 Methods: This study used a cross-sectional analytic survey design with men having sex with men (MSM) aged ≥ 18 years as respondents. The study was conducted in Dili Municipality, Timor-Leste. The sample was selected using the convenient sampling method with a total of 150 respondents. Data collected by interview method. Data analysis was performed using logistic regression to determine the Adjusted Odd Ratio of each variable.
 
 Results: The results showed that respondents who had tested in the last 1 year were 64.7% and respondents who had never tested in the last 1 year were 35.3%. The results of multivariate analysis with logistic regression showed that the variables associated with VCT utilization were perceived vulnerability (AOR = 14.761; 95% CI = 1.976-110.242; p = 0.009) and information sources (AOR = 0.038; 95% CI = 0.005-0.284; p = 0.001).
 
 Conclusion: Perceptions of vulnerability and sources of information are related to the use of VCT in MSM. So it is hoped that health workers will collaborate with NGO administrators to be more active in educating MSM regarding the importance of using VCT through VCT mobile services, using approaches through online media and direct counseling.

Virologic Failure in Different Antiretroviral Regimens Among Pediatric Patients with HIV Referring to a Voluntary Counseling and Testing (VCT) Center in Tehran, Iran (2004 - 2017)

Objectives: This study aimed to evaluate the virologic failure rate of treatment for various types of antiretroviral treatment (ART) regimens in pediatric patients with HIV. Methods: The present study was conducted among 75 HIV-positive pediatric patients characterized by the presence of a viral load of 200 or more copies per mL after six months of effective, continuous ART regimen. Therefore, treatment failure was defined based on virologic failure. We designed a questionnaire that included patients’ demographic characteristics, viral load markers, TCD4+ count, antiretroviral regimen received, and the probable treatment failure, along with the results of the drug resistance tests. Results: In total, 22 (29.2%) children experienced treatment failure. The most common primary antiretroviral regimen was Zidovudine (AZT)/Lamivudine (3TC)/Nevirapine (NVP) (59.2%), followed by AZT/3TC/Efavirenz (EFV) (29.6%). The highest rate of virologic failure was related to the AZT/3TC/NVP regimen (68.2%). In children who used NVP, the virologic failure was significantly higher than in children on other regimens (P = 0.02). Conclusions: The present study showed that patients receiving ART regimens based on reverse transcriptase non-nucleoside inhibitors, especially NVP, experienced more treatment failure than patients receiving other regimens.

Neurocognition and quality of life after reinitiating antiretroviral therapy in children randomized to planned treatment interruption.

Understanding the effects of antiretroviral treatment (ART) interruption on neurocognition and quality of life (QoL) are important for managing unplanned interruptions and planned interruptions in HIV cure research. Children previously randomized to continuous (continuous ART, n = 41) vs. planned treatment interruption (PTI, n = 47) in the Pediatric European Network for Treatment of AIDS (PENTA) 11 study were enrolled. At study end, PTI children resumed ART. At 1 and 2 years following study end, children were assessed by the coding, symbol search and digit span subtests of Wechsler Intelligence Scale for Children (6-16 years old) or Wechsler Adult Intelligence Scale (≥17 years old) and by Pediatrics QoL questionnaires for physical and psychological QoL. Transformed scaled scores for neurocognition and mean standardized scores for QoL were compared between arms by t-test and Mann-Whitney U test, respectively. Scores indicating clinical concern were compared (<7 for neurocognition and <70 for QoL tests). Characteristics were similar between arms with a median age of 12.6 years, CD4⁺ of 830 cells/μl and HIV RNA of 1.7 log10copies/ml. The median cumulative ART exposure was 9.6 in continuous ART vs. 7.7 years in PTI (P = 0.02). PTI children had a median of 12 months off ART and had resumed ART for 25.2 months at time of first assessment. Neurocognitive scores were similar between arms for all tests. Physical and psychological QoL scores were no different. About 40% had low neurocognitive and QoL scores indicating clinical concern. No differences in information processing speed, sustained attention, short-term memory and QoL functioning were observed between children previously randomized to continuous ART vs. PTI in the PENTA 11 trial.

LP21 : The macrophage activation markers soluble CD206 And CD163 predict mortality in patients with liver cirrhosis and acute-on-chronic liver failure (ACLF)

Child–Pugh A/B/C: 87/10/3%; 86% with HIV-RNA <50 copies/mL; 104 on continuous antiretroviral treatment (cART); median CD4 at baseline: 462/mm [IQR: 265–628]). History of previous HCV treatment was: naive 28%, treatment failure with PegIFN+Ribavirin (PR) 57%, treatment failure with PR+first generation protease inhibitor 11%, treatment failure with PR+others 4%. HCV genotype (Gt) were 1a (32%), 1b (12%), 1 other (10%), 2 (4%), 3 (19%) and 4 (23%). Four regimens were used: SOF+R in 22 patients (Gt1 28%; Gt2 18%; Gt3 36%; Gt4 18%), SOF+daclatasvir±R in 75 (Gt1 64%; Gt3 15%; Gt4 21%), SOF+ledipasvir in 3 (2 Gt1 and 1 Gt3) and SOF+simeprevir in 6 (2 Gt1 and 4 Gt4). On February 24th, 2015, 100%, 77%, 69% and 42% of the patients reached W4, EOT, and W4 and W12 posttreatment, respectively. No premature stop of DAA was reported in relation with tolerance or efficiency. Adverse events were reported in 22 patients (digestive 5%, anemia 36%, asthenia 14%, others 45%), and R was stopped in 3 patients and dose-adjusted in 9. During treatment and post-treatment period, clinical events in relation with cirrhosis were reported in 8% (hepatocellular carcinoma in 2 and decompensation in 5) and with HIV in 4% of the patients. VR was observed in 52% of the patients at W4, 100% at EOT. SVR4 and SVR12 were 100% and 93% for the patients reaching this endpoint, respectively. Conclusions: In this prospective real-life cohort, new all-oral DAA regimens were well tolerated and associated with very encouraging virological efficacy in cirrhotic HIV–HCV coinfected patients. This should not alleviate the surveillance for liver-related events in these patients.

Monitoring of the lactonase activity of paraoxonase-1 enzyme in HIV-1-infection.

Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme known as a free radical scavenging system (1). PON-1 has three main activities, responsible for its antioxidant and anti-inflammatory potential: paraoxonase, arylesterase and lactonase (LACase), the latest to be discovered and pointed out to be its native activity (2). Among other physiological roles, the LACase might minimize the deleterious effects of hyperhomocysteinaemia in infection, by detoxifying the highly reactive metabolite homocysteine-thiolactone (HcyTL) (3),4. In the present work, we have developed and applied a method to quantify LACase activity and to explore the role of this enzyme in HIV-infection and virological response. The LACase activity was monitored in a cohort of HIV-1-infected patients, through the titration of 3-(o-hydroxyphenyl) propionic acid, formed upon the LACase-mediated hydrolysis of the substrate dihydrocoumarin. The study protocol was approved by the Ethics Committee of Centro Hospitalar de Lisboa Central and Hospital Prof. Doutor Fernando Fonseca. All patients gave their written informed consent and were adults with documented HIV-1-infection, regardless of combined antiretroviral therapy (cART) use. Naïve patients and patients who had received continuous antiretroviral treatment for more than one month were included. A total of 179 HIV-1-infected patients were included on this study (51% Men, 39% non-Caucasian, 45±13 years old). Patients with non-suppressed viraemia, either from the non-cART (n=89, 12±4 kU/L, p<0.01) or from the cART with detectable viral load (n=11, 10±5 kU/L, p<0.05) groups, had lower activity than the cART with suppressed viraemia (n=79, 15±7 kU/L) (Kruskal–Wallis test). Among naïve patients, higher viral load (> 31,500 cps/mL, Spearman r=−0.535, p=0.003) and lower CD4+ T-cells count (< 500 cell/mm3, Pearson r=0.326, p=0.024) were associated with the LACase activity. The present study suggests that lower LACase activity is associated with uncontrolled HIV-1-infection, particularly with non-suppressed viraemia, despite of cART. This data seems to point to LACase role in HIV-infection, probably reflecting an increased formation of HcyTL deleterious species. A better knowledge of the LACase and its role in HcyTL pathophysiology might identify new therapeutic targets in HIV-1-infected patients.AcknowledgementsEXPL/DTP-FTO/0204/2012; EXPL/DTP-PIC/1758/2013.

CD4+ lymphocyte-based immunologic outcomes of perinatally HIV-infected children during antiretroviral therapy interruption.

To assess the characteristics and outcomes of antiretroviral treatment (ART) interruption (TI) in perinatally HIV-infected children. The Adolescent Master Protocol (AMP) of the Pediatric HIV/AIDS Cohort Study is a prospective cohort study that enrolled 7- to 16-year-old perinatally HIV-infected children between 2007 and 2009 from 15 sites in the United States and Puerto Rico. TI was defined as ART discontinuation for ≥ 3 months after ≥ 6 months of continuous ART. Subjects with and without TI were compared. Rates of change (slopes) in CD4 T-lymphocyte (CD4) count and percentage (%) per month during TI were calculated. Factors related to CD4 slope in univariable analyses were included in multivariable linear regression. Of 444 eligible AMP subjects, 101 (23%) had at least one TI. Subjects with TI were born in earlier years but were otherwise similar to those without TI. For 81 TI subjects with complete data, the median (range) CD4% and CD4 count slopes were -0.66% per month (-3.54% to +1.34% per month) and -12.7 cells per cubic millimeter per month (-148 cells/mm to +31 cells/mm per month), respectively. On multivariable linear regression, there was a trend for lower CD4% slope to be associated (P < 0.1) with female sex, higher CD4% at TI, and higher peak viral load before TI. Advanced HIV disease stage and numerous ART regimens were more common in TI subjects in the lowest (fastest declining) CD4% slope quartile. TIs in perinatally HIV-infected youth are common. During TIs, CD4 values decline on average but with high intersubject variability. Factors predicting CD4 slope during TI need further study.

The Impact of Antiretroviral Therapy in a Cohort of HIV Infected Patients Going in and out of the San Francisco County Jail

BackgroundJails are an important venue of HIV care and a place for identification, treatment and referral for care. HIV infected inmates in the San Francisco County jail are offered antiretroviral treatment (ART), which many take only while in jail. We evaluated the effect of ART administration in a cohort of jail inmates going in and out of jail over a nine year period.Methodology/Principal FindingsIn this retrospective study, we examined inmates with HIV going in and out of jail. Inmates were categorized by patterns of ART use: continuous ART - ART both in and out of jail, intermittent ART - ART only in jail; never on ART - eligible by national guidelines, but refused ART. CD4 and HIV viral load (VL) were compared over time in these groups. Over a 9 year period, 512 inmates were studied: 388 (76%) on intermittent ART, 79 (15%) on continuous ART and 45(9%) never-on ART. In a linear mixed model analysis, inmates on intermittent ART were 1.43; 95%CI (1.03, 1.99) times and those never on ART were 2.89; 95%CI (1.71, 4.87) times more likely to have higher VL than inmates on continuous ART. Furthermore, Inmates on intermittent ART and never-on ART lost 1.60; 95%CI (1.06, 2.13) and 1.97; 95%CI (0.96, 3.00) more CD4 cells per month, respectively, compared to continuously treated inmates. The continuous ART inmates gained 0.67CD4 cells/month.Conclusions/SignificanceContinuous ART therapy in jail inmate's benefits CD4 cell counts and control of VL especially compared to those who never took ART. Although jail inmates on intermittent ART were more likely to lose CD4 cells and experience higher VL over time than those on continuous ART, CD4 cell loss was slower in these inmates as compared to inmates never on ART. Further studies are needed to evaluate whether or not intermittent ART provides some benefit in outcome if continuous ART is not possible or likely.

Inflammation and Coagulation in HIV Infection Contributes Significantly to Patient Mortality

Evaluation of: Kuller LH, Tracey R, Belloso W et al.: Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLOS Med. 5(10), e203 (2008). The authors of this paper investigate a number of biomarkers associated with inflammation (high sensitivity C-reactive protein, IL-6, amyloid A, and amyloid P) and coagulation (D-dimer and prothrombin fragment 1+2) in the Strategies for Management of Antiretroviral Therapy (SMART) trial. In the SMART study an increased risk of all-cause mortality was demonstrated in the therapy interruption arm, as compared with standard practice of continuous antiretroviral treatment. Kuller and colleagues demonstrated that IL-6 and D-dimer levels were strongly associated with all-cause mortality. The authors postulate that HIV leads to activation of inflammation and coagulation increasing the risk of death in HIV-infected individuals and that interrupting antiretroviral treatment increases this risk.

Two-Months-off, Four-Months-on Antiretroviral Regimen Increases the Risk of Resistance, Compared with Continuous Therapy: A Randomized Trial Involving West African Adults

A randomized trial was launched in Côte d'Ivoire in 2002 to compare continuous antiretroviral treatment (hereafter, "C-ART") to an ART regimen of 2 months off and 4 months on therapy (hereafter, "2/4-ART"). We report the final analysis. A total of 435 adults who were receiving successful ART ((median CD4 cell count prior to ART, 272 cells/mm(3); 88% were receiving a zidovudine-lamivudine-efavirenz regimen) were randomized to receive C-ART or 2/4-ART. The main primary end point was the percentage of patients with <350 CD4 cells/mm(3) at 24 months. The sample size ensured 80% power to demonstrate noninferiority (noninferiority bound, -15%), assuming that 30% of the patients in the C-ART arm would have <350 CD4 cells/mm(3). Other end points were mortality, morbidity, cost of care, genotypic resistance, adherence, and toxicity. The percentage of patients with <350 CD4 cells/mm(3) at 24 months was 5.6% (6 of 107) in the C-ART arm and 14.6% (46 of 315) in the 2/4-ART arm (lower bound of the 95% CI for the difference, -14%). Cost was 18% higher in the C-ART arm, and resistance to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) was 20% higher in the 2/4-ART arm. Other end points were nonconclusive. Although 2/4-ART met the predetermined criteria for noninferiority, the percentage of patients with <350 CD4 cells/mm(3) in the C-ART arm was lower than anticipated, which makes the clinical significance of this noninferiority uncertain. In addition, 2/4-ART led to an unacceptable additional risk of selecting for drug-resistant virus. This new argument against episodic ART strategies is also a caveat against any unplanned ART interruptions in Africa, where most patients receive NNRTIs.

Inflammatory and Coagulation Biomarkers and Mortality in Patients with HIV Infection

BackgroundIn the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]).We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis.Methods and FindingsStored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case–control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 (95% confidence interval [CI], 1.0–4.1; p = 0.05), 8.3 (95% CI, 3.3–20.8; p < 0.0001), and 12.4 (95% CI, 4.2–37.0; p < 0.0001), respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p < 0.0001). In an expanded case–control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8 (95% CI, 1.1–3.1; p = 0.02) to 1.5 (95% CI, 0.8–2.8) and 1.4 (95% CI, 0.8–2.5) after adjustment for latest levels of IL-6 and D-dimer, respectively.ConclusionsIL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation. Trial Registration: ClinicalTrials.gov (NCT00027352).