Baseline Immune Phenotypes and CD4+ T Lymphocyte Responses to Antiretroviral Therapy in Younger versus Older HIV-infected Individuals

Objective

The purpose of the study was to determine associations between pre-antiretroviral therapy (ART) senescent CD8+ T lymphocytes and naïve versus non-naive CD8+ and CD4+ T lymphocyte subpopulations and CD4+ responses after initiation of ART in younger versus older individuals.

Methods

Retrospective analysis of 100 subjects with pre-ART cryopreserved peripheral blood mononuclear cells samples was performed with flow cytometry. Subjects were divided into four groups by age (30–50 years or?>?50 years) and 96-week CD4+ response (<100 or >200 cells/mm³). All subjects had 96-week viral suppression to <50 copies/mm³. Regression was utilized to investigate associations between pre-ART CD8+ and CD4+ T cell phenotypes with age and CD4+ response categories.

Results

Individuals <50 years had a lower frequency of senescent CD8+ T lymphocytes of the CD56?+?57+, CD56+, and CD28? phenotypes (95%CI ?3.6 to ?0.02; 95%CI ?4.2 to ?0.03; 95%CI ?12.5 to ?1.4, respectively) and a higher frequency of naïve (CD45RA?+?CD28+) CD8+ T lymphocytes (95%CI 2.6 to 10.9). Younger age and good CD4+ response were associated with a higher frequency of pre-ART naïve CD4+ T cells (95%CI 2.0 to 16.4 and 95%CI 1.5 to 15.6, respectively).

Conclusions

Prior to ART, younger HIV-infected individuals have a higher frequency of naïve CD4+ and CD8+ T cells and lower frequency of senescent CD8+ T cell phenotypes.

     

Varied sensitivity to therapy of HIV-1 strains in CD4<Superscript>+</Superscript> lymphocyte sub-populations upon ART initiation

Background

Although antiretroviral therapy (ART) has proven its success against HIV-1, the long lifespan of infected cells and viral latency prevent eradication. In this study we analyzed the sensitivity to ART of HIV-1 strains in naïve, central memory and effector memory CD4⁺ lymphocyte subsets.

Methods

From five patients cellular HIV-1 infection levels were quantified before and after initiation of therapy (2-5 weeks). Through sequencing the C2V3 region of the HIV-1 gp120 envelope, we studied the effect of short-term therapy on virus variants derived from naïve, central memory and effector memory CD4⁺ lymphocyte subsets.

Results

During short-term ART, HIV-1 infection levels declined in all lymphocyte subsets but not as much as RNA levels in serum. Virus diversity in the naïve and central memory lymphocyte populations remained unchanged, whilst diversity decreased in serum and the effector memory lymphocytes. ART differentially affected the virus populations co-circulating in one individual harboring a dual HIV-1 infection. Changes in V3 charge were found in all individuals after ART initiation with increases within the effector memory subset and decreases found in the naïve cell population.

Conclusions

During early ART virus diversity is affected mainly in the serum and effector memory cell compartments. Differential alterations in V3 charge were observed between effector memory and naïve populations. While certain cell populations can be targeted preferentially during early ART, some virus strains demonstrate varied sensitivity to therapy, as shown from studying two strains within a dual HIV-1 infected individual.

     

Modelling Comparative Efficacy of Drugs with Different Survival Profiles: Ipilimumab,Vemurafenib and Dacarbazine in Advanced Melanoma

Background

In the absence of head-to-head data, a common method for modelling comparative survival for cost-effectiveness analysis is estimating hazard ratios from trial publications. This assumes that the hazards of mortality are proportional between treatments and that outcomes are not polluted by subsequent therapy use. Newer techniques that compare treatments where the proportional hazards assumption is violated and adjust for use of subsequent therapies often require patient-level data, which are rarely available for all treatments.

Objective

The objective of this study was to provide a comparison of overall survival data for ipilimumab, vemurafenib and dacarbazine using data from three trials lacking a common comparator arm and confounded by the use of subsequent treatment.

Methods

We compared three estimated overall survival curves for vemurafenib and the difference compared to ipilimumab and dacarbazine. We performed a naïve comparison and adjusted it for heterogeneity between the ipilimumab and vemurafenib trials, including differences in prognostic characteristics and subsequent therapy using a published hazard function for the impact of prognostic characteristics in melanoma and trial data on the impact of second-line use of ipilimumab.

Results

The mean incremental life-years gained for patients receiving ipilimumab compared with vemurafenib were 0.34 (95 % confidence interval [CI] ?0.24 to 0.84) using the naïve comparison and 0.51 (95 % CI ?0.08 to 0.99) using the covariate-adjusted survival curve.

Conclusions

The analyses estimated the comparative efficacy of ipilimumab and vemurafenib in the absence of head-to-head patient-level data for all trials and proportional hazards in overall survival.

     

Metabolic syndrome and population attributable risk among HIV/AIDS patients: comparison between NCEP-ATPIII,IDF and AHA/NHLBI definitions

Background

Metabolic Syndrome (MetS) is based on the same individual components, but has received several amendments to the original definition. In this study, we verified the prevalence of metabolic syndrome according to different criteria, and the impact of each component on the diagnostic.

Methods

This cross-sectional study enrolled HIV infected patients from a HIV/AIDS reference Center in southern Brazil. Metabolic syndrome was identified according to the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP-ATPIII), the International Diabetes Federation (IDF) and the American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI) criteria, and using a standardized questionnaire and blood testing.

Results

A sample of 1240, out of 1295, HIV-infected patients was enrolled. Males were on average older, more educated, and had shorter time since the HIV diagnosis. The population attributable risk (PAR) for waist circumference explained 80% of the prevalence among men and women (AHA/NHLBI criteria). Triglycerides had the highest impact on prevalence of metabolic syndrome according to all criteria, independently of age, skin color and HAART use, among men.

Conclusions

In this large sample of HIV infected patients, the overall prevalence of metabolic syndrome, under either classification, was noticeable and the AHA/NHLBI definition accounted for the highest prevalence.

     

Factors Associated With Insulin Resistance in Adults With HIV Receiving Contemporary Antiretroviral Therapy: a Brief Update

Purpose of Review

This narrative review summarizes recent data on factors associated with insulin resistance (IR) in adults with HIV, including contemporary antiretroviral therapy (ART).

Recent Findings

IR remains common in persons with HIV, even those receiving contemporary ART. Generalized and abdominal obesity and ectopic fat are correlates of IR, and emerging data have identified associations with biomarkers of inflammation and immune activation. Small studies suggest associations between mitochondria and IR. In ART-naïve individuals, IR increased within 4 weeks of starting ART in persons receiving contemporary boosted protease inhibitors or an integrase inhibitor.

Summary

The importance of IR in non-diabetic persons with HIV will continue to grow as the population ages and obesity increases. Non-invasive estimates of IR appear to perform well in persons with HIV, but clinically relevant cutoffs are uncertain. Unexpected metabolic effects of newer HIV integrase inhibitors have been reported; thus, careful observation for and studies of IR are still warranted.

     

Inflammation Strikes Again: Frailty and HIV

Purpose of Review

As a consequence of antiretroviral therapy, the proportion of older HIV-infected adults is increasing, with a concomitant shift in burden of illness to age-related syndromes and disease. Frailty is an age-related syndrome of increased vulnerability to stress, predictive of major adverse clinical outcomes among HIV-infected and uninfected persons alike. Understanding frailty pathogenesis is critical to developing interventions to improve health outcomes in HIV. Here, we review the current evidence for the relationship between inflammation and frailty in HIV, and the potential for novel, inflammation-targeted interventions.

Recent Findings

Dysregulated inflammation has been consistently associated with frailty in elderly HIV-uninfected persons. Dysregulated inflammation is also central to HIV pathophysiology and several recent studies have demonstrated the important association of inflammation with frailty in HIV. Some evidence suggests that anti-inflammatory therapies may be effective in ameliorating the adverse impact of frailty among aging HIV-infected adults, though further investigation is necessary.

Summary

Inflammation has been implicated in frailty in HIV infection, and improved understanding of the role that inflammation plays in frailty pathogenesis is key to the development of effective therapies to slow or prevent frailty in the vulnerable HIV-infected population.

     

Validation of a questionnaire to monitor symptoms in HIV-infected patients during hepatitis C treatment

Background

Clinicians are incorporating patient-reported outcomes in the management of HIV-infected persons co-infected with hepatitis C virus (HCV), but there are no validated inventories to monitor symptoms of patients during HCV therapy.

Design

Five-year retrospective cohort analysis of persons living with HIV (PLWH) treated for HCV.

Methods

The HCV symptom-inventory (HCV-SI) was administered before, during, and after HCV treatment. Discriminant validity was assessed, separately, in mixed model linear regression of HCV-SI T-scores on treatment regimens (pegylated-interferon and ribavirin; pegylated-interferon, ribavirin, and telaprevir; and interferon-free antivirals); and side effect-related premature treatment discontinuation (SE-DC).

Results

From the 103 patients who completed the HCV-SI, 7% were female, 26% non-white, 32% cirrhotics and 91% had undetectable HIV viral loads. Most had genotype 1 (83%) and were HCV treatment-naïve (78%). We treated 19% of patients with pegylated-interferon and ribavirin, 22% with pegylated-interferon, ribavirin, and telaprevir and 59% received interferon-free antivirals. Overall, 77% achieved a sustained virologic response, and 6% discontinued HCV treatment due to side effects. In the treatment discrimination model, compared to the no treatment period, HCV-SI scores were significantly (p < 0.01) lower for interferon-free antivirals and higher for interferon-containing regimens. In the SE-DC model, the total HCV-SI, somatic and neuropsychiatric scores significantly predicted those patients who prematurely discontinued HCV treatment (P < 0.05).

Conclusions

The HCV-SI effectively differentiated among treatment regimens known to vary by side effect profiles and between patients with and without treatment discontinuation due to side effects. The HCV-SI may have value as a patient-reported outcome instrument predicting the risk of HCV treatment discontinuation.

     

A cluster randomized controlled trial of lay health worker support for prevention of mother to child transmission of HIV (PMTCT) in South Africa

Background

We evaluate the impact of clinic-based PMTCT community support by trained lay health workers in addition to standard clinical care on PMTCT infant outcomes.

Methods

In a cluster randomized controlled trial, twelve community health centers (CHCs) in Mpumalanga Province, South Africa, were randomized to have pregnant women living with HIV receive either: a standard care (SC) condition plus time-equivalent attention-control on disease prevention (SC; 6 CHCs; n? = 357), or an enhanced intervention (EI) condition of SC PMTCT plus the “Protect Your Family” intervention (EI; 6 CHCs; n? = 342). HIV-infected pregnant women in the SC attended four antenatal and two postnatal video sessions and those in the EI, four antenatal and two postnatal PMTCT plus “Protect Your Family” sessions led by trained lay health workers. Maternal PMTCT and HIV knowledge were assessed. Infant HIV status at 6 weeks postnatal was drawn from clinic PCR records; at 12 months, HIV status was assessed by study administered DNA PCR. Maternal adherence was assessed by dried blood spot at 32 weeks, and infant adherence was assessed by maternal report at 6 weeks. The impact of the EI was ascertained on primary outcomes (infant HIV status at 6 weeks and 12 months and ART adherence for mothers and infants), and secondary outcomes (HIV and PMTCT knowledge and HIV transmission related behaviours). A series of logistic regression and latent growth curve models were developed to test the impact of the intervention on study outcomes.

Results

In all, 699 women living with HIV were recruited during pregnancy (8–24 weeks), and assessments were completed at baseline, at 32 weeks pregnant (61.7%), and at 6 weeks (47.6%), 6 months (50.6%) and 12 months (59.5%) postnatally. Infants were tested for HIV at 6 weeks and 12 months, 73.5% living infants were tested at 6 weeks and 56.7% at 12 months. There were no significant differences between SC and EI on infant HIV status at 6 weeks and at 12 months, and no differences in maternal adherence at 32 weeks, reported infant adherence at 6 weeks, or PMTCT and HIV knowledge by study condition over time.

Conclusion

The enhanced intervention administered by trained lay health workers did not have any salutary impact on HIV infant status, ART adherence, HIV and PMTCT knowledge. Trial registration clinicaltrials.gov: number NCT02085356

     

Role of immune activation in CD4<Superscript>+</Superscript> T-cell depletion in HIV-1 infected Indian patients

Objectives

The correlation of immune activation with CD4⁺ depletion and HIV-1 disease progression has been evidenced by several studies involving mainly clade B virus. However, this needs to be investigated in developing countries such as India predominately infected with clade C virus.

Materials and methods

In a cross-sectional study of 68 antiretroviral treatment naïve, HIV-1 infected Indian patients, we studied the association between CD4⁺ T cells, plasma HIV-1 RNA levels, and immune activation markers using unadjusted and adjusted correlative analyses.

Results

Significant negative correlations of higher magnitude were observed between the CD4⁺ T cell percentages and plasma HIV-1 RNA levels in the study population when adjusted for the effects of immune activation markers. However, the negative association of CD4⁺ T cells with immune activation markers remained unaffected when controlled for the effects of plasma HIV-1 RNA levels.

Conclusions

Our results support the important role of immune activation in CD4⁺ T cell depletion and disease progression during untreated HIV-1 infection.

     

Adherence Measurements in HIV: New Advancements in Pharmacologic Methods and Real-Time Monitoring

Purpose of Review

In this review, we present new developments in antiretroviral adherence, focusing on pharmacological measures and real-time adherence monitoring. In addition, new strategies on how to incorporate these new measures into research and clinical care are proposed.

Recent Findings

Antiretroviral drug concentrations in hair and dried blood spots are two novel pharmacological measures of cumulative drug adherence and exposure that have been recently evaluated in HIV treatment and pre-exposure prophylaxis. Real-time adherence monitoring using electronic devices has also proven highly informative, feasible, and well accepted, offering the possibility for an immediate intervention when non-adherence is detected. Both approaches offer considerable advantages over traditional adherence measures in predicting efficacy.

Summary

New methods to objectively monitor adherence in real-time and over long time periods have been developed. Further research is required to better understand how these measures can optimize adherence and, ultimately, improve clinical outcomes in HIV treatment and prevention.

     

Long-Acting Antiretrovirals: Where Are We now?

Purpose of Review

Current HIV treatment options require daily use of combination antiretroviral drugs. Many persons living with HIV experience treatment fatigue and suboptimal adherence as a result. Long-acting antiretroviral drugs are being developed to expand options for HIV treatment. Here, we review the agents in development, and evaluate data from recent clinical trials. In addition, we anticipate challenges to successful widespread use of long-acting antiretrovirals.

Recent Findings

Parenteral nanosuspensions of cabotegravir and rilpivirine, and dapivirine vaginal ring are the farthest in clinical development. Long-acting modalities in earlier development stages employ drug-loaded implants, microparticles, or targeted mutagenesis, among other innovations.

Summary

Long-acting antiretroviral drugs promise new options for HIV prevention and treatment, and ways to address poor adherence and treatment fatigue. Further studies will identify the long-acting agents or combinations that are suitable for routine use. Creative solutions will be needed for anticipated implementation challenges.

     

The Fat of the Matter: Obesity and Visceral Adiposity in Treated HIV Infection

Purpose of Review

The aim of this review is to summarize knowledge of the prevalence, relevant physiology, and consequences of obesity and visceral adiposity in HIV-infected adults, including highlighting gaps in current knowledge and future research directions.

Recent Findings

Similar to the general population, obesity prevalence is increasing among HIV-infected persons, and obesity and visceral adiposity are associated with numerous metabolic and inflammatory sequelae. However, HIV- and antiretroviral therapy (ART)-specific factors may contribute to fat gain and fat quality in treated HIV infection, particularly to the development of visceral adiposity, and sex differences may exist.

Summary

Obesity and visceral adiposity commonly occur in HIV-infected persons and have significant implications for morbidity and mortality. Future research should aim to better elucidate the HIV- and ART-specific contributors to obesity and visceral adiposity in treated HIV infection, with the goal of developing targeted therapies for the prevention and treatment of obesity and visceral adiposity in the modern ART era.

     

HIV Prevention Among Transgender Populations: Knowledge Gaps and Evidence for Action

Purpose of Review

The purpose of this review is to summarize the available evidence-based HIV prevention interventions tailored for transgender people.

Recent Findings

A limited number of evidence-based HIV prevention interventions have been tested with transgender populations. Most existing interventions target behavior change among transgender women, with only one HIV prevention program evaluated for transgender men. Studies addressing biomedical interventions for transgender women are ongoing. Few interventions address social and structural barriers to HIV prevention, such as stigma, discrimination, and poverty.

Summary

Evidence-based multi-level interventions that address the structural, biomedical, and behavioral risks for HIV among transgender populations, including transgender men, are needed to address disparities in HIV prevalence. Future research should address not only pre-exposure prophylaxis uptake and condom use but also structural barriers that limit access to these prevention strategies.

     

Hospitalization causes and outcomes in HIV patients in the late antiretroviral era in Colombia

Background

Antiretroviral therapy (ART) has modified the natural history of HIV-infection: the incidence of opportunistic infections (OIs) has decreased and mortality associated to HIV has improved dramatically. The reasons for hospitalization have changed; OIs are no longer the most common reason for admission. This study describes the patient population, admission diagnosis and hospital course of HIV patients in Colombia in the ART era.

Methods

Patients admitted with HIV/AIDS at six hospitals in Medellin, Colombia between August 1, 2014 and July 31, 2015 were included. Demographic, laboratory, and clinical data were prospectively collected.

Results

551 HIV-infected patients were admitted: 76.0% were male, the median age was 37 (30–49). A new diagnosis of HIV was made in 22.0% of patients during the index admission. 56.0% of patients of the entire cohort had been diagnosed with HIV for more than 1 year and 68.9% were diagnosed in an advanced stage of the disease. More than 50.0% of patients had CD4 counts less than 200 CD4 cells/μL and viral loads greater than 100,000 copies. The main reasons for hospital admissions were OIs, tuberculosis, esophageal candidiasis and Toxoplasma encephalitis. The median hospital stay was 14 days (IQR 8–23). Admission to the intensive care unit (ICU) was required in 10.3% of patients and 14.3% were readmitted to the hospital; mortality was 5.4%.

Conclusions

Similar to other countries in the developing world, in Colombia, the leading cause of hospitalization among HIV-infected patients remain opportunistic infections. However, in-hospital mortality was low, similar to those described for high-income countries. Strategies to monitor and optimize the adherence and retention in HIV programs are fundamental to maximize the benefit of ART.

     

Socio-demographic,Marital, and Psychosocial Factors Associated with Condom Use Negotiation Self-Efficacy Among Mozambican Women at Risk for HIV Infection

Purpose

In Mozambique, women are the most affected by HIV/AIDS. Self-efficacy is one of the main predictors of effective use of a condom. Therefore, it is essential to identify the factors that influence condom-use negotiation self-efficacy in vulnerable women. The aim of this paper is to identify socio-demographic, marital, and psychosocial factors associated with condom-use negotiation self-efficacy among Mozambican women at risk for HIV infection.

Methods

Participants were women (173) who were patients at the Gynecology Department of the Central Hospital of Beira, Mozambique, and at risk for HIV infection. Women completed measures of condom-use negotiation self-efficacy, HIV prevention knowledge, and perceived barriers against safer sex.

Results

The results showed that demographic and marital variables are associated with condom-use negotiation self-efficacy, namely, those having more than 9 years of education, who are younger and not living with a partner, and who talk about AIDS with partners report higher condom-use negotiation self-efficacy. Regarding psychosocial factors, higher HIV prevention knowledge and fewer perceived barriers to safer sex predict higher condom-use negotiation self-efficacy.

Conclusion

These results can contribute to sexual health promotion and HIV/AIDS prevention in Mozambican women because they identify at-risk groups and marital and psychosocial malleable factors that can be targeted in AIDS prevention among at-risk Mozambican women.

     

Sex Differences in HIV Infection

Purpose of Review

This review will outline the multilevel effects of biological sex on HIV acquisition, pathogenesis, treatment response, and prospects for cure. Potential mechanisms will be discussed along with future research directions.

Recent Findings

HIV acquisition risk is modified by sex hormones and the vaginal microbiome, with the latter acting through both inflammation and local metabolism of pre-exposure prophylaxis drugs. Female sex associates with enhanced risk for non-AIDS morbidities including cardiovascular and cerebrovascular disease, suggesting different inflammatory profiles in men and women. Data from research on HIV cure points to sex differences in viral reservoir dynamics and a direct role for sex hormones in latency maintenance.

Summary

Biological sex remains an important variable in determining the risk of HIV infection and subsequent viral pathogenesis, and emerging data suggest sex differences relevant to curative interventions. Recruitment of women in HIV clinical research is a pathway to both optimize care for women and to identify novel therapeutics for use in both men and women.