Impact of tuberculosis on mortality among HIV-infected patients receiving antiretroviral therapy in Uganda: a prospective cohort analysis

Background

Tuberculosis (TB) disease affects survival among HIV co-infected patients on antiretroviral therapy (ART). Yet, the magnitude of TB disease on mortality is poorly understood.

Methods

Using a prospective cohort of 22,477 adult patients who initiated ART between August 2000 and June 2009 in Uganda, we assessed the effect of active pulmonary TB disease at the initiation of ART on all-cause mortality using a Cox proportional hazards model. Propensity score (PS) matching was used to control for potential confounding. Stratification and covariate adjustment for PS and not PS-based multivariable Cox models were also performed.

Results

A total of 1,609 (7.52%) patients had active pulmonary TB at the start of ART. TB patients had higher proportions of being male, suffering from AIDS-defining illnesses, having World Health Organization (WHO) disease stage III or IV, and having lower CD4 cell counts at baseline (p?<?0.001). The percentages of death during follow-up were 10.47% and 6.38% for patients with and without TB, respectively. The hazard ratio (HR) for mortality comparing TB to non-TB patients using 1,686 PS-matched pairs was 1.37 (95% confidence interval [CI]: 1.08 – 1.75), less marked than the crude estimate (HR?=?1.74, 95% CI: 1.49 – 2.04). The other PS-based methods and not PS-based multivariable Cox model produced similar results.

Conclusions

After controlling for important confounding variables, HIV patients who had TB at the initiation of ART in Uganda had an approximate 37% increased hazard of overall mortality relative to non-TB patients.

     

HIV patients stable on ART retain evidence of a high CMV load but changes to Natural Killer cell phenotypes reflect both HIV and CMV

Background

Whilst ART corrects many effects of HIV disease, T cell populations retain features of accelerated immunological aging.

Methods

Here we analyse phenotypic changes to natural killer (NK) cells in HIV patients who began ART with <200 CD4 T-cells/µl and maintained virological control for 12–17 years, compared with CMV seropositive and seronegative healthy control donors.

Results

Humoral responses to CMV antigens (lysate, gB, IE-1) remain elevated in the patients (P < 0.0001) despite the long duration of ART. Patient’s NK cells responded poorly to K562 cells when assessed by CD107a and IFNγ, but this could not be attributed to CMV as responses were low in CMV-seronegative controls. Moreover HIV (and not CMV) increased expression of CD57 on CD56^lo cells.

Conclusions

Comparisons with published studies suggest that CMV accelerates age-related increases in CD57 expression but levels plateau by 60–70 years of age, so the effect of CMV disappears. In HIV patients the plateau is higher and perhaps reached sooner.

     

Successful use of extracorporeal membrane oxygenation in a human immunodeficiency virus infected patient with severe acute respiratory distress syndrome

Introduction

We report a case of an adult patient with human immunodeficiency virus (HIV), acute respiratory distress syndrome (ARDS) and ventilator associated pneumonia (VAP) caused by multidrug resistant (MDR) bacteria that was successfully managed with veno-venous extracorporeal membrane oxygenation (ECMO).

Case report

A 25 year old male with no significant past medical history had been admitted to a local hospital due to dyspnea and fever. His pulmonary function subsequently failed necessitating mechanical ventilation (MV) and introduction of ECMO support. The patient was transported for 300 km by road on ECMO to a tertiary medical center. The diagnosis of ARDS, HIV infection and MDR bacterial and fungal VAP was made. Patient was successfully treated with antiretroviral therapy (ART), anti-infective agents and 58 days of veno-venous ECMO support, with complete resolution of the respiratory symptoms.

Conclusion

HIV infected patients with ARDS and MDR bacterial VAP whose HIV replication is controlled by ART could be successfully managed with ECMO.

     

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.

     

Plasma HIV-1 RNA viral load rebound among people who inject drugs receiving antiretroviral therapy (ART) in a Canadian setting: an ethno-epidemiological study

Background

People who inject drugs (PWID) living with HIV often experience sub-optimal antiretroviral therapy (ART) treatment outcomes, including HIV plasma viral load (PVL) rebound. While previous studies have identified risk factors for PVL rebound among PWID, no study has examined the perspectives of PWID who have experienced PVL rebound episodes. We conducted an ethno-epidemiological study to investigate the circumstances surrounding the emergence of rebound episodes among PWID in Vancouver, BC, Canada.

Methods

Comprehensive clinical records linked to a community-based prospective observational cohort of HIV-positive drug users were used to identify PWID who had recently experienced viral rebound. In-depth qualitative interviews with 16 male and 11 female participants explored participant perspectives regarding the emergence of viral rebound. A timeline depicting each participant’s HIV viral load and adherence to ART was used to elicit discussion of circumstances surrounding viral rebound.

Findings

Viral rebound episodes were shaped by interplay between various individual, social, and environmental factors that disrupted routines facilitating adherence. Structural-environmental influences resulting in non-adherence included housing transitions, changes in drug use patterns and intense drug scene involvement, and inadequate care for co-morbid health conditions. Social-environmental influences on ART adherence included poor interactions between care providers and patients producing non-adherence, and understandings of HIV treatment that fostered intentional treatment discontinuation.

Conclusions

This study describes key pathways which led to rebound episodes among PWID receiving ART and illustrates how environmental forces may increase vulnerability for non-adherence leading to treatment failure. Our findings have potential to help inform interventions and supports that address social-structural forces that foster non-adherence among PWID.

     

Sexual risk behaviour,marriage and ART: a study of HIV-positive people in Papua New Guinea

Background

The prevention of intimate partner transmission of HIV remains an important component of comprehensive HIV prevention strategies. In this paper we examine the sexual practices of people living with HIV on antiretroviral therapy (ART) in Papua New Guinea (PNG).

Method

In 2008, a total of 374 HIV-positive people over the age of 16 and on ART for more than two weeks were recruited using a non-probability, convenience sampling methodology. This accounted for around 18% of adults on ART at the time. A further 36 people participated in semi-structured interviews. All interviews were thematically analysed using NVivo qualitative data analysis software.

Results

Less than forty per cent (38%) of participants reported having had sexual intercourse in the six months prior to the survey. Marital status was by far the most important factor in determining sexual activity, but consistent condom use during vaginal intercourse with a regular partner was low. Only 46% reported consistent condom use during vaginal intercourse with a regular partner in the last six months, despite 77% of all participants reporting that consistent condom use can prevent HIV transmission. Consistent condom use was lowest amongst married couples and those in seroconcordant relationships. The vast majority (91.8%) of all participants with a regular heterosexual partner had disclosed their status to their partner. Qualitative data reinforced low rates of sexual activity and provided important insights into sexual abstinence and condom use.

Conclusions

Considering the importance of intimate partner transmission of HIV, these results on the sexual practices of people with HIV on ART in PNG suggest that one-dimensional HIV prevention messages focussing solely on condom use fail to account for the current practices and needs of HIV-positive people, especially those who are married and know their partners’ HIV status.

     

Cases of antiretroviral-associated gynaecomastia reported to the National HIV &amp; Tuberculosis Health Care Worker Hotline in South Africa

Background

Gynaecomastia is associated with exposure to antiretroviral therapy (ART), in particular efavirenz. There is limited data on clinical characteristics of patients with ART-associated gynaecomastia in resource-limited settings and little guidance on the optimal management of this adverse drug reaction (ADR). We describe the clinical characteristics, management and outcomes of gynaecomastia cases reported to the National HIV & Tuberculosis Health Care Worker Hotline in South Africa.

Methods

We identified all gynaecomastia cases in adolescent boys and men on ART reported to the hotline between June 2013 and July 2014. We collected follow up data telephonically at monthly intervals to document clinical management and outcomes.

Results

We received 51 reports of gynaecomastia between June 2013 and July 2014; 11% of the 475 patient-specific ADR queries to the hotline. All patients were on efavirenz-based ART. Mean age was 34 years (standard deviation 12) and seven were adolescents. The median onset of gynaecomastia was 15 months after efavirenz initiation (interquartile range 6–42). Gynaecomastia was bilateral in 29 patients (57%) and unilateral in 16 (31%). Serum testosterone was quantified in 25 of 35 patients with follow up data, and was low in 2 (8%). Efavirenz was replaced with an alternative antiretroviral in 29/35 patients (83%) and gynaecomastia improved in 20/29 (69%).

Conclusions

Gynaecomastia was a frequently reported ADR in our setting, occurring with prolonged efavirenz exposure. Testosterone was low in the minority of tested cases. Most clinicians elected to switch patients off efavirenz, and gynaecomastia improved in the majority.

     

Continued Interest and Controversy: Vitamin D in HIV

Purpose of Review

Vitamin D (VitD) deficiency is highly prevalent among HIV-infected individuals. Given the overlapping risk for several chronic disease and immunomodulatory outcomes from both long-standing HIV and VitD deficiency, there is great interest in clarifying the clinical role of VitD for this population.

Recent Findings

Recent studies have expanded our knowledge regarding the epidemiology and mechanisms of VitD deficiency-associated outcomes in the setting of HIV. Clinical trials focusing on VitD supplementation have demonstrated a positive impact on bone mineral density in subgroups of HIV-infected individuals initiating ART or on suppressive ART regimens; however, significant heterogeneity exists between studies and data are less consistent with other clinical outcomes.

Summary

Further research is needed to clarify uncertainly in several domains, including identifying patients at greatest risk for poor outcomes from VitD deficiency, standardizing definitions and measurement techniques, and better quantifying the benefits and risks of VitD supplementation across different demographic strata for skeletal and extra-skeletal outcomes.

     

Determinants of time to antiretroviral treatment initiation and subsequent mortality on treatment in a cohort in rural northern Malawi

Background

To optimise care HIV patients need to be promptly initiated on antiretroviral therapy (ART) and subsequently retained on treatment. In this study we report on the interval between enrolment and treatment initiation, and investigate subsequent attrition and mortality of patients on ART at a rural clinic in Malawi.

Methods

HIV-positive individuals were recruited to a cohort study between January 2008 and August 2011 at Chilumba Rural Hospital (CRH). Outcomes were ascertained, up to 7 years after enrolment, through follow-up and by linkage to ART registers and the Karonga Health and Demographic Surveillance System (KHDSS). Kaplan–Meier methods and Cox regression were used to examine ART initiation after enrolment, mortality after ART initiation, and attrition after ART initiation.

Results

Of the 617 individuals recruited, 523 initiated ART between January 2008 and January 2015. Median time from HIV testing to commencement of ART was 59 days (IQR: 10–330). By a year after enrolment 74.2 % (95 % CI 70.6–77.7 %) had initiated ART. Baseline clinical data at ART initiation and data on attrition was only available for the 438 individuals who initiated ART during active follow-up, between January 2008 and August 2011. Of these individuals, 6 were missing Ministry of Health numbers, leaving 432 included in analyses of attrition and mortality. At 4 years after ART initiation 71.3 % (95 % CI 65.7–76.2 %) of these patients were retained on treatment at the CRH and 17.2 % (95 % CI 13.8–21.4 %) had died. Participants who had a lower CD4 count at enrolment (≤350 cells/μl), enrolled in 2008, or tested for HIV at the CRH rather than through serosurveys, initiated treatment faster. Once on treatment, mortality rates were higher in patients who were HIV tested at the CRH, male, older (≥35 years), missing a CD4 count, or underweight (BMI < 18.5) at ART initiation.

Conclusions

Through linkage to the KHDSS and ART registers it was possible to continue follow-up beyond the end of the initial cohort study. Annual mortality after ART initiation remained considerable over a period of 4 years. Greater access to HIV and CD4 testing alongside initiation at higher CD4 counts, as planned in the test and treat strategy, could reduce this mortality.

     

Factors affecting affect cardiovascular health in Indonesian HIV patients beginning ART

Background

We present a small longitudinal study of how demographic factors and persistent burdens of HIV and cytomegalovirus (CMV) influence cardiovascular health in young adults beginning ART in an inner-city clinic in Jakarta, Indonesia.

Methods

ART-naïve HIV patients [n = 67; aged 31 (19 to 48) years] were enrolled in the JakCCANDO Project. Echocardiography and carotid Doppler ultrasonography were performed before ART (V0) and after 3, 6, and 12 months (V3–12). Antibodies reactive with CMV lysate or IE-1 protein were assessed at each timepoint and CMV DNA was identified at V0.

Results

Markers of adverse cardiovascular prognosis [left ventricular mass index, ejection fraction and carotid intimal media thickness (cIMT)] were similar to healthy controls, but increased at V12. Internal diameters of the carotid arteries and systolic blood pressure correlated with HIV disease severity at V0, but cardiac parameters and cIMT did not. E/A ratios (left ventricular diastolic function) were lower in patients with CMV DNA at V0, but this effect waned by V6. Levels of antibody reactive with CMV IE-1 correlated inversely with CD4 T cell counts at V0, and levels at V6–V12 correlated directly with the right cIMT.

Conclusions

Overall the severity of HIV disease and the response to ART have only subtle effects on cardiovascular health in this young Asian population. CMV replication before ART may have a transient effect on cardiac health, whilst antibody reactive with CMV IE-1 may mark a high persistent CMV burden with cumulative effects on the carotid artery.

     

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.

     

Association between quantitative varicella-zoster virus antibody levels and zoster reactivation in HIV-infected persons

Background

Varicella-zoster virus (VZV) reactivation is common but difficult to predict in HIV-infected persons.

Objective

Since qualitative VZV antibodies can determine past VZV disease or vaccination, we evaluated whether quantitative VZV antibody levels over time can predict future zoster.

Study design

US Military HIV Natural History (NHS) participants with a zoster diagnosis at least 5 years after HIV diagnosis (n?=?100) were included. Zoster-negative controls (n?=?200) were matched by age, race, gender, and CD4 count at HIV diagnosis. Repository plasma specimens collected at baseline and prior to zoster diagnosis were evaluated using a quantitative anti-VZV ELISA assay. Differences in quantitative VZV levels were analyzed by Wilcoxon Mann–Whitney and Fisher’s exact tests.

Results

Median CD4 count at HIV diagnosis was similar for cases and controls (535 [IQR 384–666] vs. 523 [IQR 377–690] cells/μL; p?=?0.940), but lower for cases at zoster diagnosis (436 [IQR 277–631] vs. 527 [IQR 367–744] cells/μL; p?=?0.007). Antiretroviral therapy (ART) use prior to zoster diagnosis was lower for cases (52.0%) compared to controls (64.5%; p?=?0.025). Cases had similar mean VZV antibody levels prior to zoster diagnosis compared to controls [2.25?±?0.85 vs. 2.44?±?0.96 index value/optical density (OD) ratio; p?=?0.151] with no difference in the change in antibody levels over time (0.08?±?0.71 vs. 0.01?±?0.94 index value/OD per year; p?=?0.276).

Conclusion

Quantitative VZV antibody levels are stable in HIV-infected persons and do not predict zoster reactivation. Low CD4 count and lack of ART use appear to be better predictors of future zoster diagnosis.

     

Serious Non-AIDS Conditions in HIV: Benefit of Early ART

Purpose of review

Optimal control of HIV can be achieved by early diagnosis followed by the initiation of antiretroviral therapy (ART). Two large randomised trials (TEMPRANO and START) have recently been published documenting the clinical benefits to HIV-positive adults of early ART initiation. Main findings are reviewed with a focus on serious non-AIDS (SNA) conditions.

Recent findings

Data from the two trials demonstrated that initiating ART early in the course of HIV infection resulted in marked reductions in the risk of opportunistic diseases and invasive bacterial infections. This indicates that HIV causes immune impairment in early infection that is remedied by controlling viral replication. Intriguingly, in START, a marked reduction in risk of cancers, both infection-related and unrelated types of cancers, was observed. Like the findings for opportunistic infections, this anti-cancer effect of early ART shows how the immune system influences important pro-oncogenic processes. In START, there was also some evidence suggesting that early ART initiation preserved kidney function, although the clinical consequence of this remains unclear. Conversely, while no adverse effects were evident, the trials did not demonstrate a clear effect on metabolic-related disease outcomes, pulmonary disease, or neurocognitive function.

Summary

HIV causes immune impairment soon after acquisition of infection. ART reverses this harm at least partially. The biological nature of the immune impairment needs further elucidation, as well as mechanisms and clinical impact of innate immune activation. Based on the findings from TEMPRANO and START, and because ART lowers the risk of onward transmission, ART initiation should be offered to all persons following their diagnosis of HIV.

     

eHealth for Stigma Reduction Efforts Designed to Improve Engagement in Care for People Living with HIV

Purpose of Review

HIV-related stigma remains a significant barrier to engagement in care for persons living with HIV (PLWH) worldwide. This review examines the use of eHealth technologies for reducing stigma as a pathway toward improved engagement in care for PLWH. We provide a brief overview of effective stigma reduction interventions for PLWH, both eHealth and others; identify gaps in the research on use of eHealth technologies for stigma reduction; and suggest potential research avenues moving forward.

Recent Findings

The majority of HIV-related eHealth studies use technology to improve ART adherence. To date, few HIV-related eHealth studies have included any measurement of stigma.

Summary

Given the current narrow evidence base, further research is needed to determine whether eHealth technologies can help to reduce stigma and improve engagement in care for PLWH.

     

Interventions for Neurocognitive Dysfunction

Purpose of Review

This study aimed to evaluate current barriers to HIV cure strategies and interventions for neurocognitive dysfunction with a particular focus on recent advancements over the last 3 years.

Recent Findings

Optimal anti-retroviral therapy (ART) poses challenges to minimise neurotoxicity, whilst ensuring blood-brain barrier penetration and minimising the risk of cerebrovascular disease. CSF biomarkers, BCL11B and neurofilament light chain may be implicated with a neuroinflammatory cascade leading to cognitive impairment. Diagnostic imaging with diffusion tensor imaging and resting-state fMRI show promise in future diagnosis and monitoring of HAND.

Summary

The introduction of ART has resulted in a dramatic decline in HIV-associated dementia. Despite this reduction, milder forms of HIV-associated neurocognitive disorder (HAND) are still prevalent and are clinically significant. The central nervous system (CNS) has been recognised as a probable reservoir and sanctuary for HIV, representing a significant barrier to management interventions.

     

Effectiveness of first-line antiretroviral therapy in the IPEC cohort,Rio de Janeiro,Brazil

Background

While Brazil has had a long-standing policy of free access to antiretroviral therapy (ART) for all in need, the epidemiological impact of ART on human immunodeficiency virus (HIV) RNA suppression in this middle-income country has not been well evaluated. We estimate first-line ART effectiveness in a large Brazilian cohort and examine the socio-demographic, behavioral, clinical and structural factors associated with virologic suppression.

Methods

Virologic suppression on first-line ART at 6, 12, and 24 months from start of ART was defined as having a viral load measurement ≤400 copies/mL without drug class modification and/or discontinuation. Drug class modification and/or discontinuation were defined based on the class of a particular drug. Quasi-Poisson regression was used to quantify the association of factors with virologic suppression.

Results

From January 2000 through June 2010, 1311 patients started first-line ART; 987 (75%) patients used NNRTI-based regimens. Virologic suppression was achieved by 77%, 76% and 68% of patients at 6, 12 and 24 months, respectively. Factors associated with virologic suppression at 12 months were: >8 years of formal education (compared to <4 years, risk ratio (RR) 1.13, 95% confidence interval (95% CI) 1.03-1.24), starting ART in 2005-2010 (compared to 2000-2004, RR 1.25 95% CI 1.15-1.35), and clinical trial participation (compared to no participation, RR 1.08 95% CI 1.01-1.16). Also at 12 months, women showed less virologic suppression compared to heterosexual men (RR 0.90 95% CI 0.82-0.99). For the 24-month endpoint, in addition to higher education, starting ART in the later period, and clinical trial participation, older age and an NNRTI-based regimen were also independently associated with virologic suppression.

Conclusions

Our results show that in Brazil, a middle-income country with free access to treatment, over three-quarters of patients receiving routine care reached virologic suppression on first-line ART by the end of the first year. Higher education, more recent ART initiation and clinical trial participation were associated with improved outcomes both for the 12-month and the 24-month endpoints, suggesting that further studies are needed to understand what aspects relating to these factors lead to higher virologic suppression.

     

eHealth and Prevention of Mother-to-Child Transmission of HIV

Purpose of Review

The goal of this paper is to describe areas in prevention of mother-to-child transmission of HIV (PMTCT) programs that could benefit from ehealth and to summarize current evidence of ehealth effectiveness in PMTCT.

Recent Findings

PMTCT programs require maternal retention, adherence to antiretroviral treatment (ART), and return for infant diagnosis of HIV. eHealth systems for PMTCT could either be integrated within MCH ehealth systems or within HIV adherence ehealth systems. PMTCT ehealth messages need to balance maternal concerns about pregnancy, childbirth, and infant care with need for clinic retention and ART adherence for PMTCT. Health approaches currently being assessed for effects on PMTCT outcomes include SMS, phone reminders, and integration of laboratory results and health worker reminders. Randomized trials are ongoing to determine effect of PMTCT ehealth interventions on retention, adherence, viral suppression, and early infant diagnosis (EID). There is evidence that ehealth for PMTCT improves early retention and EID, while data on long-term outcomes are accruing.

Summary

PMTCT ehealth interventions may be useful to enhance maternal retention and ART adherence and decrease risk of infant HIV infection. Ongoing clinical trials will be important to determine effectiveness of mhealth approaches in improving PMTCT outcomes.