The latest medical research on Infectious Disease
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Twice as Nice: Cytomegalovirus Tele-Education.Transplant Infectious Disease
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High mortality among patients hospitalized for drug-resistant tuberculosis with acquired second-line drug resistance and high HIV prevalence.HIV Medicine
We compared mortality between HIV-positive and HIV-negative South African adults with drug-resistant tuberculosis (DR-TB) and high incidence of acquired second-line drug resistance.
We performed a retrospective review of DR-TB patients with serial second-line TB drug susceptibility tests (2008-2015) who were hospitalized at a specialized TB hospital. We used Kaplan-Meier analysis and Cox models to examine associations with mortality.
Of 245 patients, the median age was 33 years, 54% were male and 40% were HIV-positive, 96% of whom had ever received antiretroviral therapy (ART). At initial drug resistance detection, 99% of patients had resistance to at least rifampicin and isoniazid, and 18% had second-line drug resistance (fluoroquinolones and/or injectable drugs). At later testing, 88% of patients had acquired additional second-line drug resistance. Patient-initiated treatment interruptions (> 2 months) occurred in 47%. Mortality was 79%. Those with HIV had a shorter time to death (p = 0.02; log-rank): median survival time from DR-TB treatment initiation was 2.44 years [95% confidence interval (CI): 2.09-3.15] versus 3.99 years (95% CI: 3.12-4.75) for HIV-negative patients. HIV-positive patients who received ART within 6 months before DR-TB treatment had a higher mortality hazard than HIV-negative patients [adjusted hazard ratio (aHR) ratio = 1.82, 95% CI: 1.21-2.74]. By contrast, HIV-positive patients who did not receive ART within 6 months before DR-TB treatment did not have a significantly higher mortality hazard than HIV-negative patients (aHR = 1.09; 95% CI: 0.72-1.65), although those on ART had lower median CD4 counts than those not on ART (157 vs. 281 cells/μL, respectively; p = 0.02).
A very high incidence of acquired second-line drug resistance and high overall mortality were observed, reinforcing the need to reduce the risk of acquired resistance and for more effective treatment.
High incidence of subclinical peripheral artery disease in people with HIV.AIDS
Atherosclerosis is common in people with HIV (PWH). Peripheral artery disease (PAD) is the peripheral manifestation of atherosclerosis, but little is known about the incidence of PAD in PWH. Our objective was to determine the PAD incidence in PWH and to investigate potential risk factors.
We performed ankle-brachial index (ABI) measurements at study entry and at 2-year follow-up and included participants with normal ABI at study entry. We defined de novo PAD as ABI ≤0.9 at follow-up. Using Poisson regression adjusted for age, sex, and smoking, we investigated the role of traditional and HIV-related risk factors, including inflammatory markers.
Of 844 PWH followed for a median duration of 2.3 years, 30 (3.6%) developed de novo PAD. All cases were subclinical. Diabetes (relative risk [RR] = 4.90 [95% confidence interval [CI]: 1.99-12.1]), current CD4 count <350 cells/μl (2.66 [1.06-6.71]), longer duration of antiretroviral therapy (antiretroviral therapy [ART], 1.88 [1.06-3.33] per decade), and concentrations of high-sensitivity C-reactive protein (1.33 [1.08-1.63] per doubling) and interleukin-6 (1.38 [1.06-1.80] per doubling), were associated with de novo PAD.
PWH had a high incidence of de novo subclinical PAD. Diabetes, low current CD4 count, duration of ART, and inflammatory markers were associated with de novo PAD, indicating a possible role in PAD pathogenesis in PWH.
Years of life lost to cancer among the US HIV population, 2006-2015.AIDS
We estimated years of life lost (YLLs) to all causes of death and YLL lost to cancer among persons with HIV (PWH) in the United States.
Mean YLL (MYLL) to all causes of death and MYLL to cancer during 2006-2015 were derived from the restricted mean survival estimated from Cox proportional hazards regression models. MYLLs were then upweighted to the national population of PWH to obtain all-cause total YLL (TYLL) and cancer-related TYLL in the United Staets during 2006-2015.
Among 466 234 PWH in the study population, 25 772 (5.5%) developed cancer during 2006-2015. Nationally, an estimated 134 986 years of life were lost to cancer of all types during 2006-2015 among PWH, representing 9.6% of TYLL to all causes. Non-Hodgkin lymphoma (NHL), Kaposi sarcoma, anal cancer, and lung cancer were the four largest cancer contributors (45% of TYLL to cancer). The largest fraction of TYLL occurred among back PWH, MSM, and PWH aged 40-59 years old.
PWH have higher mortality rates after developing cancer. NHL, Kaposi sarcoma and anal and lung cancers were large contributors to YLL to cancer in the United States population of PWH, highlighting opportunities to reduce cancer mortality through improved access to antiretroviral treatment, prevention, and screening.
Adverse perinatal outcomes associated with HAART and monotherapy: systematic review and meta-analysis.AIDS
Assess adverse perinatal outcomes in women living with HIV (WLHIV) receiving HAART or zidovudine (ZDV) monotherapy, compared with antiretroviral therapy (ART)-naive WLHIV and HIV-negative women.
We conducted a systematic literature review by searching PubMed, CINAHL, Global Health, and EMBASE for studies published during 1 January 1980 to 20 April 2020. We included studies reporting on the association of pregnant WLHIV receiving HAART or ZDV monotherapy with 11 perinatal outcomes: preterm birth (PTB), very PTB, spontaneous PTB (sPTB), low birth weight (LBW), very LBW, term LBW, preterm LBW, small for gestational age (SGA), very SGA (VSGA), stillbirth, and neonatal death. Random-effects meta-analyses were conducted.
Sixty-one cohort studies assessing 409 781 women were included. WLHIV receiving ZDV monotherapy were associated with a decreased risk of PTB [relative risk 0.70, 95% confidence interval (CI) 0.62-0.79] and LBW (0.77, 0.67-0.88), and comparable risk of SGA, compared with ART-naive WLHIV. WLHIV receiving ZDV monotherapy had a comparable risk of PTB and LBW, and an increased risk of SGA (1.16, 1.04-1.30) compared with HIV-negative women. In contrast, WLHIV receiving HAART were associated with a comparable risk of PTB and LBW, and increased risk of SGA (1.38, 1.09-1.75), compared with ART-naive WLHIV. WLHIV receiving HAART were associated with an increased risk of PTB (1.55, 1.38-1.74), sPTB (2.09, 1.48-2.96), LBW (1.79, 1.51-2.13), term LBW (1.88, 1.23-2.85), SGA (1.80,1.34-2.40), and VSGA (1.22, 1.10-1.34) compared with HIV-negative women.
Pregnant WLHIV receiving HAART have an increased risk of a wide range of perinatal outcomes compared with HIV-negative women.
Sex differences in cytokine profiles during suppressive antiretroviral therapy.AIDS
Despite lower plasma HIV RNA levels, women progress faster to AIDS than men. The reasons for these differences are not clear but might be a consequence of an elevated inflammatory response in women.
We investigated sex differences in cytokine profiles by measuring the concentrations of 36 cytokine/chemokines by Luminex in blood of women and men (sex at birth) with chronic HIV infection under suppressive therapy. We initially performed a principal component analysis to see if participants clustered by sex, and then fit a partial least squares discriminant analysis (PLS-DA) model where we used cytokines to predict sex at birth. The significance of the difference in nine cytokines with VIP greater than 1 was tested using Wilcoxon test-rank. Further, potential confounding factors were tested by multivariate linear regression models.
Overall, we predicted sex at birth in the PLS-DA model with an error rate of approximately 13%. We identified five cytokines, which were significantly higher in women compared with men, namely the pro-inflammatory chemokines CXCL1 (Gro-α), CCL5 (RANTES), CCL3 (MIP-1α), CCL4 (MIP-1β), as well as the T-cell homeostatic factor IL-7. The effect of sex remained significant after adjusting for CD4+, age, ethnicity, and race for all cytokines, except for CCL3 and race.
The observed sex-based differences in cytokines might contribute to higher immune activation in women compared with men despite suppressive therapy. Increased levels of IL-7 in women suggest that homeostatic proliferation may have a differential contribution to HIV reservoir maintenance in female and male individuals. Our study emphasizes the importance of sex-specific studies of viral pathogenesis.
Incident depression among Medicare beneficiaries with disabilities and HIV.AIDS
Despite disproportionally high prevalence of HIV and depression in persons with disabilities, no data have been published on the incidence and correlates of depression in Medicare beneficiaries with disabilities. We assessed the effect of HIV infection on developing depression in this population.
Beneficiaries with incident (n = 2438) and prevalent (n = 5758) HIV were individually matched with beneficiaries without HIV (HIV-, n = 20 778). Fine-Gray models with death as a competing risk were used to assess the effect of HIV status, age, and cohort period on developing depression by sex strata.
Beneficiaries with HIV had a higher risk of developing depression within 5 years (P < 0.0001). Sex differences were observed (P < 0.0001), with higher subdistribution hazard ratios (sHR) in males with HIV compared with controls. The risk decreased with age (P < 0.0001) and increased in recent years (P < 0.0001). There were significant age-HIV (P = 0.004) and period-HIV (P = 0.006) interactions among male individuals, but not female individuals. The sHR was also higher within the first year of follow-up among male individuals, especially those with incident HIV.
Medicare enrollees with disabilities and HIV had an increased risk of developing depression compared to those without HIV, especially among males and within the first year of HIV diagnosis. The HIV-depression association varied by sex, age, and cohort period. Our findings may help guide screening and comprehensive management of depression among subgroups in this vulnerable population.
Long-term HIV treatment outcomes and associated factors in sub-Saharan Africa: multi-country longitudinal cohort analysis.AIDS
In a multicountry prospective cohort of persons with HIV from six countries between 2007 and 2015, we evaluated long-term outcomes of first-line non-nucleoside reverse-transcriptase inhibitor-based antiretroviral therapy (ART), and risk factors for loss-to-follow-up, mortality, virological failure, and incomplete CD4+ T-cell recovery.
We calculated cumulative incidence of lost-to-follow-up, death, virological failure (VL ≥ 1000 cps/ml) and incomplete CD4+ T-cell recovery (<500 cells/μl) at successive years, using Kaplan-Meier and Cox regression.
Of 2735 participants, 58.0% were female, median age was 37 (interquartile range [IQR] 32-43) years, and median pre-ART CD4+ T-cell count was 135 (IQR 63-205)/μl. Total follow-up time was 7208 person-years (median 24.3 months, IQR 18.7-58.3). Deaths by any cause and loss to follow-up occurred mostly during the first year of ART (84%, 201/240 and 56%, 199/353, respectively). During their first 6 years of ART, 71% (95% confidence interval [CI] 69.0-73.7) were retained on first-line, and among those 90-93% sustained viral suppression (<1000 cps/ml); CD4+ T-cell recovery was incomplete in 60% (220/363) of participants. The risk factors associated with poor outcomes during long-term ART were: for loss-to-follow-up, recent VL ≥1000 cps/ml, recent CD4+ T-cell count ≤50 cells/μl, age <30 years, being underweight; for mortality, recent CD4+ T-cell count ≤50 cells/μl; and, for virological failure, age <40 years, recent CD4+ T-cell count ≤200 cells/μl, poor adherence, male sex, and low-level viremia.
To achieve long-term ART success towards the UNAIDS targets, early ART initiation is crucial, coupled with careful monitoring and retention support, particularly in the first year of ART. Male and youth-centred care delivery models are needed to improve outcomes for those vulnerable groups.
Thrombotic thrombocytopenic purpura (TTP) in Human immunodeficiency virus (HIV) infected patients: New twists on an old disease.AIDS
Investigate the presence of inflammation, endothelial dysfunction and complement activation in patients with HIV-associated thrombotic thrombocytopenic purpura (HIV-TTP) to support the hypothesis that these processes probably contribute to the development of this thrombotic microangiopathy.
The patients with HIV-TTP received therapeutic plasma therapy and supportive treatment. Demographic data, the results of routine investigations and patient outcomes were recorded. Peripheral blood samples were collected prior to and on completion of plasma therapy and the following additional parameters were assessed at both time points: activity of the von Willebrand factor (VWF) cleaving protease, a-disintegrin-and-metalloproteinase-with-thrombospondin-motifs 13 (ADAMTS-13) and the presence of ADAMTS-13 autoantibodies, levels of pro-inflammatory cytokines, interleukin-6 and tumour necrosis factor-alpha, and two endothelial cell adhesion molecules. Complement activation was assessed by sequential measurement of C3 and C4 as well as levels of the complement inhibitor, factor H.
The inflammatory and endothelial activation markers were significantly (P < 0.001) elevated in the cohort of patients prior to plasma therapy compared with levels on discharge. Complement was activated and normalized with therapy. The ADAMTS-13 levels were reduced with significant auto-antibodies to this protease at presentation.
Inflammation in HIV mediates endothelial damage and complement activation. This study proposes that these processes are probably contributory to the development of HIV-TTP, which can therefore be characterized in part as a complementopathy, resembling TTP-like syndrome.
Isoniazid preventive therapy and TB transcriptional signatures in people with HIV.AIDS
To examine the association between isoniazid preventive therapy (IPT) or nontuberculous mycobacteria (NTM) sputum culture positivity and tuberculosis (TB) transcriptional signatures in people with HIV.
We enrolled adults living with HIV who were IPT-naive or had completed IPT more than 6 months prior at HIV care clinics in western Kenya. We calculated TB signatures using gene expression data from qRT-PCR. We used multivariable linear regression to analyze the association between prior receipt of IPT or NTM sputum culture positivity with a transcriptional TB risk score, RISK6 (range 0-1). In secondary analyses, we explored the association between IPT or NTM positivity and four other TB transcriptional signatures.
Among 381 participants, 99.7% were receiving antiretroviral therapy and 86.6% had received IPT (completed median of 1.1 years prior). RISK6 scores were lower (mean difference 0.10; 95% confidence interval (CI): 0.06-0.15; P < 0.001) among participants who received IPT than those who did not. In a model that adjusted for age, sex, duration of ART, and plasma HIV RNA, the RISK6 score was 52.8% lower in those with a history of IPT (P < 0.001). No significant association between year of IPT receipt and RISK6 scores was detected. There was no association between NTM sputum culture positivity and RISK6 scores.
In people with HIV, IPT was associated with significantly lower RISK6 scores compared with persons who did not receive IPT. These data support investigations of its performance as a TB preventive therapy response biomarker.
Anti-CD4 autoantibodies in immunological non-responder people living with HIV: Cause of CD4+ T-cell depletion?AIDS
We aimed to evaluate the anti-CD4 IgG role in the poor immune recovery of immunological nonresponder people with HIV (INR).
Plasma anti-CD4 IgG levels were quantified and purified by chromatography columns for the subsequent use in a coculture of CD4+ T and NK cells. We analyzed NK cell degranulation markers (CD107a, perforin and granzyme B) and IFN-γ release, and CD4+ T-cell death. Binding affinity of anti-CD4 IgG for CD4+ T cells was also assessed.
A total of 168 individuals were enrolled (INR, 56; immunological responders, 40; treatment-naive, 39; and healthy controls, 33). The highest anti-CD4 IgG levels were found in treatment-naive PWH, followed by participants on treatment. There were no correlations between anti-CD4 IgG levels and CD4+ T-cell counts. In a 15-participant subgroup (naive, immunological responders, and INR), anti-CD4 IgG induced a slight NK-cell expression of degranulation markers and IFN-γ; however, the percentage of CD4+ T-cell death was negligible. Consistently, no significant changes in NK cell polyfunctionality were observed. In addition, purified anti-CD4 IgG showed scarce binding affinity for CD4+ T cells. These results were similar in all analyzed participant groups.
Our results suggest that autologous anti-CD4 IgG neither trigger CD4+ T-cell death by ADCC nor are responsible for CD4+ lymphocyte depletion in INR.
Opioid agonist treatment improves progression through the HIV cascade of care among people living with HIV who use unregulated opioids.AIDS
Opioid agonist treatment (OAT) has been shown to improve certain HIV-related treatment measures among people with HIV (PHIV) with opioid use disorder (OUD). However, there is limited data on the impacts of OAT along the whole HIV cascade of care.
Using data from an ongoing cohort of PHIV who use drugs in Vancouver, Canada, we used cumulative link mixed-effects models to estimate the independent effect of OAT on achieving progressive steps in the HIV cascade among participants using unregulated opioids daily, after adjusting for confounders.
Between 2005 and 2017, we recruited 639 PHIV regularly using opioids (median age 42 years, 59% male, 56% White), of whom 70% were on OAT at their baseline visit. Engagement in OAT showed a nonsignificant trend with higher linkage to HIV care (adjusted partial proportional odds ratio [APPO] = 1.75, 95% confidence interval [CI]: 0.83-3.69), and significantly higher cumulative odds of successfully achieving subsequent HIV cascade steps: on ART (APPO = 3.85, 95% CI: 2.33-6.37); adherent to ART (APPO = 3.15, 95% CI: 2.15-4.62); and HIV viral suppression (APPO = 2.18, 95% CI: 1.51-3.14).
This study found a high level of OAT engagement among PHIV using unregulated opioids and that OAT engagement resulted in significantly increased progression through some of the higher steps of the HIV cascade. While these findings are encouraging, they highlight the need to reach populations off OAT to maximize the clinical and community-level benefits of ART.