Subclinical cardiovascular remodelling in HIV-infection: A multimodal case study of 2 serodiscordant, monozygotic twins.

Cardiovascular abnormalities are increasingly recognised among people newly diagnosed with HIV, but subclinical pathology may be challenging to diagnose. We present a case study of subtle cardiovascular changes in identical twins, one without HIV-infection and the other recently diagnosed with HIV (serodiscordant). We hypothesise that cardiovascular parameters would be similar between the twins, unless non-genetic (environmental) factors are at play. These differences likely represent occult pathology secondary to the effects of early HIV-infection. A 25-year-old female incidentally diagnosed with HIV, and her HIV-uninfected identical twin, living with her since birth, underwent comprehensive cardiovascular assessments. The HIV-positive twin exhibited a globular left ventricle (LV), larger LV volumes, decreased LV strain, peak atrial longitudinal strain (PALS) and higher native T1 and T2 mapping values compared to her sister. Cardiac biomarkers high sensitivity cardiac troponin T and N-terminal proBNP, as well as the novel markers of fibrosis and remodelling, galectin-3 and soluble-ST2, were higher in the HIV-infected twin. Given the twins' shared environment and genetic makeup, these differences likely stem from HIV-infection. Our study supports previous findings and suggests potential screening markers for HIV-associated cardiovascular disease, including PALS. Further research is warranted to explore PALS' utility in this context.

A retrospective audit of young adults who received permanent pacemakers at a teaching hospital in the Western Cape, South Africa.

Introduction: While most pacemaker implantations occur in older individuals, younger patients also receive pacemakers. In these, degenerative conduction system disease is less likely to be the cause of atrioventricular block (AVB), with other diseases being more common. There is, however, a paucity of data on this group as well as on younger pacemaker recipients that have undergone pacemaker implantation for reasons other than AVB. The aim of this study was to perform an audit of young adult permanent pacemaker recipients. Method: This was a retrospective record review, conducted in the Division of Cardiology at Tygerberg Hospital, Cape Town, South Africa. We included 169 adult patients between the ages of 18 and 60, who received permanent pacemakers between 2010 and 2020. A subgroup analysis of patients 55 years and younger was also performed. Results: Third degree AVB was the most common indication for pacemaker implantation (n = 115; 68%), followed by high degree AVB (n = 23; 13.6%) and sick sinus syndrome (SSS; n = 14; 8.3%). A specific underlying cause for conduction system abnormalities was found in only 25.4% of patients (n = 43), with most of them being 55 years or younger (n = 32; 30.8% of patients ≤ 55 years). Specific causes that were identified included prosthetic valve implantation and/or valve repair (n = 14; 8.3%), myocardial infarction (n = 6; 3.6%), cardiac sarcoidosis (n = 5; 3.0%), coronary artery bypass grafting (n = 3; 1.8%), cardiomyopathy (n = 2; 1.2%), muscular dystrophy (n = 2; 1.2%), congenital heart disease (ventricular septal defect; atrioventricular septal defect; Tetralogy of Fallot; bicuspid aortic valve; n = 6; 3.6%), acute myocarditis (n = 1; 0.6%), atrial myxoma removal (n = 1; 0.6%), planned AV node ablation (n = 2; 1.2%), and following a previous stab in the chest (n = 1; 0.6%). Conclusion: Given that the mean age of our study population was high, the low number of identified underlying causes in the whole cohort (≤60 years) may reflect some AVB due to age related degeneration of the conductions system in the patients 56 to 60 years age, but also raises the possibility that these patients may be less likely to be extensively investigated for an underlying cause than those ≤55 years, where diseases such as sarcoidosis were more readily confirmed. As access to advanced diagnostic tools improves, the percentage of young pacemaker recipients with an underlying cause identified may increase.

Exploring the mechanisms responsible for reduced systolic function in high-gradient aortic stenosis.

OBJECTIVE: To characterise the mechanics responsible for the reduced ejection fraction (rEF) in high-gradient severe aortic stenosis (AS). METHODS: 21 patients with high-gradient severe AS (aortic valve area (AVA) <1.0 cm2 and mean gradient (MG) >40 mm Hg) were included. They included 9 patients with rEF (EF <50%) and 12 with preserved ejection fraction (pEF) (EF >50%). Valve area and MG were assessed echocardiographically, and myocardial fibrosis was quantified using MRI. Load-independent measures of intrinsic contractility was assessed with pressure-volume haemodynamics. RESULTS: 80% of the cohort was female, with a mean age of 64 years. Patients were matched for age, sex and body surface area. Load-independent contractile function was similar between the rEF and pEF groups: preload recruitable stroke work slope (101 vs 112 mm Hg; p=0.65), end-systolic pressure-volume relationship slope (1.91 vs 1.28 mmHg/mL; p=0.07) and Starling Contractile Index slope (3.47 vs 7.96 mm Hg/mL/s; p=0.31). End-systolic wall stress and valvuloarterial impedance were higher in cases with rEF (150 vs 83.5 N/cm2; p<0.01 and 4.8 vs 3.4 mm Hg/mL; p=0.05), driven by higher degrees of valvular stenosis (valve area 0.46 vs 0.78 cm2; p<0.01). The rEF group was more symptomatic (New York Heart Association 3.3 vs 2.3; p=0.02), with higher pulmonary pressures (50 vs 30 mm Hg; p=0.04) and more fibrosis (24% vs 13% of left ventricular mass; p=0.03). CONCLUSION: The pathophysiological problem in patients with high-gradient AS with rEF relates to an excessively increased afterload due to more severe valvular stenosis, with preserved intrinsic contractile function. Myocardial fibrosis in the rEF group did not translate into worse muscle function.

Altered cardiac structure and function in newly diagnosed people living with HIV: a prospective cardiovascular magnetic resonance study after the initiation of antiretroviral treatment.

HIV associated cardiomyopathy (HIVAC) is a poorly understood entity that may progress along a continuum. We evaluated a group of persons newly diagnosed with HIV and studied the evolution of cardiac abnormalities after ART initiation. We recruited a group of newly diagnosed, ART naïve persons with HIV and a healthy, HIV uninfected group. Participants underwent comprehensive cardiovascular evaluation, including cardiovascular magnetic resonance imaging. The HIV group was started on ART and re-evaluated 9 months later. The cardiovascular parameters of the study groups were compared at diagnosis and after 9 months. The ART naïve group's (n = 66) left- and right end diastolic volume indexed for height were larger compared with controls (n = 22) (p < 0.03). The left ventricular mass indexed for height was larger in the naïve group compared with controls (p = 0.04). The ART naïve group had decreased left- and right ventricular ejection fraction (p < 0.03) and negative, non-linear associations with high HIV viral load (p = 0.02). The left ventricular size increased after 9 months (p = 0.04), while the systolic function remained unchanged. The HIV group had a high rate of non-resolving pericardial effusions. HIV infected persons demonstrate structurally and functionally altered ventricles at diagnosis. High HIV viral load was associated with left- and right ventricular dysfunction. Cardiac parameters and pericardial effusion prevalence did not show improvement with ART. Conversely, a concerning trend of increase was observed with left ventricular size. These subclinical cardiac abnormalities may represent a stage on the continuum of HIVAC that can progress to symptomatic disease if the causes are not identified and addressed.

Women exposed to single-dose nevirapine in successive pregnancies: effectiveness and nonnucleoside reverse transcriptase inhibitor resistance.

OBJECTIVE: To assess the impact of prior exposure to single-dose nevirapine (sdNVP) on mother-to-child transmission and genotypic resistance in HIV-infected women. DESIGN: Prospective study of 120 women exposed to the HIVNET 012 sdNVP regimen in two successive pregnancies and 240 antiretroviral (ARV)-naïve, multiparous women who received sdNVP for the first time. RESULTS: One hundred and eight of 120 and 193 of 240 women returned for a postpartum visit by 6 weeks. HIV-1 was detected in 11.1% (95% confidence interval = 5.9-18.6) of the infants of women previously exposed to sdNVP and 4.2% (95% confidence interval = 1.3-7.0) of those exposed for the first time (P = 0.028). Rates of maternal HIV-1 genotypic resistance at 6 weeks postdelivery were 37.5% and 46.4%, respectively (P = 0.119). Sensitive mutation-specific real-time PCR testing found three of 12 previously exposed women who transmitted HIV-1 to their infants had either K103N or Y181C at baseline compared with one of eight ARV-naïve, transmitting women who had Y181C. None of 40 randomly selected nontransmitting women from either group had detectable NVP resistance mutations prior to sdNVP exposure. CONCLUSION: This study shows that effectiveness of sdNVP may be compromised by prior exposure to sdNVP, although the increase in transmission rate after prior exposure could not be explained by the detection of NVP resistance mutations prior to re-exposure as measured both by standard genotyping and highly sensitive allele-specific PCR assays. Furthermore, transmission rates of women with prior exposure were not higher than those reported elsewhere.

Early antiretroviral therapy and mortality among HIV-infected infants.

BACKGROUND: In countries with a high seroprevalence of human immunodeficiency virus type 1 (HIV-1), HIV infection contributes significantly to infant mortality. We investigated antiretroviral-treatment strategies in the Children with HIV Early Antiretroviral Therapy (CHER) trial. METHODS: HIV-infected infants 6 to 12 weeks of age with a CD4 lymphocyte percentage (the CD4 percentage) of 25% or more were randomly assigned to receive antiretroviral therapy (lopinavir-ritonavir, zidovudine, and lamivudine) when the CD4 percentage decreased to less than 20% (or 25% if the child was younger than 1 year) or clinical criteria were met (the deferred antiretroviral-therapy group) or to immediate initiation of limited antiretroviral therapy until 1 year of age or 2 years of age (the early antiretroviral-therapy groups). We report the early outcomes for infants who received deferred antiretroviral therapy as compared with early antiretroviral therapy. RESULTS: At a median age of 7.4 weeks (interquartile range, 6.6 to 8.9) and a CD4 percentage of 35.2% (interquartile range, 29.1 to 41.2), 125 infants were randomly assigned to receive deferred therapy, and 252 infants were randomly assigned to receive early therapy. After a median follow-up of 40 weeks (interquartile range, 24 to 58), antiretroviral therapy was initiated in 66% of infants in the deferred-therapy group. Twenty infants in the deferred-therapy group (16%) died versus 10 infants in the early-therapy groups (4%) (hazard ratio for death, 0.24; 95% confidence interval [CI], 0.11 to 0.51; P<0.001). In 32 infants in the deferred-therapy group (26%) versus 16 infants in the early-therapy groups (6%), disease progressed to Centers for Disease Control and Prevention stage C or severe stage B (hazard ratio for disease progression, 0.25; 95% CI, 0.15 to 0.41; P<0.001). Stavudine was substituted for zidovudine in four infants in the early-therapy groups because of neutropenia in three infants and anemia in one infant; no drugs were permanently discontinued. After a review by the data and safety monitoring board, the deferred-therapy group was modified, and infants in this group were all reassessed for initiation of antiretroviral therapy. CONCLUSIONS: Early HIV diagnosis and early antiretroviral therapy reduced early infant mortality by 76% and HIV progression by 75%. (ClinicalTrials.gov number, NCT00102960.)

Transmission rates in consecutive pregnancies exposed to single-dose nevirapine in Soweto, South Africa and Abidjan, Côte d'Ivoire.

BACKGROUND: Large numbers of women receive single-dose nevirapine (sdNVP) to prevent mother-to-child transmission (MTCT) of HIV; over time, an increasing proportion will return to prevention of MTCT programs for a second pregnancy. Because sdNVP selects resistance in a high percentage of women, we compared the effectiveness of sdNVP in preventing peripartum MTCT in successive pregnancies. METHODS: Prospective cohorts were recruited from MTCT programs in South Africa and Côte d'Ivoire. HIV-1-infected women and their infants exposed to sdNVP in 2 consecutive pregnancies-used alone or with zidovudine (ZDV) or ZDV plus lamivudine-were included. RESULTS: The median age of women at their initial exposure to sdNVP in Soweto (n = 120) and Abidjan (n = 41) was 26 (interquartile range [IQR]: 22-29) years and 28 (IQR: 24-31) years, respectively, and their median delivery interval was 21 (IQR: 15-29) months and 26 (IQR: 20-32) months, respectively. Transmission rates in Soweto and in Abidjan were 11.1% and 13.2% for the first pregnancy and 11.1% and 5.4% for the second pregnancy (P = 1.000 and P = 0.449 for Soweto and Abidjan, respectively, in unpaired analysis). CONCLUSION: This analysis suggests that the effectiveness of sdNVP when used in successive pregnancies is probably not impaired, possibly because viral resistance selected by prior exposure to sdNVP may wane with time.

High rates of HIV in surgical patients in Soweto, South Africa: impact on resource utilisation and recommendations for HIV testing.

Interactions between HIV and surgical diseases are relatively poorly described in high HIV prevalence settings. We report HIV prevalence and its associations in a prospective study of adults admitted to surgical units in Soweto, South Africa. Voluntary counselling and testing (VCT) for HIV was offered to surgical inpatients. Research nurses interviewed participants at enrolment and doctors reviewed records after discharge. In HIV-infected participants, CD4 counts and viral loads were ascertained. Of 1000 participants, 537 consented to VCT, of whom 176 (32.8%, 95% CI 28.8-36.9%) tested HIV positive. A history of tuberculosis (adjusted odds ratio (AOR) 3.0, 95% CI 1.5-6.2) or sexually transmitted infection (AOR 2.7, 95% CI 1.8-4.2) was associated with HIV infection. Diagnoses of cutaneous abscesses (OR 3.4, 95% CI 1.4-8.1) and anorectal sepsis (OR 3.1, 95% CI 1.1-9.0) were associated with HIV and indicated advanced disease. There were no differences in rates of operative procedures, wound sepsis, investigations or length of stay by HIV status. Hospital-acquired pneumonia was more common in HIV-infected participants (P=0.028). In conclusion, in this high HIV prevalence setting, resource utilisation is similar between HIV-infected and uninfected patients in surgical wards where high rates of HIV in young adults support routine HIV testing. WHO clinical staging of HIV should include anal sepsis as an indicator of advanced HIV disease.

Selection and persistence of viral resistance in HIV-infected children after exposure to single-dose nevirapine.

BACKGROUND: Single-dose nevirapine (sd-NVP) is the mainstay of prevention of mother-to-child transmission programs in developing countries. Exposure to sd-NVP selects for resistance mutations, however. We longitudinally assessed these mutations in HIV-1-infected infants from Soweto and Durban, South Africa. METHODS: We prospectively followed 465 infants who received sd-NVP after enrolling their mothers when pregnant. If HIV infected, their virus was genotyped, using the ViroSeq HIV-1 Genotyping System, to detect resistant mutations. Those with resistance were genotyped at 6 months and then every 6 months out to 18 months if resistance was detected at the previous visit. RESULTS: Of 53 HIV-infected infants, 24 (45.3%) had detectable resistance at their first visit, when the most frequent mutations were Y181C (75%), K103N (25%), and Y188C (12%). Of those whose visit was before 12 weeks of age, 2 of 42 infants shared identical resistance mutations with their mothers. By 18 months of age, 11 of 24 infants with resistance had died and 1 still had the Y181C mutation. CONCLUSIONS: Resistant mutations were selected in half of the infants exposed to sd-NVP, but fewer were detected over time and, unlike the case in their mothers, Y181C dominated initially and persists. Transient resistance mutations may have a negative impact on highly active antiretroviral therapy in infants and children.