Friedrich Thienemann

Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis

BACKGROUND Cryptococcal meningitis accounts for 20 to 25% of acquired immunodeficiency syndrome-related deaths in Africa. Antiretroviral therapy (ART) is essential for survival; however, the question of when ART should be initiated after diagnosis of cryptococcal meningitis remains unanswered. METHODS We assessed survival at 26 weeks among 177 human immunodeficiency virus-infected adults in Uganda and South Africa who had cryptococcal meningitis and had not previously received ART. We randomly assigned study participants to undergo either earlier ART initiation (1 to 2 weeks after diagnosis) or deferred ART initiation (5 weeks after diagnosis). Participants received amphotericin B (0.7 to 1.0 mg per kilogram of body weight per day) and fluconazole (800 mg per day) for 14 days, followed by consolidation therapy with fluconazole. RESULTS The 26-week mortality with earlier ART initiation was significantly higher than with deferred ART initiation (45% [40 of 88 patients] vs. 30% [27 of 89 patients]; hazard ratio for death, 1.73; 95% confidence interval [CI], 1.06 to 2.82; P=0.03). The excess deaths associated with earlier ART initiation occurred 2 to 5 weeks after diagnosis (P=0.007 for the comparison between groups); mortality was similar in the two groups thereafter. Among patients with few white cells in their cerebrospinal fluid (<5 per cubic millimeter) at randomization, mortality was particularly elevated with earlier ART as compared with deferred ART (hazard ratio, 3.87; 95% CI, 1.41 to 10.58; P=0.008). The incidence of recognized cryptococcal immune reconstitution inflammatory syndrome did not differ significantly between the earlier-ART group and the deferred-ART group (20% and 13%, respectively; P=0.32). All other clinical, immunologic, virologic, and microbiologic outcomes, as well as adverse events, were similar between the groups. CONCLUSIONS Deferring ART for 5 weeks after the diagnosis of cryptococcal meningitis was associated with significantly improved survival, as compared with initiating ART at 1 to 2 weeks, especially among patients with a paucity of white cells in cerebrospinal fluid. (Funded by the National Institute of Allergy and Infectious Diseases and others; COAT ClinicalTrials.gov number, NCT01075152.).

Contribution of the human immunodeficiency virus/acquired immunodeficiency syndrome epidemic to de novo presentations of heart disease in the Heart of Soweto Study cohort

AIMS The contemporary impact of the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) epidemic on heart disease in South Africa (>5 million people affected) is unknown. The Heart of Soweto Study provides a unique opportunity to identify the contribution of cardiac manifestations of this epidemic to de novo presentations of heart disease in an urban African community in epidemiological transition. METHODS AND RESULTS Chris Hani Baragwanath Hospital services the >1 million people living in Soweto, South Africa. A prospective, clinical registry captured data from all de novo cases of heart disease presenting to the Cardiology Unit during 2006-08. We describe all cases where HIV/AIDS was concurrently diagnosed. Overall, 518 of 5328 de novo cases of heart disease were identified as HIV-positive (9.7%) with 54% of these prescribed highly active anti-retroviral therapies on presentation. Women (62%) and Africans (97%) predominated with women being significantly younger than men 38 ± 13 vs. 42 ± 13 years (P = 0.002). The most common primary diagnosis attributable to HIV/AIDS was HIV-related cardiomyopathy (196 cases, 38%); being prescribed more anti-retroviral therapy (127/196 vs. 147/322; odds ratio 2.85, 95% confidence interval 1.81-3.88) with higher viral loads [median 110 000 (inter-quartile range 26 000-510 000) vs. 19 000 (3200-87 000); P = 0.018] and a lower CD4 count [median 180 (71-315) vs. 211 (96-391); P = 0.019] than the rest. An additional 128 cases (25%) were diagnosed with pericarditis/pericardial effusion with a range of other concurrent diagnoses evident, including 42 cases (8.1%) of HIV-related pulmonary arterial hypertension. Only 14 of all 581 cases of coronary artery disease (CAD) (2.4%, mean age 41 ± 13 years) were confirmed HIV-positive. CONCLUSION Cardiac manifestations of HIV/AIDS identified within this cohort were relatively infrequent. While HIV-related cardiomyopathy and pericardial disease remain important targets for early detection and treatment in this setting, HIV-related cases of CAD remain at historically low levels.

Safety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a randomised, placebo-controlled, phase 2 trial

Summary Background HIV-1 infection is associated with increased risk of tuberculosis and a safe and effective vaccine would assist control measures. We assessed the safety, immunogenicity, and efficacy of a candidate tuberculosis vaccine, modified vaccinia virus Ankara expressing antigen 85A (MVA85A), in adults infected with HIV-1. Methods We did a randomised, double-blind, placebo-controlled, phase 2 trial of MVA85A in adults infected with HIV-1, at two clinical sites, in Cape Town, South Africa and Dakar, Senegal. Eligible participants were aged 18–50 years, had no evidence of active tuberculosis, and had baseline CD4 counts greater than 350 cells per μL if they had never received antiretroviral therapy or greater than 300 cells per μL (and with undetectable viral load before randomisation) if they were receiving antiretroviral therapy; participants with latent tuberculosis infection were eligible if they had completed at least 5 months of isoniazid preventive therapy, unless they had completed treatment for tuberculosis disease within 3 years before randomisation. Participants were randomly assigned (1:1) in blocks of four by randomly generated sequence to receive two intradermal injections of either MVA85A or placebo. Randomisation was stratified by antiretroviral therapy status and study site. Participants, nurses, investigators, and laboratory staff were masked to group allocation. The second (booster) injection of MVA85A or placebo was given 6–12 months after the first vaccination. The primary study outcome was safety in all vaccinated participants (the safety analysis population). Safety was assessed throughout the trial as defined in the protocol. Secondary outcomes were immunogenicity and vaccine efficacy against Mycobacterium tuberculosis infection and disease, assessed in the per-protocol population. Immunogenicity was assessed in a subset of participants at day 7 and day 28 after the first and second vaccination, and M tuberculosis infection and disease were assessed at the end of the study. The trial is registered with ClinicalTrials.gov, number NCT01151189. Findings Between Aug 4, 2011, and April 24, 2013, 650 participants were enrolled and randomly assigned; 649 were included in the safety analysis (324 in the MVA85A group and 325 in the placebo group) and 645 in the per-protocol analysis (320 and 325). 513 (71%) participants had CD4 counts greater than 300 cells per μL and were receiving antiretroviral therapy; 136 (21%) had CD4 counts above 350 cells per μL and had never received antiretroviral therapy. 277 (43%) had received isoniazid prophylaxis before enrolment. Solicited adverse events were more frequent in participants who received MVA85A (288 [89%]) than in those given placebo (235 [72%]). 34 serious adverse events were reported, 17 (5%) in each group. MVA85A induced a significant increase in antigen 85A-specific T-cell response, which peaked 7 days after both vaccinations and was primarily monofunctional. The number of participants with negative QuantiFERON-TB Gold In-Tube findings at baseline who converted to positive by the end of the study was 38 (20%) of 186 in the MVA85A group and 40 (23%) of 173 in the placebo group, for a vaccine efficacy of 11·7% (95% CI −41·3 to 44·9). In the per-protocol population, six (2%) cases of tuberculosis disease occurred in the MVA85A group and nine (3%) occurred in the placebo group, for a vaccine efficacy of 32·8% (95% CI −111·5 to 80·3). Interpretation MVA85A was well tolerated and immunogenic in adults infected with HIV-1. However, we detected no efficacy against M tuberculosis infection or disease, although the study was underpowered to detect an effect against disease. Potential reasons for the absence of detectable efficacy in this trial include insufficient induction of a vaccine-induced immune response or the wrong type of vaccine-induced immune response, or both. Funding European & Developing Countries Clinical Trials Partnership (IP.2007.32080.002), Aeras, Bill & Melinda Gates Foundation, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium.

The Effect of Therapeutic Lumbar Punctures on Acute Mortality From Cryptococcal Meningitis

Intracranial pressure management with repeat lumbar puncture (LP) was investigated in patients with cryptococcal meningitis in sub-Saharan Africa. Conducting at least 1 additional LP soon after cryptococcal diagnosis was related to decreased risk of acute mortality regardless of initial pressure.

A comprehensive review: the evolution of animal models in pulmonary hypertension research; are we there yet?

Pulmonary hypertension (PH) is a disorder that develops as a result of remodeling of the pulmonary vasculature and is characterized by narrowing/obliteration of small pulmonary arteries, leading to increased mean pulmonary artery pressure and pulmonary vascular resistance. Subsequently, PH increases the right ventricular afterload, which leads to right ventricular hypertrophy and eventually right ventricular failure. The pathophysiology of PH is not fully elucidated, and current treatments have only a modest impact on patient survival and quality of life. Thus, there is an urgent need for improved treatments or a cure. The use of animal models has contributed extensively to the current understanding of PH pathophysiology and the investigation of experimental treatments. However, PH in current animal models may not fully represent current clinical observations. For example, PH in animal models appears to be curable with many therapeutic interventions, and the severity of PH in animal models is also believed to correlate poorly with that observed in humans. In this review, we discuss a variety of animal models in PH research, some of their contributions to the field, their shortcomings, and how these have been addressed. We highlight the fact that the constant development and evolution of animal models will help us to more closely model the severity and heterogeneity of PH observed in humans.

Central Nervous System Disorders after Starting Antiretroviral Therapy in South Africa

Objective:To describe the spectrum of central nervous system (CNS) disease during the first year of antiretroviral therapy (ART) and to determine the contribution of neurological immune reconstitution inflammatory syndrome (IRIS). Design:A prospective observational cohort study conducted over a 12-month period at a public sector referral hospital in South Africa. Methods:HIV-seropositive patients who developed new or recurrent neurological or psychiatric symptom(s) or sign(s) within the first year of starting ART were enrolled. We used the number of patients starting ART in the referral area in the preceding year as the denominator to calculate the incidence of referral for neurological deterioration. Patients with delirium and peripheral neuropathy were excluded. Outcome at 6 months was recorded. Results:Seventy-five patients were enrolled. The median nadir CD4+ cell counts was 64 cells/μl. Fifty-nine percent of the patients were receiving antituberculosis treatment. The incidence of referral for CNS deterioration in the first year of ART was 23.3 cases [95% confidence interval (CI), 18.3–29.2] per 1000 patient-years at risk. CNS tuberculosis (n = 27, 36%), cryptococcal meningitis (n = 18, 24%), intracerebral space occupying lesions (other than tuberculoma) (n = 10, 13%) and psychosis (n = 9, 12%) were the most frequent diagnoses. Paradoxical neurological IRIS was diagnosed in 21 patients (28%), related to tuberculosis in 16 and cryptococcosis in five. At 6 months, 23% of the patients had died and 20% were lost to follow-up. Conclusion:Opportunistic infections, notably tuberculosis and cryptococcosis, were the most frequent causes for neurological deterioration after starting ART. Neurological IRIS occurred in over a quarter of patients.

Melatonin as a preventive and curative therapy against pulmonary hypertension.

Pulmonary hypertension (PH) is characterized by elevated pulmonary arterial pressure, which leads to right ventricular (RV) hypertrophy and failure. The pathophysiological mechanisms of PH remain unclear but oxidative stress is believed to contribute to RV dysfunction. Melatonin is a powerful antioxidant and is cardioprotective against ischemia–reperfusion injury and hypertension. Therefore, we hypothesized that a chronic treatment with melatonin, given as a curative or preventive therapy, may confer cardiovascular benefits in PH. PH was induced in Long Evans rats (n ≥ 6 per group), with a single subcutaneous injection of monocrotaline (MCT, 80 mg/kg). Melatonin was given daily in the drinking water, with the treatment starting either on the day of the injection of MCT (dose testing: melatonin 75 ng/L and 6 mg/kg), 14 days after the injection of MCT (curative treatment: 6 mg/kg), or 5 days before the injection (preventive treatment: 6 mg/kg). The development of PH was assessed by measuring RV hypertrophy, RV function, cardiac interstitial fibrosis, and plasma oxidative stress. Compared with controls, MCT‐treated rats displayed RV hypertrophy and dysfunction, increased interstitial fibrosis, and elevated plasma oxidative stress. A chronic melatonin treatment (75 ng/L or 6 mg/kg) reduced RV hypertrophy, improved RV function and reduced plasma oxidative stress. Curative and preventive treatment improved RV functional and plasma oxidative stress parameters and reduced cardiac interstitial fibrosis. Our data demonstrate that melatonin confers cardioprotection in this model of PH. As melatonin is an inexpensive and safe drug, we propose that clinical investigation of the effects of melatonin on RV function in patients with PH should be considered.

Rationale and design of the Pan African Pulmonary hypertension Cohort (PAPUCO) study: implementing a contemporary registry on pulmonary hypertension in Africa

Introduction Pulmonary hypertension (PH) is a devastating, progressive disease with increasingly debilitating symptoms and usually shortened overall life expectancy due to a narrowing of the pulmonary vasculature and consecutive right heart failure. Little is known about PH in Africa, but limited reports suggest that PH is more prevalent in Africa compared with developed countries due to the high prevalence of risk factors in the region. Methods and analysis A multinational multicentre registry-type cohort study was established and tailored to resource-constraint settings to describe disease presentation, disease severity and aetiologies of PH, comorbidities, diagnostic and therapeutic management, and the natural course of PH in Africa. PH will be diagnosed by specialist cardiologists using echocardiography (right ventricular systolic pressure >35 mm Hg, absence of pulmonary stenosis and acute right heart failure), usually accompanied by shortness of breath, fatigue, peripheral oedema and other cardiovascular symptoms, ECG and chest X-ray changes in keeping with PH as per guidelines (European Society of Cardiology and European Respiratory Society (ESC/ERS) guidelines). Additional investigations such as a CT scan, a ventilation/perfusion scan or right heart catheterisation will be performed at the discretion of the treating physician. Functional tests include a 6 min walk test and the Karnofsky Performance Score. The WHO classification system for PH will be applied to describe the different aetiologies of PH. Several substudies have been implemented within the registry to investigate specific types of PH and their outcome at up to 24 months. Data will be analysed by an independent institution following a data analyse plan. Ethics and dissemination All local ethics committees of the participating centres approved the protocol. The data will be disseminated through peer-reviewed journals at national and international conferences and public events at local care providers.

Spectrum of cardiac disease in maternity in a low-resource cohort in South Africa

Background Lack of evidence-based data on the spectrum of cardiovascular disease (CVD) in pregnancy or in the postpartum period, as well as on maternal and fetal outcome, provides challenges for treating physicians, particularly in areas of low resources. The objectives of this study were to investigate the spectrum of disease, mode of presentation and maternal and fetal outcome of patients referred to a dedicated Cardiac Disease and Maternity Clinic (CDM). Methods The prospective cohort study was conducted at a single tertiary care centre in South Africa. Two hundred and twenty-five women presenting with CVD in pregnancy, or within 6 months postpartum, were studied over a period of 2 years. Clinical assessment, echocardiography and laboratory tests were performed at baseline and follow-up visits. Prepartum, peripartum and postpartum complications were grouped into cardiac, neonatal and obstetric events. Results Ethnicity was black African (45%), mixed ethnicity (32%), white (15%), Indian/others (8%) and 12% were HIV positive. Of the 225 consecutive women (mean age 28.8±6.4), 196 (86.7%) presented prepartum and 73 in modified WHO class I. The 152 women presenting in a higher risk group (modified WHO class II–IV) were offered close follow-up at the CDM clinic and were diagnosed with congenital heart disease (32%, 15 operated previously), valvular heart disease (26%, 15 operated previously), cardiomyopathy (27%) and other (15%). Women presenting with symptoms of CVD or heart failure postpartum (n=30) presented in a higher New York Heart Association, had higher heart rates (p<0.001) and NTproBNP levels (p<0.0005). Of the 152 patients, 9 (6%) died within the 6-month follow-up period. Eight of the nine patients died >42 days postpartum. Perinatal death occurred in 1/152 (0.7%)—translating to a perinatal mortality rate of 7/1000 live births. Conclusions Disease patterns were markedly different to that seen in the developed world. However, joint obstetric–cardiac care in the low-resource cohort was associated with excellent survival outcome rates of pregnant mothers (even with complex diseases) and their offspring and was similar to that seen in the western world. Mortality typically occurred in the postpartum period, beyond the standard date of recording maternal death.

Predictors of hospitalisations for heart failure and mortality in patients with pulmonary hypertension associated with left heart disease: a systematic review

Objectives Left heart disease (LHD) is the main cause of pulmonary hypertension (PH), but little is known regarding the predictors of adverse outcome of PH associated with LHD (PH-LHD). We conducted a systematic review to investigate the predictors of hospitalisations for heart failure and mortality in patients with PH-LHD. Design Systematic review. Data sources PubMed MEDLINE and SCOPUS from inception to August 2013 were searched, and citations identified via the ISI Web of Science. Study selection Studies that reported on hospitalisation and/or mortality in patients with PH-LHD were included if the age of participants was greater than 18 years and PH was diagnosed using Doppler echocardiography and/or right heart catheterisation. Two reviewers independently selected studies, assessed their quality and extracted relevant data. Results In all, 45 studies (38 from Europe and USA) were included among which 71.1% were of high quality. 39 studies were published between 2003 and 2013. The number of participants across studies ranged from 46 to 2385; the proportion of men from 21% to 91%; mean/median age from 63 to 82 years; and prevalence of PH from 7% to 83.3%. PH was consistently associated with increased mortality risk in all forms of LHD, except for aortic valve disease where findings were inconsistent. Six of the nine studies with data available on hospitalisations reported a significant adverse effect of PH on hospitalisation risk. Other predictors of adverse outcome were very broad and heterogeneous including right ventricular dysfunction, functional class, left ventricular function and presence of kidney disease. Conclusions PH is almost invariably associated with increased mortality risk in patients with LHD. However, effects on hospitalisation risk are yet to be fully characterised; while available evidence on the adverse effects of PH have been derived essentially from Caucasians.