Long-Term Survival, Safety and Tolerability with Selexipag in Patients with Pulmonary Arterial Hypertension: Results from GRIPHON and its Open-Label Extension.

INTRODUCTION: In the event-driven GRIPHON randomised-controlled trial, the oral prostacyclin receptor agonist selexipag significantly reduced the risk of disease progression (composite primary endpoint of morbidity/mortality), compared with placebo, in patients with pulmonary arterial hypertension (PAH). The ongoing open-label extension study (GRIPHON OL) collects further data on long-term safety, tolerability, and survival of PAH patients treated with selexipag. METHODS: Patients randomised to selexipag or placebo in GRIPHON could enter GRIPHON OL either after experiencing a morbidity event during double-blind treatment or at the end of the study. Patients were followed for adverse events (AE) and survival from selexipag initiation up to 3 days and 30 days after end of treatment, respectively. Data are presented up to a cut-off date of 1 September 2019. RESULTS: Overall, 953 patients in GRIPHON and GRIPHON OL were treated with selexipag. At the time of selexipag initiation, 81.2% of patients were receiving background PAH therapy. Median (min, max) exposure to selexipag was 31.7 months (0, 106), corresponding to a total of 3054.4 patient-years. The most frequently reported AEs were related to known prostacyclin-related effects or underlying disease. There were 305 (32.0%) patients who experienced an AE leading to treatment discontinuation. Survival during GRIPHON and GRIPHON OL was assessed for the 574 patients randomised to selexipag in GRIPHON. Kaplan-Meier survival estimates (95%CI) at 1, 3, 5 and 7 years were 92.0% (89.4, 94.0), 79.3% (75.4, 82.6), 71.2% (66.5, 75.3) and 63.0% (57.4, 68.1), respectively. CONCLUSIONS: These results provide the longest follow-up period published to date for a PAH therapy. The safety profile of selexipag over this extended treatment period was consistent with that observed in GRIPHON. A large proportion of the population was receiving background therapy at selexipag initiation, providing further insight into the long-term safety of selexipag as part of a combination therapy regimen. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01106014 and NCT01112306.

Modulation of sphingosine-1-phosphate in inflammatory bowel disease.

Inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn's disease, involve an inappropriate immune reaction in the digestive tract, causing a variety of disabling symptoms. The advent of monoclonal antibodies (anti-tumor necrosis factor, anti-integrin, anti-interleukin -23) has revolutionized IBD management. Nevertheless, these agents, with potential for immunogenicity, are associated with high rates of response loss and disease relapse over time. They are also associated with high production costs. Sphingosine-1-phosphate (S1P), a membrane-derived lysophospholipid signaling molecule, is implicated in a vast array of physiological and pathophysiological processes, primarily via extracellular activation of S1P1-S1P5 receptors. S1P1, S1P4 and S1P5 are involved in regulation of the immune system, while S1P2 and S1P3 may be associated with cardiovascular, pulmonary, and theoretical cancer-related risks. Targeting S1P receptors for inflammatory conditions has been successful in clinical trials leading to approval of the non-selective S1P modulator, fingolimod, for relapsing forms of multiple sclerosis. However, the association of this non-selective S1P modulator with serious adverse events provides the rationale for developing more selective S1P receptor modulators. Until recently, three S1P modulators with differing selectivity for S1P receptors were in clinical development for IBD: ozanimod (RPC1063), etrasimod (APD334) and amiselimod (MT-1303). The development of amiselimod has been stopped as Biogen are currently focusing on other drugs in its portfolio. Following encouraging results from the Phase 2 TOUCHSTONE trial, a Phase 3 trial of the S1P modulator ozanimod in patients with moderate-to-severe ulcerative colitis is ongoing. Etrasimod is also being tested in a phase 2 trial in ulcerative colitis. These pipeline medications can be administered orally and may avoid the formation of anti-drug antibodies that can lead to treatment failure with injectable biologic therapies for IBD. Data from ongoing clinical trials will establish the relationship between the selectivity of S1P modulators and their safety and efficacy in IBD, as well as their potential place in the clinical armamentarium for IBD.

Bioavailability, safety and immunogenicity of biosimilar infliximab (BOW015) compared to reference infliximab.

OBJECTIVES: To compare the single-dose pharmacokinetics (PK), safety, and immunogenicity of the biosimilar infliximab (BOW015) to reference infliximab (rIFX) in healthy volunteers and to establish bioequivalence. METHODS: In this randomized, double-blind, parallel-group, single-dose study, subjects received either BOW015 or rIFX. Both drugs were administered as a single IV 5 mg/kg dose over 2 hours on day 1. PK sampling occurred 10 times over 3 days and during safety and immunogenicity follow-up on day 4 and 1, 2, 3, 5, 7, 9, and 12 weeks after the infusion. RESULTS: Of the 84 healthy male Caucasian subjects randomized, 43 received BOW015 and 41 received rIFX. PK parameters (geometric mean) for BOW015 vs. rIFX were as follows; C(max) 142.47 vs. 126.74 µg/mL, AUC(0-t) 36,211 vs. 34,304 h×µg/mL, and AUC(0-inf) 36,775 vs. 34,801 h×µg/mL. The point estimates of the BOW015/rIFX geometric mean ratios (90% CI) were; C(max) 1.13 (1.07 - 1.18), AUC(0-t) 1.06 (0.98 - 1.14), and AUC(0-inf) 1.06 (0.98 - 1.15). Overall, anti-drug antibodies were detected in 18.6% of BOW015-treated subjects and 24.4% of rIFX-treated subjects. A total of 26 (60.5%) subjects in the BOW015 group reported 50 treatment-emergent adverse events (TEAEs) and 27 (65.9%) subjects in the rIFX group reported 54 TEAEs. CONCLUSIONS: Bioequivalence of BOW015 to rIFX is demonstrated as 90% CIs for the study drug mean ratios of C(max), AUC(0-t), and AUC(0-inf) were within the log-transformed ± 20% equivalence range of 0.80 - 1.25. Safety and immunogenicity were also comparable.

Efficacy of indacaterol 75 µg once-daily on dyspnea and health status: results of two double-blind, placebo-controlled 12-week studies.

Indacaterol is an inhaled, once-daily, long-acting ®(2)-agonist for the treatment of COPD. Most previous studies were conducted with doses of 150 and/or 300 µg once-daily, and data with the 75 µg dose are limited. Two identically designed studies were, therefore, conducted to evaluate the efficacy and safety of the 75 µg once-daily dose. In two double-blind studies conducted in the USA, patients with moderate-to-severe COPD were randomized to treatment with indacaterol 75 µg once-daily (n = 163 and 159) or matching placebo (n = 160 and 159) for 12 weeks. The primary variable was forced expiratory volume in 1 s measured 24 h post-dose after 12 weeks (reported elsewhere). This report describes secondary efficacy endpoints, including transition dyspnea index (TDI) and St George's Respiratory Questionnaire (SGRQ) total scores, and the percentages of patients with improvements of or above the minimal clinically important difference (MCID; ≥1 in TDI score and ≥4 in SGRQ score). Differences between indacaterol and placebo for TDI total score at week 12 were 1.23 (p < 0.001) and 0.45 (p = 0.16), with odds ratios for achieving the MCID of 2.19 (p = 0.002) and 1.58 (p = 0.065). SGRQ total score decreased (improved) from baseline by 5.8 and 4.9 units with indacaterol at week 12 (2.0 and 0.9 with placebo), with odds ratios for achieving the MCID of 1.80 (p = 0.024) and 1.71 (p = 0.031). Patients receiving indacaterol had statistically significant or numerical improvements in diary-derived symptom variables compared with placebo. Treatment with indacaterol 75 µg may provide useful improvements in patient-reported outcomes in patients with moderate-to-severe COPD.

Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised, double-blind comparison.

BACKGROUND: Current guidelines recommend treatment with one or more long-acting bronchodilators for patients with moderate or more severe chronic obstructive pulmonary disease (COPD). The authors investigated the approach of dual bronchodilation using indacaterol, a once-daily long-acting ß(2) agonist, and the long-acting muscarinic antagonist tiotropium, compared with tiotropium alone. METHODS: In two identically designed, double-blind, 12-week studies, patients with moderate to severe COPD were randomised to indacaterol 150 µg once daily or matching placebo. All patients concurrently received open-label tiotropium 18 µg once daily. The primary outcome was standardised area under the curve of forced expiratory volume in 1 s (FEV(1)) from 5 min to 8 h post dose at week 12. The key secondary outcome was 24 h post-dose ('trough') FEV(1) at week 12. Resting inspiratory capacity (IC) was measured in a subgroup. RESULTS: 1134 and 1142 patients were randomised in studies 1 and 2; 94% and 94% completed. Compared with monotherapy, concurrent therapy increased FEV(1) (area under the curve by 130 and 120 ml, trough by 80 and 70 ml; all p<0.001) and trough IC (by 130 and 100 ml, p<0.01). Cough was more common with indacaterol plus tiotropium (10% and 9%) than with tiotropium alone (4% and 4%). Most cases (∼90%) of cough were mild. Other adverse events were similar for the treatment groups. CONCLUSIONS: Compared with tiotropium monotherapy, indacaterol plus tiotropium provided greater bronchodilation and lung deflation (reflected by increased resting IC). Adverse events were similar between treatments apart from mild cough being more common with indacaterol plus tiotropium. These results support COPD guideline recommendations to combine bronchodilators with different mechanisms of action. TRIAL REGISTRATION NUMBERS: NCT00846586 and NCT00877383.

Efficacy of once-daily indacaterol relative to alternative bronchodilators in COPD: a patient-level mixed treatment comparison.

OBJECTIVE: Indacaterol was evaluated versus placebo, formoterol, and salmeterol in randomized controlled trials. No direct comparisons, however, are available for indacaterol 150 µg with formoterol or indacaterol 300 µg with salmeterol. Indacaterol trial evidence was synthesized to provide coherent estimates of indacaterol 150 µg and indacaterol 300 µg relative to formoterol, salmeterol, and tiotropium. METHODS: Four randomized controlled trials were combined with Bayesian mixed treatment comparisons by using individual patient-level data. End points of interest were trough forced expiratory volume in 1 second (FEV(1)), St. George's Respiratory Questionnaire (SGRQ) total score and response (≥ 4 points), and Transition Dyspnea Index total score and response (≥ 1 point). RESULTS: Indacaterol 150 µg demonstrated a higher FEV(1) than did formoterol at 12 weeks and 6 months (0.10 L difference; 95% credible interval [CrI] = 0.06-0.14), as did indacaterol 300 µg versus salmeterol (0.06 L difference at 12 weeks; CrI = 0.02-0.10; 0.06 L at 6 months; CrI = 0.02-0.11). Regarding SGRQ, indacaterol 150 µg demonstrated a comparable proportion of responders versus formoterol, as did indacaterol 300 µg versus salmeterol. In comparison to tiotropium, indacaterol 150 µg demonstrated a greater proportion of responders (odds ratio = 1.52 at 12 weeks; CrI 1.15-2.00). For Transition Dyspnea Index, indacaterol 150 µg and formoterol showed a similar response. Indacaterol 300 µg was more efficacious than salmeterol (odds ratio = 1.65 at 12 weeks; CrI 1.16-2.34). Overall, indacaterol 150 µg showed the greatest efficacy for SGRQ and indacaterol 300 µg for FEV(1) and Transition Dyspnea Index. CONCLUSION: Indacaterol is expected to be comparable to formoterol, salmeterol, and tiotropium, providing higher FEV(1) than formoterol and salmeterol and greater improvement in the SGRQ total score than tiotropium. Indacaterol 150 µg provided comparable improvement in dyspnea, while indacaterol 300 µg demonstrated the greatest response overall.

Efficacy and tolerability of indacaterol 75 µg once daily in patients aged ≥40 years with chronic obstructive pulmonary disease: results from 2 double-blind, placebo-controlled 12-week studies.

BACKGROUND: Indacaterol is the first once-daily, long-acting, inhaled ß(2)-agonist bronchodilator for maintenance treatment of chronic obstructive pulmonary disease (COPD). Two studies (previously reported in a Congress abstract) were performed in 2010 to provide efficacy and tolerability data to support the application for approval in the United States of indacaterol 75 µg once daily, a dose lower than that previously investigated in most studies. OBJECTIVE: The primary objective was to evaluate the efficacy of indacaterol 75 µg once daily in terms of 24-hour post-dose ("trough") forced expiratory volume in the first second of respiration (FEV(1)) compared with placebo after 12 weeks of treatment. METHODS: Patients with moderate to severe COPD were randomized to receive double-blind treatment with indacaterol 75 µg once daily (n = 163 and 159) or placebo (n = 160 and 159) for 12 weeks. In addition to trough FEV(1) after 12 weeks, rescue albuterol use, health status (St. George's Respiratory Questionnaire [SGRQ]), and tolerability were evaluated. Clinically relevant differences between active and placebo treatments were defined as ≥120 mL for trough FEV(1) and a decrease of ≥4 units in SGRQ total score. RESULTS: Of patients enrolled in the 2 studies, 54% were men, and 90% and 94% were white, with mean age 64 and 61 years. Mean duration of COPD was 7 years; smoking history was 52 pack-years; and 45% and 37% of patients were receiving inhaled corticosteroid therapy. At week 12, indacaterol demonstrated clinically relevant bronchodilator efficacy, increasing trough FEV(1) by ≥120 mL versus placebo (P < 0.001), with significant bronchodilation maintained at all time points from 5 minutes to 24 hours post-dose. Over 12 weeks, relative to placebo, in patients receiving indacaterol therapy, rescue albuterol use was reduced by 1.2 and 0.7 puffs per day (P < 0.01), and the percentage of rescue-free days was increased by 13.7 and 8.4 (P < 0.01). At week 12, the SGRQ total score differed in the indacaterol group versus the placebo group by -3.8 and -3.6, respectively (P ≤ 0.01). Adverse events were reported for 49% and 45% of patients receiving indacaterol therapy, and for 46% and 41% receiving placebo. CONCLUSIONS: Compared with placebo, indacaterol 75 µg once daily provided statistically significant and clinically relevant 24-hour bronchodilation and was well tolerated. In patients receiving indacaterol, the reduction in rescue albuterol use was statistically significant. Changes in health status also were statistically significant compared with placebo, although the differences of 3.6 and 3.8 units were below the predefined 4-unit level of clinical relevance. The results of these studies suggest that indacaterol 75 µg once daily is an effective maintenance treatment in patients with moderate to severe COPD. ClinicalTrials.gov identifiers: NCT01072448 and NCT01068600.

Correlating changes in lung function with patient outcomes in chronic obstructive pulmonary disease: a pooled analysis.

BACKGROUND: Relationships between improvements in lung function and other clinical outcomes in chronic obstructive pulmonary disease (COPD) are not documented extensively. We examined whether changes in trough forced expiratory volume in 1 second (FEV(1)) are correlated with changes in patient-reported outcomes. METHODS: Pooled data from three indacaterol studies (n = 3313) were analysed. Means and responder rates for outcomes including change from baseline in Transition Dyspnoea Index (TDI), St. George's Respiratory Questionnaire (SGRQ) scores (at 12, 26 and 52 weeks), and COPD exacerbation frequency (rate/year) were tabulated across categories of ΔFEV(1). Also, generalised linear modelling was performed adjusting for covariates such as baseline severity and inhaled corticosteroid use. RESULTS: With increasing positive ΔFEV(1), TDI and ΔSGRQ improved at all timepoints, exacerbation rate over the study duration declined (P < 0.001). Individual-level correlations were 0.03-0.18, but cohort-level correlations were 0.79-0.95. At 26 weeks, a 100 ml increase in FEV(1) was associated with improved TDI (0.46 units), ΔSGRQ (1.3-1.9 points) and exacerbation rate (12% decrease). Overall, adjustments for baseline covariates had little impact on the relationship between ΔFEV(1) and outcomes. CONCLUSIONS: These results suggest that larger improvements in FEV(1) are likely to be associated with larger patient-reported benefits across a range of clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00393458, NCT00463567, and NCT00624286.

Safety of indacaterol in the treatment of patients with COPD.

PURPOSE: Pooled data were analyzed to evaluate the safety and tolerability of indacaterol, a once-daily inhaled long-acting ß(2)-agonist for chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS: Data were pooled from clinical studies of 3-12 months' duration in patients with moderate-to-severe COPD receiving double-blind indacaterol 75 µg (n = 449), 150 µg (n = 2611), 300 µg (n = 1157), or 600 µg once daily (n = 547); formoterol 12 µg twice daily (n = 556); salmeterol 50 µg twice daily (n = 895); placebo (n = 2012); or tiotropium 18 µg once daily, given open label or blinded (n = 1214). Outcomes were adverse events, serious adverse events and deaths, plasma potassium, blood glucose, and QTc interval and vital signs. RESULTS: The commonest adverse events with indacaterol were COPD worsening, nasopharyngitis, and headache; most cases were mild or moderate and incidence was generally similar to placebo and other active treatments. The risk of acute respiratory serious adverse events (leading to hospitalization, intubation, or death) was not significantly increased with any of the active treatments compared with placebo. COPD exacerbation rates (analyzed in the intent-to-treat population) were significantly reduced with all active treatments versus placebo. Hazard ratios versus placebo for major cardiovascular adverse events were < 1 for all indacaterol doses. Notable values for vital signs and measures of systemic ß(2)-adrenoceptor activity were rare with indacaterol. The number of deaths adjusted per patient-year was lower with indacaterol (all doses combined) than with placebo (relative risk 0.21 [95% confidence interval 0.07-0.660], P = 0.008). CONCLUSION: Indacaterol has a good profile of safety and tolerability that is appropriate for the maintenance treatment of patients with COPD.

Delivery characteristics and patients' handling of two single-dose dry-powder inhalers used in COPD.

For optimal efficacy, an inhaler should deliver doses consistently and be easy for patients to use with minimal instruction. The delivery characteristics, patients' correct use, and preference of two single-dose dry powder inhalers (Breezhaler and HandiHaler) were evaluated in two complementary studies. The first study examined aerodynamic particle size distribution, using inhalation profiles of seven patients with moderate to very severe chronic obstructive pulmonary disease (COPD). The second was an open-label, two-period, 7-day crossover study, evaluating use of the inhalers with placebo capsules by 82 patients with mild to severe COPD. Patients' correct use of the inhalers was assessed after reading written instructions on Day 1, and after training and 7 days of daily use. Patients' preference was assessed after completion of both study periods. Patient inhalation profiles showed average peak inspiratory flows of 72 L/minute through Breezhaler and 36 L/minute through HandiHaler. For Breezhaler and HandiHaler, fine particle fractions were 27% and 10%, respectively. In the second study, correct use of Breezhaler and HandiHaler was achieved by > 77% of patients for any step after 7 days; 61% of patients showed an overall preference for Breezhaler and 31% for HandiHaler (P = 0.01).Breezhaler is a low-resistance inhaler suitable for use by patients with a range of disease severities. Most patients used both inhalers correctly after 7 days, but more patients showed an overall preference for the Breezhaler compared with the HandiHaler. These are important factors for optimum dose delivery and successful COPD management.

Indacaterol once-daily provides superior efficacy to salmeterol twice-daily in COPD: a 12-week study.

BACKGROUND: Indacaterol is a novel, inhaled once-daily ultra-long-acting ß(2)-agonist for the treatment of COPD. METHODS: This 12-week randomised, parallel-group study compared the efficacy of indacaterol 150 µg once-daily to salmeterol 50 µg twice-daily in patients with moderate-to-severe COPD. Assessments included FEV(1) standardised area under curve (AUC) from 5 min to 11 h 45 min at Week 12 (primary endpoint), 24-h trough FEV(1) (mean of 23 h 10 min and 23 h 45 min post-dose) at Week 12 (key secondary endpoint), FEV(1) and FVC measured over 24-h, transition dyspnoea index (TDI) and rescue medication use. RESULTS: Of 1123 patients randomised 92.1% completed. Mean ± SD age was 62.8±8.78 years, post-bronchodilator FEV(1) 51.8±12.32% predicted, FEV(1)/FVC 50.6±9.54%. At Week 12, FEV(1) AUC(5 min-11 h 45 min) for indacaterol was statistically superior (p<0.001) to salmeterol (adjusted mean difference [95% CI] 57 [35, 79] mL), as was 24-h trough FEV(1) (60 [37, 83] mL, p<0.001). Indacaterol also showed statistical superiority over salmeterol in terms of FEV(1) and FVC measured over 24-h at Week 12. For TDI at Week 12, the mean total score was statistically superior for indacaterol versus salmeterol (difference 0.63 [0.30, 0.97], p<0.001), as was the percentage of patients with a clinically relevant (i.e., ≥1 point) change from baseline (69.4% vs 62.7%, p<0.05). For rescue medication, patients on indacaterol used fewer puffs/day (difference -0.18 [-0.36, 0.00] puffs/day, p<0.05) and had a greater percentage of days with no rescue use (difference 4.4 [0.6, 8.2], p<0.05). CONCLUSION: Once-daily indacaterol provided statistically superior bronchodilation with an improvement in breathlessness and rescue use compared with twice-daily salmeterol. ClinicalTrials.gov NCT00821093.

Long-term safety and efficacy of indacaterol, a long-acting ß2-agonist, in subjects with COPD: a randomized, placebo-controlled study.

BACKGROUND: Indacaterol is an inhaled, long-acting ß(2)-agonist providing 24-h bronchodilation with once-daily dosing in patients with COPD. METHODS: Subjects with moderate to severe COPD who completed a 26-week, randomized, double-blind study were eligible for enrollment in an extension, during which treatment with double-blind indacaterol, 150 or 300 µg once daily, or placebo was continued for a further 26 weeks. The primary objective was to evaluate the long-term safety of indacaterol. Efficacy end points included trough (24 h postdose) FEV(1) at 52 weeks, exacerbations, and health status (St. George Respiratory Questionnaire [SGRQ]). RESULTS: Four hundred fifteen subjects participated in the extension. Adverse events, mostly mild or moderate, occurred in 76%, 77%, and 68% of subjects receiving indacaterol, 150 µg; indacaterol, 300 µg; and placebo, respectively. Serious adverse events occurred in 10.4%, 12.3%, and 10.5%, respectively. Indacaterol had no clinically significant effects on ECG findings (corrected QT interval) or on serum potassium or plasma glucose levels. Indacaterol increased trough FEV(1) relative to placebo throughout the study (difference of ≥ 170 mL at week 52). No tolerance to its bronchodilator effect was detected. Indacaterol treatment was accompanied by significant reductions in COPD exacerbations (rate ratios compared with placebo, 0.62-0.64; P < .05) and as-needed albuterol use (1.2-1.4 puffs/d decrease, P < .001 compared with placebo). Health status improved with indacaterol treatment, with decreases from baseline in mean total SGRQ score generally > 4 units. CONCLUSIONS: During 1 year of treatment, indacaterol was well tolerated and provided significant and well-maintained bronchodilation that was accompanied by improved clinical outcomes. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00677807; URL: www.clinicaltrials.gov.

Respiratory syncytial virus associated illness in high-risk children and national characterisation of the circulating virus genotype in South Africa.

BACKGROUND: There is limited information about respiratory syncytial virus (RSV) in high-risk children from developing countries or on the genotype characterisation of the circulating virus. OBJECTIVE: To define the proportion of children with RSV associated lower respiratory tract infections (LRTI) that had risk factors for severe disease and to genotype the circulating RSV strains across the country. STUDY DESIGN: A prospective study was performed in four distinct regions. During April 2000-December 2000 (period 1), all children, with LRTI or without underlying high risk factors for severe RSV disease were enrolled. During January to September 2001 (period 2), only children with LRTI with underlying high risk factors were enrolled. Nasopharyngeal aspirates were evaluated for RSV infection using an ELISA test. RSV isolates were also subtyped and genotyped. RESULTS: Fifty three (24%) of 220 children enrolled during period 1 had risk factors for severe RSV disease; in addition to which a further 38 high-risk children were enrolled during 2001. RSV was isolated from 16 (30%) of 53 and 37 (22%) of 167 high-risk and non-high risk children, respectively, P=0.31. High-risk children were more likely to require intensive unit care (25 vs. 2.7%, P=0.02) and were also more likely to be hospitalised for a longer duration (median 7 vs. 5 days, P=0.06) than non high-risk infants. Overall (periods 1 and 2), RSV was isolated from 34 (37.4%) of the 91 high-risk infants enrolled. Among high-risk children, those from whom RSV was isolated were more likely to require hospitalisation (73.5 vs. 54.4%, P=0.07) and admission to an intensive care unit (14.7 vs. 1.8%, P=0.03) than those from whom RSV was not isolated. Of 40 isolates subtyped during period one, 92.5% were subtype A. Further, 27 (83.3%) of 30 subtype A isolates genotyped during period 1 clustered with GA2. CONCLUSION: RSV is an important cause of LRTI among high-risk infants in a developing country such as South Africa. For the season in question, the genotype that was dominant in Johannesburg was isolated throughout the country, suggesting that successful genotypes may have the ability to spread nationwide.