Multicentre analysis of second‐line antiretroviral treatment in HIV‐infected children: adolescents at high risk of failure

Introduction : The number of HIV‐infected children and adolescents requiring second‐line antiretroviral treatment (ART) is increasing in low‐ and middle‐income countries (LMIC). However, the effectiveness of paediatric second‐line ART and potential risk factors for virologic failure are poorly characterized. We performed an aggregate analysis of second‐line ART outcomes for children and assessed the need for paediatric third‐line ART. Methods : We performed a multicentre analysis by systematically reviewing the literature to identify cohorts of children and adolescents receiving second‐line ART in LMIC, contacting the corresponding study groups and including patient‐level data on virologic and clinical outcomes. Kaplan–Meier survival estimates and Cox proportional hazard models were used to describe cumulative rates and predictors of virologic failure. Virologic failure was defined as two consecutive viral load measurements >1000 copies/ml after at least six months of second‐line treatment. Results : We included 12 cohorts representing 928 children on second‐line protease inhibitor (PI)‐based ART in 14 countries in Asia and sub‐Saharan Africa. After 24 months, 16.4% (95% confidence interval (CI): 13.9–19.4) of children experienced virologic failure. Adolescents (10–18 years) had failure rates of 14.5 (95% CI 11.9–17.6) per 100 person‐years compared to 4.5 (95% CI 3.4–5.8) for younger children (3–9 years). Risk factors for virologic failure were adolescence (adjusted hazard ratio [aHR] 3.93, p < 0.001) and short duration of first‐line ART before treatment switch (aHR 0.64 and 0.53, p = 0.008, for 24–48 months and >48 months, respectively, compared to <24 months). Conclusions : In LMIC, paediatric PI‐based second‐line ART was associated with relatively low virologic failure rates. However, adolescents showed exceptionally poor virologic outcomes in LMIC, and optimizing their HIV care requires urgent attention. In addition, 16% of children and adolescents failed PI‐based treatment and will require integrase inhibitors to construct salvage regimens. These drugs are currently not available in LMIC.     

Changes in second‐line regimen durability and continuity of care in relation to national ART guideline changes in South Africa

Introduction : Little is known about the impact of antiretroviral therapy (ART) guideline changes on the durability of second‐line ART and continuity of care. This study examines predictors of early drug substitutions and treatment interruptions using a cohort analysis of HIV positive adults switched to second‐line ART between January 2004 and September 2013 in Johannesburg, South Africa. Methods : The main outcomes were having a drug substitution or treatment interruption in the first 24 months on second‐line ART. Kaplan Meiers analyses and Cox proportional hazards regression were used to identify predictors of drug substitutions and treatment interruptions. Results : Of 3028 patients on second‐line ART, 353 (11.7%) had a drug substitution (8.6 per 100PY, 95% CI: 7.8–9.6) and 260 (8.6%) had a treatment interruption (6.3 per 100PY, 95% CI: 5.6–7.1). While treatment interruptions decreased from 32.5 per 100PY for the 2004 cohort to 2.3 per 100PY for the 2013 cohort, the rates of drug substitutions steadily increased, peaking at an incidence of 26.7 per 100PY for the 2009 cohort and then decreased to 4.2 per 100PY in the 2011 cohort. Compared to the 2004 to 2008 cohorts, the hazard of early drug substitutions was highest among patients switched to AZT + ddI + LPVr in 2009 to 2010 (aHR 5.1, 95% CI: 3.4–7.1) but remained low over time among patients switched to TDF + 3TC/FTC + LPVr or AZT/ABC + 3TC + LPVr. The main common predictor of both treatment interruption and drug substitution was drug toxicity. Conclusions : Our results show a rapid transition between 2004 and 2010 ART guidelines and concurrent improvements in continuity of care among second‐line ART patients. Drug toxicity reporting and monitoring systems need improvements to inform timely regimen changes and ensure that patients remain in care. However, reasons for drug substitutions should be closely monitored to ensure that patients do not run out of treatment options in the future.     

Evidence Obtained from anova to Reason Cross‐species Infection and Cross‐subtype Mutation in Neuraminidases of Influenza A Viruses

The current pandemic of A/H1N1 influenza raises a serious question on cross‐species infection and cross‐subtype mutation because our previous focus on possible influenza pandemic laid on H5N1 subtype and the cross‐species infection between avian and human. In this study, we analyse 3874 neuraminidases from influenza A viruses using anova to answer the question of if there is barrier between species and between subtypes. The results show that there is no cross‐species barrier in some species, and the intra‐species variation is larger than the inter‐species variation in some species hosting the viruses, and the cross‐subtype mutation is possible because there is no cross‐subtype barrier in some subtypes and the intra‐subtype variation is larger than the inter‐subtype variation in some subtypes. These results highlight the state of barrier of influenza A virus, which can help us understand the current pandemic and manufacture more effective vaccines.     

Long‐term follow‐up of beta cell replacement therapy in 10 HIV‐infected patients with renal failure secondary to type 1 diabetes mellitus

The approach to transplantation in human immunodeficiency virus (HIV)‐positive patients has been conservative due to fear of exacerbating an immunocompromised condition. As a result, HIV‐positive patients with diabetes were initially excluded from beta cell replacement therapy. Early reports of pancreas transplant in patients with HIV described high rates of early graft loss with limited follow‐up. We report long‐term follow‐up of islet or pancreas transplantation in HIV‐positive type 1 diabetic patients who received a kidney transplant concurrently or had previously undergone kidney transplantation. Although 4 patients developed polyoma viremia, highly active antiretroviral therapy and adequate infectious prophylaxis were successful in providing protection until CD4+ counts recovered. Coordination with HIV providers is critical to reduce the risk of rejection by minimizing drug‐drug interactions. Also, protocols for prophylaxis of opportunistic infections and strategies for monitoring and treating BK viremia are important given the degree of immunosuppression required. This series demonstrates that type 1 diabetic patients with well‐controlled HIV and renal failure can be appropriate candidates for beta cell replacement, with a low rate of infectious complications, early graft loss, and rejection, so excellent long‐term graft survival is possible. Additionally, patients with HIV and cardiovascular contraindications can undergo islet infusion.