Risk of death among those awaiting treatment for HIV infection in Zimbabwe: adolescents are at particular risk.

INTRODUCTION: Mortality among HIV-positive adults awaiting antiretroviral therapy (ART) has previously been found to be high. Here, we compare adolescent pre-ART mortality to that of adults in a public sector HIV care programme in Bulawayo, Zimbabwe. METHODS: In this retrospective cohort study, we compared adolescent pre-ART outcomes with those of adults enrolled for HIV care in the same clinic. Adolescents were defined as those aged 10-19 at the time of registration. Comparisons of means and proportions were carried out using two-tailed sample t-tests and chi-square tests respectively, for normally distributed data, and the Mann-Whitney U-tests for non-normally distributed data. Loss to follow-up (LTFU) was defined as missing a scheduled appointment by three or more months. RESULTS: Between 2004 and 2010, 1382 of 1628 adolescents and 7557 of 11,106 adults who registered for HIV care met the eligibility criteria for ART. Adolescents registered at a more advanced disease stage than did adults (83% vs. 73% WHO stage III/IV, respectively, p<0.001), and the median time to ART initiation was longer for adolescents than for adults [21 (10-55) days vs. 15 (7-42) days, p<0.001]. Among the 138 adolescents and 942 adults who never commenced ART, 39 (28%) of adolescents and 135 (14%) of adults died, the remainder being LTFU. Mortality among treatment-eligible adolescents awaiting ART was significantly higher than among adults (3% vs. 1.8%, respectively, p=0.004). CONCLUSIONS: Adolescents present to ART services at a later clinical stage than adults and are at an increased risk of death prior to commencing ART. Improved and innovative HIV case-finding approaches and emphasis on prompt ART initiation in adolescents are urgently needed. Following registration, defaulter tracing should be used, whether or not ART has been commenced

Loss to follow-up among children and adolescents growing up with HIV infection: age really matters.

INTRODUCTION: Globally, increasing numbers of HIV-infected children are reaching adolescence due to antiretroviral therapy (ART). We investigated rates of loss-to-follow-up (LTFU) from HIV care services among children as they transition from childhood through adolescence. METHODS: Individuals aged 5-19 years initiated on ART in a public-sector HIV clinic in Bulawayo, Zimbabwe, between 2005 and 2009 were included in a retrospective cohort study. Participants were categorized into narrow age-bands namely: 5-9 (children), 10-14 (young adolescents) and 15-19 (older adolescents). The effect of age at ART initiation, current age (using a time-updated Lexis expansion) and transitioning from one age group to the next on LTFU was estimated using Poisson regression. RESULTS: Of 2273 participants, 1013, 875 and 385 initiated ART aged 5-9, 10-14 and 15-19 years, respectively. Unlike those starting ART as children, individuals starting ART as young adolescents had higher LTFU rates after moving to the older adolescent age-band (Adjusted rate ratio (ARR) 1.54; 95% CI: 0.94-2.55) and similarly, older adolescents had higher LTFU rates after transitioning to being young adults (ARR 1.79; 95% CI: 1.05-3.07). In older adolescents, the LTFU rate among those who started ART in that age-band was higher compared to the rate among those starting ART at a younger age (ARR = 1.70; 95% CI: 1.05, 2.77). This however did not hold true for other age-groups. CONCLUSIONS: Adolescents had higher rates of LTFU compared to other age-groups, with older adolescents at particularly high risk in all analyses. Age-updated analyses that examine movement across narrow age-bands are paramount in understanding how developmental heterogeneity in children affects HIV outcomes

Risk of death among those awaiting treatment for HIV infection in Zimbabwe: adolescents are at particular risk

Abstract Introduction: Mortality among HIV-positive adults awaiting antiretroviral therapy (ART) has previously been found to be high. Here, we compare adolescent pre-ART mortality to that of adults in a public sector HIV care programme in Bulawayo, Zimbabwe. Methods: In this retrospective cohort study, we compared adolescent pre-ART outcomes with those of adults enrolled for HIV care in the same clinic. Adolescents were defined as those aged 10Á19 at the time of registration. Comparisons of means and proportions were carried out using two-tailed sample t-tests and chi-square tests respectively, for normally distributed data, and the MannÁWhitney U-tests for non-normally distributed data. Loss to follow-up (LTFU) was defined as missing a scheduled appointment by three or more months. Results: Between 2004 and 2010, 1382 of 1628 adolescents and 7557 of 11,106 adults who registered for HIV care met the eligibility criteria for ART. Adolescents registered at a more advanced disease stage than did adults (83% vs. 73% WHO stage III/ IV, respectively, pB0.001), and the median time to ART initiation was longer for adolescents than for adults [21 (10Á55) days vs. 15 (7Á42) days, p B0.001]. Among the 138 adolescents and 942 adults who never commenced ART, 39 (28%) of adolescents and 135 (14%) of adults died, the remainder being LTFU. Mortality among treatment-eligible adolescents awaiting ART was significantly higher than among adults (3% vs. 1.8%, respectively, p 00.004). Conclusions: Adolescents present to ART services at a later clinical stage than adults and are at an increased risk of death prior to commencing ART. Improved and innovative HIV case-finding approaches and emphasis on prompt ART initiation in adolescents are urgently needed. Following registration, defaulter tracing should be used, whether or not ART has been commenced

Relationship Between Time to Initiation of Antiretroviral Therapy and Treatment Outcomes: A Cohort Analysis of ART Eligible Adolescents in Zimbabwe.

BACKGROUND: Age-specific retention challenges make antiretroviral therapy (ART) initiation in adolescents difficult, often requiring a lengthy preparation process. This needs to be balanced against the benefits of starting treatment quickly. The optimal time to initiation duration in adolescents is currently unknown. OBJECTIVE: To assess the effect of time to ART initiation on mortality and loss to follow-up (LTFU) among treatment eligible adolescents. METHODS: We conducted a retrospective cohort analysis among 1499 ART eligible adolescents aged ≥10 to 14 days to ≤1 month, >1 to ≤2 months, >2 months, and before initiation were 1.59, 1.19, 1.56, 1.08, and 0.94, respectively, compared with the reference group of >7 to ≤14 days. LTFU HRs were 1.02, 1.07, 0.85, 0.97, and 3.96, respectively. Among patients not on ART, 88% of deaths and 85% of LTFU occurred during the first 3 months after becoming ART eligible, but only 37% and 29% among adolescents on ART, respectively. CONCLUSIONS: Neither mortality or LTFU was associated with varying time to ART. The initiation process can be tailored to the adolescents' needs and individual life situations without risking to increase poor treatment outcomes. Early mortality was high despite rapid ART initiation, calling for earlier rather than faster initiation through HIV testing scale-up

Mechanistic insights into the inhibition of Sec61-dependent co- and post-translational translocation by mycolactone

The virulence factor mycolactone is responsible for the immunosuppression and tissue necrosis that characterise Buruli ulcer, a disease caused by infection with Mycobacterium ulcerans. In this study, we confirm that Sec61, the protein-conducting channel that coordinates entry of secretory proteins into the endoplasmic reticulum, is a primary target of mycolactone, and characterise the nature of its inhibitory effect. We conclude that mycolactone constrains the ribosome–nascent-chain–Sec61 complex, consistent with its broad-ranging perturbation of the co-translational translocation of classical secretory proteins. In contrast, the effect of mycolactone on the post-translational ribosome-independent translocation of short secretory proteins through the Sec61 complex is dependent on both signal sequence hydrophobicity and the translocation competence of the mature domain. Changes to protease sensitivity strongly suggest that mycolactone acts by inducing a conformational change in the pore-forming Sec61α subunit. These findings establish that mycolactone inhibits Sec61-mediated protein translocation and highlight differences between the co- and post-translational routes that the Sec61 complex mediates. We propose that mycolactone also provides a useful tool for further delineating the molecular mechanisms of Sec61-dependent protein translocation