Outcomes of patients with Kaposi's sarcoma who start antiretroviral therapy under routine programme conditions in Malawi.

AIDS-associated Kaposi's sarcoma (KS) is the most common AIDS-related malignancy in sub-Saharan Africa, with a generally unfavourable prognosis. We report on six-month and 12-month cohort treatment outcomes of human immunodeficiency virus (HIV)-positive KS patients and HIV-positive non-KS patients treated with antiretroviral therapy (ART) in public sector facilities in Malawi. Data were collected from standardized antiretroviral (ARV) patient master cards and ARV patient registers. Between July and September 2005, 7905 patients started ART-488 (6%) with a diagnosis of KS and 7417 with a non-KS diagnosis. Between January and March 2005, 4580 patients started ART-326 (7%) with a diagnosis of KS and 4254 with a non-KS diagnosis. At six-months and 12-months, significantly fewer KS patients were alive and significantly more had died or defaulted compared to non-KS patients. HIV-positive KS patients on ART in Malawi have worse outcomes than other patients on ART. Methods designed to improve these outcomes must be found

A National Survey of Teachers on Antiretroviral Therapy in Malawi: Access, Retention in Therapy and Survival

BACKGROUND: HIV/AIDS is having a devastating effect on the education sector in sub-Saharan Africa. A national survey was conducted in all public sector and private sector facilities in Malawi providing antiretroviral therapy (ART) to determine the uptake of ART by teachers and their outcomes while on treatment. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective cohort study was carried out based on patient follow-up records from ART Registers and treatment master cards in all 138 ART clinics in Malawi; observations were censored on September 30(th) 2006. By this date, Malawi's 102 public sector and 36 private sector ART clinics had registered a total of 72,328 patients for treatment. Of these, 2,643 (3.7%) were teachers. Adjusting for double-registration caused by clinic transfers, it is estimated that 2,380 individual teachers had ever accessed ART. There were 15% of teachers starting ART in WHO clinical stage 1 or 2 with a CD4-lymphocyte count of <or=250/mm(3) and 85% starting in stage 3 or 4. By 30(th) September 2006, 1,850 teachers were alive on ART (3.5% of all teachers in Malawi). The probability of being alive on ART at 6-months, 12-months, 18-months and 24-months after treatment initiation was 84%, 79%, 75% and 73% respectively. Retention in treatment was better for women (adjusted HR = 1.8) and in those starting ART in WHO Clinical Stage 1 and 2 (adjusted HR = 1.8). CONCLUSION/SIGNIFICANCE: Rapid scale up of ART has allowed 2,380 HIV-positive teachers to access life-prolonging treatment. There is evidence that this intervention can help to mitigate some of the shortages of teaching personnel in resource-poor countries affected by a generalised HIV epidemic

Antiretroviral Therapy in the Malawi Defence Force: Access, Treatment Outcomes and Impact on Mortality

BACKGROUND: HIV/AIDS affects all sectors of the population and the defence forces are not exempt. A national survey was conducted in all public and private sectors in Malawi that provide antiretroviral therapy (ART) to determine the uptake of ART by army personnel, their outcomes while on treatment, and the impact of ART on mortality in the Malawi Defence Force. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective cohort analysis was carried out, collecting data on access and retention on treatment from all 103 public and 38 private sector ART clinics in Malawi, using standardised patient master cards and clinic registers. Observations were censored on December 31(st) 2006. Independent data on mortality trends in army personnel from all causes between 2002 and 2006 were available from army records. By December 31(st) 2006, there were 85,168 patients ever started on ART in both public and private sectors, of whom 547 (0.7%) were army personnel. Of these, 22% started ART in WHO clinical stage 1 or 2 with a CD4-lymphocyte count of <or=250/mm(3) and 78% started in stage 3 or 4. Treatment outcomes of army personnel by December 31(st) 2006 were:-365 (67%) alive and on ART at their registration facility, 98 (18%) transferred out to another facility, 71 (13%) dead, 9 (2%) lost to follow-up, and 4 (<1%) stopped treatment. The probability of being alive on ART at 6-, 12- and 18-months was 89.8%, 83.4% and 78.8% respectively. All-cause mortality in army personnel declined dramatically over the five year period from 2002-2006. CONCLUSION/SIGNIFICANCE: There has been a good access of army personnel to ART during the last five years with excellent outcomes, and this should serve as an example for other defence forces and large companies in the region

Estimating Infection Attack Rates and Severity in Real Time during an Influenza Pandemic: Analysis of Serial Cross-Sectional Serologic Surveillance Data

This study reports that using serological data coupled with clinical surveillance data can provide real-time estimates of the infection attack rates and severity in an emerging influenza pandemic

Controversy surrounding the increased expression of TGFβ1 in asthma

Asthma is a waxing and waning disease that leads to structural changes in the airways, such as subepithelial fibrosis, increased mass of airway smooth muscle and epithelial metaplasia. Such a remodeling of the airways futher amplifies asthma symptoms, but its etiology is unknown. Transforming growth factor β1 is a pleiotropic cytokine involved in many fibrotic, oncologic and immunologic diseases and is believed to play an essential role in airway remodeling that occurs in asthmatic patients. Since it is secreted in an inactive form, the overall activity of this cytokine is not exclusively determined by its level of expression, but also by extensive and complex post-translational mechanisms, which are all importanin modulating the magnitude of the TGFβ1 response. Even if TGFβ1 upregulation in asthma is considered as a dogma by certain investigators in the field, the overall picture of the published litterature is not that clear and the cellular origin of this cytokine in the airways of asthmatics is still a contemporaneous debate. On the other hand, it is becoming clear that TGFβ1 signaling is increased in the lungs of asthmatics, which testifies the increased activity of this cytokine in asthma pathogenesis. The current work is an impartial and exhaustive compilation of the reported papers regarding the expression of TGFβ1 in human asthmatics. For the sake of comparison, several studies performed in animal models of the disease are also included. Inconsistencies observed in human studies are discussed and conclusions as well as trends from the current state of the litterature on the matter are proposed. Finally, the different points of regulation that can affect the amplitude of the TGFβ1 response are briefly revised and the possibility that TGFβ1 is disregulated at another level in asthma, rather than simply in its expression, is highlighted

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

True outcomes for patients on antiretroviral therapy who are “lost to follow-up” in Malawi

PROBLEM: In many resource-poor countries that are scaling up antiretroviral therapy (ART), 5-25% of patients are reported as "lost to follow-up". This figure is 9% in Malawi. There is no published information about the true outcome status of these patients. APPROACH: In four facilities in northern Malawi, ART registers and master cards were used to identify patients who had not attended the facility for 3 months or more and were thus registered as "lost to follow-up". Clinic staff attempted to trace these patients and ascertain their true outcome status. LOCAL SETTING: Of 253 patients identified as "lost to follow-up", 127 (50%) were dead, 58% of these having died within 3 months of their last clinic visit. Of the 58 patients (23%) found to be alive, 21 were still receiving ART and 37 had stopped treatment (high transport costs being the main reason for 13 patients). Sixty-eight patients (27%) could not be traced, most commonly because of an incorrect address in the register. Fewer patients were alive and more patients could not be traced from the central hospital compared with the peripheral hospitals. RELEVANT CHANGES: Better documentation of patients addresses and prompt follow-up of patients who are late for their appointments are required. LESSONS LEARNED: ART clinics in resource-poor countries should ensure that patients addresses are correct and comprehensive. Clinics should also undertake contact tracing as soon as possible in the event of non-attendance, consider facilitating access to ART clinics and take loss to follow-up into consideration when assessing death rates

True outcomes for patients on antiretroviral therapy who are "lost to follow-up" in Malawi

PROBLEM: In many resource-poor countries that are scaling up antiretroviral therapy (ART), 5-25% of patients are reported as "lost to follow-up". This figure is 9% in Malawi. There is no published information about the true outcome status of these patients. APPROACH: In four facilities in northern Malawi, ART registers and master cards were used to identify patients who had not attended the facility for 3 months or more and were thus registered as "lost to follow-up". Clinic staff attempted to trace these patients and ascertain their true outcome status. LOCAL SETTING: Of 253 patients identified as "lost to follow-up", 127 (50%) were dead, 58% of these having died within 3 months of their last clinic visit. Of the 58 patients (23%) found to be alive, 21 were still receiving ART and 37 had stopped treatment (high transport costs being the main reason for 13 patients). Sixty-eight patients (27%) could not be traced, most commonly because of an incorrect address in the register. Fewer patients were alive and more patients could not be traced from the central hospital compared with the peripheral hospitals. RELEVANT CHANGES:Better documentation of patients’ addresses and prompt follow-up of patients who are late for their appointments are required. LESSONS LEARNED: ART clinics in resource-poor countries should ensure that patients’ addresses are correct and comprehensive. Clinics should also undertake contact tracing as soon as possible in the event of non-attendance, consider facilitating access to ART clinics and take loss to follow-up into consideration when assessing death rates

Risk factors for early mortality in children on adult fixed-dose combination antiretroviral treatment in a central hospital in Malawi.

OBJECTIVES: In children aged less than 15 years, to determine the cumulative proportion of deaths occurring within 3 and 6 months of starting split-tablet adult fixed-dose combination antiretroviral therapy (ART) and to identify risk factors associated with early deaths. DESIGN: A retrospective cohort analysis. METHODS: Data were collected and analysed from ART patient master cards and the ART register of all children registered for treatment between July 2004 and September 2006 in the ART clinic at Mzuzu Central Hospital, northern Malawi. RESULTS: A total of 439 children started on ART, of whom 220 (50%) were male; 37 (8%) were aged less than 18 months, 172 (39%) 18 months to 5 years, and 230 (52%) were 6-14 years. By September 2006, 49 children (11%) had died, of whom 35 (71%) died by 3 months and 44 (89%) by 6 months. The cumulative incidence of death at 3, 6, 12 and 24 months after ART was 8, 12, 13 and 15%, respectively. After multivariate analysis, being in World Health Organization clinical stage 4, having severe wasting and severe immunodeficiency were factors significantly associated with 3-month mortality and 6-month mortality, respectively. CONCLUSION: Although children do well on ART, there is high early mortality. Scaling up HIV testing and simple diagnostic tests for infants and children, expanding routine provision of cotrimoxazole prophylaxis, and investigating the role of nutritional interventions are three measures that, if implemented and expanded countrywide, may improve ART outcomes

Antiretroviral Therapy in the Malawi Police Force: Access to Therapy and Treatment Outcomes

A national survey was carried out in all the 103 public sector and 38 private sector facilities in Malawi providing antiretroviral therapy (ART) to determine uptake of ART and subsequent treatment outcomes in police force personnel. All patients registered for ART and their subsequent treatment outcomes were censored on December 31st 2006. There were 85168 patients started on ART in both public and private sectors, of whom 463 (0.6%) were police force personnel. Of police force personnel starting ART, 17% were in WHO clinical stage 1 or 2 with a CD4-lymphocyte count of ≤250 cells/μL and 83% were in stage 3 or 4. Treatment outcomes of police force personnel by the end of December 2006 were 302 (65%) alive and on ART at their registration facility, 59 (13%) dead, 30 (7%) lost to follow-up, 1 stopped treatment and 71 (15%) transferred to another facility. Their probability of being alive on ART at 6-, 12- and 18-months was 83.2%, 78.6% and 76.7% respectively. There has been a good access of police force personnel to ART since national scale up commenced with good treatment outcomes, and this should serve as an example for other police forces in the region