Mature outcomes and prognostic indices in diffuse large B-cell lymphoma in Malawi: a prospective cohort.

Outcomes for diffuse large B-cell lymphoma (DLBCL) in sub-Saharan Africa (SSA) are poorly described. We report mature data from one of the first prospective SSA cohorts. Patients aged ≥18 years with DLBCL were enrolled in Malawi 2013-2017. Participants were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy and concurrent antiretroviral therapy (ART) if positive for human immunodeficiency virus (HIV+). Eighty-six participants (mean age 47 years, standard deviation 13) were enrolled: 54 (63%) were male and 51 (59%) were HIV+, of whom 34 (67%) were on ART at DLBCL diagnosis. Median CD4 count was 0·113 cells × 109 /l (interquartile range [IQR] 0·062-0·227) and 25 (49%) had HIV viral load <400 copies/µl. Participants received median six cycles CHOP (IQR 4-6). No patients were lost to follow-up and the 2-year overall survival was 38% (95% confidence interval 28-49). In multivariable analyses, Eastern Cooperative Oncology Group performance status (PS) ≥2 and lactate dehydrogenase (LDH) >2× upper limit of normal (ULN) were associated with mortality. HIV status was not associated with mortality. A simplified prognostic model of LDH >2× ULN and PS ≥2 performed at least as well as the age-adjusted International Prognostic Index. DLBCL can be successfully treated in SSA and outcomes did not differ by HIV status. A simplified prognostic model prognosticates well and may be easier to use in resource-limited settings but requires validation.

Rapid urine-based screening for tuberculosis in HIV-positive patients admitted to hospital in Africa (STAMP): a pragmatic, multicentre, parallel-group, double-blind, randomised controlled trial.

BACKGROUND: Current diagnostics for HIV-associated tuberculosis are suboptimal, with missed diagnoses contributing to high hospital mortality and approximately 374 000 annual HIV-positive deaths globally. Urine-based assays have a good diagnostic yield; therefore, we aimed to assess whether urine-based screening in HIV-positive inpatients for tuberculosis improved outcomes. METHODS: We did a pragmatic, multicentre, double-blind, randomised controlled trial in two hospitals in Malawi and South Africa. We included HIV-positive medical inpatients aged 18 years or more who were not taking tuberculosis treatment. We randomly assigned patients (1:1), using a computer-generated list of random block size stratified by site, to either the standard-of-care or the intervention screening group, irrespective of symptoms or clinical presentation. Attending clinicians made decisions about care; and patients, clinicians, and the study team were masked to the group allocation. In both groups, sputum was tested using the Xpert MTB/RIF assay (Xpert; Cepheid, Sunnyvale, CA, USA). In the standard-of-care group, urine samples were not tested for tuberculosis. In the intervention group, urine was tested with the Alere Determine TB-LAM Ag (TB-LAM; Alere, Waltham, MA, USA), and Xpert assays. The primary outcome was all-cause 56-day mortality. Subgroup analyses for the primary outcome were prespecified based on baseline CD4 count, haemoglobin, clinical suspicion for tuberculosis; and by study site and calendar time. We used an intention-to-treat principle for our analyses. This trial is registered with the ISRCTN registry, number ISRCTN71603869. FINDINGS: Between Oct 26, 2015, and Sept 19, 2017, we screened 4788 HIV-positive adults, of which 2600 (54%) were randomly assigned to the study groups (n=1300 for each group). 13 patients were excluded after randomisation from analysis in each group, leaving 2574 in the final intention-to-treat analysis (n=1287 in each group). At admission, 1861 patients were taking antiretroviral therapy and median CD4 count was 227 cells per µL (IQR 79-436). Mortality at 56 days was reported for 272 (21%) of 1287 patients in the standard-of-care group and 235 (18%) of 1287 in the intervention group (adjusted risk reduction [aRD] -2·8%, 95% CI -5·8 to 0·3; p=0·074). In three of the 12 prespecified, but underpowered subgroups, mortality was lower in the intervention group than in the standard-of-care group for CD4 counts less than 100 cells per µL (aRD -7·1%, 95% CI -13·7 to -0·4; p=0.036), severe anaemia (-9·0%, -16·6 to -1·3; p=0·021), and patients with clinically suspected tuberculosis (-5·7%, -10·9 to -0·5; p=0·033); with no difference by site or calendar period. Adverse events were similar in both groups. INTERPRETATION: Urine-based tuberculosis screening did not reduce overall mortality in all HIV-positive inpatients, but might benefit some high-risk subgroups. Implementation could contribute towards global targets to reduce tuberculosis mortality. FUNDING: Joint Global Health Trials Scheme of the Medical Research Council, the UK Department for International Development, and the Wellcome Trust.

Relapse of HHV8-positive multicentric Castleman disease following rituximab-based therapy in HIV-positive patients.

Successful treatment of HIV-associated multicentric Castleman disease (HIV+MCD) with rituximab-based approaches has dramatically improved survival and reduced the risk of human herpesvirus 8 (HHV8)-associated lymphoma. Longer term outcomes including relapse rates have not been described and are important to establish the potential role of maintenance therapy. A prospective cohort of 84 patients with biopsy-proven HIV+MCD were treated with risk-stratified rituximab-based therapy. Four patients (5%) died of refractory HIV+MCD and 80 achieved clinical remission. The median follow-up for the 80 patients was 6.9 years and their 5-year overall survival was 92% (95% confidence interval [CI], 85 to 99). Eighteen have relapsed (all histologically confirmed), including 5 with concomitant HHV8-associated lymphoma and MCD at relapse. The 5-year relapse-free survival is 82% (95% CI, 72 to 92). No clinical or laboratory findings that were present at MCD diagnosis predicted subsequent relapse, and the median time to first relapse was 30 months (maximum, 10 years). There were no significant differences in clinicopathological features at initial diagnosis and at relapse. All patients were successfully retreated at relapse with rituximab-based therapy. Only 1 patient died of relapsed MCD (at fifth relapse 9.4 years after initial diagnosis). Despite the use of rituximab, the risk of developing HHV8-associated lymphoma was significantly elevated in this cohort, with an incidence of 11.4/1000 person-years. The relatively low relapse rate and high salvage rates at relapse reduce the potential benefit of maintenance therapy; this should only be advocated in the context of a clinical trial.

Hodgkin lymphoma at Groote Schuur Hospital, South Africa: the effect of HIV and bone marrow infiltration.

Human immunodeficiency virus (HIV) is associated with an increased risk of developing Hodgkin lymphoma (HL). South Africa (SA) has the highest HIV prevalence rate in the world. There is currently no outcome-based data for HIV-associated HL from SA. A bone marrow database was compiled of all bone marrow biopsies (BMB) reported at National Health Laboratory Service (NHLS) Groote Schuur Hospital (GSH) between January 2005 and December 2012. Patients who had a BMB performed for staging of HL or where HL was diagnosed on the BMB were included for further analysis. Clinical and laboratory data was extracted from medical and laboratory records. Primary outcome measures included histological subtype, bone marrow infiltration (BMI) by HL, CD4 count, HIV-viral load (HIV-VL), tuberculosis (TB) data, treatment with chemotherapy and 5-year overall survival (OS). The database included 6569 BMB and 219 patients of these had HL and were included for analysis. The median age at presentation (32 years) was similar in the HIV+ and HIV- populations. While males predominated in the HIV- group, females predominated in the HIV+ group (male:female ratio of 1.5:1 vs 0.7:1, respectively). The majority of patients (71%) were HIV negative (HIV-) and 29% were HIV positive (HIV+). The diagnosis of HL was made on BMB in 17% of cases. BMI was seen in 37% (82/219) overall, and was found in more HIV+ patients (61%; 39/64) than HIV- patients (28%; 43/155; p = 0.03). The histological subtype varied according to HIV status with nodular sclerosis classical Hodgkin lymphoma (NSCHL) being most frequent in the HIV- group and classical Hodgkin lymphoma (CHL)-unclassifiable the most frequent in the HIV+ group. HIV+ patients had a median CD4 count of 149 × 106/L and 39% were anti-retroviral therapy (cART) naive at HL diagnosis. HIV+ patients had received anti-TB therapy more frequently than HIV- patients (72% vs 17%; p = 0.007). More HIV+ patients did not receive chemotherapy than HIV- patients (31% vs 3%; p = 0.001). The 5-year OS was 56%. HIV+ patients with BMI had a 5-year OS of 18%. BMI, HIV status, low CD4 count, histological subtype and TB therapy had a statistical significant impact on 5-year OS (p < 0.01). The 5-year OS was 56%, with both BMI and HIV+ status being associated with poor survival. BMB provided the diagnosis of HL in 17% of cases, confirming its diagnostic utility in our setting. Our cohort showed similar survival outcomes to other countries in Africa, Asia and Central America with comparable socio-economic constraints to SA.

Antiretroviral resistance testing in HIV-positive people.

BACKGROUND: Resistance to antiretroviral therapy (ART) among people living with human immunodeficiency virus (HIV) compromises treatment effectiveness, often leading to virological failure and mortality. Antiretroviral drug resistance tests may be used at the time of initiation of therapy, or when treatment failure occurs, to inform the choice of ART regimen. Resistance tests (genotypic or phenotypic) are widely used in high-income countries, but not in resource-limited settings. This systematic review summarizes the relative merits of resistance testing in treatment-naive and treatment-exposed people living with HIV. OBJECTIVES: To evaluate the effectiveness of antiretroviral resistance testing (genotypic or phenotypic) in reducing mortality and morbidity in HIV-positive people. SEARCH METHODS: We attempted to identify all relevant studies, regardless of language or publication status, through searches of electronic databases and conference proceedings up to 26 January 2018. We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov to 26 January 2018. We searched Latin American and Caribbean Health Sciences Literature (LILACS) and the Web of Science for publications from 1996 to 26 January 2018. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) and observational studies that compared resistance testing to no resistance testing in people with HIV irrespective of their exposure to ART.Primary outcomes of interest were mortality and virological failure. Secondary outcomes were change in mean CD4-T-lymphocyte count, clinical progression to AIDS, development of a second or new opportunistic infection, change in viral load, and quality of life. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed each reference for prespecified inclusion criteria. Two review authors then independently extracted data from each included study using a standardized data extraction form. We analysed data on an intention-to-treat basis using a random-effects model. We performed subgroup analyses for the type of resistance test used (phenotypic or genotypic), use of expert advice to interpret resistance tests, and age (children and adolescents versus adults). We followed standard Cochrane methodological procedures. MAIN RESULTS: Eleven RCTs (published between 1999 and 2006), which included 2531 participants, met our inclusion criteria. All of these trials exclusively enrolled patients who had previous exposure to ART. We found no observational studies. Length of follow-up time, study settings, and types of resistance testing varied greatly. Follow-up ranged from 12 to 150 weeks. All studies were conducted in Europe, USA, or South America. Seven studies used genotypic testing, two used phenotypic testing, and two used both phenotypic and genotypic testing. Only one study was funded by a manufacturer of resistance tests.Resistance testing made little or no difference in mortality (odds ratio (OR) 0.89, 95% confidence interval (CI) 0.36 to 2.22; 5 trials, 1140 participants; moderate-certainty evidence), and may have slightly reduced the number of people with virological failure (OR 0.70, 95% CI 0.56 to 0.87; 10 trials, 1728 participants; low-certainty evidence); and probably made little or no difference in change in CD4 cell count (mean difference (MD) -1.00 cells/mm³, 95% CI -12.49 to 10.50; 7 trials, 1349 participants; moderate-certainty evidence) or progression to AIDS (OR 0.64, 95% CI 0.31 to 1.29; 3 trials, 809 participants; moderate-certainty evidence). Resistance testing made little or no difference in adverse events (OR 0.89, 95% CI 0.51 to 1.55; 4 trials, 808 participants; low-certainty evidence) and probably reduced viral load (MD -0.23, 95% CI -0.35 to -0.11; 10 trials, 1837 participants; moderate-certainty evidence). No studies reported on development of new opportunistic infections or quality of life. We found no statistically significant heterogeneity for any outcomes, and the I² statistic value ranged from 0 to 25%. We found no subgroup effects for types of resistance testing (genotypic versus phenotypic), the addition of expert advice to interpretation of resistance tests, or age. Results for mortality were consistent when we compared studies at high or unclear risk of bias versus studies at low risk of bias. AUTHORS' CONCLUSIONS: Resistance testing probably improved virological outcomes in people who have had virological failure in trials conducted 12 or more years ago. We found no evidence in treatment-naive people. Resistance testing did not demonstrate important patient benefits in terms of risk of death or progression to AIDS. The trials included very few participants from low- and middle-income countries.

Mortality after Inpatient Treatment for Severe Pneumonia in Children: a Cohort Study.

BACKGROUND: Although pneumonia is a leading cause of inpatient mortality, deaths may also occur after discharge from hospital. However, prior studies have been small, in selected groups or did not fully evaluate risk factors, particularly malnutrition and HIV. We determined 1-year post-discharge mortality and risk factors among children diagnosed with severe pneumonia. METHODS: A cohort study of children aged 1-59 months admitted to Kilifi County Hospital with severe pneumonia (2007-12). The primary outcome was death <1 year after discharge, determined through Kilifi Health and Demographic Surveillance System (KHDSS) quarterly census rounds. RESULTS: Of 4184 children (median age 9 months) admitted with severe pneumonia, 1041 (25%) had severe acute malnutrition (SAM), 267 (6.4%) had a positive HIV antibody test, and 364 (8.7%) died in hospital. After discharge, 2279 KHDSS-resident children were followed up; 70 (3.1%) died during 2163 child-years: 32 (95% confidence interval (CI) 26, 41) deaths per 1000 child years. Post-discharge mortality was greater after admission for severe pneumonia than for other diagnoses, hazard ratio 2.5 (95% CI 1.2, 5.3). Malnutrition, HIV status, age and prolonged hospitalisation, but not signs of pneumonia severity, were associated with post-discharge mortality. Fifty-two per cent (95% CI 37%, 63%) of post-discharge deaths were attributable to low mid-upper arm circumference and 11% (95% CI 3.3%, 18%) to a positive HIV test. CONCLUSIONS: Admission with severe pneumonia is an important marker of vulnerability. Risk stratification and better understanding of the mechanisms underlying post-discharge mortality, especially for undernourished children, are needed to reduce mortality after treatment for pneumonia.

Corticosteroids for tuberculous pleurisy.

BACKGROUND: Corticosteroids used in addition to antituberculous therapy have been reported to benefit people with tuberculous pleurisy. However, research findings are inconsistent and raise doubt as to whether such treatment is worthwhile. There is also concern regarding the potential adverse effects of corticosteroids, especially in HIV-positive people. OBJECTIVES: To evaluate the effects of adding corticosteroids to drug regimens for tuberculous pleural effusion. SEARCH METHODS: In April 2016, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (the Cochrane Library), MEDLINE, Embase, LILACS, Current Controlled Trials, and the reference lists of articles identified by the literature search. SELECTION CRITERIA: Randomized controlled trials (RCTs) and quasi-RCTs that compared any corticosteroid with no treatment, placebo, or other active treatment (both groups should have received the same antituberculous drug regimen) in people diagnosed with tuberculous pleurisy. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results, extracted data from the included trials, and assessed trial methodological quality using the Cochrane 'Risk of bias' tool. We analysed the data using risk ratios (RR) with 95% confidence intervals (CIs). We applied the fixed-effect model in the absence of statistically significant heterogeneity. MAIN RESULTS: Six trials with 590 participants met the inclusion criteria, which were conducted in Asia (three trials), Africa (two trials), and Europe (one trial). Two trials were in HIV-negative people, one trial was in HIV-positive people, and three trials did not report HIV status.Corticosteroids may reduce the time to resolution of pleural effusion. Risk of residual pleural effusion on chest X-ray was reduced by 45% at eight weeks (RR 0.54, 95% CI 0.37 to 0.78; 237 participants, 2 trials, low certainty evidence), and 65% at 24 weeks (RR 0.35, 95% CI 0.18 to 0.66; 237 participants, 2 trials, low certainty evidence).Compared with control, corticosteroids may reduce the risk of having pleural changes (such as pleural thickening or pleural adhesions), on chest X-ray at the end of follow-up by almost one third (RR 0.72, 95% CI 0.57 to 0.92; 393 participants, 5 trials,low certainty evidence), which translates to an absolute risk reduction of 16%.One trial reported deaths in people that were HIV-positive, with no obvious difference between the groups; the trial authors' analysis suggests that the deaths observed in this trial were related to HIV disease rather than pleural TB (RR 0.91, 95% CI 0.64 to 1.31; 197 participants, 1 trial).We found limited data on long-term functional respiratory impairment on 187 people in two trials, which reported that average percentage predicted forced vital capacity was similar in the group receiving prednisolone and in the control group (very low certainty evidence).The risk of adverse events that led to discontinuation of the trial drug was higher in people with pleural TB receiving corticosteroids (RR 2.78, 95% CI 1.11 to 6.94; 587 participants, 6 trials, low certainty evidence). The trial in HIV-positive people reported on six different HIV-related infections, with no obvious differences. However, cases of Kaposi's sarcoma were only seen in the corticosteroid group (with 6/99 cases in the steroid group compared to 0/98 in the control group) (very low certainty evidence). AUTHORS' CONCLUSIONS: Long-term respiratory function is potentially the most important outcome for assessing the effects of adjunctive treatments for people with pleural TB. However, the information on the impact of pleural TB on long-term respiratory function is unknown and could be eclipsed by other risk factors, such as concurrent pulmonary TB, smoking, and HIV. This probably needs to be quantified to help decide whether further trials of corticosteroids for pleural TB would be worthwhile.

Interleukin-2 as an adjunct to antiretroviral therapy for HIV-positive adults.

BACKGROUND: Human immunodeficiency virus (HIV) continues to be a leading cause of morbidity and mortality, particularly in sub-Saharan Africa. Although antiretroviral drugs have helped to improve the quality of life and life expectancy of HIV-positive individuals, there is still a need to explore other interventions that will help to further reduce the disease burden. One potential strategy is the use of interleukin-2 (IL-2) in combination with antiretroviral therapy (ART). IL-2 is a cytokine that regulates the proliferation and differentiation of lymphocytes and may help to boost the immune system. OBJECTIVES: To assess the effects of interleukin-2 (IL-2) as an adjunct to antiretroviral therapy for HIV-positive adults. SEARCH METHODS: We searched the following sources up to 26 May 2016: the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; Embase; the Web of Science; LILACS; the World Health Organization (WHO) International Clinical Trial Registry Platform (ICTRP); and ClinicalTrials.gov. We also checked conference abstracts, contacted experts and relevant organizations in the field, and checked the reference list of all studies identified by the above methods for any other potentially eligible studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) that evaluated the effects of IL-2 as an adjunct to ART in reducing the morbidity and mortality in HIV-positive adults. DATA COLLECTION AND ANALYSIS: Two review authors independently screened records and selected trials that met the inclusion criteria, extracted data, and assessed the risk of bias in the included trials. Where possible, we compared the effects of interventions using risk ratios (RR), and presented them with 95% confidence intervals (CI). We assessed the overall certainty of the evidence using the GRADE approach. MAIN RESULTS: Following a comprehensive literature search up to 26 May 2016, we identified 25 eligible trials. The interventions involved the use of IL-2 in combination with ART compared with ART alone. There was no difference in mortality apparent between the IL-2 group and the ART alone group (RR 0.97, 95% CI 0.80 to 1.17; 6 trials, 6565 participants, high certainty evidence). Seventeen of 21 trials reported an increase in the CD4 cell count with the use of IL-2 compared to control using different measures (21 trials, 7600 participants). Overall, there was little or no difference in the proportion of participants with a viral load of less than 50 cells/mL or less than 500 cells/mL by the end of the trials (RR 0.97, 95% CI 0.81 to 1.15; 5 trials, 805 participants, high certainty evidence) and (RR 0.96, 95% CI 0.82 to 1.12; 4 trials, 5929 participants, high certainty evidence) respectively. Overall there may be little or no difference in the occurrence of opportunistic infections (RR 0.79, 95% CI 0.55 to 1.13; 7 trials, 6141 participants, low certainty evidence). There was probably an increase in grade 3 or 4 adverse events (RR 1.47, 95% CI 1.10 to 1.96; 6 trials, 6291 participants, moderate certainty evidence). None of the included trials reported adherence. AUTHORS' CONCLUSIONS: There is high certainty evidence that IL-2 in combination with ART increases the CD4 cell count in HIV-positive adults. However, IL-2 does not confer any significant benefit in mortality, there is probably no difference in the incidence of opportunistic infections, and there is probably an increase in grade 3 or 4 adverse effects. Our findings do not support the use of IL-2 as an adjunct to ART in HIV-positive adults. Based on our findings, further trials are not justified.

Age at Entry Into Care, Timing of Antiretroviral Therapy Initiation, and 10-Year Mortality Among HIV-Seropositive Adults in the United States.

BACKGROUND: The goal of targeted antiretroviral therapy initiation is to minimize disease progression among patients with human immunodeficiency virus while minimizing the therapeutic burden on these patients. We examine whether the effect of delaying therapy initiation from 500 cells/mm(3) to 350 or 200 cells/mm(3) is modified by age at entry into care. METHODS: We used the parametric g-formula to compare 10-year mortality under 3 CD4 cell count thresholds for therapy initiation among 3532 patients who entered care at 1 of 8 sites in the United States between 1998 and 2013. Results are reported separately for patients 18 to 34, 35 to 44, and 45 to 65 years of age at study entry. RESULTS: In the observed data, 10-year mortality was 13% (165 deaths). Mortality increased from 11% under therapy initiation at 500 cells/mm(3) to 12% at 350 cells/mm(3) (risk difference [RD]: 0.87; 95% confidence interval [CI]: .56, 2.17) and to 14% at 200 cells/mm(3) (RD: 2.71; 95% CI: 1.79, 5.38). The effect of delaying therapy became greater with age: RDs comparing the 350-cells/mm(3) threshold with the 500-cells/mm(3) threshold ranged from -0.03 (95% CI: -0.15, 1.76) for patients 18 to 34 years of age to 0.99 (95% CI: -.27, 1.98) for patients 35 to 44 and to 2.30 (95% CI: 1.29, 5.42) for patients 45 to 65. CONCLUSIONS: Delaying therapy increased 10-year mortality in the full cohort. Subgroup analysis highlights that patients entering care at older ages may be more vulnerable to the consequences of delayed ART initiation than younger patients.

The Unchecked HIV/AIDS Crisis in Mississippi.

While the population of the southern United States is only 37% of the country's total, this region is experiencing 50% of new HIV diagnoses and 46% of new AIDS diagnoses. Specifically, Mississippi has the highest rates of new infection, the most AIDS deaths, the greatest number of people living with HIV/AIDS, and the fewest resources. Mississippi has the highest death rate in the country: 32.9 per 1,000. A Mississippian with HIV/AIDS is almost twice as likely to die as the average American with the virus (SHARP Report, 2010). Compounding the problem are government policy issues, such as disproportionate program funding; socio-economic issues, such as widespread poverty, housing insecurity, and the lack of access to care; and cultural issues, such as homophobia and social stigma. These factors are reflected in this study which examines the needs of people living with HIV/AIDS in a southern, rural county of Mississippi. From a representative sample of 218 HIV positive individuals, researchers identified the levels of need for housing, transportation, medical care, mental health care, substance abuse treatment, and education. The author discusses the reciprocal influences of these needs and HIV, the need for policy changes at the state and federal levels, and the need for resources that both support people living with HIV/AIDS and curb the rate of new infections.

Effect of HCV infection on cause-specific mortality after HIV seroconversion, before and after 1997.

BACKGROUND & AIMS: Individuals with human immunodeficiency virus (HIV) infection frequently also are infected with hepatitis C virus (HCV) (co-infection), but little is known about its effects on the progression of HIV-associated disease. We aimed to determine the effects of co-infection on mortality from HIV and/or acquired immune deficiency syndrome (AIDS), and hepatitis or liver disease, adjusting for the duration of HIV infection. METHODS: We analyzed data from the 16 cohorts of the Concerted Action on Seroconversion to AIDS and Death in Europe (CASCADE) collaboration, which included information on HCV infection and cause of death. A competing-risks proportional subdistribution hazards model was used to evaluate the effect of HCV infection on the following causes of death: HIV- and/or AIDS-related, hepatitis- or liver-related, natural, and non-natural. RESULTS: Of 9164 individuals with HIV infection and a known date of seroconversion, 2015 (22.0%) also were infected with HCV. Of 718 deaths, 395 (55.0%) were caused by HIV infection and/or AIDS, and 39 (5.4%) were caused by hepatitis or liver-related disease. Among individuals infected with only HIV or with co-infection, the mortality from HIV infection and/or AIDS-related causes and hepatitis or liver disease decreased significantly after 1997, when combination antiretroviral therapy became widely available. However, after 1997, HIV and/or AIDS-related mortality was higher among co-infected individuals than those with only HIV infection in each risk group: injection drug use (adjusted hazard ratio [aHR], 2.43; 95% confidence interval [CI], 1.14-5.20), sex between men and women or hemophilia (aHR, 3.43; 95% CI, 1.70-6.93), and sex between men (aHR, 3.11; 95% CI, 1.49-6.48). Compared with individuals infected with only HIV, co-infected individuals had a higher risk of death from hepatitis or liver disease. CONCLUSIONS: Based on analysis of data from the CASCADE collaboration, since 1997, when combination antiretroviral therapy became widely available, individuals co-infected with HIV and HCV have had a higher risk of death from HIV and/or AIDS, and from hepatitis or liver disease, than patients infected with only HIV. It is necessary to evaluate the effects of HCV therapy on HIV progression.

Suboptimal plasma HIV-1 RNA suppression and adherence among sex workers who use illicit drugs in a Canadian setting: an observational cohort study.

OBJECTIVE: Studies have demonstrated the central function of plasma HIV-1 RNA viral load (pVL) levels on determining the risk of HIV disease progression and transmission. However, there is limited empirical research on virologic outcomes among sex workers who use illicit drugs (SW-DU). METHODS: Data were derived from the AIDS Care Cohort to evaluate Exposure to Survival Services, a cohort of HIV-positive illicit drug users. Using generalised estimating equations, we studied the longitudinal relationship between sex work and pVL suppression. We also tested whether adherence to antiretroviral therapy (ART) mediated the relationship between sex work and pVL suppression. RESULTS: Between May 1996 and May 2012, 587 ART-exposed participants (2224 person-years of observation) were included in the study, among whom 127 (21.6%) reported sex work. In a time-updated multivariate model adjusted for various demographic, socioeconomic and clinical confounders (eg, gender, incarceration, CD4 cell count), SW-DU had an independently reduced odds of pVL suppression compared to non-SW-DU (adjusted OR (AOR)=0.66; 95% CI 0.45 to 0.96). However, adding ART adherence to the multivariate model eliminated this association (p>0.05), suggesting adherence mediated the relationship between sex work and pVL suppression. CONCLUSIONS: Evidence-based interventions to improve adherence to ART among SW-DU are urgently needed to help produce the maximum HIV treatment and prevention benefit of ART among this highly vulnerable population.

Trends in HIV diagnoses, HIV care, and uptake of antiretroviral therapy among heterosexual adults in England, Wales, and Northern Ireland.

AIM: To examine epidemiological trends among heterosexual adults (≥15 years) in England, Wales, and Northern Ireland (E,W&NI) newly diagnosed as having HIV between 1992 and 2011, or seen for HIV care in 2011. METHODS: Trend analyses of heterosexual adults newly diagnosed as having HIV in E,W&NI in 1992 to 2011 was performed, as well as univariate and multivariate analyses examining the late diagnosis of HIV, integration into care, AIDS, uptake of antiretroviral therapy, and mortality in 2002 to 2011. Data are as reported to the national HIV and AIDS Reporting System. RESULTS: The number of heterosexual adults newly diagnosed as having HIV in E,W&NI increased steadily between 1992 (731) and 2004 (4676), before declining (2631 in 2011). Nonetheless, in 2011, heterosexuals accounted for 49% (2631/5423) of all newly diagnosed adults in E,W&NI. Of 38,228 heterosexual adults as having HIV between 2002 and 2011, 72% were black African, of whom 99% were born abroad. Over the decade, there was an increase in the percentage of HIV diagnosed heterosexuals integrated into care within 28 days of diagnosis (61%-78%) and in receipt of antiretroviral therapy within 1 year of diagnosis (45%-52%) and a decline in the percentage with AIDS (16%-7%; all, P < 0.01). Late HIV diagnoses (CD4 <350 mm) among heterosexuals exceeded 60% in all years. CONCLUSIONS: Our analyses highlight the impact of migration on the epidemiology of heterosexually acquired HIV in E,W&NI. Although there was evidence of an improvement in clinical care over time, continued high rates of late diagnosis suggest that current testing policies are failing among heterosexuals.

Blood pressure level impacts risk of death among HIV seropositive adults in Kenya: a retrospective analysis of electronic health records.

BACKGROUND: Mortality among people with human immunodeficiency virus (HIV) infection is increasingly due to non-communicable causes. This has been observed mostly in developed countries and the routine care of HIV infected individuals has now expanded to include attention to cardiovascular risk factors. Cardiovascular risk factors such as high blood pressure are often overlooked among HIV seropositive (+) individuals in sub-Saharan Africa. We aimed to determine the effect of blood pressure on mortality among HIV+ adults in Kenya. METHODS: We performed a retrospective analysis of electronic medical records of a large HIV treatment program in western Kenya between 2005 and 2010. All included individuals were HIV+. We excluded participants with AIDS, who were <16 or >80 years old, or had data out of acceptable ranges. Missing data for key covariates was addressed by inverse probability weighting. Primary outcome measures were crude mortality rate and mortality hazard ratio (HR) using Cox proportional hazards models adjusted for potential confounders including HIV stage. RESULTS: There were 49,475 (74% women) HIV+ individuals who met inclusion and exclusion criteria. Mortality rates for men and women were 3.8 and 1.8/100 person-years, respectively, and highest among those with the lowest blood pressures. Low blood pressure was associated with the highest mortality incidence rate (IR) (systolic <100 mmHg IR 5.2 [4.8-5.7]; diastolic <60 mmHg IR 9.2 [8.3-10.2]). Mortality rate among men with high systolic blood pressure without advanced HIV (3.0, 95% CI: 1.6-5.5) was higher than men with normal systolic blood pressure (1.1, 95% CI: 0.7-1.7). In weighted proportional hazards regression models, men without advanced HIV disease and systolic blood pressure ≥140 mmHg carried a higher mortality risk than normotensive men (HR: 2.39, 95% CI: 0.94-6.08). CONCLUSIONS: Although there has been little attention paid to high blood pressure among HIV+ Africans, we show that blood pressure level among HIV+ patients in Kenya is related to mortality. Low blood pressure carries the highest mortality risk. High systolic blood pressure is associated with mortality among patients whose disease is not advanced. Further investigation is needed into the cause of death for such patients.

Risk factors for mortality among human immunodeficiency virus-exposed and unexposed infants admitted to a neonatal intensive care unit in Botswana.

AIM: Newborns admitted to neonatal units (NNUs) in resource-limited settings face a high risk of mortality, but the epidemiology of these deaths is poorly understood. We describe risk factors for NNU mortality in an area with high prevalence of human immunodeficiency virus (HIV). METHODS: We performed a prospective cohort study of infants admitted to the NNU at a public referral hospital in Gaborone, Botswana. The primary outcome was neonatal death, defined as death within 28 days of a live delivery. Cox proportional hazard models were used to evaluate risk factors for mortality. RESULTS: From October 2008 to April 2009, 449 neonates were admitted to the NNU. Cumulative mortality was 24.5% (110/449). Factors associated with increased risk of death included lack of enteral feeding (hazard ratio (HR) 18.8, 95% confidence interval (CI) 10.3, 34.2), gestational age <28 weeks (HR 2.0, 95% CI 1.1, 3.8) and Apgar score <7 at 10 min (HR 2.5, 95% CI 1.5, 4.2). Among 348 (78%) infants who were fed, there was no difference in mortality between infants who were breastfed compared with those who were formula fed or had mixed feeding (P = 0.76). There was no significant mortality difference by HIV exposure status; 35 (28%) of 128 HIV-exposed infants died compared with 55 (21%) of 272 HIV-unexposed infants (P = 0.19). CONCLUSIONS: This study identified low Apgar scores, extreme prematurity and lack of enteral feeding as the most important risk factors for mortality in this NNU setting. HIV exposure and formula feeding were not significantly associated with death in neonates who were very ill.

Mortality among people who inject drugs: a systematic review and meta-analysis.

OBJECTIVE: To systematically review cohort studies of mortality among people who inject drugs, examine mortality rates and causes of death in this group, and identify participant- and study-level variables associated with a higher risk of death. METHODS: Tailored search strings were used to search EMBASE, Medline and PsycINFO. The grey literature was identified through online grey literature databases. Experts were consulted to obtain additional studies and data. Random effects meta-analyses were performed to estimate pooled crude mortality rates (CMRs) and standardized mortality ratios (SMRs). FINDINGS: Sixty-seven cohorts of people who inject drugs were identified, 14 of them from low- and middle-income countries. The pooled CMR was 2.35 deaths per 100 person-years (95% confidence interval, CI: 2.12-2.58). SMRs were reported for 32 cohorts; the pooled SMR was 14.68 (95% CI: 13.01-16.35). Comparison of CMRs and the calculation of CMR ratios revealed mortality to be higher in low- and middle-income country cohorts, males and people who injected drugs that were positive for human immunodeficiency virus (HIV). It was also higher during off-treatment periods. Drug overdose and acquired immunodeficiency syndrome (AIDS) were the primary causes of death across cohorts. CONCLUSION: Compared with the general population, people who inject drugs have an elevated risk of death, although mortality rates vary across different settings. Any comprehensive approach to improving health outcomes in this group must include efforts to reduce HIV infection as well as other causes of death, particularly drug overdose.

Report of four simultaneous pancreas-kidney transplants in HIV-positive recipients with favorable outcomes.

The advent of combined antiretroviral therapy (cART) dramatically changed the view of human immunodeficiency virus (HIV) infection as an exclusion criterion for solid organ transplantation, resulting in worldwide reports of successful transplants in HIV-infected individuals. However, there are few reports on simultaneous pancreas-kidney transplant in HIV-positive recipients detailing poor outcomes. A series of four pancreas-kidney transplant performed on HIV-infected individuals between 2006 and 2009 is presented. All recipients reached stably undetectable HIV-RNA after transplantation. All patients experienced early posttransplant infections (median day 30, range 9-128) with urinary tract infections and bacteremia being most commonly observed. In all cases, surgical complications led to laparotomic revisions (median day 18, range 1-44); two patients underwent cholecystectomy. One steroid-responsive acute renal rejection (day 79) and one pancreatic graft failure (month 64) occurred. Frequent dose adjustments were required due to interference between cART and immunosuppressants. At a median follow-up of 45 months (range, 26-67) we observed 100% patient survival with CD4 cell count >300 cells/mm(3) for all patients. Although limited by its small number, this case series represents the largest reported to date with encouraging long-term outcomes in HIV-positive pancreas-kidney transplant recipients.

All-cause and liver-related mortality in HIV positive subjects compared to the general population: differences by HCV co-infection.

BACKGROUND & AIMS: We aimed at comparing overall and liver-related mortality rates, observed in HIV positive subjects followed-up in the Cohorts of Spanish Network on HIV/AIDS Research stratified by HCV co-infection status, with the expected mortality of the general population of same age and sex in Spain, for the period 1997 - 2008. METHODS: We estimated standardized mortality ratio (SMR) and excess mortality, comparing death rates from our cohort (globally and by HCV co-infection) with death rates from the general population standardized by sex in 5 year-age bands. RESULTS: Overall, 5914 HIV positive subjects were included, 37.3% of which were co-infected with HCV; 231 deaths occurred, 10.4% of which were liver-related. SMR for all causes mortality for the HIV positive subjects was 5.6 (CI 95% 4.9-6.4), 2.4 (1.9-3.1) for HCV negative subjects and 11.5 (9.9-13.4) for HCV positive ones. Having HCV co-infection and AIDS yielded an SMR of 20.8 (16.5-26.1) and having AIDS and being HCV negative had an SMR of 4.8 (3.5-6.7). SMR for liver-related mortality was 1.8 (0.6-5.7) for HCV negative subjects vs. 22.4 (14.6-34.3) for HCV positive ones. Overall, both mortality rates as SMR and excess mortality rates were higher for injecting drug users (IDUs) than men having sex with men (MSM) and heterosexuals, patients with AIDS, with and without cART and for subjects included between 1997 and 2003. CONCLUSIONS: There was an excess of all-cause and liver-related mortality in our cohorts compared with the general population. Furthermore, HCV co-infection in HIV positive patients increased the risk of death for both all causes and liver-related causes.

The impact of antiretroviral treatment on mortality trends of HIV-positive adults in rural Uganda: a longitudinal population-based study, 1999-2009.

OBJECTIVE: To investigate trends in all-cause adult mortality after the roll-out of an antiretroviral therapy (ART) programme in rural Uganda. METHODS: Longitudinal population-based cohort study of approximately 20,000 residents in rural Uganda. Mortality in adults aged 15-59 years was determined for the 5-year period (1999-2003) before introduction of ART in January 2004 and for the 5-year period afterwards. Poisson regression was used to estimate mortality rate ratios (RRs) for the period before ART, 1 year after ART introduction (from January 2004 to January 2005) and more than 1 year after ART introduction. Trends in mortality were analysed by HIV status, age and sex. RESULTS: Before ART became available, the mortality rate (deaths per 1000 person-years) was 4.0 (95% CI = 3.3-4.8) among HIV-negative individuals and 116.4 (95% CI = 101.9-133.0) among HIV-positive individuals. During the period January 2004-end November 2009, 279 individuals accessed ART. In the year after ART was introduced, the mortality rate (deaths per 1000 person-years) among HIV-negative individuals did not change significantly (adjusted RR = 0.95, 95% CI = 0.61-1.47), but among HIV-positive individuals dropped by 25% to 87.4 (adjusted RR = 0.75, 95% CI = 0.53-1.06). In the period 2005-2009, the mortality rate (deaths per 1000 person-years) among HIV-positive individuals fell further to 39.9 (adjusted RR = 0.33, 95% CI = 0.26-0.43). The effect was greatest among individuals aged 30-44 years, and trends were similar in men and women. CONCLUSION: The substantially reduced mortality rate among HIV-positive individuals after ART roll-out lends further support to the intensification of efforts to ensure universal access to ART.