Landon Myer

Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa

Two-thirds of the worlds HIV-infected people live in sub-Saharan Africa, and more than 1.5 million of them die annually. As access to antiretroviral treatment has expanded within the region; early pessimism concerning the delivery of antiretroviral treatment using a large-scale public health approach has, at least in the short term, proved to be broadly unfounded. Immunological and virological responses to ART are similar to responses in patients treated in high-income countries. Despite this, however, early mortality rates in sub-Saharan Africa are very high; between 8 and 26% of patients die in the first year of antiretroviral treatment, with most deaths occurring in the first few months. Patients typically access antiretroviral treatment with advanced symptomatic disease, and mortality is strongly associated with baseline CD4 cell count less than 50 cells/μl and WHO stage 4 disease (AIDS). Although data are limited, leading causes of death appear to be tuberculosis, acute sepsis, cryptococcal meningitis, malignancy and wasting syndrome. Mortality rates are likely to depend not only on the care delivered by antiretroviral treatment programmes, but more fundamentally on how advanced disease is at programme enrolment and the quality of preceding healthcare. In addition to improving delivery of antiretroviral treatment and providing it free of charge to the patient, strategies to reduce mortality must include earlier diagnosis of HIV infection, strengthening of longitudinal HIV care and timely initiation of antiretroviral treatment. Health systems delays in antiretroviral treatment initiation must be minimized, especially in patients who present with advanced immunodeficiency.

Screening for Serious Mental Illness in the General Population with the K6 screening scale: Results from the WHO World Mental Health (WMH) Survey Initiative

Data are reported on the background and performance of the K6 screening scale for serious mental illness (SMI) in the World Health Organization (WHO) World Mental Health (WMH) surveys. The K6 is a six‐item scale developed to provide a brief valid screen for Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM‐IV) SMI based on the criteria in the US ADAMHA Reorganization Act. Although methodological studies have documented good K6 validity in a number of countries, optimal scoring rules have never been proposed. Such rules are presented here based on analysis of K6 data in nationally or regionally representative WMH surveys in 14 countries (combined N = 41,770 respondents). Twelve‐month prevalence of DSM‐IV SMI was assessed with the fully‐structured WHO Composite International Diagnostic Interview. Nested logistic regression analysis was used to generate estimates of the predicted probability of SMI for each respondent from K6 scores, taking into consideration the possibility of variable concordance as a function of respondent age, gender, education, and country. Concordance, assessed by calculating the area under the receiver operating characteristic curve, was generally substantial (median 0.83; range 0.76–0.89; inter‐quartile range 0.81–0.85). Based on this result, optimal scaling rules are presented for use by investigators working with the K6 scale in the countries studied. Copyright

Early mortality among adults accessing a community-based antiretroviral service in South Africa: implications for programme design.

Objectives:To determine rates, risk factors and causes of death among patients accessing a community-based antiretroviral treatment (ART) programme both prior to and following initiation of treatment. Methods:All in-programme deaths were ascertained between September 2002 and March 2005 among treatment-naive patients enrolled into a prospective community-based ART cohort in Cape Town, South Africa. Results:Of 712 patients (median CD4 cell count, 94 cells/μl), 578 (81%) started triple ART a median of 29 days after enrolment. 68 (9.5%) patients died during 563 person-years of observation. The high pretreatment mortality rate of 35.6 deaths/100 person-years [95% confidence interval (CI), 23.0–55.1) decreased to 2.5/100 person-years (95% CI, 0.9–6.6) at 1 year among those who received ART. However, within the first 90 days from enrolment, 29 of 44 (66%) deaths occurred among patients awaiting ART; these would not be identified by an on-treatment analysis. Multivariate analysis showed that risk of death (both pre-treatment and on-treatment) was independently associated with baseline CD4 cell count and World Health Organization (WHO) clinical stage; stage 4 disease was the strongest risk factor. Major attributed causes of death were wasting syndrome, tuberculosis, acute bacterial infections, malignancy and immune reconstitution disease. Conclusions:Most early in-programme deaths occurred among patients with advanced immunodeficiency but who had not yet started ART. Programme evaluation using on-treatment analyses greatly underestimated early mortality. This mortality would be reduced by minimizing unnecessary in-programme delays in treatment initiation and by starting ART before development of WHO stage 4 disease.

Burden of tuberculosis in an antiretroviral treatment programme in sub-Saharan Africa : impact on treatment outcomes and implications for tuberculosis control

Objectives:To determine burden and risk factors for tuberculosis (TB) in an antiretroviral treatment (ART) programme and its impact on ART outcomes. Design:Prospective cohort study. Methods:Prevalent TB was assessed at baseline and incident TB was ascertained prospectively over 3 years among 944 patients accessing a community-based ART programme in South Africa. Results:At enrollment, median CD4 cell count was 96 cells/μl and 52% of patients had a previous history of TB. Prevalent TB (current antituberculosis treatment or active TB) was present in 25% and was strongly associated with advanced immunodeficiency. During 782 person-years of ART, 81 cases of TB were diagnosed. The incidence was 22.1/100 person-years during the first 3 months of ART and decreased to an average of 4.5/100 person-years during the second and third years. In multivariate analysis, risk of incident TB during follow-up was only associated with the current absolute CD4 cell count at that time point; an increase of 100 cells/μl was associated with a 25% lower risk (P = 0.007). Although prevalent and incident TB were associated with greater than two-fold increased mortality risk, they did not compromise immunological and virological outcomes among survivors at 48 weeks. Conclusions:Late initiation of ART was associated with a major burden of TB in this ART programme. TB reduced survival but did not impair immunovirological outcomes. Reductions in TB incidence during ART were dependent on CD4 cell count; however, after 3 years of treatment, rates were still 5- to 10-fold higher than among non-HIV-infected people. Earlier initiation of ART may reduce this burden of TB.

Tuberculosis-associated immune reconstitution disease: incidence, risk factors and impact in an antiretroviral treatment service in South Africa.

Objective:To determine the burden and impact of immune reconstitution disease (IRD) associated with tuberculosis (TB) among patients initiating antiretroviral treatment (ART) in sub-Saharan Africa. Design:Retrospective analysis of a study cohort enrolled over 3 years within a community-based ART service in South Africa. Methods:Patients receiving treatment for TB at the time ART was initiated (n = 160) were studied. Cases of TB-associated IRD during the first 4 months of ART were ascertained. Results:The median baseline CD4 cell count was 68 cells/μl [interquartile range (IQR), 29–133 cells/μl) and ART was initiated after a median of 105 days (IQR, 61–164 days) from TB diagnosis. Although IRD was diagnosed in just 12% (n = 19) of patients overall, IRD developed in 32% (n = 12) of those who started ART within 2 months of TB diagnosis. Pulmonary involvement was observed in 84% (n = 16) and intra-abdominal manifestations were also common (37%). Overall, 4% (n = 7) of the cohort required secondary level health-care for IRD and two (1%) patients died. In multivariate analysis, risk of IRD was strongly associated with early ART initiation and low baseline CD4 cell count. Of patients with CD4 counts < 50 cells/μl, the proportions who developed IRD following initiation of ART within 0–30, 31–60, 61–90, 91–120 and > 120 days of TB diagnosis were 100%, 33%, 14%, 7% and 0%, respectively. Conclusions:The risk of TB-associated IRD in this setting is very high for those with low baseline CD4 cell counts initiating ART early in the course of antituberculosis treatment. However, most cases were self-limiting; overall secondary health-care utilization and mortality risk from IRD were low.

Early loss of HIV-infected patients on potent antiretroviral therapy programmes in lower-income countries

OBJECTIVE To analyse the early loss of patients to antiretroviral therapy (ART) programmes in resource-limited settings. METHODS Using data on 5491 adult patients starting ART (median age 35 years, 46% female) in 15 treatment programmes in Africa, Asia and South America with (3) 12 months of follow-up, we investigated risk factors for no follow-up after treatment initiation, and loss to follow-up or death in the first 6 months. FINDINGS Overall, 211 patients (3.8%) had no follow-up, 880 (16.0%) were lost to follow-up and 141 (2.6%) were known to have died in the first 6 months. The probability of no follow-up was higher in 2003-2004 than in 2000 or earlier (odds ratio, OR: 5.06; 95% confidence interval, CI: 1.28-20.0), as was loss to follow-up (hazard ratio, HR: 7.62; 95% CI: 4.55-12.8) but not recorded death (HR: 1.02; 95% CI: 0.44-2.36). Compared with a baseline CD4-cell count (3) 50 cells/microl, a count < 25 cells/microl was associated with a higher probability of no follow-up (OR: 2.49; 95% CI: 1.43-4.33), loss to follow-up (HR: 1.48; 95% CI: 1.23-1.77) and death (HR: 3.34; 95% CI: 2.10-5.30). Compared to free treatment, fee-for-service programmes were associated with a higher probability of no follow-up (OR: 3.71; 95% CI: 0.97-16.05) and higher mortality (HR: 4.64; 95% CI: 1.11-19.41). CONCLUSION Early patient losses were increasingly common when programmes were scaled up and were associated with a fee for service and advanced immunodeficiency at baseline. Measures to maximize ART programme retention are required in resource-poor countries.

Short-term and long-term risk of tuberculosis associated with CD4 cell recovery during antiretroviral therapy in South Africa.

Objective:To determine the short-term and long-term risks of tuberculosis (TB) associated with CD4 cell recovery during antiretroviral therapy (ART). Design:Observational community-based ART cohort in South Africa. Methods:TB incidence was determined among patients (n = 1480) receiving ART for up to 4.5 years in a South African community-based service. Updated CD4 cell counts were measured 4-monthly. Person-time accrued within a range of CD4 cell count strata (CD4 cell strata) was calculated and used to derive CD4 cell-stratified TB rates. Factors associated with incident TB were identified using Poisson regression models. Results:Two hundred and three cases of TB were diagnosed during 2785 person-years of observation (overall incidence, 7.3 cases/100 person-years). During person-time accrued within CD4 cell strata 0–100, 101–200, 201–300, 301–400, 401–500 and more than 500 cells/μl unadjusted TB incidence rates were 16.8, 9.3, 5.5, 4.6, 4.2 and 1.5 cases/100 person-years, respectively (P < 0.001). During early ART (first 4 months), adjusted TB rates among those with CD4 cell counts 0–200 cells/μl were 1.7-fold higher than during long-term ART (P = 0.026). Updated CD4 cell counts were the only patient characteristic independently associated with long-term TB risk. Conclusion:Updated CD4 cell counts were the dominant predictor of TB risk during ART in this low-resource setting. Among those with baseline CD4 cell counts less than 200 cells/μl, the excess adjusted risk of TB during early ART was consistent with ‘unmasking’ of disease missed at baseline screening. TB incidence rates at CD4 cell counts of 200–500 cells/μl remained high and adjunctive interventions are required. TB prevention would be improved by ART policies that minimized the time patients spend with CD4 cell counts below a threshold of 500 cells/μl.

Determinants of Mortality and Nondeath Losses from an Antiretroviral Treatment Service in South Africa: Implications for Program Evaluation

BACKGROUND The scale-up of antiretroviral treatment (ART) services in resource-limited settings requires a programmatic model to deliver care to large numbers of people. Understanding the determinants of key outcome measures--including death and nondeath losses--would assist in program evaluation and development. METHODS Between September 2002 and August 2005, all in-program (pretreatment and on-treatment) deaths and nondeath losses were prospectively ascertained among treatment-naive adults (n=1235) who were enrolled in a community-based ART program in South Africa. RESULTS At study censorship, 927 patients had initiated ART after a median of 34 days after enrollment in the program. One hundred twenty-one (9.8%) patients died. Mortality rates were 33.3 (95% CI, 25.5-43.0), 19.1 (95% CI, 14.4-25.2), and 2.9 (95% CI, 1.8-4.8) deaths/100 person-years in the pretreatment interval, during the first 4 months of ART (early deaths), and after 4 months of ART (late deaths), respectively. Pretreatment and early treatment deaths together accounted for 87% of deaths, and were independently associated with advanced immunodeficiency at enrollment. Late deaths were comparatively few and were only associated with the response to ART at 4 months. Nondeath program losses (loss to follow-up, 2.3%; transfer-out, 1.9%; relocation, 0.7%) were not associated with immune status and were evenly distributed during the study period. CONCLUSIONS Loss to follow-up and late mortality rates were low, reflecting good cohort retention and treatment response. However, the extremely high pretreatment and early mortality rates indicate that patients are enrolling in ART programs with far too advanced immunodeficiency. Causes of late access to the ART program, such as delays in health care access, health system delays, or inappropriate treatment criteria, need to be addressed.

Impact of HIV Infection on the Epidemiology of Tuberculosis in a Peri-Urban Community in South Africa: The Need for Age-Specific Interventions

BACKGROUND In August 2005, the World Health Organization declared the tuberculosis (TB) epidemic in Africa to be a regional emergency. Current TB-control measures are failing, largely as a result of the human immunodeficiency virus (HIV) epidemic. Evaluation of additional control interventions requires detailed understanding of the epidemiological relationship between these diseases at the community level. METHODS We examined age- and sex-specific trends in TB notifications and their association with the prevalence of HIV infection in a peri-urban township in South Africa during 1996-2004. Denominators for TB notifications were derived from population census data. The local TB-control program used the World Health Organization directly observed treatment, short-course (DOTS) strategy. RESULTS TB notification rates increased 2.5-fold during the period, reaching a rate of 1468 cases per 100,000 persons in 2004 (P=.007, by test for trend); the estimated population prevalence of HIV infection increased from 6% to 22% during the same period. After stabilization of prevalence of HIV infection, the TB notification rate continued to increase steeply, indicating ongoing amplification of the TB epidemic. In 2004, at least 50% of children aged 0-9 years who developed TB were HIV infected. Annual TB notification rates among adolescents increased from 0 cases in 1996-1997 to 436 cases per 100,000 persons in 2003-2004, and these increases were predominantly among female. However, 20-39-year-old persons were affected most, with TB notification rates increasing from 706 to 2600 cases per 100,000 persons among subjects in their 30s. In contrast, TB rates among persons aged >50 years did not change. CONCLUSIONS HIV infection is driving the TB epidemic in this population, and use of the DOTS strategy alone is insufficient. TB notifications have reached unprecedented levels, and additional targeted, age-specific interventions for control of TB and HIV infection in such populations are needed.

Retention in care under universal antiretroviral therapy for HIV-infected pregnant and breastfeeding women ('Option B+') in Malawi

Objective:To explore the levels and determinants of loss to follow-up (LTF) under universal lifelong antiretroviral therapy (ART) for pregnant and breastfeeding women (‘Option B+’) in Malawi. Design, setting, and participants:We examined retention in care, from the date of ART initiation up to 6 months, for women in the Option B+ program. We analysed nationwide facility-level data on women who started ART at 540 facilities (n = 21 939), as well as individual-level data on patients who started ART at 19 large facilities (n = 11 534). Results:Of the women who started ART under Option B+ (n = 21 939), 17% appeared to be lost to follow-up 6 months after ART initiation. Most losses occurred in the first 3 months of therapy. Option B+ patients who started therapy during pregnancy were five times more likely than women who started ART in WHO stage 3/4 or with a CD4+ cell count 350 cells/&mgr;l or less, to never return after their initial clinic visit [odds ratio (OR) 5.0, 95% confidence interval (CI) 4.2–6.1]. Option B+ patients who started therapy while breastfeeding were twice as likely to miss their first follow-up visit (OR 2.2, 95% CI 1.8–2.8). LTF was highest in pregnant Option B+ patients who began ART at large clinics on the day they were diagnosed with HIV. LTF varied considerably between facilities, ranging from 0 to 58%. Conclusion:Decreasing LTF will improve the effectiveness of the Option B+ approach. Tailored interventions, like community or family-based models of care could improve its effectiveness.