Stephen D. Lawn

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.

Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings

The immune reconstitution inflammatory syndrome (IRIS) has emerged as an important early complication of antiretroviral therapy (ART) in resource-limited settings, especially in patients with tuberculosis. However, there are no consensus case definitions for IRIS or tuberculosis-associated IRIS. Moreover, previously proposed case definitions are not readily applicable in settings where laboratory resources are limited. As a result, existing studies on tuberculosis-associated IRIS have used a variety of non-standardised general case definitions. To rectify this problem, around 100 researchers, including microbiologists, immunologists, clinicians, epidemiologists, clinical trialists, and public-health specialists from 16 countries met in Kampala, Uganda, in November, 2006. At this meeting, consensus case definitions for paradoxical tuberculosis-associated IRIS, ART-associated tuberculosis, and unmasking tuberculosis-associated IRIS were derived, which can be used in high-income and resource-limited settings. It is envisaged that these definitions could be used by clinicians and researchers in a variety of settings to promote standardisation and comparability of data.

HIV infection and tuberculosis in South Africa: an urgent need to escalate the public health response.

One of the greatest challenges facing post-apartheid South Africa is the control of the concomitant HIV and tuberculosis epidemics. HIV continues to spread relentlessly, and tuberculosis has been declared a national emergency. In 2007, South Africa, with 0.7% of the worlds population, had 17% of the global burden of HIV infection, and one of the worlds worst tuberculosis epidemics, compounded by rising drug resistance and HIV co-infection. Until recently, the South African Governments response to these diseases has been marked by denial, lack of political will, and poor implementation of policies and programmes. Nonetheless, there have been notable achievements in disease management, including substantial improvements in access to condoms, expansion of tuberculosis control efforts, and scale-up of free antiretroviral therapy (ART). Care for acutely ill AIDS patients and long-term provision of ART are two issues that dominate medical practice and the health-care system. Decisive action is needed to implement evidence-based priorities for the control of the HIV and tuberculosis epidemics. By use of the framework of the Strategic Plans for South Africa for tuberculosis and HIV/AIDS, we provide prioritised four-step approaches for tuberculosis control, HIV prevention, and HIV treatment. Strong leadership, political will, social mobilisation, adequate human and financial resources, and sustainable development of health-care services are needed for successful implementation of these approaches.

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.

Tuberculosis among HIV-infected patients receiving HAART: long term incidence and risk factors in a South African cohort.

Objectives:To determine the long-term incidence of tuberculosis (TB) and associated risk factors among individuals receiving HAART in South Africa. Design:Prospective cohort study. Methods:Microbiologically or histologically confirmed incident TB was identified in a hospital-based cohort of 346 patients receiving HAART between 1996 and 2005 in Cape Town. Results:The TB incidence density rate was 3.5/100 person-years in the first year and significantly decreased during follow-up, reaching 1.01/100 person-years in the fifth year (P = 0.002 for trend). TB incidence during the study was highest among patients with baseline CD4 cell counts < 100 cells/μl and those with World Health Organization (WHO) clinical stage 3 or 4 disease (5.71 and 3.88/100 person-years, respectively). Risk of TB was independently associated with CD4 cell count < 100 cells/μl (adjusted risk ratio [ARR], 2.38; 95% confidence interval (CI), 1.01–5.60; P = 0.04), WHO stage 3 or 4 disease (ARR, 3.60; 95% CI, 1.32–9.80; P = 0.01) and age < 33 years (ARR, 2.86; 95% CI, 1.29–6.34; P = 0.01). Risk of TB was not independently associated with plasma viral load, previous history of TB, low socioeconomic status or sex. Despite similar virological responses to HAART, blood CD4 cell count increases were much smaller among patients who developed TB than among those who remained free of TB. Conclusions:Incidence of TB continues to decrease during the first 5 years of HAART and so HAART may contribute more to TB control in low-income countries than was previously estimated from short-term follow-up. Patients with advanced pretreatment immunodeficiency had persistently increased risk of TB during HAART; this may reflect limited capacity for immune restoration among such patients.

Soluble Forms of Toll-Like Receptor (TLR)2 Capable of Modulating TLR2 Signaling Are Present in Human Plasma and Breast Milk

Dysregulation of the initial, innate immune response to bacterial infection may lead to septic shock and death. Toll-like receptors (TLRs) play a crucial role in this innate immune response, and yet the regulatory mechanisms controlling microbial-induced TLR triggering are still to be fully understood. We have therefore sought specific regulatory mechanisms that may modulate TLR signaling. In this study, we tested for the possible existence of a functionally active soluble form of TLR2. We demonstrated the existence of natural soluble forms of TLR2 (sTLR2), which we show to be capable of modulating cell activation. We found that blood monocytes released sTLR2 constitutively and that the kinetics of sTLR2 release increased upon cell activation. Analysis of cells expressing the human TLR2 cDNA or its c-myc-tagged version indicated that sTLR2 resulted from the posttranslational modification of the TLR2 protein in an intracellular compartment. Moreover, an intracellular pool of sTLR2 is maintained. sTLR2 was found naturally expressed in breast milk and plasma. Milk sTLR2 levels mirrored those of the TLR coreceptor soluble CD14. Depletion of sTLR2 from serum resulted in an increased cellular response to bacterial lipopeptide. Notably, serum sTLR2 was lower in tuberculosis patients. Coimmunoprecipitation experiments and computational molecular docking studies showed an interaction between sTLR2 and soluble CD14 in plasma and milk. These findings suggest the existence of a novel and specific innate immune mechanism regulating microbial-induced TLR triggering, and may lead to new therapeutics for the prevention and/or treatment of severe infectious diseases.

Advances in tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects for a point-of-care test

Rapid progress has been made in the development of new diagnostic assays for tuberculosis in recent years. New technologies have been developed and assessed, and are now being implemented. The Xpert MTB/RIF assay, which enables simultaneous detection of Mycobacterium tuberculosis (MTB) and rifampicin (RIF) resistance, was endorsed by WHO in December, 2010. This assay was specifically recommended for use as the initial diagnostic test for suspected drug-resistant or HIV-associated pulmonary tuberculosis. By June, 2012, two-thirds of countries with a high tuberculosis burden and half of countries with a high multidrug-resistant tuberculosis burden had incorporated the assay into their national tuberculosis programme guidelines. Although the development of the Xpert MTB/RIF assay is undoubtedly a landmark event, clinical and programmatic effects and cost-effectiveness remain to be defined. We review the rapidly growing body of scientific literature and discuss the advantages and challenges of using the Xpert MTB/RIF assay in areas where tuberculosis is endemic. We also review other prospects within the developmental pipeline. A rapid, accurate point-of-care diagnostic test that is affordable and can be readily implemented is urgently needed. Investment in the tuberculosis diagnostics pipeline should remain a major priority for funders and researchers.

Contribution of Immune Activation to the Pathogenesis and Transmission of Human Immunodeficiency Virus Type 1 Infection

SUMMARY The life cycle of human immunodeficiency virus type 1 (HIV-1) is intricately related to the activation state of the host cells supporting viral replication. Although cellular activation is essential to mount an effective host immune response to invading pathogens, paradoxically the marked systemic immune activation that accompanies HIV-1 infection in vivo may play an important role in sustaining phenomenal rates of HIV-1 replication in infected persons. Moreover, by inducing CD4+ cell loss by apoptosis, immune activation may further be central to the increased rate of CD4+ cell turnover and eventual development of CD4+ lymphocytopenia. In addition to HIV-1-induced immune activation, exogenous immune stimuli such as opportunistic infections may further impact the rate of HIV-1 replication systemically or at localized anatomical sites. Such stimuli may also lead to genotypic and phenotypic changes in the virus pool. Together, these various immunological effects on the biology of HIV-1 may potentially enhance disease progression in HIV-infected persons and may ultimately outweigh the beneficial aspects of antiviral immune responses. This may be particularly important for those living in developing countries, where there is little or no access to antiretroviral drugs and where frequent exposure to pathogenic organisms sustains a chronically heightened state of immune activation. Moreover, immune activation associated with sexually transmitted diseases, chorioamnionitis, and mastitis may have important local effects on HIV-1 replication that may increase the risk of sexual or mother-to-child transmission of HIV-1. The aim of this paper is to provide a broad review of the interrelationship between immune activation and the immunopathogenesis, transmission, progression, and treatment of HIV-1 infection in vivo.