oa Editorial [Hot Topic: Targeting Tuberculosis and HIV/AIDS: A Global Progress Report of a Deadly Partnership (Guest Editors: Jean B. Nachega & Bernd Rosenkranz)]

The World Health Organization (WHO) estimates that 2 billion people, or one-third of the world's population, are infected with M. tuberculosis. From this seedbed of latent infection, 9.4 million new cases of active disease and 1.3 million deaths were attributed to tuberculosis in 2008 [1]. Disease due to M. tuberculosis is most common in developing nations, both in absolute numbers and incidence of new cases. Twenty-two countries account for 80 % of all cases of tuberculosis; India and China are responsible for 23 % and 17 % of cases, respectively. In general, the highest incidence of disease is found in the countries of sub-Saharan Africa where HIV infection has contributed to extraordinary increases in case rates. The global incidence of tuberculosis is increasing slightly, though population growth is resulting in higher numbers of cases each year. Declines in incidence in the developed world have been offset by increasing rates in the HIV-ravaged. In 2009, about 3 million people became newly infected with HIV, half of whom were young adults (<24 year old) with the majority residing in developing countries [1]. Interventions are urgently needed to decrease the burden of both HIV and Tuberculosis globally. In this issue, Zeier and Nachega as well as Slogrove and colleagues [2,3] report the global status of antiretroviral therapy (ART) to include topical issues such as when to start and with what treatment regimens in adults and children, respectively. The 2009 US Department of Health and Human Services (DHHS) and WHO HIV treatment guidelines are swinging towards earlier treatments at the threshold in both adults and children. Encouragingly, with the assistance of US President's Emergency Plan For AIDS Relief (PEPFAR), UN Global Funds and other, great progress have been made by providing ART to 4 million of HIV-infected globally over the last few years, about another 7 million other are still in need. However, the sad reality today is that for one HIV-infected patient started on ART, about 3 other individuals are becoming HIV-infected. So treatment efforts alone are not sustainable to dramatically control the HIV epidemic. Combined treatment and prevention efforts should be high on the global agenda. An exciting and optimistic development in the field is that effective ART in the highly adherent patient greatly reduce the likelihood of sexual transmission from infected individuals to their sexual partners. As a result, most treatment guidelines in the developed world recommend that infected partners of HIV-discordant couples should be started on ART regardless of their CD4 T-cell count, but further encourage the consistent use of other prevention methods such as condoms. More than ever, excellent ART adherence is being considered to be critical because of the benefit it can provide for the individual (decrease likelihood of viral replication, drug resistance and disease progression) but also as a prevention tool (Prevention of Sexual Transmission). The currently debated “test-and-treat” mathematical model in which universal HIV testing with immediate HIV ART for infected persons would be incorporated with other prevention strategies is likely to continue to be controversial for some time. However, if this model is feasible and affordable, it could potentially reduce HIV incidence and mortality to less than one case per 1,000 people per year by 2016. But achieving full access to these interventions for all at-risk populations may prove to be more difficult than any mathematical model could predict. There is an urgent need to validate assumptions used in such model by research which are already underway both in resource-rich and limited settings. The global status of HIV drug resistance is also addressed by Hong and colleagues [4]. Furthermore, Nachega and colleagues, review the current practices of management of active adult tuberculosis in the era of HIV pandemic and issues such when to start antiretroviral therapy in TB-HIV co-infected patients, drug-drug interactions and Tuberculosis Immune Reconstitution Syndrome (TB-IRIS) are discussed [5]. On the other hand, Marais and colleagues address several issues related to childhood tuberculosis, a somewhat neglected disease [6]. They provide an overview of current treatment practices, presenting the authors personal perspectives on issues related to the treatment of childhood tuberculosis, together with a brief synopsis of potential future treatment options. Another very important trend in tuberculosis epidemiology is the growing problem of drug-resistant tuberculosis as well as the challenge of managing TB-HIV co-infected patients. Multidrug resistant (MDR) or extensively resistant (XDR) strains of tuberculosis are an emerging global threat. Indeed, a global survey of resistance performed by the WHO and the International Union Against Tuberculosis and Lung Disease found that the median prevalence of primary drug resistance was 10 %, and the median prevalence of acquired resistance was 36 %. Moreover, ‘hot spots’ of drug-resistant tuberculosis were identified on all continents. The most notable of these are in the former Soviet nations where multidrug-resistant tuberculosis, defined as resistance to at least rifampicin and isoniazid, is identified in 10 to 20 % of all cases. Multidrug-resistant tuberculosis treatment is exceedingly difficult, since the drugs used are less effective, more costly, and poorly tolerated due to drug-related side effects. Furthermore, failure to control the spread of drug resistant tuberculosis has led to the outbreak of extensively drug resistant tuberculosis, which is defined as multidrug-resistant tuberculosis plus resistance to fluoroquinolones and at least one injectable second-line agent (capreomycin, amikacin, or kanamycin). Extensively drug-resistant tuberculosis been responsible for high rates of mortality in HIV-infected individuals in South Africa and is reported in more than 70 countries globally. Drug-resistant tuberculosis (MDR or XDR) will likely continue without effective implementation of directly observed therapy, short-course (DOTS) [6]. The development of new, safe and effective treatment options will ameliorate the burden of disease for HIV and drug resistant tuberculosis. The article by Derendorf and colleagues demonstrates that appropriate quantitative model-based concepts (socalled pharmacometrics) applied during drug development can identify the optimal dosage regimens for new antiretroviral or tuberculosis treatments by providing essential dose-exposure-response relationship information. This approach has successfully been used for example to predict the appropriate dosing regimen for the new non-nucleoside reverse transcriptase inhibitor (NNRTI), GW 420867X, and for the novel CCR5 chemokine receptor antagonist, maraviroc. Pharmacometrics is a useful method for optimizing drug combination regimens to prevent emergence of resistance during ARV treatment [7]. For example, it could be predicted that co-administration of an optimized dose of the nucleoside reverse transcriptase inhibitor (NRTI), zidovudine together with tenofovir or abacavir can prevent development of resistance against either drug. Most of the drugs currently used to treat tuberculosis have been introduced into clinical practice decades ago, and therefore knowledge about their pharmacokinetics and PK-PD relationship unfortunately is scarce. Pharmacometric approaches have been extremely useful in dosage optimization of these drugs, such as by providing a clear rationale for the use of a high-dose rifampin and rifapentine regimen [7]. Currently, the management of patients affected by these infections is far from ideal, especially in developing countries. Global effort and mobilization for timely diagnostic, treatment and prevention of both tuberculosis and HIV must remain an essential part of the strategy to combat this deadly partnership.....