Challenges and perspectives for improved management of HIV/Mycobacterium tuberculosis co-infection

SCIENTIFIC CHALLENGES

Vaccinations are the most efficient and cheapest ways to control microbial infections and, thus, there is an urgent need for effective vaccines against both HIV and TB. The major obstacles to the development of an HIV vaccine are the virus' extraordinary diversity and the difficulty in stimulating high titres of broadly cross-reactive neutralising antibodies and high-affinity cytotoxic T-cells 17–20. As HIV targets the CD4 helper T-cell population that is necessary for the generation of both adaptive immune responses, there is an intrinsic difficulty here that is connected with the viral lifestyle 21. The situation for TB is different because a vaccine already exists. Indeed, bacille Calmette–Guérin (BCG) is the most widely administered vaccine worldwide, with 100 million doses given annually; however, it is of limited efficacy, as it mainly prevents disseminated TB in children rather than pulmonary infection 22 and is contraindicated in infants with a confirmed HIV diagnosis 23. If we are to eradicate TB by 2050 24, 25, it is critical to have a vaccine that is safe and confers durable protection against pulmonary and extrapulmonary TB in both HIV-infected and noninfected infants and adults.

The presently available diagnostic and therapeutic options for HIV infection are impressive. The virus is detectable throughout the entire infection period and can be analysed genetically to provide a phenotypic drug resistance profile with high accuracy. HIV sequence information can even be used to direct optimal therapeutic regimens, allowing individualised HIV treatment in the near future 26. Furthermore, by measuring surrogate markers, such as CD4 helper T-cell numbers, the patient's state of immunodeficiency can be monitored. Similarly impressive is the progress made in antiretroviral treatment. More than 20 antivirals are on the market and highly efficient new drug classes, such as the integrase inhibitors, have recently gained official approval 27, 28. For TB, the situation is completely different. There is an urgent need for diagnostic tools that can accurately and rapidly detect paucibacillary disease, and monitor treatment in infants, children and adults. Because traditional TB control programmes rely on passive case finding of smear-positive TB, many children and people with HIV, who are more likely to be asymptomatic and have smear-negative and extrapulmonary TB, are left out of the system of care. Therefore, a point-of-care molecular diagnostic that could provide rapid results in infants, children and adults would provide more timely and accurate confirmation of disease regardless of HIV status. There is also need to shorten time to diagnosis of drug-resistant disease, improve access to care and restrict the onward transmission of untreatable disease. With respect to treatment, more effective, shorter and more tolerable treatments for drug-susceptible and drug-resistant TB, particularly among populations bearing the highest burden of morbidity and mortality, are needed. While the pipeline of new tools to prevent, diagnose and treat TB is fuller than it has been in decades, there are not enough players and not enough resources being dedicated to making these products easily accessible to those who need them most. In addition, for the five novel TB drugs in clinical studies 29, there is still a dearth of data on how best to use these products in children and people with HIV. More evidence on safety, tolerability and efficacy, as well as pharmacokinetic studies of current and new TB drugs in these populations, are necessary. Given the vast numbers of people with HIV dying of undiagnosed TB and the poor cure rates with current treatment of drug-resistant disease 6, 30, 31, promising diagnostics and treatments need to be prioritised and fast-tracked by developers and regulators.

It is vital that operational research be considered just as important as efficacy studies in the evaluation of any new technology. The usability of a new vaccine, diagnostic test or drug by healthcare providers and its uptake by patients must be assessed, as well as its impact on the health system. This can be done by incorporating operational research into national AIDS and TB control programmes, and will help to inform and facilitate the development of practical policies guiding the use of new technologies.

Despite being more resource intensive and requiring more ethical oversight and expertise, mandatory inclusion of people with HIV, particularly those on antiretroviral drugs and/or with advanced immune deficiency, and children, in the validation of any new tool is crucial to ensure that they are useful in all populations. In order to do so, industry, regulatory bodies, research institutions, funding bodies and the community are asked to commit the needed resources, to be innovative, to be collaborative and to act with a sense of urgency in improving current TB treatment and diagnosis, and developing new products.

NEED FOR STRONG POLITICAL WILL AND COMMITMENT TO ENSURE PROPER GOVERNANCE, ADEQUATE HUMAN RESOURCES AND FUNDING, AND RANKING HIV/TB AS A PRIORITY IN THE NATIONAL AGENDA

The response to HIV and TB requires support from the highest level of leadership in the integration of HIV and TB strategies, interventions, services (prevention and care) and research. In addition, policymakers and managers need to work together to ensure a combined public health and developmental perspective in the response, since HIV and TB feed on poverty and inequity 32. A successful response also requires the appropriate planning, funding and allocation of resources based on evidence and results, in combination with a strategy to build the capacity of national AIDS control and national TB programmes to work together. This will require stakeholders from within the public sector as well as HIV/TB experts, civil society, people living with HIV/TB and policymakers.

NEED FOR AN ENABLING ENVIRONMENT INCLUDING A MULTISECTOR AND PARTNERSHIP RESPONSE

The response to HIV/TB needs to involve all relevant health and nonhealth sectors (education, finance, justice, agriculture etc.) and partners (government, academia, funding bodies, people living with HIV/TB, nongovernmental and community-based organisations, cooperation agencies and multi- and bilateral organisations). Multisector and partnership approaches already exist in the field of HIV, and result in a more efficient and effective response. One example among many is provided by the KwaZulu-Natal Enhancing Care Initiative, in which a partnership approach resulted in improved access and faster programme implementation 33. WHO recommends the same approach for HIV/TB 34 and our goals should be set toward providing services for prevention, care and treatment that results in reducing the burden of TB among people with HIV and HIV among people with or at risk for TB.

NEED FOR INCREASED ACCESS TO AND BROADER COVERAGE OF PREVENTION, CARE AND TREATMENT SERVICES FOR HIV/TB

Strengthening services and increasing coverage is crucial to controlling and reducing the impact of HIV/TB, and to prevent the emergence and spread of drug-resistant strains of MTB. However, scaling up services while maintaining quality and equity of access requires political support, a focussed strategy and long-term planning. Equal consideration must be given to prevention and care, with priority given to the needs of the most vulnerable and those at highest risk (e.g. the poor, vulnerable children and females, males who have sex with other males, sex workers, drug users and marginalised populations) and should offer services regardless of sex, age, insurance and residence. Increasing coverage of HIV/TB services can only be accomplished through integration and decentralisation of services that, by nature, require a participative approach. It must be recognised that civil society has a crucial role to play in advocacy and social mobilisation in order to yield the highest return.

NEED TO STRENGTHEN NATIONAL HIV/TB RESEARCH AND DEVELOP RESEARCH AGENDAS THAT FOCUS ON COUNTRY NEEDS

Research agendas driven by donors' needs, but not necessarily corresponding to a country's research priorities, represent an impedance to progress on HIV/TB. Further limiting progress are the limited transfer of technology and knowledge between the North–South or even South–South, and assigning a limited role to local institutions, such as only the collection of data or specimens. These situations are often accepted due to the institutions' reliance on international collaboration and the lack of a strong national agenda guiding research and funding. Ethical issues and utilisation of study results also concern governments, researchers and study participants in resource-limited countries. Results from HIV/TB studies conducted in high-incidence settings may well lead to the discovery of new diagnostic methods, drugs or novel management approaches, which may benefit these countries. We need to ensure that benefits revert to the study population or country where such studies were conducted and appropriate implementation is not prevented due to high costs of interventions or other challenges facing healthcare services 35. Perhaps the greatest scientific challenge is to generate a critical mass of skilled and expert researchers, epidemiologists, clinicians statisticians, etc., that promotes and conducts national research able to respond to the country's needs.

MIDDLE-INCOME TARGET COUNTRIES WITH RELATIVELY LOW HIV/TB PREVALENCE REQUIRE FUNDS TO START OR SUSTAIN THE RESPONSE TO THE CO-INFECTION

These countries face a special challenge due to the difficulty of attracting national or international attention and support to fight the epidemic when there is still time to act to prevent major escalations. Several of these countries are already at the forefront of the battle against drug-resistant strains of MTB, in which standard treatment regimes have become largely ineffective. In these countries, it is important to engage with the private sector, who are frequently major providers of healthcare where public services are often fragmented and weak. Most of the international HIV/TB response efforts have focused on Africa. Although the high prevalence of HIV and TB found in many African countries warrants the concentration of efforts, it should become an active policy to guarantee that middle-income countries, such as India, and countries in Latin America, Eastern Europe or Asia, receive their share of attention and support. This neglect is reflected by the lack of research being conducted in and the inadequate level of international funding being allocated to middle-income, “low-priority” countries.

STIGMATISATION

A major challenge to HIV/TB control is not political, technical or financial, but social. Stigma, discrimination and fear are associated with HIV infection and TB alike. The social effects of these two highly stigmatising diseases compound individual suffering and adversely affect health-seeking behaviour.

CONCLUSIONS

To conclude, the challenges listed above are restricting global and national capacities to make an impact on the HIV/TB epidemic. We must understand that currently these challenges clearly limit the global response to the threat posed by HIV/TB co-infection and that it is, therefore, absolutely crucial to address them through research and evidence-based policies and programmes. It is further essential that international and multisector platforms, such as EUCO-Net, are generated so that representatives from science, healthcare, government, foundations, nongovernmental organisations and activist groups, and people living with HIV/TB can synergise and jointly achieve a more effective, comprehensive and coordinated response to HIV/TB co-infection. They should participate in the definition and coordination of research, demand political commitment, provide support to increase and sustain funding, and help to periodically review the progress made. By funding such a platform, the EU not only acknowledges the threat of HIV/TB for human health, but also makes a strong commitment for future activities in this area.