New therapeutic approach for latent tuberculosis infection.

Sir,

It is estimated that about 2 billion people living with latent tuberculosis infection (LTBI) represent a vast reservoir of potential cases of tuberculosis around the world.[1] LTBI occurs when Mycobacterium tuberculosis is able to survive in granulomas with a central necrotic core and an outermost layer of foamy macrophages (FM) that represent an important immunosuppressive barrier.[2] LTBI itself progress to active disease in approximately 5 to 10% of infected persons. The rate of progression is much greater in immunocompromised individuals, e.g. person with HIV infection.[3]

Current approach for the treatment of latent tuberculosis infection

The objective of treatment for LTBI is to prevent the development of overt tuberculosis (TB) disease in infected, but asymptomatic individuals. At present, a 9-month course of daily isoniazid (INH) is recommended as first line therapy for LTBI. Alternative regimens include a shorter 6-month course of INH, which is inferior to a 9-month course, or a 4-month course of daily rifampin (RIF) or a 2-month course of RIF plus pyrazinamide (PZA).[4]

Unmet medical needs

Isoniazid use is limited by its hepatotoxicity, poor compliance because of long duration, and in India, by the presence of high primary resistance to the drug (10%). On the other hand, the incidence of liver injury is higher among people receiving short-course (two-month) rifampin and pyrazinamide therapy for LTBI than among those receiving isoniazid.[4]

Alternative approach for the treatment of latent tuberculosis infection

A better chemotherapeutic treatment of LTBI patients can be achieved, by administering INH for a short period of time, i.e. 4 weeks, with only 1 or 2 doses of therapeutic vaccine. The rationale of this therapy is first to take advantage of the bactericidal properties of chemotherapy to kill active growing bacilli, eliminate the outermost layer of FM and reduce local inflammatory responses. After chemotherapy, therapeutic vaccine can be inoculated to reduce the probability of regrowth of the remaining latent bacilli.[2]

One therapeutic vaccine, currently under phase II clinical development is RUTI® (a vaccine developed in Spain). RUTI® is a therapeutic vaccine made from virulent Mycobacterium tuberculosis bacteria, grown in stressful conditions, fragmented, detoxified, heat inactivated and liposomed. RUTI® not only provides a strong humoral and cellular immune response against antigens from active growing and latent bacilli, but also against structural antigens, as it has been proved in animal models of latent tuberculosis infection and in phase I clinical trial of healthy volunteers. The preclinical experiments of RUTI® showed the induction of a mixed Th1/Th2/Th3, polyantigenic response with no local or systemic toxicity.[2] The vaccine has been designed to be used against LTBI as a therapeutic vaccine after 1-month of chemotherapeutic treatment, instead of the current treatment based on 6-9 months of chemotherapy.[12]

The therapeutic vaccine for LTBI can help in developing shorter and/or more intermittently administered regimens that are easier to supervise and that are active against multidrug-resistant latent TB infection (MDR-LTBI).[5] Thus, it can help in counteracting the hepatotoxicity, poor compliance and high resistance associated with other longer regimens commonly used in India for treating LTBI. This might be very helpful in Indian context as the prevalence rates of LTBI in India ranges from 9-80% in various populations.[1-4]