HIV TB ALOK SINHA Department of Medicine Manipal

HIV & TB ALOK SINHA Department of Medicine Manipal College of Medical Sciences Pokhara, Nepal

stem cells Lymphocytes Mature in B. marrow to become “B LYMPHOCYTE” react with free antigen directly plasma cells Thymus recognise the antigen with the help of macrophages T cells Helper T cells Cytotoxic T cells (CD 4 surface protein) activated lymphocytes enter the tissue and meet antigen again results in multiplication and secretion of cytokines or immunoglobins in order to destroy the antigen Th 1 cells - involved in cell mediated immunity. Produce interferon gamma, interleukin 2 & TNF beta. Th 2 cells: play a role in humoral responses responsible for Atopy and allergy

Immune response in T. B. Infection It manages to evoke both immunity & hypersensitivity in the body Immunity – Good for body –not good for bacteria It localizes the bacteria and clears the infection efficiently with out causing much tissue destruction Hypersensitivity – good for bacteria – not good for body Infection can not be localized Plenty of tissue destruction with on going caseation & necrosis

Introduction § Tuberculosis and HIV - closely linked since the emergence of AIDS. HIV infection has contributed to a significant increase in the worldwide incidence of tuberculosis § Over 4 million persons worldwide have been infected with HIV and tuberculosis § Most common cause of death in AIDS patients

§ Have instantly clicked together & linked since the emergence of AIDS • Love at first sight • No generation gap

HIV & TB both affect each other T. B. HIV

Effect of HIV on TB HIV T. B.

HIV increases the incidence of TB

Now answer these 2 questions: • What % of world population get Mycobacterium infection at some point in their life (without developing active disease) ? • Of them how many of develop active disease ?

HIV increases the T. B. infection § It is estimated that 1/3 rd population of the world are infected by the Mycobacterium tuberculosis § Out of them only 10% have life time chances of developing tuberculosis § This scenario is changing with the advent of HIV infection

Tuberculosis normally develop through: 1. progression of recently acquired infection primary disease 2. reactivation of latent infection 3. exogenous reinfection

§ Concomitant HIV infection increases the possibility of development of T. B. in all the above categories § People co-infected with both HIV and latent TB have an up to 800% greater risk of developing active tuberculosis disease and becoming infectious compared to people not infected with HIV

Gohn focus

Now answer these questions: l What is the main lesion in post primary T. B. l Is there hilar lymphadenopathy l Which lobes are predominently affected l What is the likelihood of pleural effusion

Clinical features of HIV-associated post primary pulmonary tuberculosis (in adults) are frequently atypical, particularly in the late stage of HIV infection 1. 2. 3. 4. Non-cavitary disease -Lack of hypersensitivity Lower lobe infiltrates Hilar lymphadenopathy Lack of immunity Pleural effusion

Immunity Hypersensitivity

� Tuberculosis can be a relatively early manifestation of HIV-1 infection � Risk of developing tuberculosis, and of disseminated infection, increases as the CD 4 T-cell count decreases

Immune system is unable to contain the infection resulting in: An increased frequency of extrapulmonary tuberculosis Positive mycobacterial blood cultures Atypical chest radiographic findings

Patients with extrapulmonary tuberculosis may present with signs and symptoms specific to the involved site, such as v lymphadenopathy v headache v meningismus v pyuria v abscess formation v back pain v abdominal pain

Increased incidence of MDR TB in HIV • Acquired resistance (Organisms are sensitive at the beginning) in MDR TB is associated with coinfection due to HIV & tuberculosis • In MDRTB outbreaks approximately 90% of the cases were HIV seropositive

• Spread of Multi Drug Resistant. TB poses a serious threat to the world health scenario

Summary Effect of HIV on TB: 1. Increases the incidence of TB by converting the latent infection into active one 2. Changes the clinical features of the post primary tuberculosis • • • 3. non-cavitary disease lower lobe infiltrates hilar lymphadenopathy pleural effusion More extrapulmonary involvement Increased incidence of MDR TB in HIV

T. B. HIV

T. B. – opportunistic infection in HIV/AIDS Relatively early manifestation of HIV-1 infection median CD 4 T-cell count was >300 cells/mm 3 Risk of developing tuberculosis & of disseminated infection, increases as the CD 4 T-cell count decreases What is normal CD 4 cell count ? 600 -1200/ml

• AIDS generally occurs when • CD 4 count is below 200/m. L • or a CD 4 lymphocyte percentage below 14% • Characterized by the appearance of opportunistic infections, eg. : v Tuberculosis v Pneumocystis carinii pneumonia v Toxoplasmosis v Meningitis and other brain infections v Fungal infections v Malignancies: lymphoma, cervical Ca. , Kaposi's sarcoma

Tuberculosis acts to accelerate the clinical course of HIV infection 5 - to 160 -fold increase in viral replication during the acute phase of untreated tuberculosis leads to increased HIV viral load

Clinical Presentation of Tuberculosis with HIV

n Diagnostic difficulties initially because the early symptom - fever, weight loss, and malaise in both TB & HIV are same n Earlier in the course of HIV disease TB is more likely to present as classical reactivation-type disease n Patients with advanced immuno suppression are more likely to present with findings consistent with primary tuberculosis

bilateral hilar lymphadenopathy with diffuse interstitial and airspace opacities. CD 4 count<200

Extensive right paratracheal lymphadenopathy

Treatment of HIV-Related Tuberculosis

l Good, early clinical response to therapy as long as the regimen contains INH and a Rifampicin l Sputum culture conversion & treatment failure rates were similar to those in patients without HIV infection

Treatment of HIV & TB together poses many problems

l Requires close monitoring because 1. Development of resistance Frequent drug toxicities 3. Possible drug-drug interactions 4. Paradoxical reactions 2.

Rifamycins: l Rifampicin or Rifampin l Rifabutin l Rifapentine – long acting so only once a week dose required

l Patients treated with a once-weekly Isoniazid /Rifapentine continuation-phase regimen Relapse with rifamycin monoresistant T. B. In HIV-seropositive tuberculosis l HIV-seropositive people with tuberculosis should not be treated with a once-weekly isoniazid/rifapentine regimen

Adverse drug reactions l Most commonly seen with Rifampicin l should be avoided/replaced Rash - Thiacetazone should not be used in the treatment of HIV-related tuberculosis because of skin reactions l l Paresthesia – B 6 should be given with INH Incidence of drug induced hepatitis is many times more in HIV+ TB patients - Frequent monitoring of liver function tests are required

Drug-Drug Interactions

Certain antituberculosis drugs may interact adversely with medications commonly used by HIV-infected individuals Rifamycin derivatives • Rifampicin (most potent inducer) • Rifabutin • Rifapentine (less potent) induce the hepatic cytochrome system P 450 enzyme

§ Results in increased metabolism & reduced serum levels of certain drugs which includes • protease inhibitors (PIs) • nonnucleoside reverse transcriptase inhibitors (NNRTIs) Used for the treatment of AIDS

This results in subtherapeutic levels and the potential development of viral resistance to these important agents Rifabutin can be substituted for Rifampicin in the treatment regimen

PIs and NNRTIs affect the metabolism of rifabutin, resulting in altered serum levels and the possibility of drug toxicity, adjustments in rifabutin dosage are often necessary Patients can take the standard rifampin-based treatment regimen if not taking PIs or NNRTIs

Paradoxical Reactions

Temporary exacerbation of symptoms, signs, or radiographic manifestations of tuberculosis seen after beginning ATT Occur in HIV-infected patients with active tuberculosis Develop after simultaneous administration of both antiretroviral & ATT

Due to increase in the cellular immunity caused by ART Diagnosis of a paradoxical reaction should be made after a thorough evaluation to exclude other etiologies, such as tuberculosis treatment failure

Initiation of Antiretroviral Therapy in coinfected Patient. No standard regimens! Lot of confusion & uncertainity prevails at present

So don’t start fighting over it!

Initiation of Antiretroviral Therapy in coinfected Patient Treatment of tuberculosis to be initiated immediately Treatment of HIV infection usually started after 2 months potentially decreasing the risk of a paradoxical reaction Tuberculosis and HIV can be treated concurrently using a Rifabutin-based regimen

Whether to start ART as soon as possible or wait until antituberculosis treatment is well established is not clear at present Decision should be made on a case-by-case basis If already receiving ART, regimen to be continued and modifications to either the tuberculosis regimen or to the antiretroviral regimen can be made as indicated

Many of the side effects like GIT upset Rash Preipheral neuropathy Flu like symptoms Can be due to both ATT or ART In case of ATT, they can be with held and started one by one again This can not be done with ART – resistance. So treatment guided by prior knowledge

Latent Tuberculosis Infection positive tuberculin skin test for HIV infected persons is >=5 mm Prevalence of (+) test decrease with decreasing CD 4 T-cell counts Why? Persons with low CD 4 T lymphocyte count should have periodic X ray chest done esp. in high risk group

HIV-infected individuals with latent TB infection have an extraordinarily high rate of progression to active tuberculosis compared to HIV-uninfected persons Treatment of LTBI very effective in preventing persons infected with M tuberculosis from developing active disease Annual screening of all HIV-infected persons for LTBI, and treatment of those coinfected with M tuberculosis, is recommended

Option Total Duration (months) I II III 6 6 6 Initial Phase Drugs Interval and Duration* Continuation Phase Drugs INH RIF PZA EMB (or SM) (HRZEor. S) Daily for 8 weeks INH RIF PZA EMB (or SM) (HRZEor. S) Daily for 2 weeks INH RIF PZA EMB (or SM) (HRZEor. S) Thrice weekly for 26 weeks then Interval and Duration # INH RIF (HR) Daily for 16 weeks INH RIF Twice weekly for 18 weeks Twice weekly for 6 week or Twice weekly for 16 weeks Recommended regimen