STD Series: Tuberculosis coinfection in HIV Patients

I. Introduction
• Overview of TB and HIV as major infectious diseases in resource-limited countries
• Impact of HIV on TB infection and mortality rates
II. Immune Response
• Role of alveolar macrophages and dendritic cells in primary pulmonary TB
• Effects of HIV infection on CD4+ T cells and immunocompromise
III. Diagnostic challenges
IV. Mode of Treatment for TB and HIV
• Challenges of treating HIV-infected TB
• Recommended treatment for active TB disease with HIV
• Guidelines for initiating ART with CD4 counts of <50 cells/mm³ and CD4 counts ≥50 cells/mm³
• Alternative antituberculosis agents for multidrug-resistant (MDR) and extensively drug resistant (XDR) strains of TB
V. Conclusion
• Importance of addressing the co-infection of TB and HIV in resource-limited countries

Tuberculosis and HIV are considered one of the major infectious diseases in resource-limited countries. Even with the availability of effective combination antiretroviral therapy (cART), according to UNAIDS, the mortality rate of AIDS-related illness in 2016 is estimated at 1 million people globally. HIV not only enables opportunistic infections because of the low CD4 count but can also worsen the manifestations of other infections as is evident with the high mortality rate particularly in sub-Saharan Africa. Hence, individuals with HIV are 26 times or 31 times at greater risk of developing an active TB. Globally, TB is considered one of the leading causes of death among HIV patients. An individual who is diagnosed with both HIV and TB disease may also have an AIDS-defining condition.

According to WHO, in 2015, an estimated 10.4 million cases of TB were identified of which 1.2 million (11%) were among HIV individuals. Hence, no wonder the co-infection with TB and HIV has been a focus of attention from the global health community. The co-infection with TB increases the risk of premature death by twice that of an HIV individual without TB even with the treatment of antiretroviral. Also, HIV infected individuals are at a high risk of developing extra-pulmonary TB that is estimated at 40 to 80% than compared to 10 to 20% among individuals without HIV.

Immune Response

M.tuberculosis infects the alveolar macrophages and dendritic cells (DCs) causing primary pulmonary TB. The immune control of the infection is mediated by the effects of various cell types including the CD4+ and CD8+ T cells. As HIV infects CD4 T cells by binding to the CD4 receptor on the cell surface, it allows fusion of the viral envelope, therefore, permitting viral entry. With the chronic period of the HIV infection, the continued replication of HIV results in the gradual decline of the CD4 count resulting in the increased immunocompromise, susceptibility to opportunistic infections and death when not treated with ART. The production of pro-inflammatory cytokine by the innate immune cells as the result of the M.tuberculosis infection can also help with the progression of HIV infection. Activated monocytes and CD4 T lymphocytes help contribute to the rise of plasma HIV viral loads during TB infection.

Diagnostic challenges

M.tuberculosis poses diagnostic and therapeutic challenges particularly in the African and Asian countries presenting an increased number of co-infected individuals. WHO recommends that individuals diagnosed with HIV infection should also be screened for TB before initiating the treatment with antiretroviral therapy.

Sputum smear microscopy, the frequently used method, involves microscopic examination of sputum for acid-fast bacilli (AFB).

Growth based detection, the culture of M.tuberculosis, also allowing strain characterization and drug susceptibility tests to diagnose TB among individuals with HIV infection.

Molecular techniques; Nucleic acid amplification testing ( NAAT) provides a more reliable diagnosis. The simplified versions of NAAT include loop-mediated isothermal amplification (LAMP), line probe assays (LPA) and fluorescence in-situ hybridization (FISH).

GEneXper-Rif: WHO endorsed it for the rapid diagnosis of TB along with the rifampicin resistance.

Serological diagnosis: the detection of antibodies, of M.tuberculosis MPB-64 (TAUNS) antigens in peripheral blood and lipoarabinomannan (LAM) in the urine. Interferon-y release assay (IGRA) is used to diagnose latent TB, and two in vitro test include QuantiFeron- TB gold (Cellestis, USA) and the T SPOT-TB test (Oxford Immunotec, USA).

Mode of treatment for TB and HIV

The treatment for HIV-infected TB is the same as the HIV uninfected individual. However, the treatment for HIV ARV therapy and anti TB treatment together involve various difficulties such as the drug to drug interactions, cumulative drug toxicities and immune reconstitution inflammatory syndrome (IRIS).

Anti-TB therapy: According to the Centers for Disease Control and Prevention (CDC), the recommended treatment for latent TB infection and HIV individuals are the isoniazid and rifapentine (3HP) for a period of twelve weeks. In the case of taking antiretroviral medications presenting drug interactions, alternative treatment includes the once a week rifapentine or daily rifampin. For the treatment of active TB disease with HIV, an intensive phase of isoniazid (INH), ethambutol (EMB), rifamycin, pyrazinamide are recommended for first 2 months followed by INH and a rifamycin for the last 4 months. Although a six month period of treatment is the minimum, prolonging to 9 months may be considered for HIV-infected individuals presenting delayed response.

HIV ARV and anti TB drug therapy: According to the guidelines published in the NIH U.S National Library of Medicine, patients with both HIV and active TB should initiate ART within 2 weeks of starting TB treatment with CD4 counts of ˂50 cells/mm³. Among those with CD4 counts ≥50 cells/mm³, ART should be initiated within 8 weeks of starting TB treatment.

Alternative antituberculosis agents

In view of the emergence of multidrug-resistant (MDR) and extensively drug resistant (XDR) strains of TB, the treatment of the infection has become complicated. The Nix-TB trial is a TB clinical trial to possibly provide an affordable treatment for XDR-TB and the combination is pretomanid, bedaquiline and linezolid which are predicted to cure XDR-TB in nine months.

The Nitroimidazoles is a class of drugs known for its antimicrobial activity. Two “next generation”, OPC-67683 and PA-825 are also under development as possible TB drugs.

Pretomanid (PA-824) – the TB Alliance is currently developing PA-824, another nitroimidazo-oxazole which potentially can be used to treat drug sensitive and drug resistant TB.

The fluoroquinolones – used as a second line TB drugs for the multi-drug resistant TB are the several members of fluoroquinoles class of drugs.

TB Drug combinations – the combination of PA-824 moxifloxacin and pyrazinamide shows great initial bactericidal activity (EBA), however, the combination of these drugs need further investigation.

Tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS)

Immune reconstitution inflammatory syndrome is the early complication resulting from the initiation of antiretroviral therapy (ART) particularly among patients with tuberculosis and is generally associated with CD4+Th1 mediated immune response. The clinical manifestations of IRIS include fever, disseminated TB, pulmonary disease, acute renal failure and systemic reaction inflammatory syndromes. Majority of the patients present a self-limiting disease course with a low mortality rate.

Vaccine on the horizon

An article published in the WHO show a promising investigational vaccine candidate M72/AS01E for the prevention of TB disease. The results of an ongoing Phase IIb trial of the vaccine candidate indicate that two-doses of M72/AS01E to HIV-negative adults diagnosed with latent tuberculosis has reduced the progression of active TB disease with 54% efficacy.

Another research article in PLOS one, published May 12, 2017, illustrate that the SRL 172, an inactivated whole cell booster obtained from a non-tuberculous mycobacterium has demonstrated efficacy in a Phase 3 trial. A three-injection series of DAR-901 induced cellular and humoral immune response to mycobacterial antigens.

References

STD Series: Tuberculosis coinfection in HIV Patients

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