18th June 2024

HIV and Tuberculosis

HIV

Background

Human immunodeficiency virus (HIV) affected an estimated 37.7 million worldwide in 2020, with 1.5 million people becoming newly infected, as per the UNAIDS statistics published in 2021. The UK AIDS Trust estimated that there were approximately 105,200 people living with HIV in the UK in 2019.

HIV is a single-stranded RNA retrovirus which is spread predominantly through penetrating sexual contact, blood exposure and perinatally. HIV’s main negative impact on health is through progressive destruction of patients’ CD4+ helper T cell population, resulting in serious illness from pathogens not otherwise anticipated in a healthy patient (opportunistic infections). Other features include enhanced susceptibility to various cancer types (most notably non-Hodgkin Lymphoma and Kaposi sarcoma), organ-specific complications associated with viraemia (i.e. thrombocytopenia and HIV-associated nephropathy) and chronic conditions exacerbated through increased atherosclerosis (i.e. cardiovascular and cerebrovascular disease).

Clinical features

Seroconversion illness

Following exposure to HIV, patients undergo a latency period before symptoms manifest or a diagnosis can be readily made through conventional testing. Symptoms usually appear 2-4 weeks following infection and can occur as late as three months after. The HIV seroconversion illness typically consists of fevers, sore throat, rash and lymphadenitis.

Natural History of HIV Infection

The stages of HIV infection have been defined by the CDC. Following the Seroconversion illness (Stage 1), a patient enters an asymptomatic phase (Stage 2), lasting for usually 5 or even 10 or more years, although some variants are associated with a more-rapid progression. Stage 3, previously (and no longer) referred to as the Acquired Immunodeficiency Syndrome (AIDS), occurs when the absolute CD4+ T cell count falls below 200 cells per mm³. Without treatment, this stage of HIV typically has a life expectancy of 2-3 years.

Diagnosis

HIV-specific antibodies do not appear until at 2-12 weeks following infection, with >90% of patients being antibody positive at four weeks. Modern 4th generation ELISA testing can detect the p24 antigen as well as HIV1/2 antibody, conferring greater sensitivity in the early phases of the infection. Positive antibody testing is confirmed via western blot (also called immunoblot). Other methods, such as salivary testing for HIV antibody, and point-of-care 4ᵗʰ generation tests are also in common use, with comparable sensitivity and specificity.

Opportunistic Infections

A normal CD4+ count typically ranges from between 500 to 1,500 cells per mm³. The majority of opportunistic infections occur at CD4+ counts of 200 cells per mm³ or fewer. The various opportunistic pathogens associated with HIV are often grouped into the range of CD4+ count at which they are most expected to cause disease

< 200 cells per mm³: Pneumocystis jirovecii, oesophageal candidiasis

<100 cells per mm³ Cryptococcus neoformans, Toxoplasma gondii, Cryptosporidium parvum

<50 cells per mm³ Mycobacterium avium complex, cytomegalovirus

HIV Treatment

Advances in antiretroviral therapy (ART) have transformed HIV into a manageable condition with an overall-normal life expectancy, provided the disease is promptly diagnosed and the treatment regimen is rigidly adhered to. Following the results of the INSIGHT START Trial in 2015, rather than waiting for the CD4+ count to fall to a certain threshold, ART is now recommended to commence as soon as possible. Typical regimens contains three drugs, usually two nucleoside reverse transcriptase inhibitors (NRTIs) (e.g. tenofovir disoproxyl fumarate, emtricitabine) plus a third agent belonging to one of the following categories:

• Non-nucleoside reverse transcriptase inhibitors (NNRTIs): commonly selected agents, earlier generations are associated with neuropsychiatric side effects. Examples include efavirenz and rilpivirine
• Protease inhibitors (PIs): agents with high barriers to resistance, however a common cause of drug-drug interactions and diarrhoea.  Examples include darunavir and lopinavir
• Integrase strand transfer inhibitors (ISTIs): very well-tolerated agents with a high barrier to resistance. They are becoming increasingly popular. Examples include dolutegravir and bictegravir

References

• UNAIDS. UNAIDS Data 2020. New York: UNAIDS; 2020.  Available from: https://www.unaids.org/sites/default/files/media_asset/2020_aids-data-book_en.pdf
• National AIDS Trust. UK HIV Statistics. London: National AIDS trust; 2022. Available from: https://www.nat.org.uk/about-hiv/hiv-statistics
• INSIGHT START Study Group, Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B, Sharma S, Avihingsanon A, Cooper DA, Fätkenheuer G, Llibre JM, Molina JM, Munderi P, Schechter M, Wood R, Klingman KL, Collins S, Lane HC, Phillips AN, Neaton JD. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med. 2015 Aug 27;373(9):795-807. doi: 10.1056/NEJMoa1506816. Epub 2015 Jul 20. PMID: 26192873; PMCID: PMC4569751
• Cohen J, Powderly W, Opal S. Infectious diseases. Amsterdam: Elsevier; 2017
• European AIDS Society. Guidelines version 11.0. October 2021

Tuberculosis

Background

Tuberculosis (TB) is caused by the Mycobacterium tuberculosis complex, a group of “mycobacteria”; slow-growing obligate aerobic bacteria, so-called for the unique properties of their cell wall. TB ranks as a leading infectious cause of morbidity and mortality worldwide, with approximately one third of the world’s population estimated to be infected and 10 million cases of active disease being estimated in 2020, causing over 1.4 million deaths.

TB is spread mainly via inhalation of aerosolised particles of those with pulmonary tuberculosis, though it may affect any organ system. Inhaled bacilli undergo phagocytosis by tissue macrophages, forming a microscopic structure called a granuloma, mediated chiefly by IFN-γ. Latent TB reactivates (causing “secondary” or “reactivation” TB) in 5-10% of patients on average, with risk factors for reactivation including malnutrition, alcohol excess, diabetes mellitus, immunomodulatory drugs (most notably IFN-γ-targeting monoclonal antibodies) and immunocompromised states (i.e.  HIV infection).

Clinical Characteristics

Given that any organ system is potentially affected by TB, clinical presentation can be varied. The broader symptoms associated with TB include weight loss and drenching night sweats. In the case of pulmonary TB (which accounts for >70% of TB cases, productive cough with haemoptysis is typical. Crucially, TB generally takes a less acute or fulminant path than most serious bacterial infections, with symptoms frequently present for weeks to months before diagnosis. Other symptoms or signs specific to other organ sites may alternatively be present; i.e. abdominal distension, intestinal obstruction with ascites or a palpable mass (peritoneal or gastrointestinal TB); reduced air entry to auscultation (pleural TB); drowsiness, focal neurology, headache and signs of raised intracranial pressure (TB meningitis); back pain with long tract signs (spinal TB, or “Pott’s” disease) or painful, red eyes (granulomatous uveitis) – to name but a few. Erythema nodosum is another important manifestation of TB.

Diagnosis

Imaging

It is not possible here to describe TB’s radiological appearance in every organ system it affects. A plain film chest radiograph, however, is the first investigation in investigating TB. Fibrotic changes can be seen in the lung apices in prior secondary TB, while consolidation with or without cavitation, mediastinal adenopathy or pleural effusion can be seen in secondary or reactivation TB. Primary TB can affect any part of the lung and typically does not feature cavitation.

Microbiological diagnosis

TB is a microbiological diagnosis ultimately; however, obtaining microbiological proof is not always possible. While the gold standard for TB diagnosis is culture (performed on the specialised Löwenstein-Jensen medium), this can take up to 7 weeks. Samples can undergo Ziehl Neelsen staining for “acid fast bacilli”, or auramine staining of samples (i.e. sputum, bronchial washings urine, tissue, CSF, etc.) for quicker results, however yield is lower than culture. In “paucibacillary” sputum samples negative for staining, nucleic acid amplification technique (NAAT) can be used to give a rapid result, as well as detecting genes associated with rifampicin or isoniazid resistance. These tests have the best evidence and best performance in respiratory samples rather than extrapulmonary sites.

Latent TB is diagnosed using a combination of history and immunological testing. Mantoux testing uses an intradermal injection of purified proteins from M.tuberculosis to generate a localised skin reaction, the diameter of the induration of which is measured. Prior BCG vaccination can lead to false positives however, and more-modern tests such as the Interferon-λ-Release Assay (IGRA), which tests blood T-cell responses to several M. tuberculosis-specific proteins for evidence of prior exposure, can be more informative.

Treatment

Treatment duration for TB depends on bacterial susceptibilities and the affected body site. For pulmonary TB with a “pan-sensitive” organism, treatment is 6 months with a combination of the first-line anti-tuberculous agents; rifampicin, isoniazid, pyrazinamide and ethambutol. Treatment in this case consists usually of a 2-month “intensive phase” of all 4 drugs, followed by a consolidation phase of typically 4 months. Other second-line anti-tuberculous agents used in the case of resistance or contraindications to components of the first-line therapy include fluoroquinolones, bedaquiline and aminoglycosides. All TB medications require regular monitoring for side effects and complications.

References

• Ryan KJ. Sherris Medical Microbiology, 7e. USA: McGraw-Hill Education; 2017
• National Institute for Health Care Excellence. Tuberculosis. London: NICE; 2021.(NICE Guideline No. 33). Available from: https://www.nice.org.uk/guidance/ng33
• Thwaites G, Fisher M, Hemingway C, Scott G, Solomon T, Innes J; British Infection Society. British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. J Infect. 2009 Sep;59(3):167-87. doi: 10.1016/j.jinf.2009.06.011. Epub 2009 Jul 4. PMID: 19643501
• American Thoracic Society. The tuberculin skin test statement of American Thoracic Society, Medical Section of the American Lung Association. Am Rev Respir Dis. 1981;124:356–63
• European Centre for Disease Prevention and Control, WHO Regional Office for Europe. Tuberculosis surveillance and monitoring in Europe 2021 – 2019 data. Copenhagen: WHO Regional Office for Europe; 2021
• Guidelines for the prevention and management of Mycobacterium tuberculosis infection and disease in adult patients with chronic kidney disease. Thorax. 2010;65(6):558-558