1. Late presenters and opportunistic infections Jane Bruton Clinical Research Nurse Imperial College

2. Definitions Late presentation: Person presenting for care with a CD4 <350/mm3 cells or presenting with an AIDS-defining event, regardless of the CD4.

3. Definitions Presentation with advanced HIV disease: Person presenting for care with a CD4 <200/mm3 or presenting with an AIDS-defining event, regardless of the CD4.

4. In 2012 half of the cases of HIV were reported as late presenters (LP) (CD4 <350/mm3) 30% of late presenters had advanced HIV infection (CD4 <200/mm3) Late diagnosis in Europe

5. Europe Rate of late presentation are declining in MSM. People over 50 are more likely to present late in infection. Immigrants more likely to be late presenters. Hofstra M et al. Late presentation of HIV infection in Europe. 14th European AIDS Conference, Brussels, abstract LBPS8/3, 2013.

6. Romania late presenters 35% of new cases in 2013 were 20 – 24 and were late presenters Heterosexuals high number of late presenters MSM early- proactive presenters IVDU early - through medical screening Many late presenters have co-morbidities (HCV, HBV, TB and STI’s) High medical and psycho-social needs Country Progress Report on AIDS Romania Reporting period January 2013 – December 2013 2014

7. COHERE study Late presentation is associated with an increased rate of AIDS/deaths, particularly in the first year after HIV diagnosis. Late presentation or very late presentation significantly increases the risk of AIDS/death in the first two years after entry into HIV care Mocroft A et al. Risk factors and outcomes for late presentation for HIV-positive persons in Europe: results from the Collaboration of Observational HIV Epidemiological Research Europe Study (COHERE). PLOS Medicine: 10:9, e1001510, 2013.

8. Why do people present late? Stigma Fear Ignorance Lack of availability of testing

9. How can we reduce late presentation? Increase HIV testing Universal Opt out testing Increasing HIV Knowledge Reducing Stigma What is feasible with limited resources?

11. Opportunistic infections Called “opportunistic” because they take advantage of the weakened immune system. With healthy immune systems exposure to certain viruses, bacteria, or parasites cause no problems. These same bacteria and viruses cause great damage to a weakened immune system.

12. Opportunistic infections CD4 > 500 cells/mm 3 usually not at risk CD4 200-500 cells/mm 3 : Candidiasis (Thrush) Kaposi’s Sarcoma (KS) Pulmonary Tuberculosis (PTB) Lung infections

13. Tuberculosis (TB) Mycobacterium tuberculosis Can occur at any CD4 TB treated first if CD4 >350 Pulmonary or extrapulmonary Risk of TB is 12-20 x greater in HIV+ve people Tx with anti TB antibiotics for 6-9 months

14. Tuberculosis (TB) Symptoms A cough that lasts for more than 2-3 weeks Coughing up phlegm or blood Chest pain Weakness or fatigue Weight loss Lack of appetite Fever or chills Night sweats

15. TB Pathogenesis Latent Infection LTBI Within 2 to 8 weeks the immune system produces special immune cells called macrophages that surround the tubercle bacilli These cells form a barrier shell that keeps the bacilli contained and under control (LTBI)

16. TB pathogenesis TB disease If the immune system CANNOT keep tubercle bacilli under control, bacilli begin to multiply rapidly and cause TB disease This process can occur in different places in the body

17. Transmission Probability that TB will be transmitted depends on: –Infectiousness of person with TB disease –Environment in which exposure occurred –Length of exposure –Virulence (strength) of the tubercle bacilli The best way to stop transmission is to: –Isolate infectious persons –Provide effective treatment to infectious persons as soon as possible

18. TB infection and NO risk factors TB infection and HIV infection (pre-Highly Active Antiretroviral Treatment [HAART]) Risk is about 5% in the first 2 years after infection and about 10% over a lifetime Risk is about 7% to 10% PER YEAR, a very high risk over a lifetime Progression to TB disease TB and HIV

19. TB in HIV TB is more difficult to diagnose in PLWH TB progresses faster in PLWH TB is more likely to be fatal in PLWH if undiagnosed or left untreated TB occurs earlier in HIV infection than other Ois (once TB infection is acquired, HIV impairs the ability to contain new TB infection)

20. Signs and Symptoms Signs and symptoms comparable to non-HIV infected individuals However in advanced HIV infection…. TB often presents atypically with extrapulmonary disease In extrapulmonary disease symptoms usually not localized to particular organ or site CXR may reveal adenopathy, atypical infiltrates, pleural effusions or miliary disease OR may reveal no abnormality at all

21. Treatment 4 drugs - initial phase 2/12 initial phase - isoniazid, rifampicin, pyrazinamide and ethambutol (if organism fully susceptible, ethambutol may be stopped) Continuation phase - 4/12 (longer depending on circumstances) isoniazid and rifampicin Pyridoxine (vitamin B6) for all patients with isoniazid dosing Duration of TB treatment the same - HIV positive and negative

22. Drug-Resistant TB Mono-resistantResistant to any one TB treatment drug Poly-resistantResistant to at least any 2 TB drugs (but not both isoniazid and rifampin) Multidrug resistant (MDR TB) Resistant to at least isoniazid and rifampin, the 2 best first-line TB treatment drugs Extensively drug resistant (XDR TB) Resistant to isoniazid and rifampin, PLUS resistant to any fluoroquinolone AND at least 1 of the 3 injectable second-line drugs (e.g., amikacin, kanamycin, or capreomycin)

23. CD4 count cells/µlWhen to treat with ARTs <100cells/µlAs soon as possible: after starting TB therapy 100-350cells/µlAs soon as possible, but can wait until after completion of 2 months of TB Rx CD4 consistently >350cells/µl At the discretion of the treating physician Suggested timing for starting ARV’s in HIV/TB co-infection (BHIVA,EACS guidelines 2011)

24. Immune Reconstitution Inflammatory Syndrome (IRIS) IRIS = worsening or appearance of new signs, symptoms or radiological abnormalities, occurring after starting ARV’s Symptoms: – Fever – Worsening infiltrates or effusion, – mediastinal & peripheral lymphadenopathy (enlarging & painful) – abscesses – intracranial tuberculomas Appears in the first 1-6 weeks of ARV Rx No diagnostic test Treat with high dose corticosteroids

25. Kaposi’s Sarcoma (KS) Human Herpes Virus-8 Purple lesions on the body, the mouth, and internal organs Occasionally gastrointestinal complaints with disseminated KS Treated with chemotherapy and ART

26. Candidiasis (Thrush) Oral/ Oesophageal thrush symptoms include: White patches on gums, tongue, throat or lining of the mouth Pain in the mouth, throat, or chest Difficulty swallowing, loss of appetite Nausea, vomiting, weight loss Treated with antifungal medicine Topical agents Fluconazole PO or IV amphotericin B

27. Opportunistic infections 100-200 cells/mm 3 : Pneumocystis Jirovecii (Carinii) Pneumonia (PCP) Histoplasmosis and Coccidioidomycosis Progressive Multifocal Leukoencephalopathy (PML)

28. Progressive Multifocal Leukoencephalopathy Rare, usually fatal Progressive damage to the white matter Caused by JC virus Weakness or paralysis Vision loss, impaired speech, cognitive deterioration Treatment ART

29. Pneumocystis Jirovecii Pneumonia (PCP) Signs and symptoms Shortness of breath, fever Dry cough, chest pain Treatment (antifungal agents) Prophylaxis with CD4<200

30. Opportunistic infections 50-100 cells/mm 3 : Toxoplasmosis Cryptosporidiosis Cryptococcal Infection Cytomegalovirus (CMV) <50 cells/mm 3 : Mycobaterium Avium complex (MAC)

31. Cytomegalovirus (CMV) Common virus Can attack several parts of the body Commonly CMV retinitis (causes blindness) Treatment with Ganciclovir then ART (after initial CMV tx)

32. Toxoplasmosis Parasite Toxoplasma gondii Causes encephalitis and neurological disease The parasite is carried by cats and birds Symptoms Headache, confusion, motor weakness, fever and seizures Treatment with anti protozoal (pyrimethamine) and antibiotics (sulphadiazine)

33. Mycobaterium Avium complex (MAC) Bacteria that can be found in soil or water Infects, lungs, intestines or dissemninated Signs and Symptoms of MAC: Fevers, night sweats, abdominal pain, fatigue, diarrhoea Treatment Antimycobactrial, (Azithromycin or clarithromycin and Ethambutol)

34. AIDS defining Pneumocystis jirovecii pneumonia  Recurrent severe bacterial pneumonia  Chronic herpes simplex infection  Candidiasis: Esophageal, bronchi, trachea or lungs  Extra pulmonary, pulmonary, disseminated tuberculosis  Kaposi’s sarcoma  Cytomegalovirus, disease and retinitis  Encephalopathy, HIV related  Herpes simplex, bronchitis, pneumonitis, esophagitis, chronic>1mth  Disseminated mycosis (extrapulmonary histoplasmosis, coccidiomycosis)  Mycobacterium (avium complex, TB, kansasii, other)  Progressive multifocal leukoencephalopathy  Chronic cryptosporidiosis  Chronic isosporiasis  Lymphoma (cerebral, Burkitt’s, immunoblastic,non-Hodgkin)  Salmonella (sepsis, recurrent)  Toxoplasmosis (brain)  Wasting syndrome  Pneumonia (recurrent)  Cervical cancer (invasive)