Module 3 opportunistic infections and hiv related conditi

MODULE 2 HIV RELATED DISEASES

OBJECTIVES List the common opportunistic infections, skin conditions and malignancies seen in HIV infected adults Describe their clinical presentation and management and preventive strategies

Important Messages about OIs Opportunistic infections cause the vast majority of the morbidity and mortality associated with HIV Most are readily treatable and/or preventable Most of these treatments are simple, available and affordable

Brainstorming session… What are the most common and the most important opportunistic infections seen in Kenya?

Common Opportunistic Infections Tuberculosis Bacterial infections Pneumonia Gram negative sepsis P neumo c ystis p neumonia - PCP (now Pneumocystis jiroveci previously carinii ) Cryptococcal meningitis Toxoplasmosis Candidiasis Infective diarrhoea Herpes Zoster Infective Dermatoses

HIV Related Malignancies Kaposi’s sarcoma Primary CNS lymphoma Carcinoma of the cervix Other lymphomas

Other conditions HIV wasting syndrome Non infective dermatoses

TB and HIV TB is the major opportunistic infection in Kenya Since the onset of the HIV epidemic in the early eighties in Kenya, the prevalence of TB stopped falling and over the past 2 decades has risen sharply HIV fuels the TB epidemic HIV is the single most important risk factor for TB >50% TB patients are HIV co-infected

TB and HIV TB occurs by reactivation of latent infection newly acquired infection HIV increases the risk of TB progression HIV increases the rate of TB progression TB may speed the progression of HIV disease ART reduces the incidence of TB in PLHA

Clinical Presentation of TB in HIV Patients Depends on immune status of patient In early HIV disease, presentation tends to be typical pulmonary TB As immune system deteriorates mycobacterial infection more likely to disseminate Extrapulmonary TB more common in HIV infected Pleural effusion, lymphadenopathy, pericardial disease, miliary, TB meningitis, peritoneal and spinal TB

Pulmonary Tuberculosis: Clinical Presentation Cough for >3 weeks Fever Night sweats Chest pain Weight loss Signs – wasting, crepitations, consolidation, effusion etc.

Diagnosis of Pulmonary TB Sputum examination Negative Sputum does not exclude TB! Sputum negative PTB more common in HIV+ Only 50% sensitive Chest radiograph No “typical” TB X-ray TB can create almost any abnormality, or even none DD – pneumonia, PCP, KS, abscess

Extrapulmonary Tuberculosis: Clinical presentation Often no focal signs in HIV Fever, weight loss and lethargy Can have focal signs: Focal lymphadenopathy Hepatosplenomegally Septic arthritis Signs of meningitis Pericarditis Peritonitis Disseminated multi-system TB can be clinically indistinguishable from “HIV Wasting Syndrome”

Diagnosis of Extrapulmonary TB Often very difficult CXR often normal and sputum if available is negative If lymph nodes enlarged - aspirate If meningism present - lumbar puncture If septic arthritis or abscess - aspirate Always request ZN Stains on samples

Diagnosis of Extrapulmonary TB Often diagnosed on clinical suspicion alone A dramatic response to a “therapeutic trial” of anti-TB drugs is diagnostic Greatly Under-diagnosed “ An HIV positive patient who is deteriorating, with profound weight loss and fever, should not be allowed to die without a therapeutic trial of TB treatment” NB : Once trial of anti-TB therapy is started it should be completed

A Patient with HIV Wasting Syndrome This can be clinically indistinguishable from advanced TB

Tuberculosis Management: Patients Not Receiving ART Intensive Phase – 2 months Rifampicin, Isoniazid, Ethambutol and Pyrazinamide Continuation Phase – 6 months Isoniazid and Ethambutol Pyridoxine should be given throughout to prevent peripheral neuropathy Patients should be counseled to report any visual changes (Ethambutol) and Neuropathy (Isoniazid)

TB Treatment: Patients Requiring ART Anti TB treatment and ART should not be initiated simultaneously Overlapping toxicities Adherence issues Always treat active TB first In severely immunocompromized patients ART should be initiated as soon as practical

TB Treatment: Patients Requiring ART Choice of ART should take into account TB drugs Efavirenz can be used with Rifampicin thus preferred in the intensive phase PIs and NVP should NOT be combined with Rifampicin because of drug interactions Remember the immune reconstitution syndrome Paradoxical worsening of symptoms due to immune recovery Fever, lymphadenopathy, worsening CXR, CNS symptoms, effusions Differential diagnosis: TB treatment failure; lymphoma

TB/HIV - Prognosis Mortality higher in TB/HIV co-infected patients ~4 fold Most early mortality caused by bacterial infections - gram negative septicemia Very important that TB/HIV patients receive cotrimoxazole prophylaxis which prevents most infections that occur in TB/HIV infected patients Relapse rates similar in HIV positive and negative patients ~5% using a Rifampicin based treatment.

TB Preventive Strategies Routine neonatal BCG in all children except for those with AIDS/severe immunosuppression Effective case finding and treatment of infected and infectious people Treatment of latent tuberculosis infection (LTBI) = INH prophylaxis Essential to screen for active TB (symptoms, signs, sputum +/- CXR) Recommended in all children < 5 years who are household contacts of infectious index case Other anti-TB drugs not recommended for chemoprophylaxis Toxicity Preservation of other drugs (resistance)

TB Preventive Strategies: Isoniazid Prophylaxis HIV is the single most important risk factor for TB INH prophylaxis is beneficial in PLHA at high risk of, but without active TB Reduces the risk of progression of recently acquired TB reactivation of latent TB infection Particularly in individuals with a positive Mantoux test Benefits last up to 2.5 years

TB Preventive Strategies: Isoniazid Prophylaxis Current recommendation : to be used where patient follow up is assured (e.g. prisons, occupational services) INH 300 mg daily for 6 months + pyridoxine 50 mg OD (exclude active TB)

TB/HIV: Conclusion TB a major cause of morbidity and mortality in HIV patients TB occurs at any stage of HIV infection EPTB/atypical presentations of TB more common in severe HIV disease All co-infected patients should be started on cotrimoxazole prophylaxis as it reduces mortality HIV patients on ART remain at risk of developing TB; active case detection important

Pneumocystis jiroveci Pneumonia (PCP) Symptoms: Shortness of breath / respiratory distress Onset of illness insidious often taking weeks. Can be acute Cough Usually dry Fever Signs: Tachypnea Tachycardia Cyanosis Lung auscultation often normal Clinical Presentation

Pneumocystis Carinii Pneumonia Diagnosis High index of suspicion Chest radiograph Classically bilateral, diffuse interstitial shadowing Can be relatively normal even with severe respiratory distress Induced sputum and Bronchoalveolar lavage Can give definitive diagnosis Rarely available or possible Clinical suspicion key to diagnosis

PCP: Management Severe disease High dose cotrimoxazole for 21 days 120mg/kg per day in 3-4 doses e.g. dose for 60kg man is 7200mg/day 7200mg = 15 x 480mg tablets = approx 4 tabs QDS If allergic to or intolerant of cotrimoxazole Clindamycin at 900mg iv 8 hourly plus primaquine 30mg orally/day. Clindamycin may also be given orally at a dose of 600mg 6 hourly. For mild to moderate disease Trimethoprim 15mg/kg/day + Dapsone 100mg/day PO for 21 days

PCP management cont’d Prednisone is beneficial if severe respiratory distress or cyanosis present. Dose-40mg BD for 5 days, then 40mg OD for 5 days, then 20mg OD for 5 days then STOP. Supportive therapy Oxygen therapy IV fluids Nutrition Monitor bloods cotrimoxazole toxicity Multi organ dysfunction in the severely ill Secondary prophylaxis needed after treatment complete

PCP Prophylaxis: Cotrimoxazole 960 mg OD Primary prophylaxis Current recommendation : ideally all HIV positive patients should be given cotrimoxazole prophylaxis, which is effective against PCP Priority should be given to the symptomatic (WHO 2,3,4), including TB co-infected patients, and those with CD4<200

Secondary Prophylaxis Prior to the availability of ART, patients who had experienced an episode of PCP were given cotrimoxazole prophylaxis for life With ART, immune reconstitution occurs In industrialized countries, primary and secondary cotrimoxazole prophylaxis is now safely discontinued once immune recovery is established

Cotrimoxazole Prophylaxis in Kenya In Africa as well as Toxo and PCP, cotrimoxazole prevents a lot of other infections/organisms including Community-acquired bacterial pneumonia, Staph. aureus Non-typhi salmonella, other gram negative GI organisms Malaria, Isospora, These infections occur at a higher incidence in PLHA than in HIV negative Cotrimoxazole has been shown to reduce Morbidity across all ranges of CD4 Mortality in those with symptoms and CD4<200 Current recommendation : cotrimoxazole (primary and secondary) prophylaxis should not be discontinued even in patients on ART

Cotrimoxazole intolerance/allergy Cotrimoxazole well tolerated in African patients If allergic to CTX desentsitization should be carried out (see clinical manual) Very important in view of the efficacy of this drug as a prophylactic agent against many organisms If above fails then use Dapsone 100mg OD Effective against PCP and Toxoplasmosis Should be discontinued following established immune reconstitution

Cryptococcal Meningitis: Clinical presentation Symptoms Headache Severe - can come on over weeks Fever Often absent in early stages Neck stiffness Often absent in early disease Signs Abnormal gait, cranial nerve palsies less common* Papilledema Confusion, convulsions and coma Caused by yeast like fungus Cryptococcus neoformans

Cryptococcal Meningitis: Diagnosis High index of clinical suspicion Lumbar puncture - most useful Raised intracranial pressure Usually mild lymphocytosis India ink stain – positive in 60-80% cases Negative India ink does not exclude CM Cr yptococcal A ntigen T est (CRAG) – if possible Highly sensitive and specific (>95%) – expensive Useful in differentiating from TB meningitis Very similar in presentation and CSF cell/biochemistry profile

Cryptococcal meningitis Indian ink stain showing budding yeast of C. neoformans

Cryptococcal Meningitis: Management For severe/advanced disease : Amphotericin B 0.7-1mg/kg daily for 2 weeks/until clinically stable Followed by: Fluconazole 400mg daily for 8-10 weeks If diagnosed early/ amphotericin unavailable: Fluconazole 400-800mg daily for 10-12 weeks alone Treatment failure and mortality higher

Cryptococcal Meningitis: Management Supportive treatment If raised ICP as indicated by severe headache, visual disturbances perform repeated lumbar puncture (e.g. 30ml CSF per day) Reduces mortality Reduces blindness Helps with pain and consciousness level No evidence of benefit from steroids These are beneficial in TB Meningitis Support of the patient with impaired consciousness

Cryptococcal Meningitis: prophylaxis Maintenance therapy -secondary prophylaxis Fluconazole 200mg OD If on ART continue until CM therapy completed AND CD4 established at >100 for more than 6 months Relapse rare with prophylaxis and immune reconstitution due to ART Primary prophylaxis: not recommended

Toxoplasmosis Caused by Toxoplasma gondii a protozoan whose definitive host is the cat Humans infected by ingestion of T. gondii in food contaminated with cat feces or undercooked meat Vertical transmission occurs serious consequences if it occurs in the 1 st trimester Asymptomatic in >90% of immunocompetent adults and children Commonly a result of reactivation of latent disease in patients with AIDS and those on chemotherapy for lymphoproliferative disorders CD4 < 100 cells/mm 3 Commonly encephalitis

Toxoplasmosis: Clinical Presentation Symptoms Can be acute or progressive Headache Occurs in about 70% Can be severe – usually no meningism Neurological deficits Fever Only in 50% at presentation Confusion Sometimes presents as subtle personality change Convulsions Signs Focal neurological deficit Progressive paralysis Blindness Cerebellar signs, incontinence Fever

Toxoplasmosis: Diagnosis Typically CD4 <100 CT ideal if available – =/>2 ring enhancing lesions High index of clinical suspicion needed “ An HIV positive patient with headache, confusion and signs of a SOL, with a relatively normal CSF has Toxoplasmosis until proven otherwise” Differential diagnosis – Tuberculoma, bacterial abscess, CVA, primary CNS lymphoma. A response to empirical treatment is virtually diagnostic Usually within 2 weeks

Toxoplasmosis: Management Pyrimethamine – 200 mg loading dose followed by 50 daily + Sulphadiazine – 1 g -1 .5 g OD + Folinic acid – 20mg daily f or 6 -8 weeks Or Cotrimoxazole - 4 -6 weeks 25mg/kg daily of sulphamethoxazole or 5mg/kg TMP in two divided doses E.g. 60kg man 1800mg/day = 3.7 Tablets = Approx 2 Tablets BD Maintenance therapy Pyrimethamine 50mg + Sulphadiazine 1g + Folinic acid 20mg OD until CD4 >200 for more than 6 months (clindamycin 300mg OD can replace sulphadiazine)

Prevention of toxoplasmosis Basic food hygiene Eating well cooked meats These may not be very important since most infection a result of reactivation of latent disease

Prevention of toxoplasmosis Primary prophylaxis Cotrimoxazole 960mg per day In the West started when CD4 < 200 cells/mm 3 Primary prevention covered with standard cotrimoxazole prophylaxis given to all HIV patients as recommended “ Secondary prophylaxis” same as maintenance therapy above Used to be life long prior to ART Can be safely discontinued after established immune reconstitution (CD4 >200 for >> 6 months)

Bacterial pneumonia Clinical presentation Acute, productive cough Fever Chest pain Breathlessness Signs of consolidation

Bacterial Pneumonia Management Amoxicillin or Erythromycin or Cephalosporin NB: Cotrimoxazole effective prevention against bacterial pneumonia

Candidiasis Vaginal Not strictly an OI unless chronic (>1month) or unresponsive to treatment Oropharyngeal Very common WHO Stage III defining - CD4 usually <300 Esophageal Significant cause of morbidity and mortality WHO Stage IV defining - CD4 usually <100

Vaginal Candidiasis Clotrimazole Vaginal Pessaries 200mg daily for 3 days OR 500mg stat Alternative Fluconazole 150mg stat Recurrent (>>4 episodes per year) Clotrimazole pessary 500mg weekly Fluconazole 100 mg weekly

Oro-pharyngeal Candidiasis White pseudomembraneous plaques, atrophic /erythematous, angular cheilitis Treatment Nystatin drops or tablet 500,000 IU QDS Miconazole Oral Gel 60mg QDS Miconazole Buccal Tablet OD for 7 days If unresponsive: Fluconazole 100mg OD for 7 days

Esophageal Candidiasis Causes painful swallowing (odynophagia) Results in inadequate oral intake Dehydration, malnutrition, wasting Treatment: Fluconazole 200mg stat, then 100mg daily for 14 days Ketoconazole 200mg daily for 14 days Maintenance therapy required unless immune reconstitution occurs. All such patients should be evaluated for ART

Infective Diarrhea Acute diarrhea (>3 loose motions/day x < 2 weeks) Stool cultures where possible If acutely unwell and pyrexial with blood in stool Consider a quinolone (ciprofloxacin 500mg BD x 10-14 days) Remember drugs as a cause of diarrhea including antibiotics Chronic/recurrent diarrhea (>1month) Copious amount of watery diarrhea associated with abdominal pain, +/- fever Symptoms intermittent. CD4 < 200 Often associated with wasting, malabsorption Cause usually not identified in practice; rule out acute infections where possible Cotrimoxazole reduces incidence of diarrhea in PLHA

Infective Diarrhea: Management Oral rehydration therapy IV fluids If severe dehydration Antimicrobials If possible, treat according to stool analysis Stool analysis often not helpful Empirical treatment justified in chronic, debilitating diarrhea Symptomatic treatment a relief to patients

Empirical Management of Chronic Diarrhea Trial of Cotrimoxazole – 2 tabs BD 5 days (not in patients already on cotrimoxazole prophylaxis) If no improvement: Trial of Metronidazole – 400mg QDS 7 days If no improvement: Trail of an Antihelminthic – e.g. Albendazole If no improvement: Symptomatic management Eg: Loperamide, Diadis, dietary advice etc. ART effective in eliminating chronic diarrhea

Skin Conditions Infective Dermatitis

Herpes Zoster Reactivation of previous varicella (chicken pox) Very common Can occur early in HIV disease Multi-dermatomal, recurrent Causes acute, severe pain Risk of debilitating post herpetic neuralgia (PHN more common in older aptient) Disfiguring keloid formation Diagnosis clinical

Opthalmic Herpes Zoster Risk of permanent visual impairment Need to treat early Need to treat aggressively (IV aciclovir if possible) Healed Opthalmic HZ

Herpes Zoster: Management Analgesics – for acute pain Paracetamol plus an NSAID (+/- an opiate) Apply calamine lotion regularly Reduces itch and secondary infection If presents with new lesions Give Aciclovir (the sooner the better) Reduces acute pain, duration of lesions, number of new lesions and systemic complaints ACV does not alter the rate of PHN

Aciclovir for Herpes Zoster Aciclovir 800mg 5 times a day for 7-10 days If visceral/extensive or disseminated or ophthalmic where possible give IV aciclovir (10mg/kg TDS)

Post Herpetic Neuralgia Difficult to treat Pain difficult for patients to define - pricking, tingling, burning Treatment Amitryptiline 25-50mg at night Carbamezipine 100mg BD (up to 200mg TDS) Can be used in combination Warn patients that it takes up to weeks to notice the benefit “ Don’t give up on the tablets too soon”

Types of Genital Herpes First episode: primary infection, non-primary infection Recurrent episode Asymptomatic episode

Genital Herpes Red, raised, tender vesicles or lesions may occur anywhere on the vulva, in the vagina, or on the cervix or anal area. Multiple vesicles may occur.

Genital Herpes Vesicles coalesce, become denuded and form large ulcers

Genital Herpes—Recurrence on the Cervix

HIV and Genital Herpes More extensive disease Frequent recurrences Chronicity Associated high genital viral load Important cofactor for transmission of HIV Treatment of fist episode as standard however higher doses may be required for longer periods especially in chronic cases

Infective Dermatoses Scabies Sarcoptes scabiei Very common – under diagnosed and under treated Papular intensely itchy rash Often not of the typical appearance Norwegian scabies - extensive skin involvement with crusting of lesins seen in immunocompromized patients Seborrheic dermatitis Pityrosporum yeast Erythematous plaques with scales at the edge of scalp around nose and ears Treat with 2.5% hydrocortisone with antifungal cream + tar based /antifungal shampoos Other fungal skin infections Can be very debilitating and disfiguring; significant cause of stigmatization

Papular Pruritic Eruption (PPE) AKA Purigo Nodularis Cause unknown Occurs with CD4<200 Severe itching, with hyperpigmented, hyperkeratotic, excoriated papules and nodules Associated thickening of skin (lichenification)and scarring This rash could be scabies or PPE

Management of Infective Dermatoses Scabies Consider an empirical trial of therapy for any patient with a very itchy rash Benzyl Benzoate at night, for 3 nights Remember itchiness may persist for 1-2 weeks after treatment Treatment of household contacts Fungal Infections Eg: Clotrimazole cream. Griseofulvin or Fluconazole if severe or resistant to treatment Calamine can relieve itch Steroids should only be used as a very last resort Greatly overused

Management of PPE PPE Chlorhexidine/Cetrimide ointment provides great benefit to some Antihistamines ART

HIV Associated Malignancies Kaposi’s Sarcoma (Human Herpes 8) Lymphomas HPV associated carcinoma (cervical and anal)

Kaposi’s Sarcoma Many times more common in HIV positive than negative Firm dark nodules, papules, patches that are not symptomatic Skin Oropharyngeal Multisystem (GI, lungs) WHO Stage IV/AIDS defining Clinical diagnosis; biopsy if uncertain

Kaposi’s Sarcoma: Management Prognosis depends on extent of disease and CD4 count ART associated with reduced incidence of KS regression of lesions prolonged survival Incurable condition; treatment aims to reduce symptoms and prevent progression

Kaposi’s Sarcoma: Management Local therapy Disease limited to skin, relatively few lesions, no systemic symptoms Radiotherapy Intra-lesional vincristine Systemic treatment for extensive disease, systemic involvement Combination chemotherapy- vincristine + bleomycin Vincristine alone These drugs are toxic and should preferably be given by a medical officer and patients should be monitored closely. If necessary refer patient

Lymphoma Primary CNS Lymphoma EBV associated Much more frequent and commonest lymphoma in HIV infected Incidence somewhat reduced by effective ART Usually CD4 low (<50) CNS symptoms without fever Diagnosis: CT scan, failure to respond to empiric Toxo treatment Treatment: refer (DXT, steroids, chemo). Poor outcome. Effective ART prolongs survival

Lymphoma Non Hodgkin’s Lymphoma More frequent in HIV infected Caused by EBV in the presence of immunosuppression (CD4<100) More likely to present with systemic symptoms (fever, hepatitis, effusions GI) Biopsy required for diagnosis Treatment: refer (combination chemo and steroids)

Cervical Cancer HIV related immunosuppression is associated with cervical intraepithelial neoplasia (CIN) and cervical cancer Invasive cervical cancer has been an AIDS defining illness since 1993. The presence of HIV infection allows permissive replication of human papilloma virus (HPV), the causative agent More aggressive and more likely to persist There may be an increased risk of rapid progression from CIN to cervical carcinoma. With highly active antiretroviral therapy (HAART) CIN tends to regress with rising CD4 count and falling viral load.

Cervical Cancer In Kenya, cervical cancer is the number 1 cancer causing death in women. less than 1% of the population at risk is screened. Kenya unable to master the resources required for a Pap smear based screening program. Visual approaches using either acetic acid (vinegar. VIA) or lugol’s iodine (VILI) to detect precursor cervical disease/cancer can be alternative in our setting Both VIA and VILI and have been shown to be much more sensitive than the standard Papanicolaou smear Visual approach based services are being set up

Cervical cancer Cervical cancer is largely a preventable disease BCC (reduction of acquisition of STIs) Cervical screening programs. Where possible HIV infected women should undergo cervical screening at enrollment (and annually)

Summary OIs and HIV related conditions cause most of the morbidity and mortality in PLHA Cotrimoxazole prophylaxis is a greatly underused, cheap, simple and highly effective preventive therapy against many OIs Most OIs are readily treatable ART with resultant immune reconstitution greatly reduces the incidence and outcome of most HIV related conditions

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