HIV

EPIDEMIOLOGY: -Global disease - 95% of all infections occurring in developing world, major brunt of epidemic in sub-Saharan Africa and S.E Asia. Routes of transmission: (1) (2) (3) (4) (5) sexual intercourse (anal+vaginal) injecting drug abuse:sharing or re-use of contaminated needles blood and blood products/organ donation mother to child(in utero,birth) breast feeding

RISK FACTORS FACILITATING SEXUAL TRANSMISSSION INCLUDE: (a) (b) seroconversion and advancing stage of disease concurrent ulcerative disease of the genitalia

Materno-fetal transmission occurs in 12-19% of pregnancies in patients with HIV/AIDS The risk of transmission from mother to baby can be reduced by: (a) caesarian section delivery (b) avoidance of breastfeeding (c) anti-retroviral therapy

THE VIRUS - member of lentivirus family - contains RNA which is transcribes to DNA via reverse transcriptase enzyme. - The main target sites of action of anti-retroviral therapy are the reverse transcriptases and proteases Two types of HIV: HIV 1: (previously HTLV III): world-wide prevalence HIV 2: common in West Africa PATHOGENESIS HIV has tropism for the following CD 4 cells: (1) (2) (3) (4) T-helper lymphocytes B-lymphocytes Macrophages CNS cells

- Causes progressive immune dysfunction, charecterised by CD 4 cell depletion. - Impairment of immunity is primarilarly cell mediated, but as the disease progresses there is a general immune dysregulation.

The following laboratory markers are associated with disease progression: (1) DECREASE in CD 4 lymphocytes count (normal > 500/mm3 or 0.5 X 10 9/l) CD 4 < 200 mm3 = AIDS, irrespective of the presence of clinical response. (2) polyclonal gammopathy (3) increased B2 microglobulin (4) increased neopterin (inflammatory marker,indicative of cytokine production) SEROCONVERSION AND HIV ANTIBODY TESTING After inoculation: window period can be up to 3 months-HIV antibodies may not be detected during this time. HIV P4 antigen may be detectable during seroconversion. Current antibody tests detect HIV 1 and HIV 2. Screening is performed with ELISA.Positive test is confirmed by repeat ELISA and Western blot. Before testing foe HIV serology one should obtain informed consent. INDICATIONS FOR HIV SEROLOGY TESTING: PERSONS IN HIGH-RISK CATEGORIES: IV drug abusers Homosexual/bisexual men + partners, persons with multiple sexual partners and those who engage in unprotected sex Hemophiliacs Person with STI/TB Received blood products before 1985
(1)

- Patient request (2) (3) (4) PREGNANT WOMEN DONORS OF BLOOD,SEMEN,ORGANS AFTER OCCUPATIONAL EXPOSURE

-One third of patients develop seroconversion illness. SEROCONVERSION ILLNESSES

fever malaise diarrhea meningo-encephalitis

rash sore throat lymphadenopathy arthralgia

CENTRE FOR DISEASE CONTROL (CDC) CLASSIFICATION OF HIV/AIDS (1992): STAGE 1 Primary seroconversion illness STAGE 2 Asymptomatic STAGE 3 Persistent generalized lymphadenopathy STAGE 4 AIDS

RESPIRATORY DISEASE ASSOCIATED WITH HIV/AIDS 1. Pneumocystis carinii pneumonia (PCP) - pneumonia is the most common opportunistic infection and clinical presentation of AIDS> - PCP constitutes 40% of all AIDS-defining illness. Symptoms of PCP: dry cough dyspnea fever malaise remarkably few abnormal signs on chest examination

INVESTIGATIONS FOR PCP Chest X-ray : abnormal in 90% Typical appearance: bilateral mid- and lower-zone shadowing and interstitial shadowing Atypical X-ray findings: cavitation, upper zone opacities, pneumothorax or unilateral consolidation, effusions-rare. Pulse oximetry: hypoxia in 90%, pO2 falls with exercise. Identification of pneumocystis cysts - samples should be obtained by sputum induction of BAL stains with silver or immunofluorescent antibody. Sensitivity for detection of cysts is 90%. If BAL is negative, lung biopsy should be performed. POOR PROGNOSTIC FEATURES IN PCP:

Respiratory failure Advanced disease TREATMENT: High dose co-trimoxazole or intravenous pentamidine or atovoquone -High incidence of intolerance to co-trimoxazole: nausea, vomiting, rash leucopenia, and thrombocytopenia. Desensitization regimens to reduce intolerance. High dose steroids improve prognosis: use if pO2 < 8 kPa(60 mmHg) 50 % risk of recurrence within 12 months. Prophylaxis if CD4 count < 200/mm3 and if had a previous episode of PCP. (2 prevention) 2. PULMONARY TUBERCULOSIS - 2.5 5% of AIDS patients are co-infected with Mycobacterium tuberculosis. - Extra-pulmonary disease is more common in these patients - Problem with drug resistance - Other atypical features include: (a) lymphatic involvement (b) atypical appearance on Chest X-ray (c) occurs at any stage of HIV disease, and at any level of CD 4 count (d) multi-drug resistant TB (e) atypical mycobacterial infections -usually Mycobacterium avuim intracellulare

DIAGNOSIS: - multiple sputum examination for acid fast bacilli TREATMENT -Standard -Drug interactions of rifamycins with HAART: especially protease inhibitors and non-nucleoside inhibitors> 3. OTHER RESPIRATORY DISEASES IN HIV/AIDS 1. VIRAL Cytomegalovirus (CMV) Herpes simplex Ebstein-Barr virus Adenovirus Influenza 2. BACTERIAL Streptococcus pneumoniae Staphylococcus aureus Mycobacterium tuberculosis Mycobacterium avuim intracellulare 3. FUNGAL Candida Histoplasmosis Cryptococcus Nocardia

4. PROTOZOAL Toxoplasma 5. TUMOUR Kaposis sarcoma Non Hodgkins lymphoma RADIOLOGICAL APPERANCE OF OTHER INFECTIONS

Cavitation: M.tuberculosis,Norcardia,S.aureus Consolidation: Streptococcus pneumoniae,Toxoplasma Effusion:S.aureus, (Kaposis sarcoma may also cause effusion)

GASTROINTESTINAL DISEASES IN PATIENTS WITH HIV/AIDS FOUR MAIN PRESENTATIONS: oral/esophageal disease abdominal pain/diarrhea biliary/pancreatic disease ano-rectal symptoms

1. Oral/esophageal disease 90% of patients will develop this condition oral/esophageal candidiasis oral hairy leukoplakia periodontal disease (including gingivitis) kaposis sarcoma herpes simplex CMV Lymphoma

- These lesion maybe aymptomatic or patients may have dysphagia or odynophagia. 2. DIARRHEA/ABDOMINAL PAIN - Weight loss and malnutrition is very common in any stage of HIV. 50% of patients have diarrhea - Specific enteropathogens are isolated in 60% cases ENTEROPATHOGENS FOUND IN HIV BACTERIA - Salmonella More frequent in HIV-infected More likely to cause bacteraemia Recurrence is common

TREATMENT: co-trimoxazole or ciprofloxacin - Campylobacter - TREATMENT: ciprofloxacin - Shigella PROTOZOA -Giardia lamblia VIRAL CMV OPPURTUNISTIC ORGANISMS
-

Bacterial : atypical mycobacteria (M.avuim intracellulare with CD4 < 100/mm3)

TREATMENT: claritromycin + ethambutol + rifampicin (3-4 drugs are recommended) - Protozoal : Isospora belli, - Cryptosporidia (intracellular protozoan) Coccidian parasite Invades the GIT 15% of HIV associated diarrhea CD4 > 200 : cryptosporidial infection is usually self-limiting Severe immunosuppression: persistent symptoms-difficult to treat. - Microsporidia

Clinical presentations: Watery diarrhea eg.Cryptosporidium Abdominal pain Bloody diarrhea e.g. CMV procto-colitis INVESTIGATION OF INFECTIVE DIARRHEA identification of organisms in stool: microscopy,culture for pathogens, ova for parasites. If stool specimen negative: stain with Ziehl-Neelsen for Cryptosporidium Sigmoidoscopy/colonoscopy with biopsy: culture of specimen for viruses, mycobacteria, bacteriology and mycology. Histopathological appearances are important in diagnosis. GASTRO-INTESTINAL TUMORS -May also cause abdominal pain and diarrhea Kaposis sarcoma Intra-abdominal lymphoma (often aggressive nonHodgkins B cell lymphoma) 3. BILIARY AND PANCREATIC DISEASE
(a)

(b)

CHOLANGIOPATHY: due to crytosporiduim,CMV,or Microsporiduim PANCREATITIS: drug induced (HIV therapy: didanosine or zalcitabine (RTI) or by the biliary organisms listed above)

4. ANO-RECTAL CONDITIONS - Usually present with proctitis. - Symptoms: anal discharge Tenesmus Pruritus ani Rectal bleeding Diarrhea - Causative organisms: herpes simplex Gonorrhea Non-specific/Chlamydia Wart virus Syphilis HIV/AIDS RELATED NEUROLOGICAL DISORDERS 10% OF AIDS present with neurological disease as the first presentation. Acute self-limiting lymphocytic meningitis may occur at the time of seroconversion Later-chronic neurological syndromes or opportunistic infections will occur in 75% of patients with advanced HIV ie.neurological disease is usually a late feature occurring after other AIDS-defining illnesses eg. PCP -The most common cause is the neurotropic effect of the virus itself. CLINICAL PRESENTATIONS: - focal: hemiparesis,seizures - generalized: drowsiness,confusion,behavioural change - asymptomatic:early in HIV disease - Proximal myopathy or drug-induced neuropathy

(DDI)/myopathy may also develop. 1.DIRECT NEUROTROPHIC EFFECTS OF HIV AIDS dementia complex most frequent neurological condition of HIV infection directly caused by the virus Impairment of concentration and memory leads to progressive decline in cognitive function. - Psychiatric symptoms may be prominent - EEG shows generalized slowing with no specific features - Imaging demonstrates cortical atrophy Vacuolar myelopathy Neuropathy -sensorimotor neuropathy associated with HIV: mild sensory symptoms and signs -Mononeuritis multiplex: less common -Chronic painful myelopathy may develop INVESTIGATIONS: (1) (2) (3) CSF analysis : raised protein, mild pleocytosis CT brain scan: cerebral atrophy Nerve conduction studies:distal symmetric sensory neuropathy

NEUROLOGICAL INFECTIONS - opportunistic infections of the CNS are common

CAUSES OF NEUROLOGICAL DISEASE Toxoplasma gondii most common CNS infection (90% of focal lesions) occurs in 10% of AIDS crescenteric trophozoite form

INVESTIGATION: - CT brain: solitary or ring enhancing lesions. - Serology: Ig G serology is of little value due to high background prevalence. TREATMENT: - pyrimethamine with sulphadiazine PROGNOSIS: 10% mortality with first episode 25% have residual neurological deficit. PREVENTION: - Avoid raw or undercooked meat. - Avoid direst contact with cat feces. It is important to differentiate from primary CNS lymphoma. Mycobacteruim tuberculosis - meningitis - tuberculosis abscess

CAUSES OF GENERALIZED NEUROLOGICAL DISEASE Cryptococcus neoformans - budding yeast - occurs in 5-10% of AIDS patients - presents as an encephalopathic illness- menigism maybe absent - Meningitis INVESTIGATIONS: Cryptococcal antigen is present in blood and CSF in 90% of cases India ink stain: positive in 70% of CSF samples POOR PROGNOSTIC FACTORS: abnormal mental state cryptococcal ag titre > 1024 WBC < 0,02 X 109/l in CSF TREATMENT fluconazole or amphotericin B +/- flucytosine 20 % mortality irrespective of therapy used Cytomegalovirus Encephalitis/retinitis Peripheral neuropathy Papovavirus Progressive multifocal leukoencephalopathy

NEUROSYPHILIS -Co-existence of HIV and syphilis results in aggressive and atypical neurosyphilis. Previous syphilis infection may re-activate -The following features are recognized: myelopathy retinitis meningitis meningovascular

DIAGNOSIS: - Syphilis serology (rising VDRL) - CSF - serology may be modified by immune dysfunction TREATMENT: -First line therapy is procaine penicillin and probenecid IMI for 15-21 days. OPTHALMIC DISORDERS AIDS may affect any layer of the eye. Ophthalmic features of HIV/AIDS Molluscum contagiosum of lid Episcleritis, keratitis Uveitis Choroidal granuloma CMV retinitis

-Usually occurs with CD 4 count < 50/mm3 Most common AIDS related opportunistic infection in the eye (25% of patients) SYMPTOMS: blurred or loss of vision,floaters SIGNS: soft exudates retinal haemorrhages PROGNOSIS: Initially unilateral involvement, ultimately bilateral involvement Kaposis sarcoma of eyelids or conjunctiva Retinal changes- retinitis is common: due to HIV (nonspecific microangiopathy (75%)) or CMV -Haemorrhages, cotton wool spots, oedema, vascular sheathing Toxoplasmosis may develop acquired or re-activation disease Candida endopthalmitis Neuro-opthalmic manifestations e.g. Cranial nerve palsies,optic neuritis,sequelae to CNS infection or space occupying lesion MALIGNANT DISEASE IN HIV/AIDS Most common tumors: Kaposis sarcoma(83%) Non-Hodgkins lymphoma(13%) Primary CNS lymphoma(4%) Cervical dysplasia

KAPOSIS SARCOMA -Occurs in 10-15% of HIV as the first AIDS-defining presentation -Derived from vascular or lymphatic endothelial cells CLINICAL PRESENTATION: CUTANEOUS or SYSTEMIC MANIFESTATIONS Purple plaques/nodules Most common system involved: GIT (30% of patients with KS skin also have GIT involvement), Lymph nodes, Respiratory system- pulmonary KS: cough, dyspnea, infiltrates, lymphadenopthy or effusion on chest X-ray. DIAGNOSIS: -Clinical appearance (biopsy in difficult cases) HIV/AIDS RELATED SKIN DISEASE Dermatological diseases occur in 75% of HIV patients, especially in AIDS. Acute HIV illness: asymptomatic maculo-papular eruption affecting the face and trunk. During seroconversion illness may also develop seborrhoeic dermatitis As disease progresses, tumors and atypical infection develop.

DERMATOLOGICAL ASSOCIATIONS OF HIV GENERAL DERMATOSES psoriasis eczema seborrhoeic dermatitis folliculitis FUNGAL/YEAST INFECTIONS Pityrosporum ovale Candidiasis Cryptococcus neoformans Histoplasma capsulatum VIRAL INFECTION Herpes zoster/herpes simplex Epstei-Barr virus Human papilloma virus Cytomegalovirus Molluscum contagiosum BACTERIAL INFECTION Tuberculosis Syphilis Bacillary angiomatosis Staphylococcus aureus MALIGNANCY Kaposis sarcoma Lymphoma Cervical intra-epithelial neoplasia Intra-oral squamous carcinoma

DRUG-INDUCED REACTIONS Co-trimoxazole: generalized maculo-papular rash Zidovudine:nail pigmentation Ciprofloxacin:increased risk of severe skin reaction DRUG THERAPIES IN HIV/AIDS Sustained inhibition of viral replication results in partial immune reconstitution and reducing the risk of clinical disease progression and death. Reservoirs of HIV in resting T lymphocytes make it unlikely that HIV can be eradicated. Treatment for HIV infection: (a) (b) (c) anti-retroviral therapy prophylaxis for and treatment of infections treatment of neoplasia

ANTI-RETROVIRAL THERAPY

Usually given as combination therapy with the following aims: Complete suppression of viral replication (< 50 copies/ml). Obtaining a synergistic effect from combination therapy. Reducing the risk of viral resistance emerging. TARGET FOR ART: 1.Virus receptor + entry: fusion inhibitors,chemokine receptor blockers

2.Reverse transcriptase : inhibitors/DNA chain terminators 3.RNAase: inhibitors 4.Intergration:viral integrase inhibitors 5.Viral-gene expression: inhibition of HIV regulating gene and their products. 6.Viral protein synthesis: enzyme inhibitors e.g. Protease inhibitors 7.Viral budding: interferons, antibodies and ligands - Monotherapy results in emergence of resistance. 1. REVERSE TRANSCRIPTASE INHIBITORS - first drugs in clinical use 1.1NUCLEOSIDE ANALOGUES: (a) (b) (c) (d) (e) (f) 1.2 (a) (b) zidovudine (AZT) : bone marrow suppression lamivudine(ZTC) didanosine (DDI): peripheral neuropathy,pancreatitis stavudine: peripheral neuropathy,hepatitis abacavir: hypersensitivity reaction,nausea zalcitabine: peripheral neuropathy,mouth ulcers NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS: nevirapine: hepatitis,Steven-johnson syndrome efavirenz: rash hypercholesterolaemia,mood changes

2. PROTEASE INHIBITORS (a) (b) indinavir: crystalluria,hepatic impairment ritonavir: hepatitis,flushing

(c) (d) (e) (f)

saquinavir: few side-effects nelfinavir:diarhea lopinavir:diarrhea amprenavir:nausea,diarrhea

ANTI-RETROVIRAL REGIMENS 1. 2 nucleoside reverse transcriptase inhibitors eg.zidovudine or stavudine + lamivudine or didanosine. PLUS either 1 non-nucleoside reverse transcriptase inhibitor: nevirapine or efavirenz OR 1 protease inhibitor: indinavir or nelfinavir OR 2 protease inhibitors: ritonavir + saquinavir 2. 3 nucleoside reverse transcriptase inhibitors: zidovudine+lamivudine+abacavir.

FACTORS DETERMINIG WHEN TO START AND CHOICE OF THERAPY: -Most clinicians start when CD4 200-300 or if symptomatic. 1. risk of clinical disease progression (CD4 count,viral load) 2. willingness of patient to start therapy 3. clinical effectiveness of combination therapy 4. ability and motivation of patient adherence to therapy 5. drug toxicity profile 6. pill burden and dosing schedule 7. transmitted drug resistance 8. future therapy options 9. likelihood of drug resistance 10. drug-drug interactions

Routine monitoring on anti-retroviral therapy includes: Clinical assessment: -Examination of the mouth (ulcers, candidiasis) -Skin and lymph nodes Chest fundoscopy weight CD4 lymphocyte counts HIV viral RNA load