Aids approach patients

STAND UNDER ACQUIRED DEFICIENCY IMMUNO SYNDROME

"You Cannot Teach Old Dogs New Tricks" Prof Adeeba

Normal Immune System …will protects the body

It consists of LYMPHOID organs and tissues ..which kills bad organism

HIV will attack THE SYSTEM AIDS and it becomes

Acquired Immunodeficiency Syndrome (AIDS) Acquired Immunodeficiency Syndrome (AIDS) is caused by a retrovirus known as the Human immunodeficiency Virus (HIV).

Acquired Immunodeficiency Syndrome (AIDS) - definition Is a conglomerate of signs and symptoms arising from the development of opportunistic infections and unusual tumours which arise as a result of a failing immune system. Clinical definition of AIDS consist:

Immunology and Natural History of HIV/AIDS

Human Immunodeficiency Virus HIV is a retrovirus. (RNA) Uses host’s DNA (lymphocytes) to make viral DNA and to replicate itself. Host lymphocytes infected with HIV have a very short lifespan. HIV continuously uses new lymphocyte to replicate itself. Up to 10 million individual viruses are produced daily. ,[object Object],[object Object]

Viral variation in HIV infection

The effect of HIV on the immune system is monitored by measuring the CD4 lymphocyte count in the blood. A normal CD4 count 600 and 1,200 cells/µ. CD4 counts <350 cells/µL indicate that some impairment of immune function. CD4 counts <200 cells/µL - risk of serious opportunistic infections

CLINICAL MANIFESTATION of HIV MOHD HANAFI RAMLEE

Incubation 2 - 4 weeks after exposure but may be as long as 6 weeks. Symptoms tend to develop abruptly and last for 1.5 - 2 weeks.

Acute Sero-conversion Phase or Primary HIV-1 infection 60-90% difficult to identify (not remember the flu-like illness, common cold). This glandular fever  2 to 6 weeks after exposure. However this mononucleosis-like illness  prolonged and may last 2-4 weeks. acute encephalitis-like illness with reversible encephalopathy disorientation, impairment of consciousness cognitive functions Recovery is complete and the patient will feel well. Occasionally the acute seroconversionillness may be completely asymptomatic.

Asymptomatic HIV infection early stages progressive fall of CD4+ T-lymphoeyte symptoms and signs will become apparent. 2 to 7 years before the appearance of constitutional symptoms which may herald the onset of AIDS.

Persistent Generalised Lymphadenopathy (PGL) - Symptoms CD4+ T-lymphocytes progressively decline The commonest not specific symptoms and signs encountered in the early stages are: · Malaise · Lethargy · Loss of appetite · Loss of weight · Diarrhoea · Intermittent fever

Persistent Generalised Lymphadenopathy (PGL) - Signs weight loss of more the 10% the ideal body weight, prolonged fevers of more than 3 months, Persistent generalised Iymphadenopathy of more than two groups of Iymph nodes. multi-dermatomalherpes zoster, oral candidiasis oral hairy leukoplakia

Herpes Zoster Herpetic lesions in HIV-infected patients are caused by reactivation of the latent virus. Although mucocutaneous lesions may appear in any region of the body, the most common sites are the genital, perianal area.

Oral Candidiasis Oral candidiasis "thrush" is an infection of yeast fungi of the genus Candida on the mucous membranes of the mouth. It is frequently caused by Candida albicans, or less commonly by Candida glabrata or Candida tropicalis. Oral Hairy Leukoplakia Hairy leukoplakia is seen in severe defects of immunity, particularly in HIV infection. The cause of this condition is an opportunistic infection by the Epstein-Barr virus (EBV). After the primary EBV infection has been overcome, the virus stays latent in the B cells and also causes lytic infection in the oropharynx, controlled by the immune system. Uncontrolled lytic infection in the oropharynx is manifested as oral hairy leukoplakia in immunosuppressed hosts. Oral hairy leukoplakia is not associated with any malignant potential.

Persistent Generalised Lymphadenopathy (PGL) - Labs Lymphopenia Leukopenia Thrombocytopenia Anaemia Reduced CD4+ T-lymphocyte count Decrease ratio of CD4+/CD8+ Raised gamma-globulins Cutaneous Anergy

Persistent Generalised Lymphadenopathy (PGL) - Markers Absolute platelet counts Total Lymphocyte count CD4+ T-lymphocyte count (cells/uL) CD4+/CD8+ Ratio p24 antigen beta 2-microglobulins Serum Neopterin PCR-RNA-HIV

AIDS 10% of patients develop an AIDS-defining illness with a CD4 count above 200 cells/mm3. The median time to development of an AIDS defining illness is 12 – 18 months (if not on opportunistic infection prophylaxis or antiretroviral therapy). Median CD4 count at the time of developing an AIDS-defining illness is 67 cells/mm3. Median survival after CD4 count falls below 200 cells/mm3 is 38 – 40 months.

AIDS Consist of Pulmonary TB, Recurrent pneumonia, Invasive Cervical Cancer CD4+ T-lymphocyte counts declining immunity opportunistic infections atypical tumours.

Advance AIDS (CD4 < 50) Median survival is 12 – 18 months (if not on opportunistic infection prophylaxis or antiretroviral therapy). Cytomegalovirus disease and disseminated Mycobacterium avium complex tend to occur at this stage.

Factors affecting rate of progression Acute HIV syndrome: Prolonged presence of symptoms correlates with a more rapid progression of disease. Strong HIV-specific CD8 cytotoxic T cell and CD4 T cell responses correlate with a slower progression of CD4 cell decline. Co-infections Hepatitis Cytomegalovirus Mode of transmission Blood transfusion recipients progress more rapidly than patients who acquire it sexually or by injection drug use.

Factors affecting rate of progression Age. Older patients progress faster than younger patients. Viral load. Patients with higher viral loads will progress more rapidly. Genetic modifiers. Strain variations.

Factors affecting rate of progression Effect of prophylaxis of opportunistic infections on the course of HIV disease PCP Disseminated MAC Experience of the medical provider

Factors affecting rate of progression Effect of antiretroviral therapy on the course of HIV disease. 3-drug therapy (HAART) >> 2-drug therapy > Monotherapy When therapy is started in the early asymptomatic infection period the estimated mean time to development of AIDS is 8 months for patients treated with monotherapy, 9.8 years with double therapy and 20 years with HAART

Kaposi’s Sarcoma tumour of the blood vessel. Classical: elderly males of Mediterranean descent. confined to the lower limbs. previously healthy young males will suggest the presence of concomitant HIV numerous and fairly extensive. confined to the skin, lungs with hemorrhagicpleural effusion.

Kaposi Sarcoma With the rise of the AIDS epidemic, KS, as initially one of the most common AIDS symptoms, was researched more intensively in hopes that it might reveal the cause of AIDS. The disease was erroneously referred to as the "AIDS rash".

Acute Retroviral Rash 5-10 mm macular or papular erythematous lesions usually on face and trunk but may involve extremities. Rash usually starts 48-72 hours after the fever starts and may last for 5 – 8 days. It may be slightly pruritic but usually is not. Oral, esophageal, anal or genital ulcerations are painful, shallow and well demarcated.

CD4 count and OIs TB PCP, thrush Toxo, Esoph thrush Below 200 PML

Pneumocystis Carinii (PCP) Pneumonia with hypoxemia Insidious CXR with bilateral disease but can vary High morbidity and mortality CD4 generally below 200 or < 14% Significant alveolar disease (elevated LDH) Silver stain of sputum or BAL for diagnosis

PCP - Interstitial Infiltrates

Treatment of PCP Determine level of hypoxemia and need for hospitalization TMP-SMX is the most efficacious treatment Alternatives exist in those allergic to sulfa Steroids indicated if pO2 < 70 May get worse before improvement seen Usually need to R/O other pathogens

Prevention of PCP Oral TMP-SMX is prophylaxis of choice Alternatives exist (dapsone, pentamidine, etc) 10 prophylaxis: CD4 < 200 20 prophylaxis with history of prior PCP Still being determined is whether prophylaxis can be withdrawn after beneficial effects of HAART

Treatment / Prevention of Toxo Rx: Sulfadiazine + Pyrimeth. + Folinic Acid Sulfa allergic: Clinda + Pyrimeth. + Folinic A. Repeat MRI to make sure lesions smaller Maintenance therapy after induction Consider steroids and anticonvulsants TMP-SMX is adequate 10 prophylaxis dapsone and pentamidine is not protective should protect when CD4 < 100 if IgG +

Cryptococcal Meningitis Very subtle presentation at times HA, fever, lethargy, nausea Imaging studies usually normal CSF generally with high opening pressure, mild lymphocytic pleocytosis CSF with + India Ink, crypto Ag, yeast Serum crypto Ag can screen HIV cohorts

Cryptococcus - India Ink Stain

Treatment of Crypto Meningitis Most induce with ampho B +/- 5FC Can also use high dose fluconazole if unable to tolerate Ampho B Will need chronic maintenance to control infection as cannot be generally cured High risk for recurrent elevated ICP which can result in hydrocephalous May require periodic removal of CSF

CMV Retinitis Results in floaters and decreased vision Seen in those with CD4 < 50-100 Diagnosis by ophthalmologic exam It is a disseminating infection Difficult systemic treatment with an induction and maintenance treatment gancyclovir, foscarnet, cidofovir

Mycobacterium Avium Complex Not uncommon when CD4 < 75 Chronic constitutional symptoms such as fever, sweats, and weight loss Labs may reveal anemia, leukopenia,and elevated alk phos CT of abdomen may see periaortic or retroperitoneal adenopathy and HSM with a relative paucity of peripheral adenopathy

MAC Diagnosis and Treatment AFB BC has high yield but takes weeks Bone marrow staining and culture Treatment requires a minimum of 2 meds chronically as it is quite resistant macrolide, ethambutol (amikacin, rifabutin, cipro) 10 Prophylaxis with macrolide in those with CD4 <75

Oropharyngeal Infections Candidiasis Oral Hairy Leukoplakia (OHL) Ulcer Disease Periodontal Disease Kaposi’s Sarcoma

Oral Candidiasis >60% of patients with CD4 <100 cells/mm3 Often Asymptomatic or altered taste, burning, odynophagia Four Forms Pseudomembranous Erythematous Angular Cheilitis Hyperkeratotic

Pseudomembranous Oral Candidiasis White patches that can be scraped off leaving erythematous base

Erythematous Oral Candidiasis Smooth red patches, found on tongue and cheeks

Angular Cheilitis Cracking and fissures at corner of mouth

Hyperkeratotic Oral Candidiasis Thickened white patches, do not scrape off

Oral Candidiasis: Diagnosis Diagnosis is often clinical, based on typical appearance KOH preparation of scraping for hyphae, pseudohyphae, and budding yeast Helpful especially for erythematous and hyperkeratotic disease

Oral Candidiasis: Treatment Initial topical therapy Clotrimazole troches 10mg 5x/day Nystatin swish & swallow 500,000 units QID Refractory to topical treatment Fluconazole 100 mg QD Itraconazole 100 mg BID

Oral Candidiasis: Treatment Fluconazole Refractory Disease Higher dose fluconazole (200-800 mg/d) Itraconazole 200 mg BID Amphotericin B 0.3-0.5 mg/kg/day Capsofungin 50mg IV QD Duration of Therapy 7-14 days or until disease resolution

Oral Candidiasis: Treatment Relapsing Disease Intermittent therapy vs. chronic suppressive treatment Decreased azole resistance with chronic suppression vs. intermittent therapy if recurrences are very frequent. Avoid maintenance therapy unless relapses are frequent – increased azole resistance

Oral Hairy Leukoplakia Caused by Epstein-Barr Virus infection Does not scrape off with tongue blade NOT a premalignant condition Targeted therapy not recommended Responds to HAART

Oral Hairy Leukoplakia Linear white patches at edge of tongue. Do not scrape off.

Oral Ulcer Diseases Several Etiologies Most Important Differential Diagnoses: Herpes Simplex Virus Cytomegalovirus Aphthous Ulcers

Herpes Simplex Virus Multiple vesicular lesions of lips, buccal mucosa, soft palate Diagnosis often clinical, also may diagnose by Tzanck smear, viral culture, immunofluorescence assay Treatment recommended in patients with HIV

Herpes Simplex Virus Multiple ulcers with some confluence of buccal mucosa

Herpes Simplex Virus Tzanck smear with multinucleated giant cells

Herpes Simplex Virus:Treatment Oral Therapy: Acyclovir 400 mg 5x/day 14-21d Famciclovir 500 mg BID x 7d Valacyclovir 1g PO BID x 7d Parenteral Therapy (severe disease) Acyclovir 5mg/kg q 8 hours Foscarnet or Cidofovir for acyclovir resistant disease

Cytomegalovirus (CMV) Visually indistinguishable from HSV oral ulcer disease Often associated with other systemic manifestations of CMV (esophagitis, colitis, retinitis) Usually diagnosed in “HSV” refractory to therapy Viral Culture/ cytology, IFA, CMV serum antigen testing, CMV PCR

CMV Oral Ulcers Viral swab demonstrated typical “owl’s eye” intracytoplasmic inclusions. CMV PCR (+)

CMV - Treatment Limited oral ulcer disease management unclear, but likely a precursor to manifestation at other site (esophagitis, colitis, retinitis) Induction Therapy Ganciclovir 5mg/kg IV Q 12 hours Valganciclovir 900 mg BID Foscarnet 90 mg IV Q 12 hours Cidofovir 5 mg/kg IV q week PLUS Probenecid (to decrease renal toxicity) Each then followed by suppressive treatment

Aphthous Ulcers Present as crops of ulcers from 1-2 mm to 2-3 cm Painful lesions lead to odynophagia, dysphagia, secondary weight loss Can involve esophagus, other parts of GI tract Visually similar to HSV and CMV

Aphthous Ulcers 1.5 cm ulcer of buccal mucosa

Aphthous Ulcers Diagnosis: viral studies for HSV, CMV (-) Biopsy: nonspecific inflammatory changes Treatment Anesthetic mouth washes Topical fluocinonide 0.05% SEVERE DISEASE Prednisone 40 mg/day 4-6 weeks Thalidomide 200 mg po QD

Kaposi’s Sarcoma Can involve any portion of the GI tract. Usually symptomatic if oral lesions or intestinal obstruction Associated with HHV-8 infection

Kaposi’s Sarcoma Presentation: Usually in patients with CD4 <200 cells/mm3 Skin most common site of involvement, but GI tract involved in 40% of visceral cases Diagnosis Usually based on pathologic specimen Must be distinguished from Bacillary Angiomatosis (Bartonella Henselae)

Kaposi’s Sarcoma: Treatment Often improves with HAART Localized Disease HAART Sclerotherapy Intralesional Chemotherapy Cryotherapy Radiation therapy Widespread Systemic Chemotherapy interferon-alfa ,etoposide, vincristine, vinblastine and bleomycin

AIDS Cholangiopathy Late manifestation of HIV CD4 < 100 cells/mm3 May be present with or without papillary stenosis Clinical Presentation Fever, RUQ pain, nausea, vomiting. Weight loss Markedly Elevated Alkaline Phosphatase Causes Include: Cryptosporidium, CMV, microsporidia 40% of cases – no clear etiology

AIDS Cholangiopathy Diagnosis Ultrasound: may be normal or show intra- and extra-hepatic ductal dilatation ERCP: allows imaging of biliary ductal system, sampling of fluid for culture and cytology Treatment Sphincterotomy for papillary stenosis, biliary stents, targeted therapy at causative agent (if identified)

Diarrhea in HIV/AIDS Occurs in 50-60% of AIDS patients Evaluation should include travel history, pets, medications, foods Stool studies Stool culture for Shigella, Salmonella, E. Coli, campylobacter Stool O&P, acid fast staining C. Difficile Toxin Assay If Fever: Blood Culture, AFB blood Culture, CMV Antigenemia/ PP65

Salmonella Commonly S. typhimurium, S. enteritidis 20-100 greater incidence in AIDS Bacteremia common Recurrent bacteremia – AIDS defining Diagnosis: stool and/or blood cultures Treatment: ciprofloxacin, ceftriaxone, amoxicillin, TMP/SMX Suppressive Therapy: consider for recurrent disease

Shigella S. flexneri, S. dysenteriae Presentation: bloody diarrhea, fever, abdominal pain Complications: megacolon, perforation, bacteremia (50%) Treatment: Same as salmonella ciprofloxacin, ceftriaxone, amoxicillin, TMP/SMX

Clostridium Difficile Approximately 8% of AIDS diarrhea Diagnosis: Detection of toxin in stool Thickened bowel wall on CT Pseudomembrane on colonoscopy Treatment Metronidazole 250 mg po QID x 10-14 days Vancomycin 125 mg po QID x 10-14 days (if failure of metronidazole)

Mycobacterium Avium Complex Usually seen with CD4 <100 cells/mm3 Presentation: fever, abdominal pain, diarrhea, weight loss Diagnosis Culture: stool, tissue, blood CT scan: hepatosplenomegally, abdominal lymphadenopathy Treatment Clarithromycin 500 mg BID OR azithromycin 500 mg po QD PLUS ethambutol 15-20 mg/kg/day

Cryptosporidium Found in stool of 10-20% of AIDS patients with diarrhea Acquired via contaminated water or fecal-oral route May also cause biliary tract disease Diagnosed by acid fast stain of stool, immunofluorescence

Cryptosporidium Acid-fast stain of stool demonstrating oocysts

Cryptosporidium: Treatment Mainstay is restoration of immunity with HAART Specific Therapy (disappointing efficacy) Paromomycin 1500-2000 mg/d x 14-28 days then 500 mg BID Paromomycin 1 g BID PLUS Azithromycin 600 mg QD x 28 days THEN Paromomycin alone Octreotide 50-500 units SQ TID Reduces stool volume Nitazoxanide 500 mg BID Currently under clinical trial

Isospora Belli Acid Fast protozoan Symptoms: watery diarrhea, weight loss, cramps AFB of stool; larger than cryptosporidium; typical elliptical shape Treatment: TMP/SMX DS po QID x 10 days Pyrimethamine (for sulfa allergy)

Isospora Belli Oocyte on modified acid-fast stain of stool

Microsporidia 2 species implicated in most diarrheal disease in AIDS Enterocytozoon bieneusi Encephalitazoon intestinalis Found in 5-50% of AIDS patients with unexplained diarrhea Clinical: chronic non-bloody diarrhea, malabsorption, cholangitis, cholecystitis

Microsporidia Diagnosis stool modified trichrome or chemofluorescent staining Small bowel biopsy Treatment: Albendazole 400-800 mg PO >21 days [for E. septata] E. bieneusi – limited efficacy Metronidazole, atovaquone

AIDS Wasting Syndrome Unintentional Loss of 10% of body weight AIDS defining illness in 15-20% of cases Contributing factors: Medication related anorexia, depression, oral/esophageal disease, malabsorption

AIDS Wasting Syndrome Treatment Nutritional Supplements Oral supplements usually adequate TPN for excessive diarrhea from cryptosporidiosis Appetite Stimulants Megestrol, Dronabinol – weight gain mostly fat Resistance Exercise

AIDS Wasting Syndrome Anabolic Steroids Most weight gain is lean body mass (anabolic>androgenic effect) Nandrolone Oxandrolone Oxymetholone Testosterone Indicated for hypogonadism with or without wasting Improved quality of life, libido, energy, lean body mass

Non TB Mycobacteria MAC rarely cause pulmonary disease M.kansasii most common CD4< 50 Interstitial / lobar pneumonia Nodules, cavities, adenopathy Diagnosis: Cx from respiratory specimen Treatment: RIF/ETB/INH 15-18 mo

CMV Pneumonias Most important AIDS associated viral pulmonary pathogen Late B/L interstitial/alveolar infiltrates Diagnosis: CMV culture( not specific) CMV inclusions

CMV: Treatment GCV 2.5 mg/kg Q 8h x 20 d or Valgancyclovir 900 mg BID + IVIG 500mg/kg QOD x 10 days then GCV 5 mg/kg/d x3-5/wk + IVIG 500mg/kg 2x/wk x8 doses Foscarnet 90 mg/kg IV Q 12h x 14-21 days then 90 mg/kg QD maintenance Cidofovir 5 mg/kg IV Q wk w/ probenecid

Pulmonary Cryptococcosis Inhaled pathogen <15% develop pneumonia UL lesions, lobar, B/L, miliary pneumonia Pleural effusion, cryptococcoma Cavity: rare meningitis primary presentation in HIV

Pulmonary Cryptococcosis Treatment Ampho B 0.7-1 mg/kg/d + 5-FC 25 mg/kg q 6h x 2 wks Then Fluconazole 400 mg/d x 10wks Suppression 200 mg/d until CD4 > 100 Surgery for cryptococcoma

Pulmonary Penicillosis Endemic: SE Asia, China, Manipur State of India Thermally dimorphic fungus Infiltrates, nodules, cavities, abscess, adenopathy Disseminated diseases Diagnosis: Fungal Culture Treatment: Ampho B Itra, 50% relapse

Rhodococcus equi GP coccobacilli Synergistic hemolysis Antagonism : IMP, β-lactam

Rhodococcus equi TB like syndrome with negative smear cavitary/nodular pneumonia bacteremia ½ extrapulmonary 2/3 mortality Tx: 2-3 drugs Vanc, IMP,AMG, cipro, Rifampim, E-mycin

Non Infectious Pulmonary Diseases KS Lymphoma Nonspecific interstitial pneumonitis Lymphocytic interstitial pneumonitis BOOP PE

TB: Early Clinical Picture General complaints: non-specific excessive fatigue weight loss anorexia irritability Symptoms of chronic infection: low-grade fever night sweats vague digestive disturbances recurrent headaches

TB: Early Clinical Picture SPUTUM: at first dry, and later productive purulent sputum hemoptysis Pleuritic pain from TB pleurisy with effusion, may be a presenting symptom in early stages Cough rarely associated with pulmonary TB in children.

Severe Pulmonary TB Most INFECTIOUS CASES Extensive cavities Positive smear High bacilli output > 10 /HPField or >500,000/ml High mortality without treatment (75%) Very infectious 50% of close contacts infected RAPID evolution

Chest Xrays in TB Control DIAGNOSTIC EXAMINATION of a suspected case EVALUATION OF A CASE during treatment BUT not a substitute to SPUTUM EXAM only sputum monitors response of MTB to drugs only sputum provides early warning about resistance BASELINE XRAY at the end of treatment Evaluation of a CONTACT or an INFECTED

Tuberculosis Screening – Skin Tests 15mm Person from LOW prevalence area NO medical risk factors NO known exposure to TB 10mm Person from HIGH prevalence area: Asia, Africa, Latin America ³1% MEDICAL RISK factors 5mm CLOSE CONTACTS to infectious TB OLD TB LESIONS HIV INFECTION

TB Treatment Start with 4 drugs in all patients INH, RIF, PZA and EMB or SM until sensitivities return If pan sensitive, D/C EMB or SM After 2 months of therapy, D/C PZA Continue INH & RIF for 4 more months for total of 6 months Must have culture conversion by 2 months 6 month regimen good for HIV(-) and (+) Can use BIW regimen / TIW for HIV (+) Monitor adherence and toxicity DOT, combination pills for self administered (exceptions)

Resistance Primary resistance to any of the 4 major drugs (INH, Rif, Emb, Sm) was estimated at 12% in the USA in 1995. It ranged in 1994-97 from a low of 2.0 in the Czech Republic to a high of 41% in the Dominican Republic (Global surveillance for anti-tb drug resistance. NEJM 1998, 338,23). Median prevalences were: INH 7.3% Streptomycin 6.5% Rifampin 1.8% Ethambutol 1% All 4 0.2%

Clinical Significance of Resistance If pan sensitive>95% chance of cure If resistant to INH>90% chance of cure If resistant to rifampin>70% chance of cure If resistant to INH and RIF~50% chance of cure Before chemotherapy~50% chance of cure

Causes of Resistance Irregular Self Administration with Failure to closely supervise Care of patients by non specialists Increased immigration

Epidemiology of TB and HIV Both have afflicted similar populations Both are socially stigmatizing Globally, TB is the 2nd leading cause of death from an infectious disease (behind HIV) TB is the leading cause of death in HIV globally Active TB may accelerate HIV replication

TB/HIV: Epidemiology Thirty-six million HIV infected individuals worldwide One-third of them co-infected with MTB 68%- Sub Saharan Africa, 22%- SEA Leading cause of death amongst HIV infected individuals worldwide Prevalence of HIV in TB patients (India) 20%

TB/HIV: Pathogenesis Immunity to MTB partly under control of MHC Class II restricted CD4 cells Loss of CD4 cells increases risk of Reactivation of latent infection Primary infection Active TB up-regulates HIV replication, leading to accelerated progression of HIV

TB/HIV: Pathogenesis Life time risk in HIV negative persons: 10% 5% within first two years 5% remainder of their lives HIV positive persons have 8% risk per year HIV+ incidence: 5-16/100 person-years Two mechanism Reactivation Re-infection Immune reconstitution TB on HAART

HIV/TB: Treatment Do you need to add higher number of drugs? Do you need to prolong duration of therapy? Can ARV be used concomitantly with ATT (anti-Tuberculosis Therapy)? Is there increased incidence of AE’s? Is there increased incidence of MDR-TB? Should latent tuberculosis be treated? (international)

Baseline Laboratory Tests CD4 count and viral load to establish the stage of the disease Exposed other infectious diseases Other recommended baseline tests include: ,[object Object]

Laboratory features Leukopenia and lymphopenia initially, then lymphocytosis. Elevated CD8 cells, decreased CD4 cells.

Diagnosis of Acute HIV Seroconversion usually occurs within 4 –10 weeks (median 63 days). Plasma viral load peaks in three weeks post-exposure (100,000 – 1,000,000 copies RNA/mm3) and then declines to nadir at ~120 days. p24 antigen levels may be as high as 100 pg/ml.

Management of HIV infection MOHD HANAFI RAMLEE

Clinical Care (medical & nursing) VCT , PMTCT preventive therapy (OIs, TB) management of STIs and OIs palliative care, nutritional support antiretroviral therapy Socioeconomic Support Psychosocial Support counseling material support orphan care economic security n community support services food security p spiritual support o Human Rights & Legal Support r stigma & discrimination reduction e i succession planning PLHA participation v e n Adults and Children Affected by HIV/AIDS t

Mx 1 – Risk Assessment full history + detailed sexual + drug history physical examination  stage Initial laboratory tests will include: a. A Full Blood Count with differential count, particular attention to be given to platelet and Iymphocyte counts b. A Mantoux Test with 1 Tuberculin unit intradermally c. A Chest Radiograph

Mx 2 – Establish Diagnosis HIV antibody Testing: ELISA and or Particle agglutination tests Confirmed by supplementary test a. voluntary basis b. anonymously or c. confidential basis

Mx 3 – Ascertain Stage to assess progression of the disease is by measuring the CD4+ Tlymphocyte count and percentage. recommended  all HIV infected individuals should have a baseline CD4+ Infants born  ELISApositive. If the infant is not HIV infected  ELISA fall within 18 months after birth. Therefore, a better indicator of HIV infection in an infant younger then 18 months will be the measurement of p24 antigen, by doing a polymerase chain reaction (PCR) test, or detection of the virus itself

SPECTRUM OF HIV MohdHanafiRamlee

Group 1 HIV disease (acute seroconversion illness) Acute neurological disease meningitis encephalitis olyneuritis myelopathy brachial neuritis GuillianBarre syndrome 2-4 weeks after the initial HIV The symptoms include: Flu-like illness fever arthralgia malaise myalgia headache photophobia maculopapularrash GI disturbances and neurological manifestations lasts 2-4 weeks  low platelet and Iymphocyte counts, and a low CD4+ T-lymphocyte counts, with a reversed CD4+/CD8+ ratio. In the asymptomatic phase the CD4+ Tlymphocyte counts will rise to almost normal levels (600-1200/uL).

Group 2 Asymptomatic Phase disease 3-7 years from the initial HIV infection. feels and looks well CD4+ T-cell counts can be normal. counselled towards change of behaviour, maintain good health and practise behaviour prevent further transmission of HIV. assessment for antiretroviral therapy 6-monthly CD4+ T cell count.

Symptomatic Phase (Group 3 and 4) disease Viral markers p24 antigen polymerase chain reaction (PCR) p24 antibody (babies, health care workers) clinical predictors herpes zoster (multi-dermatornal) oral candidiasis oral hairy leukoplakia Prolonged fever, might sweets Progressive weight loss Laboratory predictors of progression to AIDS: thrombocytopenia falling CD4+ T. cell counts high p24 antigen Preliminary investigations Chest X-ray Full blood count and differential count, ESR Stool examination for cryptosporidia/ isospora (when diarrhoea is present) Blood cultures for MAI/Mtb, Cryptococcus, Salmonella sp. Toxoplasma, Cytomegalovirus, Herpes Antibody titres. Sputum for PCP Immunological markers CD4+ T-cell counts CD4+/CD8+ ratio CD4+ percentage

Perinatal HIV Transmission Can occur: during pregnancy (intrauterine), 25%--40% during labor and delivery (intrapartum), 60%--75% after delivery through breast-feeding (postpartum). In a randomized trial of formula feeding versus breast-feeding, approximately 44% of HIV infection was attributed to breast-feeding Risk factors are associated with perinatal HIV transmission immunologically or clinically advanced HIV disease in the mother high plasma viral load maternal injection-drug use during pregnancy preterm delivery breast-feeding No antiretroviral therapy HIV subtype Obstetric factors : Delivery >4 hours after the rupture of the fetal membranes; maternal infection with another sexually transmitted disease or coinfection with HSV-2 increased risk of HIV transmission; chorioamnionitis

Diagnosis of HIV Infection in Newborns Nearly all infants born to HIV-infected mothers passively acquire maternal antibody and, antibody will remain positive until age 18 months regardless of whetherthey are infected. Definitive diagnosis of HIV infection in early infancy requires: nucleic acid amplification (e.g., polymerase chain reaction [PCR]) or viral culture. HIV infection is diagnosed by two positive assays (PCR or viral culture) on twoseparate specimens. Infant HIV testing should be done as soon after birth as possible so appropriate treatment interventions can be implemented quickly. UMMC: PCR quantitative assay

HIV: Reproductive and Women’s Health Issues Differences in HIV disease between men and women Levels of HIV RNA may be lower in women at seroconversion. Mean VL becomes similar within 5-6 yrs. CD4 may be higher in women. Rates of disease progression do not differ No changes in treatment guidelines Abnormal Pap Smears 30%-60% Pap smears have cytologic abnormality Cervical cancer presents with high grade pathologic features - Uniform relapse after therapy (prior to HAART) - Short survival HAART has been independently associated with regression of cervical disease.

NRTI / NNRTI Protease inhibitor Entry inhibitor Receptor inhibitors CCR5 or CXCR4 Integrase inhibitors

Immune Reconstitution Syndrome Immune Reconstitution Syndrome The use antiretroviral therapy resulted dramatic improvement in outcomes typically associated with an increase in CD4+ lymphocytes, reduced HIV viral loads and partial recovery of T-cell–specific immune responses. Recovery of immune function correlates with the number of circulating CD4+ cells. It is safe to discontinue prophylaxis (primary or secondary) for a variety of pathogens including Pneumocystis jiroveci, Mycobacterium avium complex (MAC), and Toxoplasma gondii. Some patients experience a clinical deterioration following the introduction of potent antiretroviral therapy believed to be related to the restored ability to mount an inflammatory response. The incidence of IRS to be 10% to 25%. In patients undergoing simultaneous treatment of HIV infection and tuberculosis, the incidence of IRS has been reported to be 11% to 45%.

MANAGEMENT OF ADVANCED HIV DISEASE MOHD HANAFI RAMLEE

Antiretroviral Agent: Zidovudine Zidovudine (ZDV) a nucleoside analogue, when it is phosphorylated inside HIV -infected cell, inhibits reverse transcriptase. Usage improved survival decreases frequency of opportunistic infections Improve quality of life cuts down length of hospital stay. effective against replicating virus can inhibit replication of sensitive strains. gold standard in HIV management.

Zidovudine: When to Start? assessment first weight opportunistic infections immunological status if the CD4+ counts are below 200/uL, Give zidovudine at 500-600mg per day in 2 or 3 divided doses (250mg b.i.d. or 200mg t.i.d). If the CD4+ counts are 200 or less, chemoprophylaxis against Pneumocystis carinii pneumonia (PCP) Close monitoring & Follow up: 1x/2w  1x/3m 1x/36ml

Commencing Antiretroviral Therapy WHEN ?

General Goals of Antiretroviral Therapy to prolong survival decrease morbidity in those infected to improve the patient’s quality of life and reduce the burden on his family and the community. To promote prevention of transmission

Specific Goals of Antiretroviral Therapy to suppress HIV replication to reduce plasma viral load to below undetectable levels for a maximum duration to improve, maintain and prevent the ongoing decline of CD4 cells.

Recommendation on when to commence HAART [MSIDC]

Selection of Antiretroviral Agents

Successful Antiretroviral Therapy: Critical Factors Efficacy Tolerability Convenience - - Adherence Successful Therapy Durable viral load Suppression

Antiretroviral Agents in Malaysia

Commencing Antiretroviral Therapy WHAT ?

HAART H = Highly A = Active SLOWS DOWN A = Anti- VIRAL R = Retroviral REPLICATION! T = Therapy 3 or more ARVs. Only recommended ARV treatment – for long term effect.

What makes ARVs work? Function of ARVs  suppress viral replication Virus suppressed  immune system recovers Immune system recovery means  CD4 count goes up CD4 count up no more opportunistic infections

Protease Inhibitor Integrase Inhibitor NNRTI NRTI Mechanism of Action of ARVs Fusion Inhibitor & Chemokine Receptor Antagonist Illustration by David Klemm

[object Object], CD4 cell The virus   NNRTI NVP, Stocrin NRTI (nukes) & nucleotide  3TC, d4T  The ‘factory’ ,[object Object], ‘budding’

3. Integration into host cell’s nucleus 4. Reproduction of viral components Assembly and release of new viruses 2. The virus changes from RNA to DNA How do PIs work? 1. Attachment to host cell

Pharmacokinetics Absorption, Distribution, Metabolism, Elimination Renal Elimination Liver/GI Metabolism Phase I: Oxidation (ie, CYP 450 enzymes) Phase II: Conjugation (ie, glucuronidation) Antiretrovirals Many ARVs (and other medications) undergo Phase I metabolism Many ARVs increase or decrease activity of CYP450 (Phase I) enzymes

CYP 450 Inhibition Leads to blocking of the specific CYP 450 enzyme If a drug is metabolized by the CYP 450 enzyme that is blocked  drug concentration Example: Ritonavir

CYP 450 Induction Leads to production of more CYP 450 enzyme If a drug is metabolized by the CYP 450 enzyme that is now in high amounts  drug concentration Example: Efavirenz

NRTIs (Nucleoside Reverse Transcriptase Inhibitors) Cytidine Tymidine Adenosine Guanosine Zidovudine (AZT)

NRTIs (Nucleoside Reverse Transcriptase Inhibitors) ,[object Object],*dose reduce for renal dysfunction

NRTIs *dose reduce for renal dysfunction

NNRTIs (Non-nucleoside reverse transcriptase inhibitors)

Protease Inhibitors (PIs): Protease enzyme cleaves HIV precursor proteins (gag/pol polyproteins) into active proteins that are needed to assemble a new, mature HIV virus. PIs bind to protease preventing the cleavage and inhibiting the assembly of new HIV viruses

Ritonavir as a PI Booster Ritonavir used only to ‘boost’ concentrations of other protease inhibitors Dosed 100-200mg QD-BID Available as 100mg capsules and tablets Side effects: GI upset; hyperlipidemia*; insulin resistance* * All PIs except atazanavir alone

Lipodystrophy Illustrations “Buffalo hump” “Central obesity” “Facial and peripheral wasting”

Protease Inhibitors (1) Take with Food (2) Must be refrigerated ** All PIs except atazanavir can increase lipids and cause insulin resistance

Entry Inhibitors:Fuzeon : Enfuvirtide (T-20) FDA-approved fusion inhibitor; 36 AA peptide Requires 106 steps to manufacture Dose: 90 mg sq bid side effects: injection site rxn, hypersensitivity (rare) resistance: changes in gp41 (cell surface protein)

Chemokine Receptor Antagonists Maraviroc (Selzentry®) CCR5 or CXCR4 receptors on cell surface Virus will bind to one of the 2 receptors Some patients’ virus will bind to either receptor Maraviroc blocks viral entry at CCR5 Dosed 300mg BID 150mg BID with P450 inhibitors 600mg BID with P450 inducers Tropism

Integrase Inhibitors Raltegravir (Isentress™) Dosed 400mg BID (1 tab BID) No induction or inhibition on CYP450 enzymes or Pgp Metabolized by UGT1A1 (glucuronidation) Only affected by drugs that inhibit or induce UGTs (ie, rifampin)

Metabolic Dysfunction in HIV-Infected Patients on HAART HIV INFECTION InsulinResistance Dyslipidemia Body Fat Redistribution HAART 215

Toxicities in Summary NRTIs: Lactic acidosis Zidovudine: Anemia Stavudine and Didanosine: Pancreatitis and Peripheral Neuropathy Abacavir: Hypersensitivity (can lead to death); ? CVD Tenofovir: renal toxicity NNRTIs: Efavirenz: nervous system side effects; rash Nevirapine: rash, liver toxicity Etravirine: rash PIs: GI effects, increased lipids, increased BG Atazanavir: increased bilirubin, PR prolongation Indinavir: kidney stones (LOTS of water) Fosamprenavir: rash Tipranavir: liver toxicity; bleeding

Antiretroviral Therapy DHHS Guidelines Last updated December 1, 2009 www.aidsinfo.nih.gov International AIDS Society- 2008 Hammer, et al. JAMA Aug 6, 2008 IDSA Primary Care HIV Guidelines-2009 Aberg, et al CID Sept 1, 2009

Factors to Consider for Initial Regimen Selection Potential drug interactions Pre-treatment CD4+ T cell count Gender Pregnancy potential Patient lifestyle/ social situation Co-morbidities Adherence potential Dosing convenience (pill burden, dosing frequency, food, fluid restriction) Potential adverse effects HIV Resistance Testing DHHS 4/7/2005, http://AIDSinfo.nih.gov

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