UNDERSTANDACQUIRED

IMMUNODEFICIENCYSYNDROME

WE NEED TO KILL THEM

BEFORE THEY KILL US?

SOWE

KEEP TRYINGMUST

…AND K

EEP TRYIN

G

THE ENDUNTIL

Prof Adeeba

Normal Immune System

…will protects the body

It consists ofLYMPHOIDorgans andtissues

..which killsbad organism

HIV will attackTHE SYSTEM

and it becomesAIDS

AIDSCOMES FROM

also from…

blood transfusion

Mot

her

to

baby

IF UHAVE THESE

ORAL CANDIDIASIS

Oral Hairy Leukoplakia

…or these…

The human immunodeficiency virus, upon entry into the human body seeks out the CD4+ receptors on T-helper Iymphocytes and other cells with CD4+ molecule.

The virus then enters into the cell and incorporates itself into the cellular genome eventually causing cell death.

With the decline in CD4+ Tlymphocytes, the body's defence mechanism will be compromised.

This will allow opportunistic organisms to cause life-threatening infections.

Atypical tumours may also develop.

Acquired Immunodeficiency Syndrome (AIDS)

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

HIV-1

HIV -1 is known to cause AIDS

It is thought that 80% of people infected with HIV-1 will progress to clinical AIDS

within 10 years.

HIV-2HIV -2 may eventually lead to an

immunodeficiency state

severe immunodeficiency due to HIV-2 may require a longer latent period.

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:

1. A positive test for HIV antibodies by the ELISA and or Particle Agglutination test(s), and a positive supplementary test

2. AIDS Defining Diagnosis

3. A CD4+ T cell Iymphocyte count of less then 200/uL

AIDS defining diagnosis

disseminated TB

oesophageal candidiasis

kaposis sarcoma

CMV retinitis NHL cryptosporidial diarrhoea

PCPAIDS

associated dementia

IMMUNOLOGY AND NATURAL HISTORY OF HIV/AIDS

The Normal lmmune System

Protects the body

Consists of lymphoid organs and tissues

Produce B-cells and T-cells(CD4 lymphocytes)

Regulate the immune system and kill invading organisms

When the immune system is weakened and destroyed by a virus such as HIV, the body is vulnerable to opportunistic infections (OIs)

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. Causing severe damage to and eventually destroys the immune system.

HIV Co-receptors

C-C chemokine receptor CCR-5

• - expressed by monocytes and lymphocytes

• - mediates entry of non-syncytium-inducing (NSI), monocytotropic stains of HIV

• - ccr5delta32, resistant to HIV infections

C-X-C chemokine receptor CXCR-4 (fusin)

• - expressed only on T lymphocytes

• - mediates entry of syncytium-inducing (SI), T-cell tropic strains

CCR-2 and CCR-3 chemokine receptors

• - mediates HIV-1 entry on circumstances

Viral variation in HIV infection

Early after HIV infection,

most patients harbor NSI virus. NSI virus grows relatively slowly, does not induce fusion of T cells (syncytium formation) in vitro, grows equally well in monocytes and lymphocytes. NSI stains are called R5 strains, use only the CCR-5 co-receptor.

Later HIV infection,

a highly cytopathic, SI variant appeared. SI virus grows more rapidly than NSI, characterized by the ability to grow in T-cell lines (T-cell tropism). Emergence of SI variants is associated with rapid decline in CD4+ lymphocytes, progress more rapidly to AIDS and SI isolateis a significant independent risk factor for disease progression and death. SI isolates utilize CXCR-4 (fusin) co-receptor and CCR-5, also referred as X4 stains SI isolates are not inhibited by RANTES, MIP-1 alpha or beta.

Duotropic R5/X4 viruses

use both CCR-5 and CXCR-4 co-receptors, infect monocytes and CD4+ lymphocytes, intermediate forms in the evolution.

• 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

HIV: Two Types RecognizedHIV-1 HIV-2

Both transmitted through sexual contact, blood, from mother to child, and cause

indistinguishable AIDSPredominant virus Less easily

transmittable

Due to high rate of replication, mutates rapidly into subtypes

Period between initial infection and illness

longer than HIV-1

Epidemiology

Fourth biggest killer in the world

Estimated 42 million persons

living with HIV/AIDS

About one-third are between 15-

24 years

Most people are unaware they are

infected.

Malaysia: 70 000 reported

cases

AIDS - Classification

Group 1- Acute Seroconversion illness.

Group 2 - Asymptomatic HIV infection

Group 3 - Persistent Generalised Lymphadenopathy (PGL)

Group 4 - AIDS

HIV CLASSIFY BY TREATMENT

1 Asymptomatic HIV infection

2 Advanced HIV disease

3 Opportunistic Infections

4 AIDS-related tumours and Neuro-Psychiatric disease

Modes of Transmission

• Male-to-female, • female-to-male, • male-to-male,• female-to-female

Sexual contact

• Blood transfusion, • IDU through needle-sharing, • needle stick accidentsParenteral

• In utero, • during labor/delivery, postpartum through BFPerinatal

CLINICAL MANIFESTATION OF HIVMOHD HANAFI RAMLEE

The human immunodeficiency virus, upon entry into the human body seeks out the CD4+ receptors on T-helper Iymphocytes and other cells with CD4+ molecule.

The virus then enters into the cell and incorporates itself into the cellular genome eventually causing cell death.

With the decline in CD4+ Tlymphocytes, the body's defence mechanism will be compromised.

This will allow opportunistic organisms to cause life-threatening infections.

Atypical tumours may also develop.

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 seroconversion illness 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-dermatomal herpes zoster, • oral candidiasis • oral hairy leukoplakia

Herpes ZosterHerpetic 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 CandidiasisOral 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 LeukoplakiaHairy 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 hemorrhagic

pleural effusion.

Kaposi SarcomaWith 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".

Natural History:

Primary HIV Infection

• 2-4 week period of intense viral replication.

• Non specific symptoms – flu like, neurological, gastro, skin.

• Lasts from 1-2 weeks and occurs in 53% to 93% of cases.

• Clinical manifestations resolve as antibodies to the virus become detectable in patient serum.

Stage of Disease Progression

• Patients then enter a stage of asymptomatic infection

• Lasts months to years.• CD4 declines• Opportunistic infection eg

bacterial, fungal, viral

Clinical Features

Nausea / Vomiting;

27

Hep-atosplenomegaly;

14

Weight Loss; 13

Oral Thrush; 12

Meningoen-cephalitis /

Lymphocytic; 6

Peripheral Neu-ropathy; 6

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.

OPPORTUNISTIC INFECTION

CD4 count and OIs

Below 200

TB

PCP, thrush

Toxo, Esoph thrush

PML

HIV-Related Complications

CD4>300

• Lymphadenopathy• Pneumonia (Strep)

Thrush• TB• Cryptosporidium• KS Lymphoma

CD4 < 200

• Esophagitis• Candida Vaginitis• PCP• Cryptococcus

CD4<100

• Toxoplasmosis• Zoster, PML, CMV,

MAC

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

CNS Toxo vs CNS Lymphoma

Toxoplasmosis

Toxo IgG +

Multiple Lesions

No TMP-SMX

Responds empirically

Lymphoma

Toxo IgG -

Single Lesion

TMP-SMX prophylaxis

No Response

Toxoplasmosis

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

Oral Kaposi’s Sarcoma

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

Tuberculin Test

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)

LABORATORY TESTING

Serologic Tests

ELISA/EIA

• Screening test• Positive result

means sample needs to be tested by western blot or different ELISA test

Western blot test (WB)

• Confirmatory test

DNA PCR

• Primarily used for viral detection with :- neonatal infection

• indeterminate serology

Rapid Tests

• Various tests that provide results in ~10 minutes

• Useful in situations where immediate results are important to manage decisions

Baseline Laboratory Tests

• CD4 count and viral load to establish the stage of the disease

• Exposed other infectious diseases• Other recommended baseline tests include:

• CBC• Serum Chemistry Panel• Syphilis serology• Chest X-ray

• Mantoux • PAP smears Hep B and C

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 INFECTIONMOHD HANAFI RAMLEE

Medical and Nursing CareCounseling and

testing

Prophylaxis of opportunistic

infections (OIs)

Management of HIV-related illnesses,

including OIsTB control

STI management Management of HIV disease Palliative care Access to HIV-related

drugs

Interventions to reduce parent-to-child transmission

Clinical HIV/AIDS care for mothers and

infants

Support systems such as functional

laboratories and drug management systems

Nutritional support

Health education Adequate universal precautions

Human Rights & Legal Support

stigma & discrimination reductionsuccession planning PLHA participation

Clinical Care (medical & nursing)

VCT , PMTCTpreventive therapy (OIs, TB) management of STIs and OIs

palliative care, nutritional support antiretroviral therapy

Socioeconomic Support

material supporteconomic security

food security

Psychosocial Support

counseling orphan care

community support servicesspiritual support

Adults and Children Affected by

HIV/AIDS

r

ev

e

p

i

n

o

n

t

Stage of Management

Risk Assessm

ent

Establish

Diagnosis

aScertain Stage

Useful

Laboratory tests

Initiate

Antiretroviral

therapy

Initiate

PCP prophylaxi

s

Asymptomatic HIV infection Advanced HIV disease,

AIDS-related Opportunistic Infections and

Tumours.

Neuropsychiatric illness

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 ELISA positive. • 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 HIVMohd Hanafi Ramlee

Group 1 HIV disease (acute seroconversion illness)

• 2-4 weeks after the initial HIV• The symptoms include:

– Flu-like illness– fever– arthralgia– malaise– myalgia– headache– photophobia– maculopapular rash– GI disturbances and– neurological manifestations

Acute neurological disease meningitis encephalitis olyneuritis myelopathy brachial neuritis Guillian Barre syndrome

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

• 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

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

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 inhibitorsCCR5 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%.

Diagnosis of IRS

Required Criteria

• Worsening symptoms of inflammation/infection

• Temporal relationship with starting antiretroviral therapy

• Symptoms not explained by newly acquired infection or disease, or the usual course of a previously acquired disease

• ≥1 log10 decrease in HIV RNA level

Supportive Criteria

• Increase in CD4+ count of ≥ 25 cells/µL

• Biopsy demonstrating granulomatous inflammation or unusually exuberant inflammatory response

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

Zidovudine: Site effects

General symptoms (first few weeks of

therapy)

• Headache• Nausea• Diarrhoea• Myalgia• Anorexia• Vomitting• Malaise• Fatigue

Haematologic

• Macrocytosis• Anaemia• Neutropenia

Others

• Proximal myopathy• Encephalomyelopat

hy• Hepatotoxicity• Nail pigmentation

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

Factors to be considered

Pharmacology

Adherence

Potency

Drug Interacti

on

Convenience

Adverse Effects

Efficacy Tolerability Convenience

Adherence

Successful Therapy Durable viral load Suppression

-

-

Successful Antiretroviral Therapy: Critical Factors

Antiretroviral Agents in Malaysia

Nucleoside reverse transcriptase

inhibitors

• Zidovudine (AZT/ Retrovir)

• Didanosine (ddI/Videx)

• Zalcitabine (ddC/Hivid)

• Lamivudine (3TC/Epivir)

• Stavudine (d4T/Zerit)

• Combivir (AZT+3TC)

Protease inhibitors

• Indinavir (Crixivan) • Ritonavir (Norvir) • Saquinavir- hgc

(Invirase)• Saquinavir- sgc

(Fortovase)• Nelfinavir (Viracept)

Non-nucleoside reverse transcriptase

inhibitors

• Efavirenz ( Stocrin )• Nevirapine

(Viramune )

COMMENCING ANTIRETROVIRAL THERAPY

WHAT ?

HAART

H = HighlyA = Active SLOWS DOWNA = Anti- VIRALR = 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

Mechanism of Action of ARVs

NNRTI

NRTI

Protease Inhibitor

Illustration by David Klemm

Fusion Inhibitor &ChemokineReceptor Antagonist

Integrase Inhibitor

The virus

Entering CD4 cell

New virus ‘budding’

The ‘factory’

NRTI (nukes) & nucleotide

3TC, d4T

NNRTI

NVP, Stocrin

How do PIs work?

1. Attachment to host cell

4. Reproduction of viral components

3. Integration into

host cell’s nucleus

5. Assembly and release of new viruses

2. The virus changes from RNA to DNA

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

Drug Interaction Potential

NRTIs (Nucleoside Reverse Transcriptase Inhibitors)

Zidovudine (AZT)

Tymidine

Adenosine

Cytidine

Guanosine

NRTIs (Nucleoside Reverse Transcriptase Inhibitors)

Drug Standard Dose* Dosage forms Common Side Effects

Metabolism/

Elimination

Zidovudine (ZDV/AZT) Retrovir

300mg bid* 300mg tab, 100mg cap, iv, oral soln

Fatigue, headachemyalgia, anemia, GI, lactic acidosis, hepatic steatosis

Renal

Lamivudine (3TC) Epivir

150mg bid* or 300mg qd

150, 300mg tab, oral soln

Well tolerated Renal

Emtricitabine(FTC) Emtriva

200mg qd* 200mg cap Well tolerated Renal

Didanosine (ddI) Videx

400mg EC qd ( 60kg)250mg EC qd (<60kg)*

125,200,250, 400mg cap, pwdr for soln

Pancreatitis, peripheral neuropathy, LA/HS

Renal

*dose reduce for renal dysfunction

•Note: Lactic acidosis can occur with any NRTIs

NRTIs

Drug Standard Dose* Dosage forms Common Side Effects

Metabolism/Elimination

Stavudine (d4T) Zerit IR

40mg bid ( 60kg) 30mg bid (<60kg) *

15,20,30,40 mg cap,oral soln

Peripheral neuropathy,

Pancreatitis, LA/HS,Lipoatrophy, facial

wasting

Renal

Abacavir (ABC) Ziagen

300mg bid, 600mg qd

300mg tabs, oral soln

hypersensitivity Hepatic by alcohol

dehydrogenase and glucuronyl

transferase

Tenofovir(TDF) Viread

300mg qd* 300mg tabs Few SEs, renal toxicity

Renal

Zidovudine/ Lamivudine

(COM) Combivir

300/150mg BID 300/150mg tabs See above See above

Abacavir/ Lamivudine

(EPZ) Epzicom

600/300mg QD 600/300mg tabs See above See above

Tenofovir/ Emtricitabine (TRU) Truvada

300/200mg QD 300/200mg tabs See above See above

*dose reduce for renal dysfunction

NNRTIs (Non-nucleoside reverse

transcriptase inhibitors)

NNRTIsDrug Standar

d DoseDosage forms

Common AEs

Metabolism

Delavirdine (DLV) Rescriptor

400 mg tid 100mg tab, 200mg cap

Rash Potent CYP3A inhibitor; 3A4 substrate

Nevirapine (NVP) Viramune

200 mg qd x 14 d then200 mg bid

200mg tabs, Oral susp

Rash (SJ), hepatotoxicity

CYP3A inducer, auto inducer; 3A4, 2B6 substrate

Efavirenz* (EFV) Sustiva

600 mg qhs 50, 100, 200mg cap, 600mg tab

Vivid dreams, drowsiness or insomnia, rash (SJ), hyperlipidemia

CYP3A, 2B6 inducer; 2B6, 3A4 substrate

Etravirine(ETV)Intelence

200 mg bid 100mg tabs Rash, nausea CYP3A inducer, CYP2C9 and 2C19 inhibitor; CYP3A, 2C9, 2C19 substrate;

Tenofovir/ Emtricitabine/ Efavirenz*Atripla

300/200/ 600 mg qd

300/200/600 mg tabs

See above See Above

*Pregnancy Class D

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

X

Protease Inhibitors

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 InhibitorsStandard

DoseDosage Forms Metabolism Common AEs**

Saquinavir(Invirase) (1)

1000/ rtv 100 bid or 1600/ rtv 100 qd

200mg caps, 500mg tabs

3A, Pgp substrate; weak 3A inhibitor

GI intolerance

Nelfinavir (Viracept) (1)

1250 bid, 750mg tid 250mg, 625mg tabs, 50mg/g oral pwdr

2C19 (M83A) substrate; weak 3A inhibitor

Diarrhea

Lopinavir/ritonavir(Kaletra) (1,2)

400/100 bid 200/50 mg tabs, 80/20mg/5mL soln

3A, Pgp substrate; 3A inhibitor; 2C9, 2C19 inducer

Dyspepsia, Nausea, vomiting, diarrhea, flatulence

Indinavir(Crixivan) (1-when taken with rtv)

800/ rtv 100 bid, 800mg tid

100, 200, 333, 400mg caps

3A, Pgp substrate; weak 3A inhibitor

Nephrolithiasis Drink 7-8 glasses of water per day; hyperbilirubinemia

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

Protease InhibitorsStandard

DoseDosage Forms Metabolism Common

AEs**

Atazanavir (Reyataz) (1)

400qd or 300/ rtv 100qd

150, 200, 300 mg caps

3A substrate; 3A and UGT1A1 inhibitor

Hyperbilirubinemia, PR prolongation

Fosamprenavir (Lexiva) (1)

1400mg bid; 700/100 RTV mg bid; 1400/200 RTV mg qd

700mg tabs (Agenerase-APV liq available)

3A4, Pgp substrate; 3A4 inducer/Inhibitor

Rash, GI intolerance, caution with sulfur allergy

Tipranavir(Aptivus) (1,2)

500/200 RTV mg bid

250mg caps 3A4, Pgp substrate; 3A4, inducer/inhibitor??; Pgp inducer

Hepatotoxicity, Increased bleedingcaution with sulfur allergy

Darunavir(Prezista) (1)

600/100 RTV mg bid

400, 600mg tabs 3A4 substrate;3A4 inhibitors

Diarrhea, nausea, HA, nasopharyngitis

(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)

Integrase Inhibitor

215

Metabolic Dysfunction in HIV-Infected Patients on HAART

Body Fat Redistributio

n

HIV INFECTION

HAART

DyslipidemiaInsulin

Resistance

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

HOW DO WE TREAT HIV?

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

• Co-morbidities• Adherence potential• Dosing convenience (pill

burden, dosing frequency, food, fluid restriction)

• Potential adverse effects

• HIV Resistance Testing

• Potential drug interactions

• Pre-treatment CD4+ T cell count

• Gender• Pregnancy potential• Patient lifestyle/ social

situation

DHHS 4/7/2005, http://AIDSinfo.nih.gov

Initiating Therapy in Treatment Naïve Patients

• If AIDS-defining illness or CD4 < 350• Regardless of CD4 count in:

– Pregnancy– HIV-associated nephropathy – HBV co-infection

• Recommended if CD4 count between 350 – 500• Panel split on initiating in CD4 > 500• Make a lifelong commitment and understand

adherence importance

DHHS 2009 Guidelines

Preferred Regimens for Naïve Patients

NNRTI-based regimen – Efavirenz+ tenofovir+ emtricitabine

PI-based regimen – Atazanavir/r + tenofovir+ emtricitabine– Darunavir/r QD + tenofovir + emtricitabine

INSTI-based regimen– Raltegravir + tenofovir+ emtricitabine

DHHS 2009 Guidelines

HIV Resistance Testing• Genotypes

– Sequences patient’s virus by blood sample– Mutations reported as compared to wild type

• Phenotypes– Similar to antimicrobial susceptibility testing– Reports IC50 for patient’s virus – Compares to wild type virus

• Virtual Phenotypes– Often reported along with genotypes– Information obtained from a database of

genotypes and matching phenotypes– An estimate of patient’s phenotype

Summary• HIV infection rates are not declining• Combination Therapy is CRITICAL• 100% Adherence is ABSOLUTELY NECESSARY• Drug Interactions are ANTICIPATED• Adverse Effects occur often

– Some can be managed– Some are dangerous

• If any doubt, call the physician or ME!