Introduction to HIV

AIM

• Epidemiology • Testing for HIV infection• Natural history of disease• When to start ART (guidelines/trends in the field)• Antiretroviral agents• Common toxicities• Opportunistic infections• OI prophylaxis

December 2009

Global summary of the AIDS epidemic, 2008

Total 33.4 million [31.1 – 35.8] Adults 31.3 million [29.2 – 33.7] Women (aged 15 and above)

15.7 million [14.2 – 17.2] Children under 15 years 2.1 million [1.2 – 2.9]

Total 2.7 million [2.4 – 3.0]Adults 2.3 million [2.0 – 2.5]Children under 15 years 430 000 [240 K – 610K]

Total 2.0 million [1.7 – 2.4]Adults 1.7 million [1.4 – 2.1]Children under 15 years 280 000 [150 K – 410 K]

Number of people living with HIV in 2008

People newly infected with HIV in 2008

AIDS-related deaths in 2008

Case

• 23-year old woman presents to Emergency Department with one week history of fever, malaise, myalgias, headache and sore throat

• Five days PTA she noted the onset of a new non-pruritic rash, on her face, torso, extremities

• Two days PTA developed mouth sores that were so painful she was unable to eat or drink

• PMH- negative• Soc Hx- sexually active, single, in grad school

Case

• Physical Examination in EDT 40oC. BP 104/76 P 108 R 20Appears unwellHEENT: Multiple oral ulcerations

Non-exudative pharyngitisMultiple cervical nodes (slightly

tender)Diffuse maculopapular Rash

Case

• Laboratory data in ED• H/H 12/36• WBC 3100 (65 segs, 25 lymphs, 6 atyp

lymphs, 4 monos)• Platelets 71,000• ALT 124, AST 75• Urine drug screen negative• All other labs normal

Differential Diagnosis

• Infectious Mononucleosis• CMV• HIV• Enterovirus- Coxsackie• Adenovirus• Streptococcal pharyngitis• Arcanobacterium hemolyticum• Syphilis

Principles of testing

• HIV infected patients produce antibodies which recognize HIV proteins

• ELISA• Western Blot• Immunofluorescence• Radioimmunoprecipitation

Proteins Detected by HIV Western Blot

RU3U5 p24 vif vpu env gp120 nefvprR

rev

tat

5’ 3’

env gp41p17

gag

IN PRO RT

pol

HIV-1 HIV-2}gp135/120ENV{

p55GAGp61POL

p51POL

p31POLp30GAG

p18GAG

}gp160/120{

p61POLp55GAGp51POL

p31POL

p24GAG

p17GAG

gp41ENVgp36ENV

Figure 6

Interpretation of Western Blot

– Positive: ANY Two: p24, gp41, gp160/120Positive: ANY Two: p24, gp41, gp160/120– Negative: NO positive bandsNegative: NO positive bands– Indeterminate: the remainderIndeterminate: the remainder

• Isolated p24 band most common indeterminateIsolated p24 band most common indeterminate• Isolated gp160/120 band suspicious for early Isolated gp160/120 band suspicious for early infectioninfection

• A 38 year old multiparous nurse is evaluated because of an abnormal ELISA for HIV when she attempted to donate blood. A follow up Western Blot analysis has an indeterminate result. The patient is asymptomatic. She and her husband have a monogamous relationship and neither have used illicit drugs. Patient has never received a blood transfusion, and reports a needle stick injury approximately 8 years ago from an HIV negative individual. Her physical examination is normal, her CD4 count is normal, but her plasma viral load is 82 copies/ml. Which of the following is the most appropriate management at this time?

– Recheck the plasma viral load now– Recheck the HIV serologic study in 3 months and 6 months– Begin HAART– Begin HAART if her CD4 count drops to <350/µL

WB Interpretation

• Infections (HIV-2 , HTLV-I, schisto)

• Neoplasms• Dialysis

• Ethnicity-Africans• Thyroiditis• Elevated Bilirubin• Rheumatologic diseases• Multiple pregnancy• Immunization (Tetanus, HIV)• Nephrotic proteinuria (massive)• Error in laboratory

• Window period• Common variable immunodeficiency• NOT Subtype

– Newest assays should identify even O

IndeterminateFalse Negative

RU3U5 p24 vif vpu env gp120 nefvprR

rev

tat

5’ 3’

env gp41p17

gag

IN PRO RT

pol

Detection limit

HIV Infection Profile

Relative Level

Time Post-Infection

HIV RNA

P24 antigen

Anti-Envantibody

Natural history of the disease

• Seroconversion- Median time from exposure to antibody-63 days (4 -10 wks)

• Clinical latent period• Average rate of decline of CD4 cells after 1 yr

is 50 cells (range- 30-90)- correlated with the viral load

• PGL• Early symptomatic HIV infection• AIDS

HIV Transmission Factors

• Stage of the disease• Viral load• STD• Genital lesions• Frequency of unprotected sex• Circumcision

Case

• A 35 year old asymptomatic male with a CD4 count of 325, viral load of 15,000 presents to the clinic for routine evaluation. Hepatitis testing reveals that the patient has a positive HBsAg, AST-80 and ALT of 85. Which of the following is the most appropriate ART regimen– Delay treatment till he is symptomatic– Begin azt/3tc/efv– Begin abc/3tc/efv– Begin tfv/ftc/efv

Response To Therapy

• Potency of antiretroviral therapy• Lower viral load• Higher CD4 count• Rapid reduction in plasma viral load in

response to therapy• Approximately 70% achieve this goal and 80%

of patients in clinical trial settings achieve this goal

Indications to start ART

CD4 BASED

• ART is recommended for patients with CD4 counts between 350 and 500

• 50% of the panel members would start ART in patients with CD4 counts greater than 500

IRRESPECTIVE OF CD4 COUNT

• History of an AIDS defining illness

• HIV associated nephropathy• Concomitant hep B with

indications to initiate hep B treatment

• Pregnancy

Probability of AIDS/Death

Life Cycle of HIV

Furtado MR et al. NEJM 1999;340:1614-22.

Life Cycle of HIV

Furtado MR et al. NEJM 1999;340:1614-22.

NRTI

NNRTI

PI

Fusion Inhibitor

INTEGRASE INHIBITORS

CCR5 INHIBITORS

Maturation inhibitors

Current Antiretroviral Medications

NRTI• Abacavir• Didanosine• Emtricitabine• Lamivudine• Stavudine• Zidovudine• Zalcitabine• Tenofovir

NNRTIFirst• Delavirdine• Efavirenz• Nevirapine

Second• Etravirine

PI• Amprenavir

• Fosamprenavir• Atazanavir

• Indinavir• Lopinavir• Nelfinavir• Ritonavir• Saquinavir

– soft gel– hard gel

• Tipranavir• Darunavir

Fusion inhibitor Enfurtivide

Integrase inhibitor Raltegravir

CCR5 inhibitor Maraviroc

Drugs in the pipeline

• NNRTI inhibitors

Rilpivirine

•Integrase inhibitors

Elvitegravir

•CCR5 inhibitors

Vicriviroc

• CXCR4 inhibitors

• Maturation inhibitors

• CD4 blockers

Initial Treatment: Preferred Components

NNRTI

• Efavirenz

PI

• Boosted Atazanavir• Boosted Darunavir

INTEGRASE

• Raltegravir

NRTI

• Tenofovir • Emtricitabine

Initial Treatment: Alternative Components

NNRTI

• Nevirapine

PI

• Lopinavir/Ritonavir • Boosted Fosamprenavir

•Boosted Saquinavir

NRTI

• Abacavir

• Zidovudine

• Lamuvidine

Drugs with activity against hepatitis B and HIV activity

• Tenofovir• Emtricitabine• Lamuvidine• Entecavir

NRTI

• Toxicities– Bone marrow toxicity, macrocytic anemia, neutropenia

GI-nausea, vomiting-AZT– General-headache, insomnia, asthenia-AZT– Lactic acidosis-D4T>DDI>AZT>TFV/ABC– Pancreatitis-DDI& D4T– Peripheral neuropathy-DDI/D4T>AZT>TFV– Lipoatrophy/lipodystrophy-D4T– Myopathy (including cardiomyopathy)-AZT– Hyperlipidemia-D4T>AZT>TFV/ABC– Rapidly progressive ascending muscle weakness-D4T

NRTI

• Abacavir– Abacavir hypersensitivity reaction– Fever, Rash– HLA type association with abacavir hypersensitivity– CAD

• Tenofovir– Fanconi syndrome– Renal insufficiency– Dosage adjustment for Crcl<50– Bone abnormalities in monkeys and ?fetal risks– ? osteopenia

Non-Nucleoside Reverse Transcriptase inhibitors (NNRTI)

• Efavirenz– CNS toxicity– Rash– Teratogenicity– False positive cannabinoid reaction

• Nevirapine– Hepatotoxicity– Highest risk in women whose CD4 count was greater than 250

at the time of NVP initiation (11.0% vs 0.9%)– Men with CD4 counts greater than 400 (6.3%vs 1.2%)– Rash, with reports of TEN and SJS

Protease inhibitors• Metabolic toxicities

– Hyperlipidemia/Hypertriglyceridemia-RTV– Hyperbilirubinemia-ATZ and IDV– Nephrolithiasis-IDV (a few case reports with ATZ)– Pyuria and Interstitial nephritis-IDV– Hyperglycemia-IDV and LPV/RTV– Diarrhea-LPV/RTV (cap)& NFV– CAD– Lipodystrophy– Drug drug interactions– Increased bleeding among hemophiliacs– PR interval prolongation-ATZ

Life threatening toxicities

• Abacavir hypersensitivity reaction• Lactic Acidosis with NRTI• Nevirapine related hepatotoxicity• Steven Johnson’s syndrome

Fusion inhibitors

• Injection site reaction almost universal• Hypersensitivity reaction <1%- do not

rechallenge• Increased rate of bacterial pneumonia

• A 35 year old female with HIV infection presents to the office. She was diagnosed with PCP and at that time had a CD4 count of 92/µL, viral load-105,000 copies/ml. AZT/3TC/EFV was initiated and 6 months post therapy her CD4 count was 323/µL and her VL was ND. Approximately 1 year ago she started missing appointments and 4 months prior her VL was 878 copies/ml and today her CD4 count is 300/µL and her VL is 5375 copies/ml. She remains asymptomatic. Which of the following is the most appropriate management?

– Continue the current regimen– Substitute Nevirapine for Efavirenz– Add Nevirapine to the current regimen– Order an HIV genotype resistance assay– Recommend a drug holiday until she becomes symptomatic.

DHHS guidelines

• Monitoring of therapy– Average gains- 50-150 cells/first year and 50- 100

cells/year (assuming viral control) thereafter until a set point is reached

– Viral load suppression to below undetectable should be achieved in 16-24 weeks in an ARV naïve patient

– A 1 log decline in viral load in 2-8 weeks– Viral suppression in 12-24 weeks

Pathogen Indication Preferred Alternative

PCP CD4<200,

oropharyngeal candidiasis

Bactrim DS qd

Bactrim SS qd

Bactrim 1 DS triweekly

Dapsone

Aero-pentamidine

Atovaquone

Toxoplasmosis CD4<100

Pos Toxo serology

Bactrim DS qd Bactrim 1 SS qd

Dapsone+pyrimethamine and leucovorin

Atovaquone/pyrimethamine/leucovorin

M.tuberculosis TST>5mm

Exposure to active TB

Prior pos untreated TST

INH-300 mg po qd

Rifampin-600 mg po qd

M.Avium intracellulare

CD4<50 Azithro-1200 q weekly

Claritho-500 bid

Rifabutin-300 qd

Opportunistic Infections

• Fever and Pulmonary infiltrate• CNS manifestations• Ophthalmologic manifestations• Diarrhea

Fever and Pulmonary infiltrate

• A 32 year old male presents to the clinic with a 2 week history of non-productive cough, worsening SOB and fever. The patient was recently diagnosed with HIV and his CD4 count is 150 cells/µL.

• O/E- HR-100, RR-22, T-100, Pulse ox-85% RA. • RS- examination reveals a few scattered rales

and rhonchi.

Differential Diagnosis• PCP- the most commonly diagnosed OI in North America• M.tuberculosis• Community acquired pneumonia• C.neoformans• H.capsulatum• C.immitis• R.equi• Atypical Mycobacteria (M.kansasii)• HSV• CMV• KS• Malignancies

Case

• A 40 year female is bought in by her family. Over the past few weeks her family has noticed that she has been forgetful, lethargic and confused. The patient has a CD4 count of 35 and has not been on ART or prophylaxis.

• Examination reveals a right sided hemiparesis and VII nerve palsy

Differential Diagnosis By Presenting Symptoms, Exam Findings

Nonfocal- Cryptococcal meningitis- CMV encephalitis- AIDS dementia- Lymphomatous

meningitis- Other (TB, fungal)

Focal- Toxoplasmosis- Lymphoma- PML- Cryptococcoma- VZV- Meningovascular- syphilis- Other (TB, fungal)

Is This CNS Toxoplasmosis?

Factors that lessen the likelihood:- On TMP-SMX or other prophylaxis- CD4 count > 100/μl- Negative serologies- Solitary lesion on MRI (multiple and bilateral lesions more

c/w toxo)- No contrast enhancement- No MRI improvement on 2-3 weeks of therapy- Uptake on SPECT

Primary AIDS-Related CNS Lymphoma

Mean CD4 = 30/μl

EBV associated

RARE among HIV negative patients about 2% of AIDS patients

Evolution: 2-8 weeks

Survival after diagnosis is usually limited to months

PCR of CSF is usually positive for EBV

Case

• 32 year old african american male last documented CD4 count of 10 presents to the clinic with symptoms of lethargy, headache and a skin rash. O/E- he is awake, but appears minimally lethargic, there is no neck stiffness. CSF exam-reveals a WBC count of 3, protein-100, glucose-30.

Case

• A 35 year old AA male with a CD4 count of 65 presents to the clinic with c/o progressive loss of vision and left sided hemiparesis. A LP and MRI are performed. PCR of the CSF is positive for JC virus. Which of the following is the most appropriate treatment for this patient– 1-Start acyclovir– 2-Start radiation and dexamethasone– 3- Start sulfadiazine and pyrimethamine– 4-Start HAART

• A 40 year old male with AIDS presents with a 1 days history of blurred vision and a several hour history of acute loss of vision in the right eye. On physical examination, vitals signs are normal. Pupils are equal and readily reactive to light. Examination of the right fundus shows a localized area of hemorrhagic necrosis of the fovea. The remainder of the examination is normal. There are no exudates and no uveal disorders. After hospitalizing the patient, which one of The following intravenous agents is most appropriate?

BactrimAcyclovirGancyclovirPenicllinA corticosteroid

Case

• A 35 year old male with a CD4 count of 45 presents to the clinic with a 1 week history of blurred vision, floaters in his right eye. There is no pain or photophobia, external examination is normal, fundoscopy reveals.

http://hivinsite.ucsf.edu/InSite

Case

• Which one of the following antivirals would you like to use– Valgancyclovir– Gancyclovir– Acyclovir– Valacyclovir

Case

• A 45 year old HIV positive male whose CD4 count is 78 presents to the clinic with c/o diarrhea. The diarrhea is non-bloody, painless. He denies fevers. He states that his he recently acquired a puppy. His labs reveal normal electrolytes and a Hb-12.5. His serum alkaline phosphatase is also within normal limits. Stool cultures are negative

Protozoal Agents positive on AFB staining

Isospora Cyclospora

Cryptosporidium

Microsporidium

Size (μ) 20-30 8-10 4-6 1-5

Mod afb Positive Positive Positive Negative

Therapy Tmp-smx, cipro, pyrimethamine

Tmp-smx, cipro

HAART, paromomycin, nitazoxinide

albendazole

Case

• A 18 year old male previously treated for TB with ATT was recently diagnosed with HIV. He is started on an AZT/3TC/Nevirapine based regimen. Approximately 3 weeks after starting ART he presents to the clinic with worsening SOB. His CD4 count at ART initiation was 55 cells/µL and viral load is 85,000 copies/ml. His viral load at presentation was 85 copies/ml.

Immune Reconstitution Inflammatory Syndrome (IRIS)

– Seen after HAART with immune recovery– M.tuberculosis, Cryptococcus, CMV, MAC, PML,– Manifest with rheumatologic manifestations as

well as Graves disease– Continue HAART and treat underlying infection if

possible– Sometimes need steroids to decrease

inflammation

References• Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-infected

adults and adolescents. Department of Health and Human Services.. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentsGL.pdf.

• Clotet B et al Lancet 2007;369:1169-1178Efficacy and safety of darunavir-ritonavir at week 48 in treatment experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomized trials.

• The stages and natural history of HIV infection J. Bartlett-Uptodate

• SMART study group NEJM 2006;355:2283-2296 CD4+ Count-Guided Interruption of Antiretroviral Treatment

• Cooper D et al. Results of BENCHMRK-1, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstracts 105aLB.

• Steigbigel R et al. Results of BENCHMRK-2, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstracts 105bLB.

• Markowitz M, Nguyen BY, Gotuzzo E, et al. Rapid onset and durable antiretroviral effect of raltegravir (MK-0518), a novel HIV-1 integrase inhibitor, as part of combination ART in treatment-naive HIV-1 infected patients: 48-week results. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUAB104.

References• Selzentry- prescribing information

http://media.pfizer.com/files/products/uspi_maraviroc.pdf, accessed aug 21,2007• HIV drug resistance database http://hivdb.stanford.edu accessed Aug 18,2007• Shafer RW Clinical Microbiology Reviews Apr 2002;15: 247-277 Genotype testing for Human

Immunodeficiency Virus type I drug resistance• Slides from the Personal Collection of Dr. Maldarelli• Principles and Practices of infectious Diseases • MKSAP 14• 2002 USPHS/IDSA Guidelines for the prevention of opportunistic infections in persons

infected with the HIV virus http://www.aidsinfo.nih.gov/guidelines/Guideline accessed Aug 28,2009

• Treating opportunistic infections among HIV infected adults and adoloscents- December 17,2004 http://www.aidsinfo.nih.gov/guidelines/Guideline accessed Aug 28,2008