HIV Management 2011

John K. Midturi

April 16, 2011

Objectives

• Recognize HIV/AIDS prevalence rates in USA

• Recognize populations at highest risk for HIV infections

• Understand rationale for CDC recommendations on routine testing

• Be able to decide when to initiate HAART• Be able to select initial antiretroviral regimen

Epidemiology

• Reported 25 yrs ago

• Industrialized nations– Chronic manageable disease

• Developing world– Devastating effects on individuals, family

units, general community– High mortality and morbidity rates

Quarter-Year

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er

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1985198619871988198919901991199219931994199519961997199819990

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15,000

20,000

25,0001993 definitionimplementationDeaths

Prevalence

AIDS

0

150,000

100,000

50,000

200,000

250,000

300,000

350,000

Estimated Incidence of AIDS, Deaths, and Prevalence by Quarter-Year of Diagnosis/Death,

United States, 1985-1999*

Pre

vale

nce

Estimated Rates for Adults and Adolescents Living With HIV Infection (not AIDS)34 States and 5 U.S. Dependent Areas, 2007

Estimated HIV Rateper 100,000

Confidential name-basedHIV infection reporting not implemented as of 2003

2.2 – 51.7

51.8 – 103.8

103.9 – 170.5

170.6 – 282.0Data classed using quartilesTotal rate: 154.2 per 100,000

Note: Rates have been adjusted for reporting delays. Inset maps not to scale. HIV/AIDS Surveillance Report, 2007. Vol 19, table 11.

U.S. Virgin Islands

AKHI

Puerto Rico

American Samoa

NorthernMarianaIslands

Guam

DC

6

7

Awareness of HIV Status in the US

1CDC. HIV prevalence estimate—United States, 2006. MMWR. 2008;57(39):1073-1076.2Hall HI, et al. Estimation of HIV incidence in the United States of America. JAMA. 2008;300:520-529.

3CDC. HIV/AIDS surveillance report—cases of HIV infection and AIDS in the United States and dependent areas, 2007;19.http://www.cdc.gov/hiv/topics/surveillance/resources/reports/2007report/default.htm. Accessed July 23, 2009.

HIV estimated prevalence1 1,056,400 - 1,156,400

Undiagnosed1 232,700

Estimated newannual infections (2006)2

56,300

• From 2004 to 2007, the estimated number of newly diagnosed HIV/AIDS cases increased 15%3

8

US Population Demographics: Total Population and HIV/AIDS Cases by Race/Ethnicity

White71%

Other4%

Black12%

Hispanic13%

Total US Population (2006)(N = 247.1 million)1

Campsmith M, Rhodes P, Hall HI. 16th CROI; 2009; Montreal. Abstract #1036.

Estimated HIV/AIDS Prevalence by Race/Ethnicity (2006)

(N = 1,106,400)2

Black46%

White35%

Hispanic/Latino18%

Other<2%

9

Estimated HIV/AIDS Prevalence and New Infections by Transmission Category in the US (2006)

MSM48%

High-Risk Heterosexual

Contact (Male)9%

IDU (Male)12%

MSM + IDU5%

High-Risk Heterosexual

Contact (Female)

18%

IDU (Female)

7%

Other1%

CDC. HIV Incidence. Available at http://www.cdc.gov/hiv/topics/surveillance/incidence.htm.

MSM53%

High-Risk Heterosexual

Contact31%

IDU12%

MSM + IDU4%

Estimated New HIV DiagnosesEstimated Prevalence of HIV/AIDS

A global view of HIV infection33 million people [30–36 million] living with HIV, 2007

Pathophysiology and Natural History

• Family of Retroviruses– Subfamilies– Oncoviruses– Lentiviruses- slow viruses

• HIV- long replication periods prior to clinical manifestations

– Spumaviruses- not associated with human disease

• HIV genome consists of three structural genes

• gag- codes for viral capsid proteins, p15, p17, p24

• pol- codes for proteins responsible for viral replication, and reverse transciptase

• env- codes for envelope proteins gp120, gp41

Ontogeny of HIV• Simian immunodeficiency virus (SIV) is

evolutionarily adapted to its natural hosts, chimpanzees and sooty mangeby monkeys

• Inoculation of SIV into other primates typically produces an HIV-like disease

• SIV is the closest known relative of HIV-1 and 2• These findings suggest that the HIV pandemic

began with infection of humans by SIV variants• Phylogenetic analysis suggests that HIV became

established in humans early in the 20th century

HIV Types 1 and 2• Geographic distribution

• HIV-1: Global• HIV-2: West Africa

• Transmission• Identical for the two virus types

• Pathogenicity• HIV-2 appears to be less pathogenic

than HIV-1

HIV-1 Classification System

• Group M (main)• Subtypes (clades) A to D, F, G, H to K• Recombinant forms

• Group O (outlier)

• Group N (non-M/non-O)

Subtype, circulating recombinant forms

HIV-1 Subtypes: Implications for Diagnosis and Treatment

• Several studies suggest differential rates of HIV disease progression and transmission by subtype

• There may be differential rates of emergence of resistance to ARVs by subtype

Transmission

• Probability of infection– Blood transfusion/ transplant

95%-100%– MTCT with ART: ~25%– Needle Sharing: 1/150,

~0.6%– Occupational needle stick,

1/300, ~0.3%– Sexual contact (single event):

0.2%

Un.org

Medipulse.com

Brandonyeoh.com

HIV Life Cycle

Maturation2. Membrane

fusion & entry

9. Budding

3. Uncoating & reverse

transcription

4. Nuclearuptake 5. Integration

6. Transcription & RNA processing

7. Nuclearexport 8. Translation

& Assembly

1. Receptorbinding

Immunopathogenesis of HIV

• CD4+ cells are the principle targets of HIV in the host• Helper/inducer T-lymphocytes• Fetal thymocytes• Macrophages/monocytes• Dendritic cells• Microglia• Placental trophoblast cells

Clinical Presentation

Acute infection

• 40-90% of primary infections develop mononucleosis like syndrome– 2-6 weeks after exposure– Acute retroviral syndrome– Signs/symptoms

• Fever 96%, LAD 74%, Exudative pharyngitis 70%, myalgia's/arthralgia 54%, diarrhea 32%, headache 32%

– Duration of illness is <2weeks– Diagnosis

• HIV RNA viral load (high) and HIV antibody (+/-)

• Progressive loss of CD4 lymphocytes– 50-80 CD4 cells/uL

per year– Infection to

development of AIDS- 6-8years

– Dependent on viral load, CD4 count, age, socioeconomic status, host genetics

• Rapid progressor• Long term non-

progressors• Elite controllers

(viral load <48copies w/o therapy)

Chronic Infection

WHO HIV clinical stages

Definitions for AIDS

1993 Centers for Disease Control and Prevention Revised Surveillance Definitions of AIDS

A CD4+ T-cell count below 200 cells/μL or a CD4+ T-cell percentage of total lymphocytes of ≤ 14% and/or the following AIDS-defining infections:

 Candidiasis of bronchi, trachea, or lungs

 Esophageal Candida

 Coccidioidomycosis, disseminated or extrapulmonary

 Cryptococcosis, extrapulmonary

 Cryptosporidiosis, chronic intestinal for > 1 mo

 Cytomegalovirus disease (other than liver, spleen, or lymph nodes)

 Encephalopathy (HIV-related)

 Herpes simplex: chronic ulcer(s) for > 1 mo; or bronchitis, pneumonitis, or esophagitis

 Histoplasmosis, disseminated or extrapulmonary

 Isosporiasis chronic intestinal (for > 1 mo)

 Mycobacterium avium complex

 Mycobacterium, other species, disseminated or extrapulmonary

 Pneumocystis jiroveci (formerly carinii) pneumonia

 Pneumonia recurrent (> 1 recurrent episode in a 12-mo period)

 Progressive multifocal leukoencephalopathy

 Salmonella septicaemiae (recurrent)

 Toxoplasmosis of the brain

 Tuberculosis

 Wasting syndrome due to HIV

And/or the following AIDS-defining malignancies:

 Cervical cancer (invasive)

 Lymphoma: Burkitt's, immunoblastic or primary brain

 Kaposi's sarcoma

Wikimedia.com

Emedicine.com

www.brown.edu

www.bmj.com

Screening and Diagnosis

• CDC recommendations – 13-64 years of age– Routine HIV testing in all health care settings– Informed to opt out, no written consent required– Must screen for HIV

• TB treatment• STD treatment

– High risk behavior• IV drug users• Exchange sex for money• Sex partners of HIV infected person• Men who have sex with men• Heterosexual persons or partners with more than one partner since

last test

www.stdexpress.com

Routine HIV Testing: Who to Test

Which patients should be offered routine HIV testing? What guidelines and recommendations exist regarding routine HIV testing?Short answer: All individuals between the ages of 13 and 64 yrs should be routinely screened for HIV infection in healthcare settings.

CDC Recommendations for Routine HIV Testing

• Routine, voluntary HIV screening in healthcare settings recommended for all patients 13-64 yrs of age– Except in populations with documented prevalence of

undiagnosed HIV infection < 0.1%– Without prevalence data, voluntary HIV screening

appropriate until diagnostic yield < 1/1000 patients screened is established

• Separate written consent not recommended• Pre- or post-test prevention counseling should not be

required with testing or screening programs

Branson BM, et al. MMWR Recomm Rep. 2006;55:1-17.

USPSTF HIV Testing Recommendations

• Screening strongly recommended for all adolescents and adults at increased risk for HIV and all pregnant womenIncreased risk defined as individuals with ≥ 1 risk individual factor or

individuals receiving healthcare in a high-prevalence or high-risk clinical setting

Individual Risk Factors High-Prevalence or High-Risk Settings

Men who have had sex with men after 1975 Men and women having unprotected sex with multiple partners Past or present IDUsMen and women who exchange sex for money or drugs or have sex partners who doIndividuals whose past or present sex partners were HIV infected, bisexual, or IDUs Persons being treated for STDs Persons with a history of blood transfusion between 1978 and 1985Persons who request an HIV test despite reporting no individual risk factors may be considered at increased risk

STD clinics Correctional facilities Homeless shelters Tuberculosis clinicsClinics serving men who have sex with menAdolescent health clinics with a high prevalence of STDsAny clinical setting with a known HIV prevalence ≥ 1% among the patient population being served

USPSTF recommendations. July 2005.

Diagnosis

• Enzyme linked immunosorbent assay (ELISA) followed by confirmatory Western blot assay if ELISA positive

• ELISA 99% specific, 98.5% sensitive• Western blot 100% sensitive, and 100%

specific for chronically infected– Detects antibodies to HIV proteins– Core (p17, p24, p55)– Polymerase (p31, p51, p66)– Envelope (gp41, gp120, gp160)

Oraquick

Western Blot

• CDC criteria 1– p160, p120 AND p41

• CDC criteria 2– p160, p120 OR p41 PLUS p24

– Positive= reactive to gp120 and either gp41, p24

– Negative= non reactive– Indeterminate= presence of other band

pattern not positive

p160 p120 p41 p68 p53 p32 p55 p40 p24 p18G

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Diagnosis

• HIV antibodies appear in circulation 2-12 weeks after exposure

• Window period- serologic testing is negative– Repeat test in 6 weeks to 3 months

• Rapid serologic tests results in 20 minutes– Sensitivity and specificity 99%

Management

• H&P• Social support system• Reaction to HIV infection

– Anxiety, depression, adjustment disorders

• Lab– Baseline- assessment of liver, bone marrow,

and kidney function, lipids• Cd4, viral load, CBC with diff, LFTs, lipid, hep Bs

antigen and antibody, hep c antibody, Toxoplas IgG, cmv IgG, tst, rpr, pap smear, g6pd level, genotype

Preventative measures

• Routine immunizations

• Cervical cancer screening

• Medication for primary or secondary prophylaxis

Immunizations

• Pneumococcal vaccine– Every 5 years x 2 doses

• Hepatitis A and B• Give when CD4 above 200cell/uL• TST/T-Spot

– Annually– >5mm considered positive

• CXR and if no symptoms and CXR clear therapy for LTBI

Women & HIV

• Women– Increased incidence of cervical dysplasia and

invasive cervical carcinoma• More frequent Pap smear screenings• 2 Pap smears 6 months apart and then annually if

results are normal• Abnormality- colposcopy

– HSV- suppressive therapy indicated for frequent anogenital outbreaks

Kasheun.com

Care of Pregnant HIV-Infected Women

• The current recommendations focus on use of HAART by known HIV-infected pregnant women, regardless of maternal health needs– reduce the risk of mother-to-child

transmission

• Perinatal transmission rates—to less than 2%—in the United States.– Identifying HIV infection in pregnant women

with previously undiagnosed or newly acquired HIV infections

– Preventing HIV transmission to infants through the use of chemoprophylaxis antiretroviral therapy

– Avoiding breastfeedinghttp://www.hiv.gov.gy/ads/pstr_protectbaby.jpg

Antiretroviral Therapy During Pregnancy

• HAART should be initiated in all HIV-infected pregnant women regardless of CD4+ cell count or HIV-1 RNA level. – Antiretroviral resistance testing before initiating HAART– CBC & CMP testing before treatment initiation. – OI prophylaxis-based on current CD4+ cell count.

• HAART (2 NRTIs and either a PI with ritonavir boosting or a NNRTI) – Efficacy of antiretroviral therapy in preventing maternal to fetal

transmission is primarily through lowering plasma HIV-1 RNA.

• Transmission can occur at any plasma HIV-1 RNA level, including undetectable plasma HIV-1 RNA– All HIV-infected pregnant women should be offered HAART.

Viral Load and Transmission

00

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HIV-1 RNAHIV-1 RNA Transmission %Transmission %

<1000 copies/mL<1000 copies/mL

1000 - 10,0001000 - 10,000

10,001- 50,00010,001- 50,000

50,001-100,00050,001-100,000

>100,000>100,000

NN

0/570/57

32/19332/193

39/18339/183

17/5417/54

26/6426/64

Women & Infants Transmission Study (WITS) Garcia, et al, NEJM 1999

Mode of Delivery • HIV-1 RNA remains > 1000 copies/mL- caesarian section

– Scheduled for 38-39 weeks gestation• Intravenous zidovudine infusion initiated 4 hours before the caesarian delivery

(2 mg/kg over 1-hour loading dose, then 1 mg/kg/hour continuous infusion until delivery, ie, umbilical cord ligated)

– Caesarian section delivery probably confers little added benefit in women with plasma HIV-1 RNA < 1000 copies/mL (Management Guidelines).[DHHS Perinatal]

• HIV-1 RNA is < 1000 copies/mL, a vaginal delivery – Induction of labor at 38-39 weeks. – Invasive fetal monitoring or operative delivery with vacuum devices or forceps

should be avoided in HIV-infected women• increase risk of transmission.[Mofenson 1999; Shapiro 1999]

– Artificial or prolonged rupture of membranes should be avoided• caesarian delivery if labor does not progress 4 hours after membranes have

ruptured– Intravenous infusion with zidovudine should be initiated at the onset of labor

• Intravenous zidovudine (2 mg/kg over 1-hour loading dose, then 1 mg/kg/hour continuous infusion until delivery, ie, umbilical cord ligated)

Prophylaxis

• CD4 cell count is an indicator of immune competence– CD4 <200, CD4% <14%, recurrent

candidiasis, persistent fever, previous PCP: Pneumocystis jirovecii pneumonia

• TMP/SMX• Dapsone• Atovaquone• Pentamidine (aerosolized)

Prophylaxis

• CD4 <100 and positive IgG Toxo titer:– Toxoplasmosis:

• TMP/SMX• Dapsone• Pyrimethamine• Leucovorin

• CD4 <50– MAC

• Azithromycin• Clarithromycin• Rifabutin

Discontinuation of Prophylaxis

• Discontinue primary and secondary prophylaxis for certain OI if sustained rise in CD4 cell count above threshold for prophylaxis initiation

• PJP (>200)• Toxoplasmosis (>100)• MAC (>50)• Secondary prophylaxis

– Cytomegalovirus (>150)

• Re-initiate prophylaxis if CD4 decreased below threshold

Treatment

• Goal: – prolong life– avoid destruction of immune system– allow reconstitution of immune system– prevent OI– provide improved quality of life by reduction HIV-related

symptoms

• Effective therapy: <50copies/ml– Improve prognosis, minimize the development of

resistance, and prolong duration of antiretroviral response

www.abc.net.au

Antiretroviral Agents - 1

• Nucleoside / nucleotide analogues (NRTIs)Abacavir C – No studies. Concern for

hypersensitivityDidanosine B – Concern for lactic acidosis (do not use

w/ d4T)Emtricitabine B – No studies.Lamivudine C – Well tolerated. Widely used.Stavudine C – Concern for lactic acidosis (do not use

w/ ddI)Tenofovir B – No studies. Animal reports of bone

abnlsZalcitabine C – No studies. Teratogenic in animals.Zidovudine C – Well tolerated. The most experience.

Antiretroviral Agents - 2

• Non-nucleoside RT inhibitors (NNRTIs)Delavirdine C – No studies.Efavirenz D – Teratogenic. 4/142 birth

defects. Avoid in 1st trimesterNevirapine C – Well tolerated. Avoid initiating if CD4

>250 cells/mm3.

Antiretroviral Agents - 3

• Protease inhibitors (PIs)Amprenavir C – No studies. Oral solution contraindicated.Atazanvir B – No studies. Concern hyperbilirubinemiaFosamprenavir C – No studiesIndinavir C – Unboosted: poor blood levels in pregLopinavir/ritonavirC – No studiesNelfinavir B – Registry data shows no incr in birth defRitonavir B –Not used alone due to GI side effectsSaquinavir B – Well tolerated, used boostedTripanavir C – No studies

Antiretroviral Agents- 4

• Integrase Inhibitors (INSTI)– Raltegravir C-No studies

Antiretroviral Agents- 5

• Entry Inhibitors– Maraviroc B- No studies, requires Tropism

test– Enfuvirtide B- No studies, subcut injection

0

200

400

600

800

1,000

1,200

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HIV Infected Diagnosed In Care On ART

Pa

tie

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00

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1,056 – 1,156

835 – 915

560

~79%

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Sources:* February, 2009 CDC estimates as of the end of 2006** Synovate Healthcare U.S. HIV Monitor Q3 2008

Significant Numbers of People with HIVin the US Are Not on Antiretroviral Therapy

FACTOR RECOMMENDATION FOR TREATMENT

AIDS Treat Treat Treat Treat Treat

CD4 <500

• Treat <200

• Offer <350

• Indiv. >350

•Treat <350

• Risks/ Benefits if >350

Viral Load >20,000 >55,000 > 100,000No specific viral

load

Other Factors

• Pregnant women

• HBV co-infected

• HIVAN DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, 1998 – 2008.

When to Treat: History of DHHS Recommendations

1998 2001 2002 2004 2008

Recommendations for Initiation of Therapy in Antiretroviral Naïve HIV-infected PatientsCondition Recommendation

In presence of

• AIDS-defining illness

• Pregnancy

• HIV-associated nephropathy

• HBV co-infection when HBV therapy is indicated

and/or

• CD4 count <350 cells/mm3

Start ART

CD4 count

350-500 cells/mm3

ART is recommended

• 55% of Panel members strongly recommended starting ART

• 45% moderately recommended starting ART

CD4 count

>500 cells/mm3

ART is recommended or optional

• 50% recommended starting ART

• 50% viewed starting ART as optional

DHHS 2009 Guidelines

DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. December 1, 2009. Available at: http://www.aidsinfo.nih.gov.

Recommendations for Initiation of Therapy in Antiretroviral Naïve HIV-infected Patients

• Patients initiating antiretroviral therapy should be willing and able to commit to lifelong treatment and should understand the benefits and risks of therapy and the importance of adherence

• Patients may choose to postpone therapy, and providers may elect to defer therapy, based on clinical and/or psychosocial factors on a case-by-case basis

DHHS 2009 Guidelines

DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. December 1, 2009. Available at: http://www.aidsinfo.nih.gov.

60

Recommendations for Earlier ART Initiation: Summary of Benefits and Limitations

Benefits Potential Limitations• Reduction in mortality and/or AIDS-

associated morbidity

• Improved outcomes in patients with certain co-morbidities, including HIVAN and HIV/HBV co-infection

• Potential to reduce risk of endothelial dysfunction and cardiovascular disease

• Reduced risk of AIDS-defining and non-AIDS-defining malignancies

• More robust immunologic response when treatment is initiated at a younger age

• Prevention of HIV transmission

• Fewer long-term safety data on newer ARVs

• Concerns for some unknown adverse consequences / complications of lifelong ART

• Potential for reduced quality of life associated with side effects in some patients, particularly those who are asymptomatic at the time of ART initiation

• Earlier emergent drug resistance, particularly in nonadherent patients, resulting in loss of drugs and drug classes and transmission of drug-resistant HIV

• Annual cost of medication

DHHS 2009 Guidelines

DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. December 1, 2009. Available at: http://www.aidsinfo.nih.gov.

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Treatment Responses in 1st Year of HAARTImproving Over Time

• 4143 subjects from 5 clinic cohorts in Europe and Canada• Treatment-naive; started HAART from 1996-2002 risk of virologic failure, med. CD4 count increase in later years

– Most “failure” now due to loss to follow-up or treatment discontinuation

Lampe F, et al. CROI 2005. Abstract 593

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count normalization with earlier therapyKeruly J, et al. Clin Infect Dis. 2007;44(3):441-446. Gras L, et al. J Acquir Immune Defic Syndr. 2007;45(2):183-192.

Likelihood of Achieving a Normal CD4 Cell Count Dependent on CD4 at Initiation of

Therapy

1000

800

600

400

200

00 48 96 144 192 240 288 336

ATHENA National Cohort

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>500350-500200-35050-200<50

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Initial Treatment: Preferred

NNRTI based •EFV/TDF/FTC1,2

PI based •ATV/r + TDF/FTC²•DRV/r (QD) + TDF/FTC²

II based •RAL + TDF/FTC²

Pregnant Women •LPV/r (BID)³ + ZDV/3TC

1. EFV should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception. 2. 3TC can be used in place of FTC and vice versa.

Initial Treatment: AlternativesNNRTI based •EFV¹ + (ABC/3TC) or (ZDV/3TC)²

•NVP4 + ZDV/3TC

PI based •ATV/r + (ABC/3TC) or (ZDV/3TC)2,3

•FPV/r (QD or BID) + (ABC/3TC) or (ZDV/3TC) or (TDF/FTC)2,3

•LPV/r (QD or BID) + (ABC/3TC) or (ZDV/3TC) or (TDF/FTC)2,3

•SQV/r + TDF/FTC2

1. EFV should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception. 2. 3TC can be used in place of FTC and vice versa.3. ABC should not be used in patients who test positive for HLA B*5701; caution if HIV RNA >100,000 copies/mL, or if high risk of cardiovascular disease.4. NVP should not be started if pre-ARV CD4 >250 in women or >400 in men.

ARVs Not Recommended inInitial Treatment

High rate of early virologic failure

• ddI + TDF

Inferior virologic efficacy

• ABC + 3TC + ZDV as 3-NRTI regimen• ABC + 3TC + ZDV + TDF as 4-NRTI regimen• DLV• NFV• SQV as sole PI (unboosted)• TPV/r

High incidence of toxicities

• d4T + 3TC• IDV/r• RTV as sole PI

Questions

HIV Entry Is Triggered by Receptor Engagement

Attachmentto CD4+ cell

Triggered by coreceptor

Membranefusion

1 2 3

Maraviroc Enfuvirtide

Licensed entry inhibitors

Co-receptor antagonists

• Block major entry step by binding to chemokine receptors (CCR5 or CXC4)

What Are Viral Coreceptors?

• There are 2 viral coreceptors that matter– CCR5 and CXCR4– Both are chemokine

receptors• Most viruses can use only

CCR5: R5 viruses• Many can use both

coreceptors: R5/X4 (D/M)• A few can use only CXCR4: X4

viruses

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LK

K

LFK T

S AQ H

VSRGSS

A

TS

GIL S K

G K R

TESESSS

F

GHSSVSH

S S

VA

ANW

KNF

NANE E R F C

PEKM

SDYD

GSGMEETYND S

T Y I S I G E M - NH2

Ser/Thr rich

*

*

*

N

Cytoplasmic

39-

-65 75-

-97 110-

-133 154-

-176 -202

224- -239

-262-282

308-

-352

F

CXCR-4

A

= Predicted G-protein binding domains

CXCR4

Summary: Appropriate Use of CCR5 Antagonists

• CCR5 inhibitors beneficial when used in treatment-experienced patients with no detectable D/M or X4 virus at BL

• In antiretroviral-naive patients with R5-only virus, CCR5 antagonist plus 2 NRTIs showed substantial activity, though not noninferior vs efavirenz plus 2 NRTIs

• Phenotyping tests likely to be used to identify tropism of patient’s viral population having detectable X4 or D/M virus– Clinician can then determine if patient is appropriate

candidate for CCR5 inhibitor therapy

Adverse Effects: CCR5 Antagonist

• MVC – Drug-drug interactions– Abdominal pain– Upper respiratory tract infections– Cough– Hepatotoxicity– Musculoskeletal symptoms– Rash– Orthostatic hypotension

Fusion Inhibitors

• Impair membrane fusion of HIV to T cells

• Subcutaneous injection twice daily

Adverse Effects: Fusion Inhibitor

• ENF – Injection-site reactions– Hypersensitivity reaction– Increased risk of bacterial pneumonia

Co-receptors-Conclusion

• HIV entry process offers several opportunities for therapeutic intervention

• Understanding Env protein is key to development and use of entry inhibitors

• Coreceptor binding offers important target to disrupt HIV infection

• Coreceptors are evolving target for inhibitors– Development of resistance likely and will pose

challenges in how to use therapies• Effective use of entry inhibitors will require careful use of

phenotypic coreceptor tropism assays

Summary: Viral Envelope and Coreceptor Use

• HIV binds to CD4 and a coreceptor

– R5 viruses use CCR5 and are common

– X4 viruses use only CXCR4 and are rare

– D/M viruses can use both coreceptors and are common in later-stage patients

• Coreceptor use largely defines HIV tropism

• New infections almost always due to R5 viruses

• In some patients, D/M and/or X4 viruses emerge years after infection

• Coreceptor switch associated with faster progression

Nucleoside/Nucleotide reverse transcriptase inhibitors (NTRI)

• Nucleoside and nucleotide analogues

• Impair transcription of viral RNA into DNA

Adverse Effects: NRTIs

• All NRTIs: – Lactic acidosis and hepatic steatosis (highest

incidence with d4T, then ddI and ZDV, lower with TDF, ABC, 3TC, and FTC)

– Lipodystrophy(higher incidence with d4T)

Adverse Effects: NRTIs (2)

• ABC– HSR*

– Rash

– Possible ↑ risk of MI

• ddI – GI intolerance

– Peripheral neuropathy

– Pancreatitis

– Possible noncirrhotic portal hypertension

* Screen for HLA-B*5709 before treatment with ABC; ABC should not be given to patients who test positive for HLA-B*5709.

Adverse Effects: NRTIs (3)• d4T

– Peripheral neuropathy– Pancreatitis

• TDF– Renal impairment – Possible decrease in bone mineral density– Headache– GI intolerance

• ZDV

– Headache– GI intolerance– Bone marrow suppression

Non-nucleoside reverse transciptase inhibitors (NNRTI)

• Inhibit reverse transciptase by binding to the enzyme

ARV Components in Initial Therapy: NNRTIs

ADVANTAGES• Long half-lives• Less metabolic toxicity

(dyslipidemia, insulin resistance) than with some PIs

• PIs and II preserved for future use

DISADVANTAGES• Low genetic barrier to

resistance – single mutation

• Cross-resistance among most NNRTIs

• Rash; hepatotoxicity• Potential drug interactions

(CYP450)• Transmitted resistance to

NNRTIs more common than resistance to PIs

Adverse Effects: NNRTIs

• All NNRTIs:– Rash, including Stevens-Johnson syndrome– Drug-drug interactions

• EFV– Neuropsychiatric– Teratogenic in nonhuman primates + cases of neural tube defects in

human infants after first trimester exposure

• NVP– Higher rate of rash – Hepatotoxicity (may be severe and life-threatening;

risk higher in patients with higher CD4 counts at the time they start NVP)

Protease Inhibitors (PI)

• Impair the packaging of viral particles into mature virus capable of budding from the cell

ARV Components in Initial Therapy: PIs

ADVANTAGES• Higher genetic barrier

to resistance• PI resistance

uncommon with failure (boosted PI)

• NNRTIs and II preserved for future use

DISADVANTAGES• Metabolic complications

(fat maldistribution, dyslipidemia, insulin resistance)

• GI intolerance

• Potential for drug interactions (CYP450), especially with RTV

Adverse Effects: PIs

• All PIs: – Hyperlipidemia – Insulin resistance and diabetes– Lipodystrophy – Elevated LFTs– Possibility of increased bleeding risk

for hemophiliacs– Drug-drug interactions

Adverse Effects: PIs (2)

• ATV– Hyperbilirubinemia– PR prolongation– Nephrolithiasis

• DRV – Rash– Liver toxicity

• FPV– GI intolerance– Rash– Possible increased risk of MI

Adverse Effects: PIs (3)

• IDV– Nephrolithiasis– GI intolerance

• LPV/r – GI intolerance– Possible increased risk of MI– PR and QT prolongation

• NFV – Diarrhea

Adverse Effects: PIs (4)

• RTV

– GI intolerance– Hepatitis

• SQV – GI intolerance

• TPV – GI intolerance– Rash– Hyperlipidemia– Liver toxicity– Cases of intracranial hemorrhage

Integrase Inhibitors

• Prevent incorporation of viral DNA into host cell genome

ARV Components in Initial Therapy: II (Raltegravir)

ADVANTAGES• Virologic response

noninferior to EFV• Fewer adverse events

than with EFV• Fewer drug-drug

interactions than with PIs or NNRTIs

• NNRTIs and PIs preserved for future use

DISADVANTAGES• Less experience with IIs,

limited data• Twice-daily dosing• Lower genetic barrier to

resistance than PIs• No data with NRTIs other

than TDF/FTC in initial therapy

Adverse Effects: II• RAL

– Nausea– Headache– Diarrhea– CPK elevation

Integrase Enzyme• Viral enzyme essential to replication of

both HIV-1 and HIV-2

• Integration– Follows reverse transcription, which

synthesizes double-stranded DNA copy of HIV-1 RNA after infection

– Essential step before viral DNA can be transcribed back into viral RNA

– Incorporates or “integrates” viral DNA into host cell’s DNA

Integrase Strand Transfer Inhibitors

• Raltegravir (pyrimidinone analogue, formerly known as MK-0518)[1]

– First approved integrase inhibitor

– Originally approved for use in treatment-experienced patients; recently approved for treatment-naive patients

• Elvitegravir (diketoacid derivative of dihydroquinoline-3-carboxylic acid, formerly known as GS-9137)[2]

– Currently in phase III clinical trials

• S/GSK1349572[3]

– New integrase inhibitor active against raltegravir- and elvitegravir-resistant isolates in vitro

– Currently in phase IIb clinical trials1. Markowitz M, et al. J Acquir Immune Defic Syndr. 2006;43:509-515. 2. DeJesus E, et al. J Acquir Immune Defic Syndr. 2006;43:1-5. 3. Lalezari J, et al. IAS 2009. Abstract TUAB105.