1. HIV Management 2011 John K. Midturi April 16, 2011

2. 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

3. 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

4. Quarter-Year Number of Cases/Deaths *Adjusted for reporting delays 198519861987198819891990199119921993199419951996199719981999 0 5,000 10,000 15,000 20,000 25,000 1993 definition implementation Deaths 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* Prevalence

6. Estimated Rates for Adults and Adolescents Living With HIV Infection (not AIDS) 34 States and 5 U.S. Dependent Areas, 2007 Estimated HIV Rate per 100,000 Confidential name-based HIV infection reporting not implemented as of 2003 2.2 – 51.7 51.8 – 103.8 103.9 – 170.5 170.6 – 282.0 Data classed using quartiles Total 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 AK HI Puerto Rico American Samoa Northern Mariana Islands Guam DC 6

7. 7 Awareness of HIV Status in the US 1 CDC. HIV prevalence estimate—United States, 2006. MMWR. 2008;57(39):1073-1076. 2 Hall HI, et al. Estimation of HIV incidence in the United States of America. JAMA. 2008;300:520-529. 3 CDC. 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 prevalence 1 1,056,400 - 1,156,400 Undiagnosed 1 232,700 Estimated new annual infections (2006) 2 56,300 From 2004 to 2007, the estimated number of newly diagnosed HIV/AIDS cases increased 15% 3

8. 8 US Population Demographics: Total Population and HIV/AIDS Cases by Race/Ethnicity White 71% Other 4% Black 12% Hispanic 13% 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 Black 46% White 35% Hispanic/ Latino 18% Other <2%

9. 9 Estimated HIV/AIDS Prevalence and New Infections by Transmission Category in the US (2006) MSM 48% High-Risk Heterosexual Contact (Male) 9% IDU (Male) 12% MSM + IDU 5% High-Risk Heterosexual Contact (Female) 18% IDU (Female) 7% Other 1% CDC. HIV Incidence. Available at http://www.cdc.gov/hiv/topics/surveillance/incidence.htm. MSM 53% High-Risk Heterosexual Contact 31% IDU 12% MSM + IDU 4% Estimated New HIV DiagnosesEstimated Prevalence of HIV/AIDS

12. A global view of HIV infection 33 million people [30–36 million] living with HIV, 2007

13. 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

14. 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

15. 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 20 th century

16. 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

17. 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)

18. Subtype, circulating recombinant forms

19. 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

20. 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

21. HIV Life Cycle Maturation 2. Membrane fusion & entry 9. Budding 3. Uncoating & reverse transcription 4. Nuclear uptake 5. Integration 6. Transcription & RNA processing 7. Nuclear export 8. Translation & Assembly 1. Receptor binding

22. 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

23. Clinical Presentation

24. 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 (+/-)

25. 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

26. WHO HIV clinical stages

27. 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

28. 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

29. 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.

30. 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.

31. USPSTF HIV Testing Recommendations Screening strongly recommended for all adolescents and adults at increased risk for HIV and all pregnant women Increased 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 IDUs  Men and women who exchange sex for money or drugs or have sex partners who do  Individuals 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 1985  Persons who request an HIV test despite reporting no individual risk factors may be considered at increased risk  STD clinics  Correctional facilities  Homeless shelters  Tuberculosis clinics  Clinics serving men who have sex with men  Adolescent health clinics with a high prevalence of STDs  Any clinical setting with a known HIV prevalence ≥ 1% among the patient population being served USPSTF recommendations. July 2005.

32. 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

33. 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  p18 GAG POL ENV

34. 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%

35. 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

36. Preventative measures Routine immunizations Cervical cancer screening Medication for primary or secondary prophylaxis

37. 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

38. 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

39. 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 breastfeeding http://www.hiv.gov.gy/ads/pstr_protectbaby.jpg

42. 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)ritonavir –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.

43. Viral Load and Transmission 016.621.330.940.6 HIV-1 RNA Transmission % <1000 copies/mL 1000 - 10,000 10,001- 50,000 50,001-100,000>100,000N 0/57 0/5732/19339/18317/5426/64 Women & Infants Transmission Study (WITS) Garcia, et al, NEJM 1999

44. 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)zidovudine –Caesarian section delivery probably confers little added benefit in women with plasma HIV-1 RNA < 1000 copies/mL (Management Guidelines).[DHHS Perinatal]Management GuidelinesDHHS 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]Mofenson 1999Shapiro 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 laborzidovudine Intravenous zidovudine (2 mg/kg over 1-hour loading dose, then 1 mg/kg/hour continuous infusion until delivery, ie, umbilical cord ligated)zidovudine

45. 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)

46. Prophylaxis CD4 <100 and positive IgG Toxo titer: –Toxoplasmosis: TMP/SMX Dapsone Pyrimethamine Leucovorin CD4 <50 –MAC Azithromycin Clarithromycin Rifabutin

47. 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

48. 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

51. Antiretroviral Agents - 1 Nucleoside / nucleotide analogues (NRTIs)  AbacavirC – No studies. Concern for hypersensitivity  DidanosineB – Concern for lactic acidosis (do not use w/ d4T)  EmtricitabineB – No studies.  LamivudineC – Well tolerated. Widely used.  StavudineC – Concern for lactic acidosis (do not use w/ ddI)  TenofovirB – No studies. Animal reports of bone abnls  ZalcitabineC – No studies. Teratogenic in animals.  ZidovudineC – Well tolerated. The most experience.

52. Antiretroviral Agents - 2 Non-nucleoside RT inhibitors (NNRTIs)  Delavirdine C – No studies.  EfavirenzD – Teratogenic. 4/142 birth defects. Avoid in 1 st trimester  NevirapineC – Well tolerated. Avoid initiating if CD4 >250 cells/mm3.

53. Antiretroviral Agents - 3 Protease inhibitors (PIs) AmprenavirC – No studies. Oral solution contraindicated. AtazanvirB – No studies. Concern hyperbilirubinemia FosamprenavirC – No studies IndinavirC – Unboosted: poor blood levels in preg Lopinavir/ritonavirC – No studies Nelfinavir B – Registry data shows no incr in birth def RitonavirB –Not used alone due to GI side effects Saquinavir B – Well tolerated, used boosted TripanavirC – No studies

54. Antiretroviral Agents- 4 Integrase Inhibitors (INSTI) –Raltegravir C-No studies

55. Antiretroviral Agents- 5 Entry Inhibitors –MaravirocB- No studies, requires Tropism test –EnfuvirtideB- No studies, subcut injection

56. 1,056 – 1,156 835 – 915 560 ~79%~83% 675 ~75% Sources: * February, 2009 CDC estimates as of the end of 2006 ** Synovate Healthcare U.S. HIV Monitor Q3 2008 Significant Numbers of People with HIV in the US Are Not on Antiretroviral Therapy

57. FACTORRECOMMENDATION FOR TREATMENT AIDSTreat CD4<500 Treat <200 Offer <350 Indiv. >350 Treat <350 Risks/ Benefits if >350 Viral Load>20,000>55,000> 100,000 No 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

58. Recommendations for Initiation of Therapy in Antiretroviral Naïve HIV-infected Patients Condition 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/mm 3 Start ART CD4 count 350-500 cells/mm 3 ART is recommended 55% of Panel members strongly recommended starting ART 45% moderately recommended starting ART CD4 count >500 cells/mm 3 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.

59. 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. 60 Recommendations for Earlier ART Initiation: Summary of Benefits and Limitations BenefitsPotential 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.

61. 0 15 30 45 60 75 90 105 120 135 150 Median CD4 Increase 97 119 120 121 127 125 150 Median CD4 increase Treatment Responses in 1st Year of HAART Improving 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 24.8 23.0 17.3 12.4 10 8 8.4 0 10 20 30 40 50 199619971998199920002001 2002 % with VL > 500 c/mL 60 70 80 90 100 % With VL >500 on ART

62. Magnitude of increase in CD4 cell count greatest if therapy started at low CD4 cell counts, but greater likelihood of CD4 cell count normalization with earlier therapy Keruly 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 Years on ART Johns Hopkins HIV Clinical Cohort Mean CD4 Cell Count (cells/mm 3 ) 2346 200 400 600 800 0 1000 >350 200-350 <200 510

64. Initial Treatment: Preferred NNRTI basedEFV/TDF/FTC 1,2 PI basedATV/r + TDF/FTC² DRV/r (QD) + TDF/FTC² II basedRAL + TDF/FTC² Pregnant WomenLPV/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.

65. Initial Treatment: Alternatives NNRTI 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/FTC 2 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.

66. ARVs Not Recommended in Initial 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

67. Questions

68. HIV Entry Is Triggered by Receptor Engagement Attachment to CD4+ cell Triggered by coreceptor Membrane fusion 123 MaravirocEnfuvirtide Licensed entry inhibitors

69. Co-receptor antagonists Block major entry step by binding to chemokine receptors (CCR5 or CXC4)

70. 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 CCR5 CXCR4

71. 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

72. Adverse Effects: CCR5 Antagonist MVC –Drug-drug interactions –Abdominal pain –Upper respiratory tract infections –Cough –Hepatotoxicity –Musculoskeletal symptoms –Rash –Orthostatic hypotension

73. Fusion Inhibitors Impair membrane fusion of HIV to T cells Subcutaneous injection twice daily

74. Adverse Effects: Fusion Inhibitor ENF –Injection-site reactions –Hypersensitivity reaction –Increased risk of bacterial pneumonia

75. 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

76. 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

77. Nucleoside/Nucleotide reverse transcriptase inhibitors (NTRI) Nucleoside and nucleotide analogues Impair transcription of viral RNA into DNA

78. 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)

79. 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.

80. 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

81. Non-nucleoside reverse transciptase inhibitors (NNRTI) Inhibit reverse transciptase by binding to the enzyme

82. 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

83. 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)

84. Protease Inhibitors (PI) Impair the packaging of viral particles into mature virus capable of budding from the cell

85. 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

86. Adverse Effects: PIs All PIs: –Hyperlipidemia –Insulin resistance and diabetes –Lipodystrophy –Elevated LFTs –Possibility of increased bleeding risk for hemophiliacs –Drug-drug interactions

87. Adverse Effects: PIs (2) ATV –Hyperbilirubinemia –PR prolongation –Nephrolithiasis DRV –Rash –Liver toxicity FPV –GI intolerance –Rash –Possible increased risk of MI

88. Adverse Effects: PIs (3) IDV –Nephrolithiasis –GI intolerance LPV/r –GI intolerance –Possible increased risk of MI –PR and QT prolongation NFV –Diarrhea

89. Adverse Effects: PIs (4) RTV –GI intolerance –Hepatitis SQV –GI intolerance TPV –GI intolerance –Rash –Hyperlipidemia –Liver toxicity –Cases of intracranial hemorrhage

90. Integrase Inhibitors Prevent incorporation of viral DNA into host cell genome

91. 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

92. Adverse Effects: II RAL –Nausea –Headache –Diarrhea –CPK elevation

93. 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

94. 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 trials 1. 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.