Clinical Manifestations And Treatment Of HIV
Clinical Manifestations andTreatment of HIVRonald Mitsuyasu, MDProfessor of MedicineDirector, UCLA Center for ClinicalAIDS Research and Education(CARE Center)
The Natural History of HIV InfectionPantaleo G, et al. N Engl J Med 1993;328;327.
Clinical Manifestations of HIV Early signs and symptomsOral manifestationsMalignanciesOpportunistic InfectionsNeuro-psychiatric illnessesWomen and HIV Notin today’s presentation,
Signs and Symptoms
CDC Stage of HIV Disease Stage IStage IIStage IIIStage IV–A–B–C C1 C2–D–EAcute HIV infectionAsymptomatic HIVEarly Symptomatic HIVLate Symptomatic HIVConstitutional DiseaseNeurological DiseaseSecondary InfectionsAIDS definingOther infectionsSecondary CancersOther Conditions
Acute Retroviral Syndrome ight LossNeurologic symptoms96%74%70%70%54%32%32%27%14%13%12%
Oral Manifestations of HIV
WHO Clinical Staging of OralManifestations of HIVStageAdults and Adolescents ( 15 yo)Children 15 yo12No diseaseAngular cheilitisRecurrent oral ulcerationNo diseaseAngular CheilitisLinear gingival erythema, extensive wartsRecurrent oral ulcerations, parotid enlarge3Persistent oral candidiasisOral hairy leukoplakiaAcute necrotizing ulcerativestomatitis, gingivitis,periodontitisPersistent oral candidiasis (after 8ws)Oral hairy leukoplakiaAcute necrotizing ulcerative gingivitis orperiodontitis4Chronic ( 1 mo) orolabial HSVKaposi’s sarcomaNon-Hodgkin’s lymphomaChronic ( 1 mo) orolabial HSVKaposi’s sarcomaNon-Hodgkin’s lymphomaWHO, Classification of HIV, 2007 0307.pdf
HIV-related Oral Lesions Infections– Fungal, Viral, Bacterial Neoplasms– Kaposi’s Sarcoma, Non-Hodgkin’sLymphoma Other– Aphthous-like Ulcers, Lichenoid orDrug Reactions, Salivary GlandDisease
Oral CandidiasisClinical HS/HIV/PP
Hairy Leukoplakia Treatment and Management:– Generally does not requiretreatment– Antiviral treatment and topicalpodophyllum resin have been usedto treat -- the result is temporary– May wax and wane withouttreatment
Oral Ulcers Herpes simplexinfection Cytomegalovirusinfection Aphthous ulcers Histoplasmosis HPV lesions Lymphoma Necrotizingulcerative gingivitis(NUG) Necrotizingulcerativeperiodontitis (NUP) Necrotizingstomatitis (NS)
Aphthous LesionsClinical TypesMinor (Lip)Minor (Tongue)MajorDHS/ HIV/PP
Oral Aphthous LesionsTreatment Options Topical Therapy- Topical Corticosteroids Intralesional- Triamcinolone: 40 mg /ml (0.5 ml-1.0 mlinjected bid) Systemic Therapy- Prednisone: 0.5-1.0 mg/kg qd x 7-10d,then taper- Thalidomide: 200 mg PO qdDHS/HIV/PP
Lesions Caused By HumanPapilloma Virus (HPV) Appearance: exophytic, papillary,oral mucosal lesions Several different types of HPV havebeen reported to cause lesions May be multiple Often difficult to treat due to a highrisk of recurrence
Kaposi’s Sarcoma Appearance: Oral lesions appear asreddish purple, raised or flat Size ranges from small to extensive Behavior is unpredictable Definitive diagnosis: biopsy and histologicexamination No curative therapy--antiretroviraltherapy, radiation treatment,chemotherapy and sclerosing agentshave been, used to control oral lesions
Cancers in HIV
Number of people living with AIDS, AIDS-defining cancers,Cancer IncidencesininUSAnon-AIDS-definingcancers, andinall HIVcancersthe USAduring 1991–2005.Shiels M S et al. J Natl Cancer Inst 2011;103:753-762
Categorizing Cancers in PWHA AIDS Defining Cancer(decreasing) Non AIDS definingCancers (increasing)– KS– Anal Cancer– NHL (BL, CNS, DLCBL)– Lung Cancer– Cervical Cancer ( added in1993)– Hodgkin Lymphoma Elevated risk but rare– Merkel Carcinoma– Leiomyosarcoma– Salivary gland LEC– Liver Cancer Unchanged risk– Breast– Colorectal– Prostate– Follicular lymphoma
Cancers in HIV DiseaseAIDS-DefiningVirus Kaposi’s SarcomaHHV-8 Non-Hodgkin’s LymphomaEBV, HHV-8(systemic and CNS) Invasive Cervical CarcinomaHPVNon-AIDS Defining Anal CancerHPV Hodgkin’s DiseaseEBV Leiomyosarcoma (pediatric)EBV Squamous Carcinoma (oral)HPV Merkel cell CarcinomaMCV HepatomaHBV, HCV
Breakdown of causes of death: France 2005AIDSCancerHepatitis CCVDSuicideNon-AIDS infectionAccidentHepatitis BLiver diseaseOD / drug tabolicpsychiatricotherunknownN 937 deaths0510Hessamfar-Bonarek Int. J. Epid 2010;39:135-1461520Percent25303540Lewden JAIDS 2008, 48:590-9
Non-AIDS Defining CancersNADC
Non AIDS-defining CancersEmerging Epidemiologic Features1991-19951996-2002Proportion of Cancers in HIVNADC31%58%Standardized Incidence Ratio 62.86.71.81002.79.13.7Engels EA, Int J Cancer. 2008;123:187-194
Factors Contributing to the Increasein Cancer cases in HIV 4-fold increase in HIV/AIDS Population Greater and earlier start to smoking in HIV Rising proportion of HIV pts 50 yo Cancer incidence increases with age Increase in some CA incidence rate among HIV– Lung (3X), anal (29X), liver (3X), HL (11X)– Suggests may be additional risk from HIV
NADC Incidence and Mortality Retrospective survey of Kaiser Permanente, N. and S.California; 22,081 HIV , 230,069 HIV- matched by age,sex, clinic and initial yr of F/U 5-yr survival for incident prostate, anal, lung,colorectal cancers or Hodgkin lymphoma. All causemortality rates and mortality hazard ratios Earlier mean age at dx in HIV for anal, lung andcolorectal, but not for prostate or HL HIV dx at higher stage for lung and HL HIV reduced survival for HL, lung and prostate, butnot for anal and colorectalSilverberg M et al. 19th CROI, Seattle, 2012, abs 903.
NADC Mortality HIV vs HIV-Hodgkin LymphomaHR 3.0 (1.3-10.8)Anal1.7 (0.6-5.4)Lung1.7 (1.3-2.2)Prostate2.2 (1.2-4.3)Colorectal1.6 (0.8-3.1)Silverberg M et al. 19th CROI, Seattle, 2012, abs 903.
Pathogenesis of Cancer in HIV Many are virally-induced cancers, but not all Immune activation, inflammation and decreasedimmune surveillance HIV may activate cellular genes or proto-oncogenes orinhibit tumor suppressor genes HIV induces genetic instability (e.g 6 fold highernumber of MA in HIV lung CA over non-HIV)1 Increase susceptibility to effects of carcinogens Endothelial abnormalities may allow for cancerdevelopment Population differences based on genetics andexposure to carcinogensWistuba Il, Pathogenesis of NADC: a review. AIDS Pt Care 1999;13:415-26
Lymphomas
Pathology of AIDS-RelatedNon-Hodgkin’s LymphomaSlide #36 Small noncleaved-cell lymphoma– Burkitt’s lymphoma and Burkitt-like lymphoma Immunoblastic lymphoma (primary CNS) Diffuse large-cell lymphoma (90% CD20 )– Large noncleaved-cell lymphoma– CD30 anaplastic large B-cell lymphoma Plasmablastic lymphoma Advanced stage ( 75% III or IV) Extranodal involvement– Central nervous system, liver, bone marrow, gastrointestinalTirelli U, et al. AIDS. 2000;14:1675-1688.
AIDS-related Lymphoma Experience SuggestsCancer Treatment Outcome Can be Equivalentto General Population100Percent SurvivalAMC 034 EPOCH CD4 100NCI EPOCH1997-1998: HAART Era501991-1994: Pre-HAARTNCI DLBCL non-AIDS0061218243648MonthsBesson et al. Blood. 2001; 98: 2339-2344Little et al Blood. 2003; 101: 4653-4659Sparano et al. Blood, 2010;115:3008-16
Cancer Screening in HIV
ACS, NCI and USPSTF CancerScreening Guidelines Cervical CA – begin within 3 yrs of 1st intercourse or 21 yoand q 1-2 yrs. If 30-70 and 3 normal Paps q3 yrs Prostate CA – discuss with MD at 50. DRE yearly andindividualized PSA testing Breast CA – clinical breast exam q 3 yr 20-30, yearly at 40,yearly mammogram start age 50 Colon CA – flex sig q 5yrs or colon q 10 yrs and FOBTyearly Others – periodic health exams after age 20, with healthcounseling and oral, skin, lymph nodes, testes, ovaries andthyroid exam Other tests based on family history, other known cancerrisk exposures or known risk factors
HIV Patient Screening Routine screening for HIV patients seems to be doneLESS frequently than age-appropriate SOC screeningfor breast (67% vs 79%) and colon (56% vs 77.8%) andprostate biopsies– Preston-Martin. Prev Med 2002;34:386-92– Reinhold JP. Am J Gastroenterol 2005;100:1805-12– Hsiao W, Science World J 2009;9:102-8 Concerns about higher false positive rate in HIV (eg,NLST found reduction in lung cancer mortality (20%)in older cigarette smokers with CT) but also high falsepositive rates, which may be true in HIV as well
Why is anogenital cancer important? Cervical cancer is the most common cancer inwomen worldwide and anal cancer is ascommon in MSM (75/100,000) as cervicalcancer in unscreened populations of women(50-150/100,000 person-yr) Anal cancer particularly common in HIV MSM Anal cancer occurs in women as well Anal cancer is one of several cancers whoseincidence in the HAART era is increasing, notdecreasing
Screening for cervical andanal dysplasia No USA national or international guideline foranal screening other than NYS DOH anal Papscreening guidelines. Many HIV groups recommend yearly cervicaland anal PAP, with colposcopy and/or HRAand biopsy of any suspicious lesions andq 6m F/U for those with abnormalities noted Many cervical cancer screen and treatprogram now operating in resource-limitedsettingsChiao EY et al. Clin Infect Dis 2006;43:223-33Goldie SJ et al. JAMA 1999;282:1822-9
Cancer Prevention Smoking Cessation – Highest priority– Varenicline not hepatic met and no ART drug interactionexpected Hepatitis B and HPV vaccinationTreat active Hepatitis CYearly cervical and anal Paps – Gyn and HRAAdvise sun screen and avoid overexposureMaintain high index of suspicion for cancerComplete family history for malignanciesBreast, prostate and colon screening as perguidelines for general population CT Lung and liver ultrasound controversial Treat all HIV patients with HAART
Summary As HIV population ages with persistent immuneabnormalities, cancers will increase in number The risk of NADC is high with lung, anal, liver and HLaccounting for most of this increase. The risk of colon,breast and prostate cancers not elevated in HIV. HLoccurs at older age, but may reflect lack of youngerage peak, as all cases in HIV are EBV As a minimum, we should conduct age/genderappropriate screening for cancer. Counsel patients onways to reduce cancer risks Only through prospective clinical trials research canprevention strategies and new treatments beeffectively evaluated
Thank You For information on AMC clinical trials see:http://www.aidscancer.org For information on NCI programs in HIVcancer see:http://www.cancer.gov/cancertopics/types/AIDS To refer for AMC clinical trials in LA, callUCLA CARE Center 310-557-1891 ask forMaricela Gonzalez or page/email Dr.Mitsuyasu, 310-825-6301.
Use of Antiretroviral Therapy
Overview Benefits and limitations of HAARTWhen to startWhat to start withSimplified drug regimens and treatmentadherence When to change therapy Second line therapies
Benefits of ART Prevention of mother to child transmissionPost exposure prophylaxis (PEP)Secondary prevention of HIV transmissionPrimary prevention (PrEP)Clinical management of patients with HIV Reduces HIV replication Increase or maintain CD4 numbers Maintain “less fit” mutated HIV
Current antiretroviral targetsFusion InhibitorEnfuvirtideEntry InhibitorsCCR5, MRVRNAReversetranscriptaseInhibitorsZDV, ddI,ddC, d4T,3TC, ABC,TDF, FTCDLV, NVP,EFV, ETVRPVRTRNADNARTDNADNARNAViral ATZIntegraseProvirusRaltegravir TPVElvitegravir DRV
Antiretroviral Drugs 2013Reverse Transcriptase Inhibitors(13) Protease Inhibitors (10)Nucleoside analogues saquinavir (SQV) zidovudine (AZT,ZDV) didanosine (ddI) zalcitabine (ddC) stavudine (d4T) lamivudine (3TC) abacavir (ABC) emtricitabine (FTC)Nucleotide analogue tenofovir (TFV) Integrase Inhibitor (2) raltegravir (RAL) elvitegravir (ELV) Non-nucleoside analogues Fusion Inhibitor nevirapine (NVP) fuzeon (T20) delavirdine (DLV)Entry Inhibitor (CCR5) efavirenz (EFV) maraviroc (MVC) etravirine (ETV) rilpivirine (RPV)ritonavir (RTV)indinavir (IDV)nelfinavir (NFV)amprenavir (APV)lopinavir/r (LPV/r)fosamprenavir (FPV)atazanavir (ATV)tipranavir (TPV)darunavir (DRV)dolutegravir (DTG)
Overview Benefits and limitations of HAART When to start What to start with Simplified drug regimens andtreatment adherence When to change therapy Second line therapies
Case 47 yo Black Male Diagnosed on routine insurance examination PMHx remarkable for HTN, diet controlled No AIDS associated diseases or symptoms No medications Understands treatment issues and wants tobegin therapy if you think it is appropriate Has insurance that can pay for his meds
If his viral load is 30,000 c/ml, at which CD4count would you recommend startingtherapy?1.2.3.4.5.6.7.8.Would treat at any CD4 count750 cells / ul500 cells / ul350 cells / ul250 cells / ul 200 cells /ul 50 cells /ulWould not recommend ART
When to Start Therapy: BalanceTipping in Favor of Earlier Initiation Potency, durability, simplicity Drug toxicity Preservation of limited Rx options CostDelayedCD4and safety of current regimens Improved formulations and PK New classes of drugs Excess morbidity/mortality athigher CD4Earlier
Reasons to Start Early The Biology Association of Inflammation andDisease Better Tolerated/Easier to TakeMedications Randomized Controlled Trial Data Cohort Data Irreversible Damage Public Health
Latently InfectedCD4 LymphocytesHIV InfectedCellsHIV virionsAntiretroviral RxUninfected ActivatedCD4 LymphocytesM Saag, UABUninfected RestingCD4 Lymphocytes
Incidence per 1000 PYFU (95%CI)Opportunistic Infections Occur atHigher CD4 Cell Count Strata100CMV / MAC / TOXOPCP /ECTB1010.1302174444 110 000120 990230 990340 990499 500 110 000120 990230 990340 990499 500 110 000120 990230 990340 990499 5000.01Latest CD4 countN events134 45139228955613513161291011 1114Podlekareva et al. J Infect Dis 2006;194:633
When to start?:ART Cohort Collaboration 10,855 patients included,with 61,000 personyears of F/U (median 2.7yrs) 934 progressed to AIDSor died IDUs excluded frommodelCumulative Probability of AIDS/Death by CD4Count at Initiation of ARTProbability of AIDS or Death Modeled data101-200 cells/mm3201-350 cells/mm3351-500 cells/mm30.120.100.080.060.040.020.0001234Years Since Initiation of HAARTAntiretroviral Therapy (ART) Cohort Collaboration, AIDS 2007;21:1185-97.5
Delayed Initiation of ART andIncreased Risk of DeathVariableCD4 count351-500 cells/mlRelative RiskCD4 count 500 cells/mlPValue0.002Relative Risk1.9(1.2-2.9)PValue0.006ART deferral1.6(1.2-2.2)Female sex1.9(1.7-2.1)0.041.4(0.9-2.1)0.20Older age (10yr)1.9(1.7-2.1 0.0011.8(1.6-2.1) 0.001Baseline CD4 (100 cell increment)0.7(0.6-1.0)0.061.0(0.4-1.0)0.45Baseline HIV RNA(log 10 increment)1.1(1.0-1.3)0.151.1(1.0-1.3)0.14Kitahata et al, New Eng J Med 2009;360:1815 (adapted)
Cumulative Mortality Estimates0.20Calculated Using Extended Kaplan-Meier Survival Estimates0.100.15CD4 500 &Defer HAART(N 6,539)0.000.05CD4 500 &Initiate HAART(N 2,616)0246810Years after 1996Kitahata MM, et al. CROI 2009. Abstract 71.
Most New Infections Transmitted byPersons who Do Not Know TheirStatus 25%UnawareofInfection 75%AwareofInfectionaccount for 54%NewInfections 46%of NewInfectionsSource: G. Marks et al. AIDS 2006
HPTN 0521763 HIV discordant couples(HIV partner CD4 350-550)886 immediateHAART877 delayedHAART (CD4 250)All receiving HIV prevention services1 transmission*& 3 cases ofextrapulmonaryTBCohen MS, N Engl J Med. 2011:493-50527 transmissions*& 17 cases ofextrapulmonaryTB*96% reduction in HIV transmission to HIV-negativepartner median follow-up 2 years
Reasons to Start Early The BiologyAssociation of Inflammation and DiseaseBetter Tolerated Medications TodayRandomized Controlled Trial DataCohort DataPublic HealthCommon Sense!
Relative Time on Treatment 40 years on RxHARM?CD4 650/ul35 years on Rx5 yearsCD4 500/ul303540455055AGE (years)776570
So .what is the harm? Destruction of Lymphoid TissueInflammationIncreased Cardiovascular EventsIncreased incidence of certainmalignancies Accelerated ‘Aging’ Accelerated Cognitive Decline
Conclusions Balance of data support starting Rx in allindividuals regardless of CD4 T cell counts– Understanding of HIV pathogenesis– Cohort data– Public health implications– No randomized clinical trial data forhigher CD4 counts 500 yet (STARTstudy is enrolling) Waiting until RCT data could well lead toharm that likely will not be reversible
When to Start Treatment2/13/13DHHSGuidelinesCD4 CountHIV RNAClinical Category(cells/mm3)(copies/mL)AIDS-defining illnessor severe symptomsAny valueAny valueTreat 500Any valueTreat 500Any valueTreatPregnant womenAny valueAny valueTreatHIV-associatednephropathyAny valueAny valueTreatHIV/HBV coinfectionwhen HBV treatmentis indicatedAny valueAny valueTreatAsymptomatic2012IAS-USAGuidelines*Unless elite controller (HIV RNA 50 copies/mL) or has stable CD4 cell count and low-level viremia in absence of therapy.The IAS-USA guidelines also recommends initiating antiretroviral therapy in HIV-infected patients with active hepatitis C virusinfection, active or high risk for cardiovascular disease, and symptomatic primary HIV infection.DHHS. Available at: dolescentGL.pdf.Revision February 2013; Thompson MA, et al. JAMA. 2012;308:387-402.
When To Start Treatment:Summary of Current GuidelinesGuidelineCD4 350 CD4 350-500British HIVAtreatConsider unless: HBV or HCV,High CV risk, HIVAN, pregnantthen treatUnknowntreatConsider unless: HCV, HIVAN,HBV needing Tx; CD4 decline 50-100/yr, pregnant – mber, 2012European ACSwww.eacs.eu/guideNovember, 2012IAS-USA:www.iasusa.orgJuly, 2012DHHS:www.aidsinfo.nih.govFebruary, 2013CD4 500
When to Start Therapy: BalanceTipping in Favor of Earlier Initiation Potency, durability, simplicityand safety of current regimens Improved formulations and PK Enhanced adherence Diminished emergence ofresistance New classes of drugs Excess morbidity/mortality athigher CD4 Drug toxicity Preservation of limited Rx options Cost 350CD4Everyone ?
Overview Changing epidemiology of AIDS in theUnited States Benefits and limitations of HAART When to start What to start with Simplified drug regimens and treatmentadherence Second line therapy
Factors to consider in choosingfirst-line therapy Patient’s willingness to commit to therapyBaseline resistanceEfficacy dataTolerabilityConvenienceComorbid conditionsConsequences of failure (resistance)Since the introduction of potent ARV therapypreferred regimens all include NRTIs thirddrug
DHHS Guidelines for Adolescents/Adults:What to StartPreferredRegimens EFV/TDF/FTC ATV/r TDF/FTC DRV/r (once daily) TDF/FTC RAL TDF/FTC[Pregnant Women Only: LPV/r (twice daily) ZDV/3TC]AlternativeRegimens EFV ABC/3TC RPV (TDF or ABC)/(FTC or 3TC) ATV/r or DRV/r ABC/3TC FPV/r or LPV/r (qd or bid) ABC/3TC or TDF/FTC RAL ABC/3TC EVG/COBI/TDF/FTC (9/18/12)AcceptableRegimens EFV or RPV ZDV/3TC NVP TDF/FTC or ZDV/3TC or ABC/3TC ATV (ABC or ZDV)/3TC ATV/r, DRV/r, LPV/r, FPV/r , RAL ZDV/3TC MVC ZDV or ABC/3TC SQV/r TDF/FTC or ABC/3TC or ZDV/3TC (with caution)DHHS Guidelines. Available es/adultandadolescentgl.pdf . Revision Feb, 2013.
Boosted-Protease InhibitorsKLEAN1(ITT‐E, TLOVR)48 weeks100100806665CASTLE3(ITT, NC F)96 weeksARTEMIS2(ITT, TLOVR)96 weeks801007971807777774040402020200n 434 N 444LPV/rFPV/r400/100 700/100BIDBID0n 346 n 343LPV/r DRV/rQD or 800/100BIDQD06874n 443 n 440LPV/rATV/r400/100 300/100BIDQDAdapted from: 1. Eron J, et al. Lancet 2006; 368:476-482; 2. Mills A, et al. AIDS May 29, 20093. Molina J-M, et al. 48th ICAAC/46th IDSA , Washington, DC, 2008. Abst. H-1250d
ATV/r vs. EFVPrimary EndpointDaar ES, et al. Ann Intern Med 2011; 154:445-456.
Pooled* ECHO and THRIVE W48 analysis:VL 50 copies/mL over 48 weeks (ITT-TLOVR)Virologic responders (%, 95% CI)RPV 25mg qd (N 686)100EFV 600mg qd (N 682)84.3%82.3%8060402000 2 4812 1624324048Time (weeks) Each of the trials reached their primary objective of noninferiority of RPV to EFV in confirmed virologicresponse†CI confidence interval; *Pooled analyses were preplanned†Difference (95% CI) in response rates estimated by logisticregression adjusted for stratification factors: 1.6 (–2.2, 5.3)Cohen JAIDS 2012
STARTMRK: RAL vs. EFVITT, NC FPercentage of Patients withHIV RNA Levels 50 Copies/mL10086817576696771808279776140CD4 Change: RAL 374 vs. EFV 312200Weeks012 280281281282281282277282279279Number of Contributing PatientsRaltegravir 400 mg BIDEfavirenz 770 mg QHS281 278 279282 282 282Rockstroh J, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. LBPE19.
Elvitegravir/Cobicistat/FTC/TDF (Quad) vs.EFV/FTC/TDF (Study 236-102)n 350Quad QDEFV/FTC/TDF QHSPlaceboTreatment-NaïveAny CD4 count Randomized 1:1 Stratification by HIV-1 RNA( 100,000 c/mL)n 350EFV/FTC/TDF QHSQuad Placebo QDWeek 48Week 192Primary Endpoint: Proportion with HIV-1 RNA 50 copies/mL at Week 48 FDA snapshot analysis (ITT), 12% non-inferiority marginSax P, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 101.
Study 236-102: Primary Endpoint:HIV-1 RNA 50 copies/mL 3.6%, 95% CI 3.6 (-1.6% to 8.8%)CD4 change: Quad 239 vs. EFV 206 c/mm3 (p 0.009)Sax P, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 101.
Elvitegravir/Cobicistat/FTC/TDF (Quad) vs.ATV/r FTC/TDF (Study 236-103)Multicenter, international, randomized, blinded 192-week studyART-naïve subjectsHIV RNA 5,000 c/mLeGFR 70ml/min(N 708)Stratification byHIV RNA ( or 100,000 c/mL)Quad QDATV/r FTC/TDFPlacebo QDBaseline: HIV RNA 100,000 c/mL 40-43%CD4 Count 364-375 cells/mm3ATV/r FTC/TDF QDQuad Placebo QDWeek 48Week 192Primary Endpoint: Proportion with HIV-1 RNA 50 c/mL at Week 48– FDA snapshot analysis, 12% non-inferiority marginDeJesus E, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 627.
Percent with HIV RNA 50 c/mL (ITT, M F)Study 236-103: HIV-1 RNA 50 c/mL Through Week 4810092%9088%80Diff: 3.5% (95% CI: -1.0 to 8.0)7060QUADATV/r50403020HIV RNA 50 c/mL Snapshot Analysis: Quad 90% vs. ATV/r/FTC/TDF 87% (P NS)Changes in CD4 count: Quad 207 vs. ATV/r 211 cells/mm3 (p 0.61)100BL 248121624WeekDeJesus E, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 627.324048
Comparisons of First Line RegimensAnchor DrugAnchor statTied
Slide 82 of 77A5202: Study DesignArmAHIV-1 RNA 1000 c/mLAny CD4 count 16 years of ageART-naïve1857N 1858enrolledBRandomizedRandomized 1:1:1:11:1:1:1CStratified by screening HIV-1 RNA( or 100,000 c/mL)Enrolled 2005-2007DFollowed through Sept 2009, 96 wks afterlast pt enrolledTDF/FTC QDABC/3TC Placebo QDABC/3TC QDTDF/FTC Placebo QDTDF/FTC QDABC/3TC Placebo QDABC/3TC QDTDF/FTC Placebo QDEFVQDEFVQDATV/rQDATV/rQD
Slide 83 of 77A5202: Time to Virologic Failure inPatients with HIV RNA 100,000 c/mLProbability of No Virologic FailureProbability of No VirologicFailure (%)100TDF‐FTC (26 events)80ABC‐3TC (57 events)6040P 0.001, log‐rank testHazard ratio, 2.33 (95% CI, 1.46‐3.72)20001224No. at Risk3648607284Weeks since 20TDF-FTC3993613212842362041771046523Sax PE, et al. NEJM 2009;361:2230-2240.
ABC/3TC vs. TDF/FTCLow Viral Load StratumSax PE, et al. JID 2011: 204:1191-1201.Slide 84 of 77
Slide 85 of 77Concerns regarding NRTIs For individuals with higher viral loads (e.g. 100,000 c/ml) TDF/FTC superior to ABC/3TC) Conflicting results regarding relationshipbetween ABC and CV events TDF‐associated with greater decline in bonemineral density TDF‐associated with variable decline in renalfunction Given rise to preferred regimens of TDF/FTC withABC/3TC as alternative
What Not to UseGuidelines: IAS-USA1, WHO2, DHHS3 Any mono- or dual-therapy comboAZT 3TC ABV FTC (first line)Nelfinavir (first line)ddI TDFddI d4TAZT d4TATZ IDVSQV or DRV or TPV unboostedRIT (full dose therapy)EFV in pregnancyNevirapine in naïve women CD4 250 or men 400Etravirine with unboosted PI or withATZ/r, FOS/r, TPV/r13Thompson, et al. JAMA 2010;304:32; 2Available at: www.UNAIDS.org;Available at: http://aidsinfo.nih.gov/Default.aspx. Revision March 27, 2012.
Side Effects and Toxicities
Patients Don’t Like Surprises: Short-Term SideEffects to Discuss Before Starting Therapy NNRTIs– Efavirenz: neuropsychiatric side effects, rash– Nevirapine: hepatotoxicity, rash PIs– Gastrointestinal toxicity– Atazanavir: jaundice and scleral icterus NRTIs– Zidovudine: nausea, anemia, fatigue– Didanosine: gastrointestinal toxicity,neuropathy, pancreatitis– Stavudine: neuropathy, pancreatitis
HAART:Long-Term ComplicationsDyslipidemia/CHDAbnormalities ofBody CompositionHepatotoxicity
Overview Changing epidemiology of AIDS in theUnited States Benefits and limitations of HAART When to start What to start with Simplified drug regimens andtreatment adherence When to change therapy Second line therapies
The Move TowardSimpler 3-Drug Regimens19962006 Didanosine stavudine saquinavir Emtricitabine/tenofovirDF efavirenz (Atripla)– 24 pills/dose, 5 doses– 1 pills qd– No food restrictions Saquinavir: 6 q8h withfatty food Didanosine: 2 bid ½ hourac or 2 hours pc Stavudine: 1 pill bid
One pill, once a day ART EFV TDF FTC (Atripla)RPV TDF FTC (Complera)EVG TDF FTC COBI (Stribild)NVP d4T 3TC (not available in west)
Overview Changing epidemiology of AIDS in UnitedStates Benefits and limitations of HAART When to start What to start with Simplified drug regimens and treatmentadherence When to change therapy Second line therapies
When to Change Therapy?Virologic failure 0.5-0.75 log reduction in HIV RNA by 4 weeksor 1.0 log reduction by 8 weeks Failure to suppress HIV RNA BLD by 3 months Repeated detection of HIV RNA aftersuppression BLDImmunologic failure Persistently declining CD 4 cell countsClinical failure Clinical deterioration or disease progression
Why Do Treatment Fail Patients? Poor adherenceBaseline resistance or cross-resistanceUse of less potent antiretroviral regimensSequential mono- or dual-therapyDrug levels and drug interactionsTissue reservoir penetrationOther, unknown reasons
Long-Term Risk ofDeveloping Drug ResistanceTime to Multiclass ResistanceRisk of developingantiretroviral drugresistance from UK CHICStudy (n 4306)– Longitudinal cohort from6 clinics in London– Started antiretroviraltherapy with 2 NRTIsplus a third agent Overall risk of treatmentfailure25Resistance (% patients) 202 classes3 classes15105– 38% over 6 years Risk of accumulatingresistance mutations toany drug– 27% overall02 Years4 Years6 YearsPhilips A, et al. Lancet 2007; 370:1923-8.
Overview Changing Epidemiology of AIDS in theUnited States Benefits and limitations of HAART When to start What to start with Simplified drug regimens and treatmentadherence When to change therapy Second line therapies
Strategic Therapy Considerations forthe Treatment-Experienced Patient HIV drug resistance testing– Optimize available treatment options Pharmacokinetic enhancement– PK-boosting regimens (ritonavir or cobicistat) Availability of new drugs (and drug classes)– Combine as many new drugs as possible– Utilize new agents with favorable resistance profiles Maintenance of reduced viral fitness (lesscritical now)– Example: adding lamivudine/emtricitabine or abacavirto maintain M184V mutation
Treatment Goals and ChallengesTreatment Experienced Patient All patients– Zero tolerance for virologic failure ( 2 VL detectable)– At least 2 fully active agents Do we always need 3 fully active agents– A boosted PI plus TDF/FTC enough if no TDF resistance There is a balance between complexity of the second regimenwith including 3 fully active agents– High bar for safety in treatment experienced patients
Drug Resistance Testing: Caveats Resistance tests are most accurate inassessing resistance to the currentregimen Absence of resistance to a previouslyused drug does not rule out archivedresistant virus that might emerge after reinitiation of that drug Reduced potency should be expectedfrom recycled drugs
New Paradigm in Therapy Complete suppression of plasma HIV-1 RNAshould be the goal in all patients with HIVgiven the availability of new drugs Maximize virus suppression whileminimizing drug toxicity For those who do not tolerate new agents,goal should be to maintain CD4 count ashigh as possible Second line therapy should be chosen onthe basis of resistance testing, treatmenthistory, tolerability
Think Strategically“Long-term strategic anti-HIV therapy issimilar to a chess game against avastly superior opponent, in which theobjective is to avoid checkmate andremain on the board after 20 years”DD Richman, Science 1993
Clinical Manifestations andTreatment of HIVQuestionsRonald Mitsuyasu, MDProfessor of MedicineDirector, UCLA Center for Clinical AIDS ResearchUniversity of California, Los Angeles
Pathogenesis of Cancer in HIV Many are virally-induced cancers, but not all Immune activation, inflammation and decreased immune surveillance HIV may activate cellular genes or proto-oncogenes or inhibit tumor suppressor genes HIV induces genetic instability (e.g 6 fold higher number of MA in HIV lung CA over non-HIV)1 Increase susceptibility to effects of carcinogens
extra esophageal manifestations have been classified basically in three groups: breathing manifestations, thoracic atypical pain and manifestations of the oto- . more than twice a week, (ii) erosions of the esophagus near the junction with the . Diet and GERD . Map of Digestive Disorders & Diseases (MDD) 9
Clinical manifestations of hypoglycemia approach The clinical manifestations of hypoglycemia are nonspe-cific, occurring with a variety of other neonatal problems.13 Even in the presence of an arbitrary low glucose level, the physician must assess the general status of the infant to rule out other disease entities and processes that may need addi-
The Clinical Program is administered by the Clinical Training Committee (CTC) under the leadership of the Director of Clinical Training (DCT) and the Associate Director of Clinical Training (ADCT). The program consists of three APA defined Major Areas of Study: Clinical Psychology (CP), Clinical Child Psychology (CCP), Clinical Neuropsychology .
The sequence of treatment processes through which wastewater passes is usually characterized as: 1. Preliminary treatment 2. Primary treatment 3. Secondary treatment 4. Tertiary treatment This discussion is an introduction to advanced treatment methods and processes. Advanced treatment is primarily a tertiary treatment.
The sequence of treatment processes through which wastewater passes is usually characterized as: 1. Preliminary treatment 2. Primary treatment 3. Secondary treatment 4. Tertiary treatment This discussion is an introduction to advanced treatment methods and processes. Advanced treatment is primarily a tertiary treatment.
Chapter 26. Hypercalcemia: Pathogenesis, Clinical Manifestations, Differential Diagnosis, and Management Elizabeth Shane1 and Dinaz Irani2 1Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York; and 2Metabolic Bone Disease Research Program, Columbia University Medical Center, New York, New York
39 Associte professor Sadik Al Ghazawi 17-Oct-19 Clinical Manifestations cont Intellectual Function 1 Memory and judgment may be impaired 2 Left-brain stroke: more likely to result in memory problems related to language Clinical Manifestations 3 Memory and judgment m
4.1. Time of sowing by seed treatment 41 4.2. Cultivar by seed treatment 49 4.3. Time of harvest by seed treatment 57 4.4. Experimental treatment 60 5.0. Discussion 5.1. Time of sowing by seed treatment 64 5.2. Cultivar by seed treatment 68 5.3. Time of harvest by seed treatment 72 5.4. Expe
