Clinical Manifestations and Treatment of HIV

Clinical Manifestations and Treatment of HIV
Ronald Mitsuyasu, MD Professor of Medicine Director, UCLA Center for Clinical AIDS Research and Education (CARE Center) Ronald Mitsuyasu - Epi May 2013

The Natural History of HIV Infection Traditional conception of natural history assumed a long period of clinical latency in which HIV replication was suppressed and slow decline of CD4 cell counts Pantaleo G, et al. N Engl J Med 1993;328;327. Ronald Mitsuyasu - Epi May 2013 2

Clinical Manifestations of HIV
Early signs and symptoms Oral manifestations Malignancies Opportunistic Infections Neuro-psychiatric illnesses Women and HIV = Not in today’s presentation,

Signs and Symptoms

CDC Stage of HIV Disease
Stage I Acute HIV infection Stage II Asymptomatic HIV Stage III Early Symptomatic HIV Stage IV Late Symptomatic HIV A Constitutional Disease B Neurological Disease C Secondary Infections C1 AIDS defining C2 Other infections D Secondary Cancers E Other Conditions

Acute Retroviral Syndrome
Fever % Lymphadenopathy 74% Pharyngitis 70% Rash % Myalgia/Arthraligia 54% Diarrhea % Headaches 32% Nausea/Vomiting 27% Hepatomegaly 14% Weight Loss 13% Neurologic symptoms 12%

Oral Manifestations of HIV

WHO Clinical Staging of Oral Manifestations of HIV
Stage Adults and Adolescents (>15 yo) Children < 15 yo No disease Angular Cheilitis Linear gingival erythema, extensive warts Recurrent oral ulcerations, parotid enlarge Persistent oral candidiasis (after 8ws) Oral hairy leukoplakia Acute necrotizing ulcerative gingivitis or periodontitis Chronic (>1 mo) orolabial HSV Kaposi’s sarcoma Non-Hodgkin’s lymphoma 1 No disease Angular cheilitis Recurrent oral ulceration Persistent oral candidiasis Oral hairy leukoplakia Acute necrotizing ulcerative stomatitis, gingivitis, periodontitis Chronic (>1 mo) orolabial HSV Kaposi’s sarcoma Non-Hodgkin’s lymphoma 2 3 4 WHO, Classification of HIV, int/hiv/pub/guidelines/HIVstaging pdf

HIV-related Oral Lesions
Clinical Manifestations and Treatment of HIV HIV-related Oral Lesions Infections Fungal, Viral, Bacterial Neoplasms Kaposi’s Sarcoma, Non-Hodgkin’s Lymphoma Other Aphthous-like Ulcers, Lichenoid or Drug Reactions, Salivary Gland Disease The spectrum of HIV related oral lesions includes opportunistic infections, opportunistic neoplasms, immunologically related lesions and conditions which are either identical to or resemble autoimmune diseases. Opportunistic infections that have been identified include viral infections, fungal and bacterial infections. Oral neoplastic diseases include Kaposi’s sarcoma and Non-Hodgkin’s lymphoma. Immunological diseases include minor aphthous ulcers and major apthous-like ulcers, non-specific ulcers, lichenoid lesions and salivary gland disease. Spontaneous gingival bleeding due to autoimmune type thrombocytopenia also occurs in HIV patients. Ronald Mitsuyasu - Epi May 2013

Oral Candidiasis Clinical Types
Clinical Manifestations and Treatment of HIV Oral Candidiasis Clinical Types Erythematous Pseudomembranous Angular Cheilitis DHS/HIV/PP Ronald Mitsuyasu - Epi May 2013 1

Hairy Leukoplakia Treatment and Management: Generally does not require treatment Antiviral treatment and topical podophyllum resin have been used to treat -- the result is temporary May wax and wane without treatment Hairy leukoplakia generally does not require treatment. Antiviral treatment (acylovir/valacyclovir) and topical podophyllum resin have been used to treat hairy leukoplakia. The result is temporary and lesions generally recur. Hairy leukoplakia may wax and wane spontaneously. Ronald Mitsuyasu - Epi May 2013

Oral Ulcers HPV lesions Lymphoma Necrotizing ulcerative gingivitis (NUG) Necrotizing ulcerative periodontitis (NUP) Necrotizing stomatitis (NS) Herpes simplex infection Cytomegalovirus infection Aphthous ulcers Histoplasmosis There are many different causes of oral ulceration in patients with HIV infection. These include Herpes simplex infection, Varicella zoster infection also called herpes zoster or shingles, cytomegalovirus infection, aphthous ulcers, histoplasmosis, lymphoma, necrotizing ulcerative gingivitis (NUG), necrotizing ulcerativeperiodontitis, and necrotizing stomatitis. Accurate diagnosis and appropriate management of oral ulceration in patients with HIV infection generally results in complete healing of the ulceration. Ronald Mitsuyasu - Epi May 2013

Aphthous Lesions Clinical Types
Clinical Manifestations and Treatment of HIV Aphthous Lesions Clinical Types Minor (Lip) Minor (Tongue) Major DHS/ HIV/PP Ronald Mitsuyasu - Epi May 2013 1

Oral Aphthous Lesions Treatment Options
Clinical Manifestations and Treatment of HIV Oral Aphthous Lesions Treatment Options Topical Therapy - Topical Corticosteroids Intralesional - Triamcinolone: 40 mg /ml (0.5 ml-1.0 ml injected bid) Systemic Therapy - Prednisone: mg/kg qd x 7-10d, then taper - Thalidomide: 200 mg PO qd DHS/HIV/PP Ronald Mitsuyasu - Epi May 2013 1

Lesions Caused By Human Papilloma Virus (HPV)
Clinical Manifestations and Treatment of HIV Lesions Caused By Human Papilloma Virus (HPV) Appearance: exophytic, papillary, oral mucosal lesions Several different types of HPV have been reported to cause lesions May be multiple Often difficult to treat due to a high risk of recurrence Lesions caused by human papilloma virus (HPV) appear as exophytic, papillary oral mucosal lesions. Papillary lesions are often multiple. Several different types of HPV have been reported to cause lesions in HIV infected individuals. These lesions are often difficult to treat due to the high risk of recurrence; cauterization is frequently used. Ronald Mitsuyasu - Epi May 2013

Kaposi’s Sarcoma Appearance: Oral lesions appear as reddish purple, raised or flat Size ranges from small to extensive Behavior is unpredictable Definitive diagnosis: biopsy and histologic examination No curative therapy--antiretroviral therapy, radiation treatment, chemotherapy and sclerosing agents have been, used to control oral lesions Oral lesions of Kaposi’s sarcoma appear as reddish-purple, flat or raised lesions. The size of the lesions ranges from small to extensive and oral lesions may be single or multiple. Kaposi’s sarcoma is the most common malignant tumor associated with HIV infection. The majority of patients with Kaposi’s sarcoma are male. Recent investigations have implicated a herpes virus (HHV-8) in the etiology of Kaposi's ’arcoma. The behavior of Kaposi’s sarcoma is unpredictable. Lesions may interfere with function, may be cosmetically objectionable and may proliferate uncontrollable. The palate and gingival are the most commonly affected oral sites. The definitive diagnosis is made by biopsy and histologic examination. There is no curative therapy—radiation treatment, systemic and intralesional chemotherapy and sclerosing agents have been used to control lesions. Ronald Mitsuyasu - Epi May 2013

Cancers in HIV

Number of people living with AIDS, AIDS-defining cancers, non-AIDS-defining cancers, and all cancers in the USA during 1991–2005. Cancer Incidences in HIV in USA Number of people living with AIDS, AIDS-defining cancers, non-AIDS-defining cancers, and all cancers in the United States during 1991–2005. A) US AIDS population by calendar year and age group. B) The estimated counts and standardized rates of AIDS-defining cancers among people living with AIDS in the United States by calendar year and age group. C) The estimated counts and standardized rates of non-AIDS-defining cancers among people living with AIDS in the United States by calendar year and age group. Of note, the bars for 0–12 year olds in panels (B) and (C) are difficult to see because of small numbers of cancers in this age group during 1991–2005 (122 AIDS-defining cancers and 25 non-AIDS-defining cancers). D) The estimated counts and standardized incidence rates of total cancers among people living with AIDS in the United States, stratified by AIDS-defining cancers, non-AIDS-defining cancers, and poorly specified cancers. Bars depict the estimated number of cancers, and points connected by lines depict incidence rates standardized to the 2000 US AIDS population by age group, race, and sex. Shiels M S et al. J Natl Cancer Inst 2011;103: Ronald Mitsuyasu - Epi May 2013

Categorizing Cancers in PWHA
Clinical Manifestations and Treatment of HIV Categorizing Cancers in PWHA AIDS Defining Cancer (decreasing) KS NHL (BL, CNS, DLCBL) Cervical Cancer ( added in 1993) Non AIDS defining Cancers (increasing) Anal Cancer Lung Cancer Hodgkin Lymphoma Liver Cancer Elevated risk but rare Merkel Carcinoma Leiomyosarcoma Salivary gland LEC Unchanged risk Breast Colorectal Prostate Follicular lymphoma Ronald Mitsuyasu - Epi May 2013 26

Cancers in HIV Disease Clinical Manifestations and Treatment of HIV AIDS-Defining Virus Kaposi’s Sarcoma HHV-8 Non-Hodgkin’s Lymphoma EBV, HHV-8 (systemic and CNS) Invasive Cervical Carcinoma HPV Non-AIDS Defining Anal Cancer HPV Hodgkin’s Disease EBV Leiomyosarcoma (pediatric) EBV Squamous Carcinoma (oral) HPV Merkel cell Carcinoma MCV Hepatoma HBV, HCV Ronald Mitsuyasu - Epi May 2013 27

Breakdown of causes of death: France 2005 AIDS Cancer Hepatitis C CVD Suicide Non-AIDS infection Accident Hepatitis B Liver disease OD / drug abuse neurologic renal pulmonary digestive iatrogenic metabolic psychiatric other unknown N = 937 deaths This shows the breakdown of cause of death from a study of deaths in 2005 in people with HIV in France. The proportion of deaths due to AIDS is only 36%, leaving the majority due to other causes. Looking at detail in the causes of death, the most common after AIDS are non-AIDS malignancy, hepatitis C, cardiovascular disease, suicide and non-AIDS infection. Percent Lewden JAIDS 2008, 48:590-9 Hessamfar-Bonarek Int. J. Epid 2010;39: Ronald Mitsuyasu - Epi May 2013 28

Non-AIDS Defining Cancers NADC

Non AIDS-defining Cancers Emerging Epidemiologic Features
Proportion of Cancers in HIV NADC 31% 58% Standardized Incidence Ratio HIV:non-HIV Lung 2.6 Hodgkin lymphoma 2.8 6.7 Larynx 1.8 2.7 Anus 10 9.1 Liver 3.7 Engels EA, Int J Cancer. 2008;123:

Factors Contributing to the Increase in 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 cause mortality rates and mortality hazard ratios Earlier mean age at dx in HIV+ for anal, lung and colorectal, but not for prostate or HL HIV+ dx at higher stage for lung and HL HIV+ reduced survival for HL, lung and prostate, but not for anal and colorectal Silverberg M et al. 19th CROI, Seattle, 2012, abs 903.

NADC Mortality HIV+ vs HIV-
Hodgkin Lymphoma HR 3.0 ( ) Lung 1.7 ( ) Prostate 2.2 ( ) Anal 1.7 ( ) Colorectal 1.6 ( ) 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 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 Endothelial abnormalities may allow for cancer development Population differences based on genetics and exposure to carcinogens Wistuba Il, Pathogenesis of NADC: a review. AIDS Pt Care 1999;13:415-26

Lymphomas

Pathology of AIDS-Related Non-Hodgkin’s Lymphoma
Clinical Manifestations and Treatment of HIV Pathology of AIDS-Related Non-Hodgkin’s Lymphoma 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, gastrointestinal Slide #15: Pathology of AIDS-Related Non-Hodgkin’s Lymphoma Non-Hodgkin’s lymphoma is among the most commonly diagnosed cancers in the patients with HIV disease.1 Two main histologic categories:1 Small noncleaved-cell lymphoma (SNCCL). Include Burkitt’s lymphoma and Burkitt-like lymphoma Make up 40% of all cases of non-Hodgkin’s lymphoma. Diffuse large-cell lymphoma (DLCL). Large noncleaved-cell lymphoma and immunoblastic lymphoma plasmocytoid are the most prevalent types of DLCLs, and they represent 25% each of all non-Hodgkin’s lymphomas. CD30+ anaplastic large B-cell lymphoma is another AIDS-related non-Hodgkin’s lymphoma. It is important that these lymphomas are accurately diagnosed and categorized as either SNCCL or DLCL, as the lymphoma type reveals pertinent information regarding the prognosis.1 Reference 1. Tirelli U, Spina M, Gaidano G, Vaccher E, Franceschi S, Carbone A. Epidemiological, biological, and clinical features of HIV-related lymphomas in the era of highly active antiretroviral therapy. AIDS. 2000;14: Tirelli U, et al. AIDS. 2000;14: Ronald Mitsuyasu - Epi May 2013 36

AIDS-related Lymphoma Experience Suggests Cancer Treatment Outcome Can be Equivalent to General Population Besson et al. Blood. 2001; 98: Little et al Blood. 2003; 101: Sparano et al. Blood, 2010;115:

Cancer Screening in HIV

ACS, NCI and USPSTF Cancer Screening Guidelines
Cervical CA – begin within 3 yrs of 1st intercourse or 21 yo and q 1-2 yrs. If and 3 normal Paps q3 yrs Prostate CA – discuss with MD at 50. DRE yearly and individualized 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 FOBT yearly Others – periodic health exams after age 20, with health counseling and oral, skin, lymph nodes, testes, ovaries and thyroid exam Other tests based on family history, other known cancer risk exposures or known risk factors

HIV Patient Screening Routine screening for HIV patients seems to be done LESS frequently than age-appropriate SOC screening for breast (67% vs 79%) and colon (56% vs 77.8%) and prostate biopsies Preston-Martin. Prev Med 2002;34:386-92 Reinhold JP. Am J Gastroenterol 2005;100: 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 false positive rates, which may be true in HIV as well

Why is anogenital cancer important?
Cervical cancer is the most common cancer in women worldwide and anal cancer is as common in MSM (75/100,000) as cervical cancer 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 whose incidence in the HAART era is increasing, not decreasing

Screening for cervical and anal dysplasia
No USA national or international guideline for anal screening other than NYS DOH anal Pap screening guidelines. Many HIV groups recommend yearly cervical and anal PAP, with colposcopy and/or HRA and biopsy of any suspicious lesions and q 6m F/U for those with abnormalities noted Many cervical cancer screen and treat program now operating in resource-limited settings Chiao EY et al. Clin Infect Dis 2006;43:223-33 Goldie SJ et al. JAMA 1999;282:1822-9

Cancer Prevention Smoking Cessation – Highest priority
Varenicline not hepatic met and no ART drug interaction expected Hepatitis B and HPV vaccination Treat active Hepatitis C Yearly cervical and anal Paps – Gyn and HRA Advise sun screen and avoid overexposure Maintain high index of suspicion for cancer Complete family history for malignancies Breast, prostate and colon screening as per guidelines for general population CT Lung and liver ultrasound controversial Treat all HIV patients with HAART

Summary As HIV population ages with persistent immune abnormalities, cancers will increase in number The risk of NADC is high with lung, anal, liver and HL accounting for most of this increase. The risk of colon, breast and prostate cancers not elevated in HIV. HL occurs at older age, but may reflect lack of younger age peak, as all cases in HIV are EBV+ As a minimum, we should conduct age/gender appropriate screening for cancer. Counsel patients on ways to reduce cancer risks Only through prospective clinical trials research can prevention strategies and new treatments be effectively evaluated

Thank You For information on AMC clinical trials see: For information on NCI programs in HIV cancer see: To refer for AMC clinical trials in LA, call UCLA CARE Center ask for Maricela Gonzalez or page/ Dr. Mitsuyasu,

Use of Antiretroviral Therapy

Overview Benefits and limitations of HAART When to start What to start with Simplified drug regimens and treatment adherence When to change therapy Second line therapies Slide: Overview This section will address the preferred PI- and NNRTI-based HAART regimens and the NRTI backbones of choice for initial HIV therapy . Ronald Mitsuyasu - Epi May 2013

Benefits of ART Prevention of mother to child transmission Post exposure prophylaxis (PEP) Secondary prevention of HIV transmission Primary prevention (PrEP) Clinical management of patients with HIV Reduces HIV replication Increase or maintain CD4 numbers Maintain “less fit” mutated HIV Ronald Mitsuyasu - Epi May 2013

Current antiretroviral targets
Clinical Manifestations and Treatment of HIV Current antiretroviral targets Fusion Inhibitor Enfuvirtide Entry Inhibitors CCR5, MRV Viral protease Inhibitors RNA RNA Proteins Reverse transcriptase Inhibitors SQV RTV IDV NFV APV LPV FOS ATZ TPV DRV RT RNA ZDV, ddI, ddC, d4T, 3TC, ABC, TDF, FTC DLV, NVP, EFV, ETV RPV RNA DNA RT DNA Integrase Raltegravir Elvitegravir DNA Provirus Ronald Mitsuyasu - Epi May 2013

Protease Inhibitors (10) saquinavir (SQV) ritonavir (RTV) indinavir (IDV) nelfinavir (NFV) amprenavir (APV) lopinavir/r (LPV/r) fosamprenavir (FPV) atazanavir (ATV) tipranavir (TPV) darunavir (DRV) dolutegravir (DTG) Antiretroviral Drugs 2013 Reverse Transcriptase Inhibitors(13) Nucleoside analogues zidovudine (AZT, ZDV) didanosine (ddI) zalcitabine (ddC) stavudine (d4T) lamivudine (3TC) abacavir (ABC) emtricitabine (FTC) Nucleotide analogue tenofovir (TFV) Non-nucleoside analogues nevirapine (NVP) delavirdine (DLV) efavirenz (EFV) etravirine (ETV) rilpivirine (RPV) Integrase Inhibitor (2) raltegravir (RAL) elvitegravir (ELV) Fusion Inhibitor fuzeon (T20) Entry Inhibitor (CCR5) maraviroc (MVC) Ronald Mitsuyasu - Epi May 2013

Overview Benefits and limitations of HAART When to start What to start with Simplified drug regimens and treatment adherence When to change therapy Second line therapies Slide: Overview This section will address the evolving data used to make recommendations when to start HAART. Ronald Mitsuyasu - Epi May 2013

Case Diagnosed on routine insurance examination
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 to begin 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 CD4 count would you recommend starting therapy?
Would treat at any CD4 count 750 cells / ul 500 cells / ul 350 cells / ul 250 cells / ul < 200 cells /ul < 50 cells /ul Would not recommend ART

When to Start Therapy: Balance Tipping in Favor of Earlier Initiation
Clinical Manifestations and Treatment of HIV When to Start Therapy: Balance Tipping in Favor of Earlier Initiation Potency, durability, simplicity and safety of current regimens Improved formulations and PK New classes of drugs Excess morbidity/mortality at higher CD4 Drug toxicity Preservation of limited Rx options Cost Delayed CD Earlier Ronald Mitsuyasu - Epi May 2013

Reasons to Start Early The Biology Association of Inflammation and Disease Better Tolerated/Easier to Take Medications Randomized Controlled Trial Data Cohort Data Irreversible Damage Public Health Ronald Mitsuyasu - Epi May 2013 55

Latently Infected CD4+ Lymphocytes HIV Infected Cells HIV virions Antiretroviral Rx Uninfected Activated CD4+ Lymphocytes Uninfected Resting CD4+ Lymphocytes M Saag, UAB Ronald Mitsuyasu - Epi May 2013 56

Opportunistic Infections Occur at Higher CD4+ Cell Count Strata
CMV / MAC / TOXO PCP /EC TB Incidence per 1000 PYFU (95%CI) 302 174 444 Latest CD4 count N events Podlekareva et al. J Infect Dis 2006;194:633.

When to start?: ART Cohort Collaboration Modeled data 10,855 patients included, with >61,000 person-years of F/U (median 2.7 yrs) 934 progressed to AIDS or died IDUs excluded from model Cumulative Probability of AIDS/Death by CD4 Count at Initiation of ART cells/mm cells/mm cells/mm3 0.12 0.10 0.08 Probability of AIDS or Death 0.06 0.04 For more information, go to the Capsule Summary at 0.02 0.00 1 2 3 4 5 Years Since Initiation of HAART Antiretroviral Therapy (ART) Cohort Collaboration, AIDS 2007;21: Ronald Mitsuyasu - Epi May 2013 58

Delayed Initiation of ART and Increased Risk of Death
Clinical Manifestations and Treatment of HIV Delayed Initiation of ART and Increased Risk of Death Variable CD4+ count cells/ml >500 cells/ml Relative Risk P Value ART deferral 1.6 ( ) 0.002 1.9 ( ) 0.006 Female sex ( ) 0.04 1.4 ( ) 0.20 Older age (10yr) ( <0.001 1.8 ( ) Baseline CD4+ (100 cell increment) 0.7 ( ) 0.06 1.0 ( ) 0.45 Baseline HIV RNA (log 10 increment) 1.1 ( ) 0.15 0.14 In another study that included several cohorts, the incidence of death was analyzed at two thresholds. Deferral of ART was associated with increased risk of death at these thresholds. Kitahata et al, New Eng J Med 2009;360:1815 (adapted) Ronald Mitsuyasu - Epi May 2013 59

Cumulative Mortality Estimates
Calculated Using Extended Kaplan-Meier Survival Estimates 0.20 CD4 > 500 & Defer HAART (N=6,539) 0.15 0.10 CD4 > 500 & Initiate HAART (N= 2,616) 0.05 0.00 2 4 6 8 10 Years after 1996 Kitahata MM, et al. CROI Abstract 71.

Most New Infections Transmitted by Persons who Do Not Know Their Status account for… ~25% Unaware of Infection ~54% New Infections ~75% Aware of Infection It is estimated that sexual transmission accounts for 80% of the 40,000 new infections each year. Conservative estimates based on the changes in behavior observed once people find out they are infected with HIV indicate that the 25% of people who are unaware that they are infected account for at least 54%, and potentially as much as 70%, of the new sexually transmitted infections each year. The transmission rate among those who don’t know they are infected is 3.5 times higher than for people who know about their HIV infection. This highlights how important it is to get these individuals tested and into care that includes both treatment and prevention interventions. ~46% of New Infections Source: G. Marks et al. AIDS 2006 Ronald Mitsuyasu - Epi May 2013 61

HPTN 052 Clinical Manifestations and Treatment of HIV 1763 HIV discordant couples (HIV+ partner CD ) 877 delayed HAART (CD4 250) *96% reduction in HIV transmission to HIV-negative partner median follow-up 2 years 1 transmission* & 3 cases of extrapulmonary TB 886 immediate HAART All receiving HIV prevention services Cohen MS, N Engl J Med. 2011: 27 transmissions* & 17 cases of extrapulmonary TB Ronald Mitsuyasu - Epi May 2013 62

Reasons to Start Early The Biology Association of Inflammation and Disease Better Tolerated Medications Today Randomized Controlled Trial Data Cohort Data Public Health Common Sense! Ronald Mitsuyasu - Epi May 2013 63

Relative Time on Treatment…
Clinical Manifestations and Treatment of HIV Relative Time on Treatment… 40 years on Rx HARM? CD4 650/ul 35 years on Rx 5 years CD4 500/ul AGE (years) Ronald Mitsuyasu - Epi May 2013

So ….what is the harm? Destruction of Lymphoid Tissue Inflammation Increased Cardiovascular Events Increased incidence of certain malignancies Accelerated ‘Aging’ Accelerated Cognitive Decline Ronald Mitsuyasu - Epi May 2013 65

Conclusions Balance of data support starting Rx in ~ all individuals regardless of CD4+ T cell counts Understanding of HIV pathogenesis Cohort data Public health implications No randomized clinical trial data for higher CD4 counts > 500 yet (START study is enrolling) Waiting until RCT data could well lead to harm that likely will not be reversible Ronald Mitsuyasu - Epi May 2013 66

When to Start Treatment
Clinical Manifestations and Treatment of HIV When to Start Treatment Clinical Category CD4 Count (cells/mm3) HIV RNA (copies/mL) 2/13/13 DHHS Guidelines 2012 IAS-USA AIDS-defining illness or severe symptoms Any value Treat Asymptomatic <500 >500 Pregnant women HIV-associated nephropathy HIV/HBV coinfection when HBV treatment is indicated *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 virus infection, active or high risk for cardiovascular disease, and symptomatic primary HIV infection. DHHS. Available at: Revision February 2013; Thompson MA, et al. JAMA. 2012;308: Ronald Mitsuyasu - Epi May 2013 67

When To Start Treatment: Summary of Current Guidelines
CD4 < 350 CD CD4 >500 British HIVA September, 2012 treat Consider unless: HBV or HCV, High CV risk, HIVAN, pregnant- then treat Unknown European ACS November, 2012 Consider unless: HCV, HIVAN, HBV needing Tx; CD4 decline >50-100/yr, pregnant – Treat IAS-USA: July, 2012 DHHS: February, 2013

When to Start Therapy: Balance Tipping in Favor of Earlier Initiation
Clinical Manifestations and Treatment of HIV When to Start Therapy: Balance Tipping in Favor of Earlier Initiation Potency, durability, simplicity and safety of current regimens Improved formulations and PK Enhanced adherence Diminished emergence of resistance New classes of drugs Excess morbidity/mortality at higher CD4 Drug toxicity Preservation of limited Rx options Cost < CD Everyone ? Ronald Mitsuyasu - Epi May 2013

Overview Changing epidemiology of AIDS in the United States Benefits and limitations of HAART When to start What to start with Simplified drug regimens and treatment adherence Second line therapy Slide: Overview This section will address the preferred PI- and NNRTI-based HAART regimens and the NRTI backbones of choice for initial HIV therapy . Ronald Mitsuyasu - Epi May 2013

Factors to consider in choosing first-line therapy
Clinical Manifestations and Treatment of HIV Factors to consider in choosing first-line therapy Patient’s willingness to commit to therapy Baseline resistance Efficacy data Tolerability Convenience Comorbid conditions Consequences of failure (resistance) Since the introduction of potent ARV therapy preferred regimens all include NRTIs + third drug Ronald Mitsuyasu - Epi May 2013 71

DHHS Guidelines for Adolescents/Adults: What to Start
Clinical Manifestations and Treatment of HIV DHHS Guidelines for Adolescents/Adults: What to Start Preferred Regimens • 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] Alternative Regimens • 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) Acceptable • 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 at: . Revision Feb, 2013. Ronald Mitsuyasu - Epi May 2013 72

Boosted-Protease Inhibitors
Clinical Manifestations and Treatment of HIV Boosted-Protease Inhibitors ARTEMIS2 (ITT, TLOVR) 96 weeks LPV/r QD or BID DRV/r 800/ QD 79 71 n=343 n=346 20 40 77 80 100 CASTLE3 (ITT, NC=F) ATV/r 300/100 QD 400/100 68 74 n=443 n=440 KLEAN1 (ITT-E, TLOVR) 48 weeks FPV/r 700/100 BID 66 65 N=444 n=434 Adapted from: 1. Eron J, et al. Lancet 2006; 368: ; 2. Mills A, et al. AIDS May 29, 2009 3. Molina J-M, et al. 48th ICAAC/46th IDSA , Washington, DC, Abst. H-1250d Ronald Mitsuyasu - Epi May 2013 73 73 73

ATV/r vs. EFV Primary Endpoint
Clinical Manifestations and Treatment of HIV ATV/r vs. EFV Primary Endpoint Daar ES, et al. Ann Intern Med 2011; 154: Ronald Mitsuyasu - Epi May 2013

Pooled* ECHO and THRIVE W48 analysis: VL <50 copies/mL over 48 weeks (ITT-TLOVR) RPV 25mg qd (N=686) 100 80 60 40 20 EFV 600mg qd (N=682) 84.3% 82.3% Virologic responders (%, 95% CI) Time (weeks) Each of the trials reached their primary objective of non-inferiority of RPV to EFV in confirmed virologic response† CI = confidence interval; *Pooled analyses were preplanned †Difference (95% CI) in response rates estimated by logistic regression adjusted for stratification factors: 1.6 (–2.2, 5.3) Cohen JAIDS 2012 Ronald Mitsuyasu - Epi May 2013

(MK-###) (PN###) "CONFIDENTIAL - LIMITED ACCESS", Interim Deck-Expires when CSR Deck is Available Clinical Manifestations and Treatment of HIV 4/16/ :02 PM STARTMRK: RAL vs. EFV ITT, NC=F 12 24 48 72 96 120 144 168 192 216 240 Weeks 20 40 77 80 100 Percentage of Patients with HIV RNA Levels <50 Copies/mL 86 82 81 79 75 69 76 67 71 61 CD4 Change: RAL +374 vs. EFV +312 281 278 279 280 277 282 Raltegravir 400 mg BID Efavirenz 770 mg QHS Number of Contributing Patients Rockstroh J, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. LBPE19. Ronald Mitsuyasu - Epi May 2013 White Template MASTER ppt 76

Elvitegravir/Cobicistat/FTC/TDF (Quad) vs. EFV/FTC/TDF (Study 236-102)
Clinical Manifestations and Treatment of HIV Elvitegravir/Cobicistat/FTC/TDF (Quad) vs. EFV/FTC/TDF (Study ) Quad QD EFV/FTC/TDF QHS Placebo Quad Placebo QD n=350 Week 48 Week 192 Treatment-Naïve Any CD4 count Randomized 1:1 Stratification by HIV-1 RNA (>100,000 c/mL) Study was one of two studies presented at CROI that evaluated two new agents, Elvitegravir ( a new integrase agent) and Cobicistat ( a new boosting agent). These new medications were combined into a single tablet regimen with Tenofovir (TDF) and Emtricitabine (FTC) and compared to EFV/TDF/FTC. The two different regimens had to be taken at different times and so it was not a true comparison of a once daily regimen. Primary Endpoint: Proportion with HIV-1 RNA < 50 copies/mL at Week 48 FDA snapshot analysis (ITT), 12% non-inferiority margin Sax P, et al. 19th CROI; Seattle, WA; March 5-8, Abst. 101. Ronald Mitsuyasu - Epi May 2013

Study 236-102: Primary Endpoint: HIV-1 RNA < 50 copies/mL
Clinical Manifestations and Treatment of HIV Study : Primary Endpoint: HIV-1 RNA < 50 copies/mL +3.6%, 95% CI 3.6 (-1.6% to +8.8%) 88% of the subjects on Quad achieved < 50 c/mL compared to 84% for EFV/FTC/TDF. This did not exceed the predetermined confidence interval of 12% and therefore demonstrated non inferiority between the two regimens. The rates of virologic non suppression were similar between the two regimens as well. CD4+ change: Quad +239 vs. EFV c/mm3 (p=0.009) Sax P, et al. 19th CROI; Seattle, WA; March 5-8, Abst. 101. Ronald Mitsuyasu - Epi May 2013 78

Elvitegravir/Cobicistat/FTC/TDF (Quad) vs. ATV/r + FTC/TDF (Study ) Multicenter, international, randomized, blinded 192-week study Quad QD ATV/r + FTC/TDF Placebo QD ATV/r + FTC/TDF QD Quad Placebo QD Week 48 Week 192 ART-naïve subjects HIV RNA >5,000 c/mL eGFR > 70ml/min (N = 708) Baseline: HIV RNA >100,000 c/mL 40-43% CD4 Count cells/mm3 Stratification by HIV RNA (> or ≤100,000 c/mL) The second study with Quad compared virologic efficacy with Atazanavir boosted with Ritonavir. The baseline groups were well matched and a GFR of ≥ 70 ml/min was the minimum threshold of entry. This GFR was the same threshold for both studies with QUAD, as the Phase II studies only evaluated safety and efficacy in patients whose GFR exceeded 70 ml/min Primary Endpoint: Proportion with HIV-1 RNA < 50 c/mL at Week 48 FDA snapshot analysis, 12% non-inferiority margin DeJesus E, et al. 19th CROI; Seattle, WA; March 5-8, Abst. 627. Ronald Mitsuyasu - Epi May 2013 79 79

Study 236-103: HIV-1 RNA < 50 c/mL Through Week 48
Clinical Manifestations and Treatment of HIV Study : HIV-1 RNA < 50 c/mL Through Week 48 100 90 80 70 60 50 40 30 20 10 92% 88% Diff: 3.5% (95% CI: -1.0 to 8.0) Percent with HIV RNA <50 c/mL (ITT, M=F) QUAD ATV/r The primary analysis for the study was the FDA mandated snapshot analysis which revealed 90% suppression rate for Quad vs 87% for ATV/r. The net difference of 3% was not statistically different and the two regimens were therefore judged to be non inferior. An additional analysis of ITT M=F revealed a 3.5 % difference favoring Quad ( 92% vs 88%) and this difference was also non inferior. The Quad arm attained suppression more rapidly as has been described with integrase based regimens, but by 48 weeks these differences were similar. HIV 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) BL Week DeJesus E, et al. 19th CROI; Seattle, WA; March 5-8, Abst. 627. Ronald Mitsuyasu - Epi May 2013 80

Comparisons of First Line Regimens
Anchor Drug Result Efavirenz Lopinavir/r Superior ATV/r Tied RAL Rilpivirine Maraviroc Elvitegravir/cobisistat

A5202: Study Design Arm TDF/FTC QD TDF/FTC QD EFV EFV A QD QD ABC/3TC Placebo QD HIV-1 RNA ≥1000 c/mL Any CD4+ count > 16 years of age ABC/3TC QD ABC/3TC QD EFV EFV B QD QD ART ART - - naïve naïve TDF/FTC Placebo QD TDF/FTC Placebo QD 1857 enrolled N=1858 Randomized 1:1:1:1 Randomized 1:1:1:1 TDF/FTC QD TDF/FTC QD ATV/r ATV/r C QD QD ABC/3TC Placebo QD ABC/3TC Placebo QD Stratified by screening HIV-1 RNA (< or ≥ 100,000 c/mL) Enrolled Followed through Sept 2009, 96 wks after last pt enrolled ABC/3TC QD ABC/3TC QD ATV/r ATV/r D QD QD TDF/FTC Placebo QD TDF/FTC Placebo QD Ronald Mitsuyasu - Epi May 2013

A5202: Time to Virologic Failure in Patients with HIV RNA >100,000 c/mL TDF-FTC (26 events) ABC-3TC (57 events) Probability of No Virologic Failure P<0.001, log-rank test Hazard ratio, 2.33 (95% CI, ) No. at Risk ABC-3TC 398 363 313 267 222 188 137 87 49 20 TDF-FTC 399 361 321 284 236 204 177 104 65 23 Sax PE, et al. NEJM 2009;361: Ronald Mitsuyasu - Epi May 2013 83

ABC/3TC vs. TDF/FTC Low Viral Load Stratum
Clinical Manifestations and Treatment of HIV ABC/3TC vs. TDF/FTC Low Viral Load Stratum Sax PE, et al. JID 2011: 204: Ronald Mitsuyasu - Epi May 2013

Concerns regarding NRTIs
Clinical Manifestations and Treatment of HIV Concerns regarding NRTIs For individuals with higher viral loads (e.g. >100,000 c/ml) TDF/FTC superior to ABC/3TC) Conflicting results regarding relationship between ABC and CV events TDF-associated with greater decline in bone mineral density TDF-associated with variable decline in renal function Given rise to preferred regimens of TDF/FTC with ABC/3TC as alternative Ronald Mitsuyasu - Epi May 2013 85

What Not to Use Guidelines: IAS-USA1, WHO2, DHHS3
Clinical Manifestations and Treatment of HIV What Not to Use Guidelines: IAS-USA1, WHO2, DHHS3 Any mono- or dual-therapy combo AZT + 3TC + ABV + FTC (first line) Nelfinavir (first line) ddI + TDF ddI + d4T AZT + d4T ATZ + IDV SQV or DRV or TPV unboosted RIT (full dose therapy) EFV in pregnancy Nevirapine in naïve women CD4>250 or men >400 Etravirine with unboosted PI or with ATZ/r, FOS/r, TPV/r Slide #10: Guideline Revisions 2006 There updates to 3 major guidelines for HIV treatment in 2006, namely the International AIDS Society-USA, the World Health Organization, and the DHHS.1-3 There were no major changes to the “When to start?” section. There was consensus among the 3 guidelines on this topic. The IAS-USA offered a table to simplify treatment choices in the “What to start?” section. NRTI co-formulations recommended included emtricitabine/tenofovir DF, zidovudine/abacavir, and zidovudine/lamivudine. Other NRTI combinations “if above cannot be used.” NNRTIs: efavirenz was preferred over nevirapine. PIs: only boosted PIs are recommended, no alternatives recommended. - Lopinavir/ritonavir and ritonavir-boosted atazanavir, saquinavir, or fosamprenavir. References Hammer SM, Saag MS, Schechter M, et al. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel. JAMA. 2006;296: Available at: UNAIDS.org. Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: Revision: May 4, 2006. 1Thompson, et al. JAMA 2010;304:32; 2Available at: 3Available at: Revision March 27, 2012. Ronald Mitsuyasu - Epi May 2013

Side Effects and Toxicities

Patients Don’t Like Surprises: Short-Term Side Effects 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 Ronald Mitsuyasu - Epi May 2013

HAART: Long-Term Complications
Clinical Manifestations and Treatment of HIV HAART: Long-Term Complications Dyslipidemia/CHD Abnormalities of Body Composition Slide: HAART: Long-Term Complications This slide illustrates the most common long-term complications associated with HAART: dyslipidemia/coronary heart disease, hepatotoxicity, and abnormalities of body composition. Hepatotoxicity Ronald Mitsuyasu - Epi May 2013

Overview Changing epidemiology of AIDS in the United States Benefits and limitations of HAART When to start What to start with Simplified drug regimens and treatment adherence When to change therapy Second line therapies Slide: Overview This section will address the continuous move towards simpler HAART regimens in the initial treatment of HIV infection. Ronald Mitsuyasu - Epi May 2013

The Move Toward Simpler 3-Drug Regimens
Clinical Manifestations and Treatment of HIV The Move Toward Simpler 3-Drug Regimens 1996 2006 Didanosine + stavudine + saquinavir 24 pills/dose, 5 doses Saquinavir: 6 q8h with fatty food Didanosine: 2 bid ½ hour ac or 2 hours pc Stavudine: 1 pill bid Emtricitabine/tenofovir DF + efavirenz (Atripla) 1 pills qd No food restrictions Slide: The Move Toward Simpler 3-Drug Regimens Tremendous progress has been made towards simplifying HAART regimens. In 1996, a typical regimen of didanosine + stavudine + saquinavir consisted of 24 pills/dose with 5 doses and was associated with significant long-term toxicity. Saquinavir: 6 q8h with fatty food. Didanosine: 2 bid ½ hour ac or 2 hours pc. Stavudine: 1 pill bid. In 2006, emtricitabine/tenofovir DF or abacavir/lamivudine + efavirenz can be administered as 2 pills once-daily with no food restrictions. Ronald Mitsuyasu - Epi May 2013

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 United States Benefits and limitations of HAART When to start What to start with Simplified drug regimens and treatment adherence When to change therapy Second line therapies Slide: Overview This section will address the preferred PI- and NNRTI-based HAART regimens and the NRTI backbones of choice for initial HIV therapy . Ronald Mitsuyasu - Epi May 2013

When to Change Therapy? Virologic failure < log reduction in HIV RNA by 4 weeks or <1.0 log reduction by 8 weeks Failure to suppress HIV RNA BLD by 3 months Repeated detection of HIV RNA after suppression BLD Immunologic failure Persistently declining CD 4 cell counts Clinical failure Clinical deterioration or disease progression DHHS Guidelines, 1/28/00 Ronald Mitsuyasu - Epi May 2013

Why Do Treatment Fail Patients?
Clinical Manifestations and Treatment of HIV Why Do Treatment Fail Patients? Poor adherence Baseline resistance or cross-resistance Use of less potent antiretroviral regimens Sequential mono- or dual-therapy Drug levels and drug interactions Tissue reservoir penetration Other, unknown reasons Ronald Mitsuyasu - Epi May 2013

Long-Term Risk of Developing Drug Resistance
Clinical Manifestations and Treatment of HIV Long-Term Risk of Developing Drug Resistance Time to Multiclass Resistance Risk of developing antiretroviral drug resistance from UK CHIC Study (n=4306) Longitudinal cohort from 6 clinics in London Started antiretroviral therapy with 2 NRTIs plus a third agent Overall risk of treatment failure 38% over 6 years Risk of accumulating resistance mutations to any drug 27% overall 2 classes 3 classes Resistance (% patients) 2 Years 4 Years 6 Years Philips A, et al. Lancet 2007; 370: Ronald Mitsuyasu - Epi May 2013

Overview Changing Epidemiology of AIDS in the United States Benefits and limitations of HAART When to start What to start with Simplified drug regimens and treatment adherence When to change therapy Second line therapies Slide: Overview This section will address the preferred PI- and NNRTI-based HAART regimens and the NRTI backbones of choice for initial HIV therapy . Ronald Mitsuyasu - Epi May 2013

Strategic Therapy Considerations for the Treatment-Experienced Patient
Clinical Manifestations and Treatment of HIV Strategic Therapy Considerations for the 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 (less critical now) Example: adding lamivudine/emtricitabine or abacavir to maintain M184V mutation Ronald Mitsuyasu - Epi May 2013

Treatment Goals and Challenges Treatment 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 regimen with including 3 fully active agents High bar for safety in treatment experienced patients

Drug Resistance Testing: Caveats
Clinical Manifestations and Treatment of HIV Drug Resistance Testing: Caveats Resistance tests are most accurate in assessing resistance to the current regimen Absence of resistance to a previously used drug does not rule out archived resistant virus that might emerge after re-initiation of that drug Reduced potency should be expected from recycled drugs Ronald Mitsuyasu - Epi May 2013

New Paradigm in Therapy
Clinical Manifestations and Treatment of HIV New Paradigm in Therapy Complete suppression of plasma HIV-1 RNA should be the goal in all patients with HIV given the availability of new drugs Maximize virus suppression while minimizing drug toxicity For those who do not tolerate new agents, goal should be to maintain CD4 count as high as possible Second line therapy should be chosen on the basis of resistance testing, treatment history, tolerability Ronald Mitsuyasu - Epi May 2013

Think Strategically “Long-term strategic anti-HIV therapy is similar to a chess game against a vastly superior opponent, in which the objective is to avoid checkmate and remain on the board after 20 years” DD Richman, Science 1993

Questions Ronald Mitsuyasu, MD Professor of Medicine Director, UCLA Center for Clinical AIDS Research University of California, Los Angeles

Clinical Manifestations and Treatment of HIV

Similar presentations

Presentation on theme: "Clinical Manifestations and Treatment of HIV"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Clinical Manifestations and Treatment of HIV

Similar presentations

Presentation on theme: "Clinical Manifestations and Treatment of HIV"— Presentation transcript:

Similar presentations

About project

Feedback