DHS/HIV/AIDS/PP HIV/AIDS Antiretroviral Therapy: 2001 David H. Spach, MD Medical Director, AIDS Education Northwest AIDS Education & Training Center Associate Professor of Medicine Division of Infectious Diseases University of Washington, Seattle

DHS/HIV/ARV RX/PP Antiretroviral Therapy: 2001  Initial Therapy  Resistance/Failure  Antiretroviral Toxicity  Structured Treatment Interruptions  Postexposure Prophylaxis  Discontinuing OI Prophylaxis

DHS/HIV/ARV RX/PP Initial Therapy

DHS/ HIV/PP HIV: Case History  A 29-year old woman comes to the clinic for routine HIV care; she has been HIV-infected for about 4 years. Her labs show a CD4 count is 485 and his viral load is 88,000. a) Would you start antiretroviral therapy? b) Would your answer been different if her viral load was 6,000? c) If you start, what kind of response are you looking for?

FrAdapted from: Walker B. IDSA 1998 HIV: Antiretroviral Therapy RNA DNA HIV Nucleus Host Cell Nucleoside Analogues Non-NucleosidesProtease Inhibitors

NIH Panel: Antiretroviral Guidelines: 2001 Initial Therapy: Preferred Regimens DHS/ARV Rx/PP Picture 2 Nucleoside Analogues + Efavirenz 2 Nucleoside Analogues + Protease Inhibitor 2 Nucleoside Analogues + 2 Protease Inhibitors Source: CD4 < 350 cells/mm 3 or HIV RNA > 30,000 (bDNA) HIV RNA > 55,000 (RT-PCR) or HIV-Related Manifestations

NIH Panel: Antiretroviral Guidelines: 2001 Initial Therapy: Preferred Regimens DHS/ARV Rx/PP Column A Efavirenz Indinavir Nelfinavir Ritonavir + Indinavir Ritonavir + Lopinavir Ritonavir + Saquinavir Stavudine + Didanosine Stavudine + Lamivudine Zidovudine + Didanosine Zidovudine + Lamivudine Column B

NIH Panel: Antiretroviral Guidelines: 2001 Initial Therapy: Alternative Regimens DHS/ARV Rx/PP Column A Abacavir Amprenavir Delavirdine Nelfinavir + Saquinavir-SGC Nevirapine Ritonavir Saquinavir-SGC Didanosine + Lamivudine Zidovudine + Zalcitabine Column B

DHS/ARV Rx /PP Efavirenz: Study 006 From: Staszewski S. N Engl J Med 1999;341:  Patients (N=450) - CD4 > 50 cells/mm 3 - HIV RNA > 10,000 copies/ml - Naive to PI, non-nucleoside, and 3TC  Regimens - AZT + 3TC + IDV - EFV + IDV - AZT + 3TC + EFV

From: Staszewski S. JAMA 2001;285: DHS/ ARV Rx /PP Abacavir: Study 3005 AZT + 3TC + ABC vs AZT + 3TC + IDV  Patients (N = 562) - Antiretroviral-naive adults - HIV RNA > 10,000 - CD4 > 100 cells/mm 3  Regimens - AZT + 3TC + Abacavir (ABC) - AZT + 3TC + Indinavir (IDV) Study Design48 Week Data: HIV RNA <50 HIV RNA > 100,000

DHS/ARV Rx/PP Antiretroviral Therapy: Optimal Response Medications Started 50

DHS/ HIV/PP HIV: Case History  A 32-year-old man with an HIV RNA level of 313,000 and a CD4 count of 22 cells/mm 3 presents with PCP and newly diagnosed with HIV; he was probably infected about 7 years ago. He is highly motivated and states he will take any regimen you recommend for him. a) What would you recommend? b) Would you order resistance testing prior to starting therapy?

From Resistance Testing: Acute vs. Established HIV Wild-type HIV Resistant HIV Acute HIVEstablished HIV No ARV Rx

DHS/HIV/ARV RX/PP Resistance/Failure

DHS/ HIV/PP HIV: Case History  A 26-year-old man with an HIV RNA level of 106,000 and a CD4 count of 121 cells/mm 3 starts on a regimen of Zidovudine (Retrovir) plus Lamivudine (Epivir) plus Nelfinavir (Viracept) and has an initial excellent response (HIV RNA < 50 at months 3, 6, and 9). At the 12 month visit, he asks how many missed doses in a month would it take for resistance to develop. a) How would you answer this?

DHS/ARV Rx /PP Adherence and Virologic Failure From: Paterson Dl et al. Ann Intern Med 2000;133: N = 81 Patients on Protease Inhibitor-Based RX

DHS/ HIV/PP HIV: Case History  This 12 month HIV RNA level comes back at 624 copies per ml. The lab is repeated 2 weeks later and returns at 822 copies/ml. a) Would you do a resistance test?

Use of Resistance Testing: Recommendations DHS/ARV Rx/PP Clinical Setting Virologic failure during HAART Suboptimal suppression (Initiation of Rx) Acute HIV Chronic HIV (Initiation of Rx) After stopping ARV Rx HIV RNA < 1,000 Recommend Consider Not Recommended Recommendation From: 2001 DHHS/NIH Antiretroviral Therapy Guidelines

DHS/ARV Rx/PP Antiretroviral Therapy: Viral Failure 500 Medications Started

DHS/ARV Rx/PP Antiretroviral Therapy: Failure to Suppress 500 Medications Started

DHS/HIV/ARV RX/PP HIV Resistance Testing Assays  Genotypic Assays - Detect mutations in RT & Protease genes - Generally require > 1,000 copies/ml  Phenotypic Assays - Determine amount of drug required to suppress HIV replication in vitro - Generally require > 1,000 copies

HIV Resistance Testing Virtual Phenotype Genotype ProteaseRTHIV Access Data Genotype & Phenotype Data Virtual Phenotype

DHS/HIV/Resistance /PP HIV Primary Infection Isolates From: Little SJ. JAMA 1999;282: Little SJ. 8th Conf Retrovirus. Abstract 756 N = 108 Patients Newly HIV-Infected Phenotypic Data: 10-fold Resistance

DHS/ HIV/PP HIV: Case History  A 29-year-old woman with a CD4 count of 336 and a HIV RNA of 94,000 starts on Stavudine/d4T (Zerit) + Lamivudine/3TC (Epivir) + Nevirapine (Viramune). She does well for about 9 months with HIV RNA of <50 copies/ml. She starts to develop breakthrough viremia, with HIV RNA levels increasing from <50, to 323, to 978, to Resistance testing shows the K103N mutation suggesting resistance to Nevirapine (Viramune). a) Would you recommend switching the Nevirapine (Viramune) to Efavirenz (Sustiva)?

DHS/ HIV/PP HIV: Case History  A 35-year-old man with a CD4 count of 236 is started on AZT + 3TC (Combivir) + Indinavir (Crixivan); he does well for approximately 6 months (at one point with HIV RNA < 50), but on last 2 visits has HIV RNA levels greater than 500 (1220 and 2480). He states recently he has had a mild depression and has experienced trouble with the Indinavir (Crixivan) schedule. Resistance testing is ordered. a) Why should you specifically ask if they are taking any naturopathic or herbal medicines? b) What are some of the options you have? Will adding a non- nucleoside be important?

DHS/ HIV/PP HIV: Case History  A 59-year-old man with a baseline CD4 count of 45 and baseline HIV RNA 86,000 starts on Stavudine (Zerit) + Lamivudine (Epivir) + Indinavir (Crixivan). He has excellent response for 2 years (with HIV RNA < 50), but develops significant peripheral neuropathy and stops taking the d4T (Zerit) on his own. HIV RNA now is 3,900 and repeat 2 weeks later is 5,700. Resistance testing shows reverse transcriptase gene with 184 (M184V); protease gene shows 46 (M46I) and 82 (V82S). a) What type of response would you expect from Abacavir (Ziagen)? b) If you saw an insertion mutation (for reverse transcriptase gene) at Q151M or at 69 what would you conclude? c) Is Indinavir (Crixivan) likely to continue to work?

DHS/ HIV/PP HIV: Case History  A 38-year-old woman has an HIV RNA of 176,000 and a CD4 count of 79; she is started on d4T (Zerit) + 3TC (Epivir) + nelfinavir (Viracept) and does well for 3 months with an HIV RNA of 485 at month 3. At month 4 the HIV RNA is 920 and at month 5 it is 3010; she admits to intermittent problems with adherence, but now has the situation under control and is reliably taking her medications. Genotypic resistance testing is performed. The RT gene shows the 184 mutation, but no mutations to suggest d4T resistance; protease gene shows the 30 mutation (D30N). a) Does the lack of resistance with d4T influence you? b) Do you think this patient has resistance to nelfinavir (Viracept) and do you think they would respond to a salvage regimen?

DHS/HIV/ARV RX/PP Antiretroviral Toxicity

DHS/ HIV/PP HIV: Case History  A 34-year-old man with a CD4 count of 326 and an HIV RNA load of 56,000 is started on an antiretroviral therapy regimen of Zidovudine + Lamivudine (Combivir) + Nevirapine (Viramune). Two weeks into the regimen the patient is tolerating the combination well, but at week 3 he calls and says he has severe fatigue and his urine looks dark. The patient has a 1-month follow-up visit in 1 week. a) What is likely going on? b) Should the patient come in to the clinic now or reasonable to wait several days to see if it resolves?

DHS/HIV/AIDS /PP HIV Postexposure Prophylaxis Serious Adverse Events Associated with Nevirapine From: CDC. MMWR 2001;49 (51); N = 22 Serious Adverse Events - Hepatotoxicity = 12 (2 with liver failure) - Skin Reaction = 14

DHS/ HIV/PP HIV: Case History  A 31-year-old man has a CD4 count of 221 and an HIV RNA of 144,000 and has been on a regimen of Zidovudine (Retrovir) + Didanosine (Videx) + Indinavir (Crixivan) + Ritonavir (Norvir) and has had a very good response to this therapy. He calls with left-sided back pain and dark urine. a) What should you do? b) Can they continue this regimen? c) What may help to prevent this?

DHS/ HIV/PP HIV: Case History  A 29-year-old woman has a CD4 count of 134 and an HIV RNA of 43,000 and has been on salvage regimen of Zidovudine (Retrovir) + Didanosine (Videx) + Hydroxyurea (Hydrea) + Nevirapine (Viramune) + Nelfinavir (Viracept) and she has had a very good response to this therapy. She calls stating she has been vomiting for two days and has terrible abdominal pain, especially after she eats. a) What could be going on and what labs would you order? b) Could the Hydroxyurea be contributing to the problem?

DHS/ HIV/PP HIV: Case History  A 35-year-old woman with a CD4 count of 423 and an HIV RNA level of 64,000 starts on Zidovudine + Lamivudine + Abacavir (Trizivir). After approximately 2 weeks of starting the medication, she develops fatigue, a low grade fever, sore throat, and a mild non-productive cough. She states one of her kids has recently had a “cold”. a) What are you worried about and what further questions would you ask? b) Is it safe to continue the regimen for another day or two?

From Abacavir (Ziagen) Hypersensitivity  Incidence and Timing - Incidence < 3% - Onset typically within 4 weeks  Symptoms - Rash - Fever - Nausea - Throat/mouth lesions - Conjunctivitis/respiratory symptoms DHS/ARV Rx/PP From: Hetherington S, et al. 12th World AIDS Conference, Geneva, 1998: Abstract 12353

DHS/ HIV/PP HIV: Case History  A 29-year-old HIV-infected woman has done very well on a regimen of Stavudine (Zerit) + Lamivudine (Epivir) + Ritonavir (Norvir) + Amprenavir (Agenerase), but presents with 3 weeks of severe fatigue. A chemistry panel shows a decreased HCO3- level. They are breathing deeper and faster than usual. a) What could be going on? b) What further lab tests would be appropriate to order? c) How would you manage this?

DHS/HIV/ARV RX/PP Hyperlactatemia & Lactic Acidosis Symptoms  Nausea/vomiting  Abdominal pain  Malaise/fatigue  Anorexia  Hyperventilation/dyspnea

DHS/HIV/ARV RX/PP Hyperlactatemia & Lactic Acidosis Pathogenesis NRTI inhibits mitochondrial DNA polymerase-gamma Blocks oxidative phosphorylation Shifts to anaerobic metabolism via Kreb’s cycle Increased serum lactate levels

DHS/HIV/ARV RX/PP Hyperlactatemia & Lactic Acidosis Proposed Definitions  Mild Hyperlactatemia - Lactate level > 2 and < 5 mmol/L - Estimated 10-20% frequency  Serious Hyperlactatemia - Lactate level > 5 mmol/L - Estimated 1-2% frequency  Lactic Acidosis - Lactate level > 5 mmol/L + HCO3 - < 20 mmol/L - Estimated < 1% frequency From: Brinkman K. Clin Infect Dis 2000;31:167-9.

DHS/HIV/ARV RX/PP Hyperlactatemia & Lactic Acidosis Measuring Serum Lactate Levels  Have person rest for 5-10 minutes  Draw without tourniquet (if possible)  Avoid fist clinching  Place on ice and promptly send to lab  If increased, repeat with no EtOH x 24h

DHS/ HIV/PP HIV: Case History  A 248-year-old HIV-infected man has done very well on a regimen of Zidovudine + Lamivuine (Combivir) + Ritonavir (Norvir) + Saquinavir (Fortivase), but develops an increased cholesterol (ranging ). The increased cholesterol has not responded to diet therapy. a) What would you recommend? b) What would you have done if triglycerides had also been markedly increased?

Hyperlipidemia and ARV Therapy DHS/ARV Rx/PP Lipid Abnormality Increased LDL Increased LDL and TG Increased TG Statin Statin or Fibrate Fibrate Recommendation From: Dube MP et al. Clin Infect Dis 2000;31:

Lipid Lowering Agents and ARV Therapy DHS/ARV Rx/PP Agent Pravastatin Atorvastatin Lovastatin Simvastatin Gemfibrozil Fenofibrate Niacin No dose adjustment Dose titration Avoid No dose adjustment Avoid Recommendation From: Dube MP et al. Clin Infect Dis 2000;31:

DHS/ HIV/PP HIV: Case History  A 44-year-old man with a baseline CD4 count of 34 and HIV RNA of 106,000 has taken Stavudine (Zerit) + Lamivudine (Epivir) + Indinavir (Crixivan) for approximately 3 years with an excellent response. He now has a CD4 of 301 and an HIV RNA < 50, but has developed significant fat accumulation (abdominal, neck, and breast region) and fat wasting in the face and buttock region. He wants to explore options for improving the fat maldistribution problem. a) Would it likely help to switch the antiretroviral therapy? b) What about Liposuction? Testosterone? Growth hormone? Metformin

DHS/ARV Rx /PP Metformin Therapy in Lipodystrophy Syndrome From: Hadigan C et al. JAMA 2000;284: P = 0.005P = 0.08 N = 26

DHS/HIV/ARV RX/PP Structured Treatment Interruptions

DHS/ HIV/PP HIV: Case History  A 38-year-old man has a CD4 count of 47 and an HIV RNA of 325,000 and has been on a multiple different antiretroviral regimens but does not have long-term tolerance for any regimen. He currently is taking Zidovudine + Lamivuine (Combivir) + Ritonavir/Lopinavir (Kaletra). He comes in asking about treatment interruptions a) How should you respond? b) What are the reasonable goals?

DHS/HIV/ARV RX/PP Antiretroviral Therapy: Treatment Interruptions  Temporary interruption  Structured treatment interruption (STI)  Interruption prior to salvage therapy

DHS/ARV Rx/PP ARV RX: Temporary Interruption 50 Stop Rx Start RxRestart Rx

DHS/ARV Rx/PP ARV RX: Structured Treatment Interruptions 50 Start Rx Stop Rx

DHS/ARV Rx/PP ARV RX: Interruption Prior to Salvage Rx 50 Stop Rx Start RxStart Salvage Rx

From Treatment Interruption Prior to Salvage Rx Wild-type HIV Resistant HIV Failing ARV RxOff Therapy Stop ARV Rx

DHS/Pathogenesis/PP Immune Response to Acute HIV Infection Acute HIV Weak CTL Moderate CTL Strong CTL Rapid Progression Moderate Progression Slow Progression From: Walker BD. Nature 2000;407: months

DHS/ARV Rx/PP STI After Treatment of Acute HIV 500 Restart ARV Rx ACUTE HIV Stop Rx Start ARV Rx Stop Rx Restart ARV Rx From: Rosenberg ES et al. Nature 2000;407: Off Therapy

DHS/HIV/ARV RX/PP Postexposure Prophylaxis

From  A 36-year-old physician sticks herself in the finger with a needle during a procedure on an HIV-infected patient. The source patient’s most recent CD4 count was 195 cells/mm 3 and HIV RNA 45,600; the source patient is on Stavudine (Zerit) + Lamivudine (Epivir) + Nevirapine (Viramune) and is about to go on a new regimen. a) What PEP regimen would you recommend? DHS/Occupational Exposure/PP Case History

DHS/Occupational /PP Risk Factors for HIV Seroconversion in HCWs Risk Factor Adjusted Odds Ratio* Deep Injury 15.0 Visible Blood on Device 6.2 Terminal Illness in Source Patient 5.6 Needle in Source Vein/Artery 4.3 PEP with Zidovudine (AZT) 0.2 From: NEJM 1997;337: *All Risk Factors were significant (P < 0.01)

Post-Exposure Prophylaxis: HIV 28-Day Regimen DHS/Occupational/PP Picture Expanded Regimen # Zidovudine (AZT) +Lamivudine (3TC) + Indinavir or Nelfinavir HIV Exposure Basic Regimen* Zidovudine (AZT) + Lamivudine (3TC) From: CDC. MMWR 1998;47:No. RR-7. # Increased Risk of Transmission -Increased blood volume or -Higher virus titer *Recognized Risk of Transmission

DHS/Occupational/HIV PMPA for SIV PEP in Macaques  Methods - HIV inoculated IV - N = 24 macaques  Regimens - Control vs. PMPA regimens - PEP 24, 48, or 72 h - PEP Rx for 3, 10, or 28d Study DesignResults for PEP 24h From: J Virol 1998;72:

DHS/Occupational HIV /PP Tolerability of HIV PEP in HCWs From: Parkin JM. Lancet 2000;355:722-3.

DHS/Occupational HIV /PP Tolerability of HIV PEP in HCWs From: Wang SA. Infect Control Hosp Epidemiol 2000;231:780-5.

DHS/HIV/AIDS /PP HIV Postexposure Prophylaxis Serious Adverse Events Associated with Nevirapine From: CDC. MMWR 2001;49 (51); N = 22 Serious Adverse Events - Hepatotoxicity = 12 (2 with liver failure) - Skin Reaction = 14

DHS/Occupational /PP Occupational HIV Exposure: PEP Follow-Up  HIV Antibody Testing: Baseline, 6w, 12w, 6m, ?12m  Routine use of HIV RNA: not recommended  Drug Toxicity Monitoring: baseline and at 2 weeks From: CDC. MMWR 1998;47:No. RR-7.

DHS/Occupational /PP HIV: PEP Resources  PEPline (National Clinicians' Post-Exposure Prophylaxis Hotline):   CDC (seroconversion):

From  A 29-year-old HIV-negative woman comes into the clinic for potential HIV postexposure prophylaxis. The prior evening a condom broke while she was having vaginal sex with her HIV-infected boyfriend. She is not sure what medications her boyfriend is taking. a) What would you recommend? DHS/Occupational Exposure/PP Case History

DHS/HIV/ARV RX/PP Feasibility of Nonoccupational PEP  Background - PEP after sexual or IDU exposures to HIV was evaluated - PEP provided within 72 h - PEP: 4 weeks of ARV Rx + risk-reduction counseling  Findings - N= 401; 94% sexual exposures - Median time from exposure to treatment was 33 h - 97% received dual RTIs & 78% completed 4-week Rx - 6 months after the exposure, none seroconverted - Repeat PEP provided to 12% From: Kahn JO. J Infect Dis 2001;183:

DHS/HIV/ARV RX/PP Discontinuing OI Prophylaxis

DHS/ HIV/PP HIV: Case History  A 31-year-old with with a baseline CD4 count of 4 and HIV RNA of 216,000 has been on antiretroviral therapy for approximately 3 years with an excellent response. Her CD4 count is now 421 and she has consistently had an HIV RNA < 50. She is taking daily TMP-SMX (Bactrim/Septra) and weekly Azithromycin (Zithromax) for opportunistic infection prophylaxis. a) Can she stop her OI prophylaxis?

From: Furrer H, et al. N Engl J Med 2000;340: DHS/ OI /PP Discontinuing Primary PCP Prophylaxis  Patients - N = 262 HIV-infected - CD4 200 > 12 weeks  Intervention - D/C PCP prophylaxis Study DesignFollow-Up: Mean 11 Months

From: El-Sadr WM, et al. N Engl J Med 1999;353: DHS/ ARV Rx /PP Discontinuing MAC Prophylaxis  Patients - N = 520 HIV-infected - CD4 100) - On aggressive ARV therapy  Regimens - Azithromycin: 1200 mg q7d - Placebo Study DesignFollow-Up: Median 12 Months