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/AIDS/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/ARV RX/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?
DHS/ HIV/PP
HIV: Antiretroviral Therapy
HIV
Nucleoside Analogues
RNA
DNA
Nucleus
Host Cell
Non-Nucleosides
FrAdapted from: Walker B. IDSA 1998
Protease Inhibitors
NIH Panel: Antiretroviral Guidelines: 2001
Initial Therapy: Preferred Regimens
CD4 < 350 cells/mm3 or HIV RNA > 30,000 (bDNA) HIV RNA > 55,000 (RT-PCR) or HIV-Related Manifestations
2 Nucleoside Analogues + Efavirenz
2 Nucleoside Analogues + Protease Inhibitor
Picture
2 Nucleoside Analogues + 2 Protease Inhibitors
Source: www.hivatis.org
DHS/ARV Rx/PP
NIH Panel: Antiretroviral Guidelines: 2001
Initial Therapy: Preferred Regimens
Column A
Efavirenz Indinavir
Column B
Stavudine + Didanosine Stavudine + Lamivudine Zidovudine + Didanosine Zidovudine + Lamivudine
Nelfinavir
Ritonavir + Indinavir
Ritonavir + Lopinavir
Ritonavir + Saquinavir
DHS/ARV Rx/PP
NIH Panel: Antiretroviral Guidelines: 2001
Initial Therapy: Alternative Regimens Column A Column B
Abacavir Didanosine + Lamivudine Amprenavir Zidovudine + Zalcitabine Delavirdine Nelfinavir + Saquinavir-SGC Nevirapine Ritonavir Saquinavir-SGC DHS/ARV Rx/PP
Efavirenz: Study 006
Patients (N=450)
48 Week Data: HIV RNA < 50 copies/ml
AZT + 3TC + EFV 100 80
Patients %
- CD4 > 50 cells/mm3 - HIV RNA > 10,000 copies/ml - Naive to PI, non-nucleoside, and 3TC
AZT + 3TC + IDV 90% 79% 75% 64% 43% 47% EFV + IDV
Regimens
- AZT + 3TC + IDV - EFV + IDV - AZT + 3TC + EFV
60 40 20 0 On Treatment
ITT (NC=F)
DHS/ARV Rx /PP
From: Staszewski S. N Engl J Med 1999;341:1865-73.
Abacavir: Study 3005
AZT + 3TC + ABC vs AZT + 3TC + IDV
Study Design 48 Week Data: HIV RNA <50
100
Patients (N = 562)
Patients (%) HIV RNA < 50
AZT/3TC/ABC AZT/3TC/IDV
82% 69%
HIV RNA > 100,000
- Antiretroviral-naive adults - HIV RNA > 10,000 - CD4 > 100 cells/mm3
80
60
Regimens
- AZT + 3TC + Abacavir (ABC) - AZT + 3TC + Indinavir (IDV)
40
40%
46% 31%
45%
20
0
As Rx
ITT
ITT
From: Staszewski S. JAMA 2001;285:1155-63.
DHS/ ARV Rx /PP
Antiretroviral Therapy: Optimal Response
1000000 100000
HIV RNA
Medications Started
10000 1000 100 10 0 1 2 3 4 Months
DHS/ARV Rx/PP
50
50
5
6
7
8
HIV: Case History
A 32-year-old man with an HIV RNA level of 313,000 and a CD4 count of 22 cells/mm3 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?
DHS/ HIV/PP
Resistance Testing: Acute vs. Established HIV
Acute HIV Established HIV
No ARV Rx
From
Wild-type HIV Resistant HIV
Resistance/Failure
DHS/HIV/ARV RX/PP
HIV: Case History
A 26-year-old man with an HIV RNA level of 106,000 and a CD4 count of 121 cells/mm3 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/ HIV/PP
Adherence and Virologic Failure
100
N = 81 Patients on Protease Inhibitor-Based RX
HIV RNA >400 copies/ml
80
82% 67% 55% 71%
60 40 20 0 > 94% 90-94%
22%
80-89% 70-79% < 70%
Level of Adherence
From: Paterson Dl et al. Ann Intern Med 2000;133:21-30.
DHS/ARV Rx /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?
DHS/ HIV/PP
Use of Resistance Testing: Recommendations
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
From: 2001 DHHS/NIH Antiretroviral Therapy Guidelines
Recommendation
Recommend Recommend Consider Not Recommended Not Recommended Not Recommended
DHS/ARV Rx/PP
Antiretroviral Therapy: Viral Failure
100000
Medications Started
10000
HIV RNA
1000
500
100
500
50
10
DHS/ARV Rx/PP
50
Antiretroviral Therapy: Failure to Suppress
100000
Medications Started
10000
HIV RNA
1000
500
100
500
50
10
DHS/ARV Rx/PP
50
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
DHS/HIV/ARV RX/PP
HIV Resistance Testing
Virtual Phenotype
Genotype Access Data
HIV
RT
Protease Genotype & Phenotype Data
Virtual Phenotype
HIV Primary Infection Isolates
N = 108 Patients 10 Newly HIV-Infected Phenotypic Data: 10-fold Resistance
8 1996-1998 1999-2000
Resistant Isolates %
7 6
6
4 2 2
3 2 1
0 NRTI NNRTI PI
From: Little SJ. JAMA 1999;282:1142-9. Little SJ. 8th Conf Retrovirus. Abstract 756
DHS/HIV/Resistance /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 1786. 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 nonnucleoside 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/PP
Antiretroviral Toxicity
DHS/HIV/ARV RX/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/PP
HIV Postexposure Prophylaxis
Serious Adverse Events Associated with Nevirapine
N = 22 Serious Adverse Events - Hepatotoxicity = 12 (2 with liver failure) - Skin Reaction = 14
10 8
Number
7
6
6 5 4
4 2 0 1997 1998
1999
2000
DHS/HIV/AIDS /PP
From: CDC. MMWR 2001;49 (51);1153-6.
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?
DHS/ HIV/PP
Abacavir (Ziagen) Hypersensitivity
Incidence and Timing - Incidence < 3% - Onset typically within 4 weeks
Symptoms - Rash - Fever - Nausea - Throat/mouth lesions - Conjunctivitis/respiratory symptoms
From
DHS/ARV Rx/PP
From: Hetherington S, et al. 12th World AIDS Conference, Geneva, 1998: Abstract 12353
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/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
DHS/HIV/ARV RX/PP
From: Brinkman K. Clin Infect Dis 2000;31:167-9.
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/ARV RX/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 250-275). 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?
DHS/ HIV/PP
Hyperlipidemia and ARV Therapy
Lipid Abnormality Increased LDL Increased LDL and TG Increased TG Recommendation Statin Statin or Fibrate Fibrate
From: Dube MP et al. Clin Infect Dis 2000;31:1216-24.
DHS/ARV Rx/PP
Lipid Lowering Agents and ARV Therapy
Agent
Pravastatin Atorvastatin
Recommendation
No dose adjustment Dose titration
Lovastatin
Simvastatin Gemfibrozil Fenofibrate Niacin
Avoid
Avoid No dose adjustment No dose adjustment Avoid
DHS/ARV Rx/PP
From: Dube MP et al. Clin Infect Dis 2000;31:1216-24.
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/ HIV/PP
Metformin Therapy in Lipodystrophy Syndrome
Insulin Levels
4000
N = 26
2000
Visceral Abdominal Fat
Placebo x 12 weeks
Mean Change in Visceral Abdominal Fat, mm 2
Placebo x 12 weeks Metformin 500 mg bid x 12 weeks
Metformin 500 mg bid x 12 weeks +1191
Insulin AUC (120 min), ulU/mL
2000
1000
P = 0.005
P = 0.08
0
0
-414
-2000
-1000
-1115
-2930
-4000
-2000
From: Hadigan C et al. JAMA 2000;284:472-7.
DHS/ARV Rx /PP
Structured Treatment Interruptions
DHS/HIV/ARV RX/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/PP
Antiretroviral Therapy: Treatment Interruptions
Temporary interruption Structured treatment interruption (STI) Interruption prior to salvage therapy
DHS/HIV/ARV RX/PP
ARV RX: Temporary Interruption
100000
Start Rx Restart Rx
10000
HIV RNA
1000
100
50 50
10
Stop Rx
DHS/ARV Rx/PP
ARV RX: Structured Treatment Interruptions
Start Rx
100000
Start Rx
Start Rx
10000
Start Rx
HIV RNA
1000
100
50 50
10
Stop Rx
DHS/ARV Rx/PP
Stop Rx
Stop Rx
ARV RX: Interruption Prior to Salvage Rx
100000
Start Rx Start Salvage Rx
10000
HIV RNA
1000
Stop Rx
100
50 50
10
DHS/ARV Rx/PP
Treatment Interruption Prior to Salvage Rx
Failing ARV Rx Off Therapy
Stop ARV Rx
From
Wild-type HIV Resistant HIV
Immune Response to Acute HIV Infection
Acute HIV
100 80
HIV RNA
Weak CTL
Rapid Progression
Moderate CTL
60
Moderate Progression
40 20 0 0 1 2
Strong CTL
Slow Progression
6 months
3
4
5Time6
7
8
DHS/Pathogenesis/PP
From: Walker BD. Nature 2000;407:313-4.
STI After Treatment of Acute HIV
1000000 100000
ACUTE HIV Restart ARV Rx Start ARV Rx
Restart ARV Rx
HIV RNA
10000 1000
500 500
100
Off Therapy
10
From: Rosenberg ES et al. Nature 2000;407:523-6. Stop Rx Stop Rx Stop Rx
DHS/ARV Rx/PP
Postexposure Prophylaxis
DHS/HIV/ARV RX/PP
Case History
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/mm3 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
From
Risk Factors for HIV Seroconversion in HCWs
Risk Factor Adjusted Odds Ratio*
15.0 6.2 5.6 4.3 0.2
Deep Injury Visible Blood on Device Terminal Illness in Source Patient Needle in Source Vein/Artery PEP with Zidovudine (AZT)
From: NEJM 1997;337:1485-90.
*All Risk Factors were significant (P < 0.01)
DHS/Occupational /PP
Post-Exposure Prophylaxis: HIV
28-Day Regimen
*Recognized Risk of Transmission
#Increased Risk of Transmission
HIV Exposure
-Increased blood volume or -Higher virus titer
Basic Regimen* Zidovudine (AZT) + Lamivudine (3TC)
Expanded Regimen# Zidovudine (AZT) +Lamivudine (3TC) + Indinavir or Nelfinavir
Picture
From: CDC. MMWR 1998;47:No. RR-7.
DHS/Occupational/PP
PMPA for SIV PEP in Macaques
Study Design Results for PEP Started @ 24h
100 100%
SIV Infected (%)
Methods
- HIV inoculated IV - N = 24 macaques
80 60 40 20 50%
3-Day Rx 10-Day Rx 28-Day Rx
Regimens
- Control vs. PMPA regimens - PEP started @ 24, 48, or 72 h - PEP Rx for 3, 10, or 28d
From: J Virol 1998;72:4265-73.
DHS/Occupational/HIV
0
0%
Tolerability of HIV PEP in HCWs
Side Effects of Indinavir-Containing Regimens
11 11 11 42 74 0 20 40 Percent 60 80 100
Dysuria Headache Flu-Like Illness Fatigue Nausea & Vomiting
From: Parkin JM. Lancet 2000;355:722-3.
DHS/Occupational HIV /PP
Tolerability of HIV PEP in HCWs
Side Effects of PEP Regimens
Myalgias Diarrhea Vomiting Headache Fatigue Nausea 0 20 40 Percent 6 14 16 18 38 57 60 80 100
From: Wang SA. Infect Control Hosp Epidemiol 2000;231:780-5.
DHS/Occupational HIV /PP
HIV Postexposure Prophylaxis
Serious Adverse Events Associated with Nevirapine
N = 22 Serious Adverse Events - Hepatotoxicity = 12 (2 with liver failure) - Skin Reaction = 14
10 8
Number
7
6
6 5 4
4 2 0 1997 1998
1999
2000
DHS/HIV/AIDS /PP
From: CDC. MMWR 2001;49 (51);1153-6.
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): 1-888-448-4911
http://pepline.ucsf.edu/pepline/
CDC (seroconversion): 404-639-6425
DHS/Occupational /PP
Case History
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
From
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 - 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;183:707-14.
DHS/HIV/ARV RX/PP
Findings
Discontinuing OI Prophylaxis
DHS/HIV/ARV RX/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?
DHS/ HIV/PP
Discontinuing Primary PCP Prophylaxis
Study Design Follow-Up: Mean 11 Months
PCP Pneumonia
100 80
Patients (%)
Patients - N = 262 HIV-infected - CD4 < 200 prior to ARV Rx - Potent ARV Rx - CD4 > 200 > 12 weeks Intervention - D/C PCP prophylaxis
60 40 20
0%
0
From: Furrer H, et al. N Engl J Med 2000;340:1301-6.
DHS/ OI /PP
Discontinuing MAC Prophylaxis
Study Design Follow-Up: Median 12 Months
Azithromycin
10
Patients (%)
Patients - N = 520 HIV-infected - CD4 < 50 (increase to >100) - On aggressive ARV therapy Regimens - Azithromycin: 1200 mg q7d - Placebo
Placebo
8
6
4
2
1.2% 0% 0%
1.9%
0
MAC
From: El-Sadr WM, et al. N Engl J Med 1999;353:2195-99.
Bacterial Pneumonia
DHS/ ARV Rx /PP