1. What Every Internist Should Know About HAART in 2003
Christopher Mathews, M.D.
Director, Owen Clinic
University of California, San Diego

2. Outline Historical milestones in HIV treatment
Current treatment strategies
Drug toxicities
Resistance testing
Drug interactions
Medication Adherence
Immune Recovery Inflammatory Diseases
Resources for staying up to date

3. Milestones of Therapy
Licensure of antiretroviral agents in the United States
Trends in virologic suppression among patients under care
Trends in mortality

4. There are currently 16 different antiretroviral agents licensed in the United States. Of these, 6 are nucleoside reverse transcriptase inhibitors, 3 are non-nucleoside reverse transcriptase inhibitors, 1 a nucleotide reverse transcriptase inhibitor, and 6 are protease inhibitors.

5. Proportion of Patients with Undetectable Viral Load, by Quarter Year
1.00
0.80
0.60
Proportion <=400 copies
0.40
Among patients under care for HIV infection, even in the era of highly active antiretroviral therapy, only about 60% have plasma viral loads less than 400 copies at any given point in time.
0.20
1997Q1
1998Q1
1999Q1
2000Q1
2001Q1
2002Q1
Time in Quarter Years
Proportion<=400 copies,Owen Clinic, n=4438

6. Trends in Survival, Owen Clinic, 1990-1998
Note the steady improvement in survival, even before the introduction of protease inhibitors in Much of the early improvement was due to better prevention and treatment of opportunistic infection, and also to the efficacy of less potent antiretroviral therapies.

8. Antiretroviral Treatment Strategies
Viral targets for antiretroviral therapy
Rationale for and timing of antiretroviral treatment

9. HIV Life Cycle Step 1: Fusion Step 3: Integration Step 5: Packaging
reverse
transcriptase
HIV
Step 5: Packaging
and Budding
Step 2: Transcription
Step 4: Cleavage

10. Prognosis without HAART
Viral load >60, , , ,000 <1000
3-year probability of AIDS in 1604 men enrolled in the Multicenter AIDS Cohort Study (MACS)
from Mellors Ann Int Med 1997

11. Considerations in Initiating Therapy HIV Asymptomatic
Theoretical benefit
No proven long-term clinical benefit for CD4 >200 cells/ml3
Expert opinion advises initiation of therapy for CD4 <350 cells/ml3 at any viral load
Consider the viral load when > 350 cells/ml3 CD4+ T cell
The “downside” of antiretroviral regimens
 QOL
Short- and long-term toxicities
A major dilemma confronting patients and practitioners is that the antiretroviral regimens currently available that have the greatest potency in terms of viral suppression and CD4+ T cell preservation are medically complex, are associated with a number of specific side effects and drug interactions, and pose a substantial challenge for adherence. Thus, decisions regarding treatment of asymptomatic, chronically infected individuals must balance a number of competing factors that influence risk and benefit.

12. Risks and Benefits of Delayed Initiation of Therapy
Benefits of delayed therapy
Avoid negative effects on quality of life (e.g. inconvenience)
Avoid drug-related adverse events
Delay in development of drug resistance
Preserve maximum number of available and future drug options when HIV disease risk is greatest
Risks of delayed therapy
Possible risk of irreversible immune system depletion
Possible greater difficulty in suppressing viral replication
Possible increase risk of HIV transmission

13. Risks and benefits of early initiation of therapy
Benefits of early therapy
Control of viral replication easier to achieve and maintain
Delay or prevention of immune system compromise
Lower risk of resistance with complete viral suppression
Possible decreased risk of HIV transmission
Risks of early therapy
Drug-related reduction in quality of life
Greater cumulative drug-related adverse events
Earlier development of drug resistance, if viral suppression is suboptimal
Limitation of future antiretroviral treatment options

14. Goals of Therapy Maximal and durable suppression of viral load
Restoration and/or preservation of immunologic function
Improvement of quality of life
Reduction of HIV-related morbidity and mortality

15. Tools to Achieve Goals of Therapy
Maximize adherence to the antiretroviral regimen
Rational sequencing of drugs
Preservation of future treatment options
Use of resistance testing in selected clinical settings

16. Considerations in Initiating Therapy HIV Asymptomatic
Willingness of patient to begin and the likelihood of adherence
Degree of immunodeficiency
Plasma HIV RNA
Risk of disease progression
Potential risks and benefits
In this regard, no individual patient should automatically be excluded from consideration for antiretroviral therapy simply because he or she exhibits a behavior or other characteristics judged by some to lend itself to nonadherence. Rather, the likelihood of patient adherence to a complex drug regimen should be discussed and determined by the individual patient and physician before therapy is initiated. To achieve the level of adherence necessary for effective therapy, providers are encouraged to utilize strategies for assessing and assisting adherence that have been developed in the context of chronic treatment for other serious diseases; in this regard, intensive patient education regarding the critical need for adherence should be provided, specific goals of therapy should be established and mutually agreed upon and a long-term treatment plan should be developed with the patient. Intensive follow up should take place to assess adherence to treatment and to continue patient counseling for the prevention of sexual and drug injection-related transmission.

17. Indications for ART in the Chronically HIV-Infected Patient
TREAT ALL
(regardless of viral load)
Symptomatic (AIDS, severe symptoms)
Asymptomatic, CD4+ <200 cells/mm3
Asymptomatic, CD4+ >200/mm3 but <350 cells/ mm3 *
* Treatment should generally be offered, though controversy exists

18. Indications for ART in the Chronically HIV-Infected Patient
TREAT
Asymptomatic,
CD4+ >350/mm3 and
HIV RNA>55,000(RT-PCR or bDNA)*
* Some experts would recommend initiating therapy, recognizing that the 3 year risk of developing AIDS in untreated patients is >30%. In the absence of very high levels of plasma HIV RNA, some would defer therapy and monitor the CD4+ and level of plasma HIV RNA more frequently. Clinical outcomes data after initiating therapy are lacking.

19. Indications for ART in the Chronically HIV-Infected Patient
DEFER TREATMENT
Asymptomatic
CD4+ cells > 350/mm3
HIV RNA <55,000(RT-PCR or bDNA)*
* Many experts would defer therapy and observe, recognizing that the 3 year risk of developing AIDS in untreated patients is <15%.

20. Initial Treatment Strongly Recommended
One Choice Each From Column A and B
Column B
Didanosine+ Lamivudine
Stavudine + Lamivudine
Stavudine + Didanosine
Zidovudine + Lamivudine
Zidovudine + Didanosine
Column A
Efavirenz
Indinavir
Nelfinavir
Ritonavir + Saquinavir (SGC or HGC)*
Ritonavir + Lopinavir**
Ritonavir + Indinavir***
When initiating therapy in the patient naïve to antiretroviral therapy, one should begin with a regimen that is expected to achieve sustained suppression of plasma HIV RNA, a sustained increase in CD4+ T cell count, and a favorable clinical outcome (i.e. delayed progression to AIDS and death). Additional consideration should be given to the regimen's pill burden, dosing frequency, food requirements, convenience, toxicity, and drug interaction profile compared with other regimens. Strongly recommended regimens include either efavirenz, indinavir, nelfinavir, ritonavir + saquinavir, ritonavir + lopinavir, ritonavir + indinavir, or efavirenz in combination with one of several 2 NRTI combinations (Table IX). Clinical outcome data support the use of a PI in combination with 2 NRTIs (25-27) (BI).
* Saquinavir-SGC, soft-gel capsule (Fortovase): Saquinavir-HGC, hard-gel capsule (Invirase)
** Co-formulated as Kaletra
*** Based largely on expert opinion

21. Initial Treatment Alternative Recommendation
One Choice Each From Column A and B
Column A
Abacavir
Amprenavir
Delavirdine
Nelfinavir + Saquinavir-SGC
Nevirapine
Ritonavir
Saquinavir-SGC
Column B
Zidovudine + Zalcitabine
Disappointing results with antiretroviral regimens prescribed in the setting of virologic failure with a previous regimen suggest that the first regimen affords the best opportunity for long-term control of viral replication. Because the genetic barrier to resistance is greatest with PIs, many would consider a PI + 2 NRTIs to be the preferred initial regimen. However, efavirenz + 2 NRTIs appears to be at least as effective as PI + 2 NRTIs in suppressing plasma viremia and increasing CD4+ T cell counts (55), and many would argue that such a regimen is the preferred initial regimen because it may spare the toxicities of PIs for a considerable time (BII). Although no direct comparative trials exist that would allow a ranking of the relative efficacy of the NNRTIs, the demonstrated ability of efavirenz in combination with 2 NRTIs to suppress viral replication and increase CD4+ T cell counts to a similar degree as a PI with 2 NRTIs support a preference for efavirenz over the other available NNRTIs at this time. Abacavir + 2 NRTIs, a triple NRTI regimen, has been used with some success as well (56) (CII). Such a regimen, however, may have short-lived efficacy when the baseline viral load is >100,000 copies/ml Using 2 NRTIs alone does not achieve the goal of suppressing viremia to below detectable levels as consistently as does a regimen in the "strongly recommended" or "alternative" categories and should be used only if more potent treatment is not possible (DI).
Use of antiretroviral agents as monotherapy is contraindicated (DI), except when there are no other options, or in pregnancy to reduce perinatal transmission as noted below. When initiating antiretroviral therapy, all drugs should be started simultaneously at full dose with the following three exceptions: dose escalation regimens are recommended for ritonavir, nevirapine, and in some cases, ritonavir plus saquinavir.
Detailed information comparing the different nucleoside RT inhibitors, non-nucleoside RT inhibitors, the protease inhibitors, and drug interactions between the protease inhibitors and other agents can be found in Tables X-XVI. In addition, because certain investigational new drugs are available to physicians for use in selected patients, Table XVII has been provided for the physician treating patients under investigational protocols. Particular attention should be paid to Tables XII-XV regarding drug interactions between the protease inhibitors and other agents, as these are extensive and often require dose modification or substitution of various drugs. Toxicity assessment is an ongoing process; assessment at least twice during the first month of therapy and every 3 months thereafter is a reasonable management approach.
CONTRAINDICATED
ART monotherapy*
Zidovudine and Stavudine
* exception for prevention of perinatal transmission (see ACOG guidelines)

22. The Advantage of Sequencing Drugs
To extend the overall long-term effectiveness of the available therapy options
Delay the risk of certain side effects uniquely associated with a single class of drugs
Anticipates up to 50% of failure rate and preserves future treatment options
Another tool to maximize the benefits of antiretroviral therapy is the rational sequencing of drugs and the preservation of future treatment options for as long as possible. Another tool to maximize the benefits of antiretroviral therapy is the rational sequencing of drugs and the preservation of future treatment options for as long as possible. Table VII shows the possible advantages and disadvantages of three alternative regimens, including a PI with 2 NRTIs, an NNRTI with 2 NRTIs, or a 3 NRTI regimen. The goal of a class-sparing regimen is to preserve or "spare" one or more than one class of drugs for later use. By sequencing drugs in this fashion, it may be possible to extend the overall long-term effectiveness of the available therapy options. Moreover, this strategy makes it possible to selectively delay the risk of certain side effects uniquely associated with a single class of drugs. The efficacy of PI- containing HAART regimens has been demonstrated to include durable viral load suppression, partial immunologic restoration, and decreased incidence of AIDS and death. Viral load suppression and CD4+ T cell responses that are similar to those observed with PI-containing regimens have been achieved with selected PI-sparing regimens, such as efavirenz + 2 NRTIs or abacavir + 2 NRTIs; however, it is not yet known whether such PI-sparing regimens will provide comparable efficacy with regard to clinical endpoints.

23. (Perrin & Telenti. Science 1998;280:1871-1873)

24. Nucleoside Analogues (NA’s) or NRTI’s

25. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI’s)

26. Protease Inhibitors (PI’s)

27. Dual Protease Inhibitor Combinations
Exploits the enzyme inhibition properties of PI’s, specifically RTV
Lessens pill burden
Theoretical ability to suppress resistant HIV strains by enhancement of PI plasma levels

28. Basic Pharmacology Principles
Cmax
Drug Level
Cmin
IC90
Area of Potential HIV Replication
IC50
Dosing Interval
Time
Dose
Dose

29. Indinavir/Ritonavir Pharmacokinetics
10,000
IDV/RTV q12h:
800/200 High-fat Meal
800/100 High-fat Meal
400/400 High-fat Meal
IDV q8h:
800 mg Fasted
Indinavir Plasma Concentration (nM)
1,000
100 2 4 6 8 10 12
Time Postdose (hours)
6th Conference on Retroviruses and Opportunistic Infections; Abstract 362.

30. Selected Antiretroviral Agent Toxicities
Nucleoside analogs
Mitochondrial toxicity
Abacavir hypersensitivity
Non-nucleoside RT inhibitors
Nevirapine hepatotoxicity
Protease inhibitors
Lipodystrophy
Metabolic abnormalities
Indinavir nephropathy

31. Mitochondrial Toxicity Syndromes
Hyperlactatemia or lactic acidosis
Hepatic steatosis
Non-specific GI symptoms (bloating, nausea)
Mild transaminase elevation
Due to nucleoside analog HIV reverse transcriptase inhibitor therapy (D4T most commonly)
May have normal anion gap despite elevated lactate.

32. Abacavir hypersensitity
Occurs in up to 5% of patients
Most common symptoms:
Fever, rash, nausea, malaise/fatigue, GI symptoms
Respiratory symptoms may occur
Onset usually first two weeks of therapy
Symptoms worsen with each dose
Can be fatal if continued or restarted
NEVER re-challenge
Patient counseling and follow-up mandatory
HLA association

33. Nevirapine Hepatotoxicity
September 2000 two instances of life-threatening HEPATOTOXICITY in health-care workers taking NVP for PEP reported to CDC
One of the two HCW’s required a liver transplantation for fulminant hepatic failure
Serious adverse effects associated with NVP-containing PEP regimens reported in 22 cases (16 occupational expsures)

34. Protease Inhibitors Toxicities
Hepatotoxicities
especially with HCV coinfection
Lipodystrophy
Lipid abnormalities (T total chol, triglycerides,  HDL)
Hyperglycemia, insulin resistance

35. HAART Toxicities: Lipodystrophy
Body habitus changes
Central fat accumulation
Peripheral fat wasting
Mixed pattern
Risk factors
female gender (maybe get it worse)
older age
HAART
Protease Inhibitor use

36. Dorsocervical fat pad (“buffalo hump’) in HAART-treated patient

37. Dorsocervical fat pad and gynecomastia in patient on HAART

38. Peripheral Lipoatrophy

39. Facial Lipoatrophy

40. HIV/HAART Toxicities: Lipid Abnormalities
Hypertriglyceridemia; risk of pancreatitis
Low HDL, high LDL
Increased CAD not yet documented
Generally treated w/ fibrates and/or statins
Inconsistent results from switch studies
Beware of CYP p450 drug interactions, risk of myositis and hepatitis

41. HIV/HAART Toxicities: Insulin Resistance
Progression to frank diabetes mellitus possible
Monitor with fasting glucose values
Improvement often seen with switching from PI-based regimens
Some success w/ metformin (Glucophage™), although caution advised if on NRTIs with mitochondrial toxicity potential

42. HIV-1 Drug Resistance Testing: Clinical Applications

43. Technical Considerations
Phenotype Assay
Genotype Assay
Laboratory Requirements
Both tests require highly specialized laboratories
Measurement
Measures ability of patient virus-derived, PCR-amplified RT and protease to replicate in presence of specific drugs
Measures genetic structure of the protease and RT genes
Availability and Cost
2 commercially available assays:
Antivirogram (Virco)
PheonSense (Virologic)
Cost ~$800
Multiple laboratories, kit-based or “home brew”
Less expensive ~$

44. Technical Considerations
Phenotype Assay
Genotype Assay
Turn-around time
Virologic ~ 14 days
Virco ~ 4 weeks
10-14 days
Reproducibility
Highly reproducible
Repeat results vary <2.5 fold from initial value
Highly reproducible, but only with strict adherence to laboratory standards and experienced laboratory personnel
Interlaboratory reproducibility varies from 50% to 99.6%
Minimum RNA level to perform assay
copies/mL
1000 copies/mL
Relationship between genotype and phenotype
Concern how complex mutation patterns relate to phenotype
Rule based vs. database derived genotypic interpretation (“Virtual Phenotype”)

45. Assay Advantages Disadvantages Genotypic Relatives simple to perform
Widely available
More rapid turn-around time
Less expensive
More sensitive for early resistance
Use may improve virologic outcome
Indirect measure of susceptibility
Requires samples with plasma HIV RNA > 1000 copies/mL
Can only identify mutations that have been described and characterized; complex interactions between mutations make interpretation difficult
Insensitive to presence of minor variants
May not correlate with phenotype
False positives from lab contamination carryover

46. Assay Advantages Disadvantages Phenotypic
Direct measure of susceptibility that assess “net” effect of mutations on drug susceptibility
Provides data on cross-resistance
More familiar results, intuitive to understand
More useful when there are multiple mutations in both RT and protease
Use on phenotyping may improve virologic outcome
Insensitive to presence of minor variants
Clinically significant cut-off values incompletely defined
Time-consuming and expensive to perform
Complexity of assays limits availability outside a few laboratories
Slow turn-around time

49. “Take home” messages
Resistance testing is most useful in determining if a reason for current regimen failure is resistance
Implication: Test on a stable regimen for at least 1 month
Susceptibility to an agent the patient previously took but is not currently on does not rule out resistance
Reversion to “wild type”

50. “Take home” messages
Resistance tests evaluate the predominant circulating quasispecies
Detection of minor species varies by drug and by laboratory (ENVA-2 data)
Interpretations of mutational patterns (genotypes) are ruled-based
in vitro susceptibility (phenotype) may vary considerably among samples with same genotype pattern

51. “Take home” messages
Susceptibility “cutoffs” on phenotype reports have not been uniformly validated against clinical response
Sometimes a drug will work even though the report suggests reduced susceptibility (e.g. by increasing Cmin through pharmacologic boosting strategies)

52. “Take home” messages
Situations when a drug might be used even though resistance is highly likely
Continue 3TC to enhance response to tenofovir or adefovir or ZDV
Continue 3TC if patient also has Hepatitis B
Maintain drug selection of resistant but less fit virus

53. Take home messages
Gene charts (rules for interpreting genotype patterns) may not yet reflect evolving knowledge of new mutations, “transitional mutations” and complex mutational interactions

54. “Take home” messages
Resistance is not the only reason for regimen failure
Adherence
Drug interactions
Pharmacologic factors
phosphorylation inhibition/competition
cellular factors (P-glycoprotein)
protein binding
Regimen potency

55. Antivirogram™ Report
All 14 approved NRTIs, NNRTIs & PIs reported (plus adefovir)
Richman, 11/99

56. VircoGEN II

57. Richman, 11/99

58. Drug Interactions and Cytochrome p450 Systems
A 50 year old man was being treated with verapamil and propranolol to control blood pressure in setting of chronic aortic dissection. He was diagnosed with HIV infection and was started on antiretroviral therapy including a protease inhibitor. He was found pulseless in asystole 3 days later. Resuscitation was successful and there were no major sequaelae (luckily).

59. Cytochrome P-450, HIV-1 Protease Inhibitors and NNRTIs

61. Drug Interactions and PK
“Never prescribe a new drug to a patient on antiretroviral therapy without first checking for potential drug interactions”
Be aware of variable pharmakokinetic patterns among antiretroviral agents
e.g. Stopping all drugs at once may result in functional monotherapy for several days with NNRTIs

62. Treatment Adherence

63. Treatment Adherence (Altice & Friedland
Treatment Adherence (Altice & Friedland. Ann Intern Med 1998;129: )
“…compared with therapies for other chronic diseases, which are often forgiving of lapses in adherence, HIV therapy is unforgiving.”
Nonadherence may mean:
Not taking medication at all
Taking reduced amounts
Not taking doses at prescribed frequencies or intervals
Not matching medication to food requirements

64. Factors affecting Adherence (Mehta et al,AIDS, 1997)
Demographics
Psychiatric illness
Substance Abuse
Health beliefs
benefits
risks:side effects
barriers
suspectibility/severity
cues to action
self efficacy
Social support
Motivation
Knowledge
Regimen complexity
Provider interactions
Extrinsic factors
cost
access
Symptoms

67. Average Treatment Completion, by Week after ART Start or Change, Owen Clinic 1998

69. Immune Recovery Inflammatory Diseases

75. Table 1: Clinical Presentation of Specific Opportunistic Infections in HIV-1-infected Patients with and without Highly Active Antiretroviral Therapy
DeSimone et al. Ann Intern Med 2000;133:

76. Good Web Sites for Physician Education about HIV Care
AIDS Education and Training Centers
HIV/AIDS Treatment Information Services
Johns Hopkins AIDS Service
HIV insite
JAMA HIV/AIDS Information Center