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

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

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

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.

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

Trends in Survival, Owen Clinic, 1990-1998 Note the steady improvement in survival, even before the introduction of protease inhibitors in 1996. 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.

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

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

Prognosis without HAART Viral load >60,000 20 - 60,000 6 - 20,000 1 - 5,000 <1000 3-year probability of AIDS in 1604 men enrolled in the Multicenter AIDS Cohort Study (MACS) 1984-1985 from Mellors Ann Int Med 1997

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.

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

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

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

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

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.

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

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.

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%.

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

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)

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.

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

Nucleoside Analogues (NA’s) or NRTI’s

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI’s)

Protease Inhibitors (PI’s)

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

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

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; 1999. Abstract 362.

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

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.

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

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)

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

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

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

Dorsocervical fat pad and gynecomastia in patient on HAART

Peripheral Lipoatrophy

Facial Lipoatrophy

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

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

HIV-1 Drug Resistance Testing: Clinical Applications

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 ~$350-500

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 500-1000 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”)

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

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

“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”

“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

“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)

“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

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

“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

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

VircoGEN II

Richman, 11/99

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).

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

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

Treatment Adherence

Treatment Adherence (Altice & Friedland Treatment Adherence (Altice & Friedland. Ann Intern Med 1998;129:503-505) “…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

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

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

Immune Recovery Inflammatory Diseases

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;133:447-454

Good Web Sites for Physician Education about HIV Care AIDS Education and Training Centers www.aidsetc.org HIV/AIDS Treatment Information Services http://www.aidsinfo.nih.gov/ Johns Hopkins AIDS Service http://www.hopkins-aids.edu HIV insite http://hivinsite.ucsd.edu JAMA HIV/AIDS Information Center http://www.ama-assn.org/special/hiv/hivhome.htm