Mariela Diaz-Linares, Pharm.D.
Spring 1999

Human Immunodeficiency Virus (HIV) and Acquired Immune Deficiency Syndrome (AIDS)

1. Background
2. HIV Life Cycle
3. Modes of Transmission
4. Definitions and Classification of HIV Infection
5. Surrogate Markers
6. Clinical Course of HIV Infection
7. Management of HIV Disease

Goals and Objectives:

By the end of this lecture the student should be able to:

1. Describe the course of HIV infection
2. Identify the various risk factors associated with HIV infection.
3. Discuss the complications of HIV disease.
4. Understand the life-cycle of HIV and the potential target sites for drug activity.
5. Discuss early intervention methods.
6. List laboratory tests used to determine the stage of HIV disease.
7. Identify adverse drug effects and drug interactions for currently approved antiviral agents.
8. Design a rational therapeutic plan based on stage of disease and patient history.

Required Readings:

1. Carpenter CCJ, Fischl MA, Hammer S, et al. Antiretriviral therapy for HIV infection in 1998.Updated recommendations of the International AIDS Society-USA panel. JAMA 1998;280:78-86.
2. DPHS Guidelines for the use of antiretroviral therapy agents in HIV-infected adults and adolescents. MMWR April 24, 1998, vol. 47, NO. RR-5. Updated on December 1, 1998 (updated guidelines available at www.cdcnpin.org )

I. Epidemiology and Trends

The WHO have estimated that there are currently 30.6 million people living with HIV/AIDS of whom 5.8 million were newly infected during 1997, including 590, 000 children. This amounts to 16,000 new infections per day. There are an estimated 860,000 adults and children living with HIV/AIDS in the U.S. and Canada.

A total of 20,398 AIDS cases had been reported in Illinois as of January 1, 1998. Illinois does not require HIV case reporting, and shows 7,328 people living with AIDS in the state.

Historically, the majority of patients with AIDS were men who have sex with men and in particular white males. In recent years the trends have changed with heterosexual contact and injection drug users accounting for the majority of the new cases. In addition, new infection rates among females and ethnic minorities (hispanics and African-Americans) has also increased.

WHO Weekly Epidemiological Record (WER), November 1997:72(48)/CDC NAC Database/MMWR February 28, 1997:46(8).

II. The HIV Life Cycle

• Free virus enters the blood during infection
• Virus envelope glycoprotein (gp120) attaches to CD4 receptors, primarily found on the helper T cells, but also recognized on macrophages, B cells and brain cells
• The virus sheds its envelope and enters the native cell
• The inner core is removed resulting in release of viral RNA
• By way of the retroviral reverse transcriptase viral DNA synthesis is initiated
• The proviral DNA enters the nuclear cytoplasm and is integrated into the native cell's DNA
• Retroviral synthesis is begun, directed by the cell's infected DNA
• New virus cores are assembled
• Envelopes enclose the virus core via budding
• The complete virus is extruded into the bloodstream

III. Modes of Transmission

1. Sexual contact – homosexual (men who have sex with men), bisexual and heterosexual. Appropriate use of latex condom is > 90% protective.
2. Blood or blood product exposure

1. injecting drug users (IDU): via sharing of infected needles
2. Blood transfusions: incidence has been decreased with the implementation of blood product screening.
3. Occupational exposure: inadvertent needle stick or exposure during high-risk procedures. Incidence extremely low.
4. Maternal-infant transmission: may occur in utero, during delivery, or through breast feeding.

IV. Definitions and Classification of HIV Infection

1. HIV infection – seroconversion documented by the presence of HIV-antibodies (ELISA, Western Blot).

1. ELISA – Enzyme-linked Immunosorbent assay – Measures serum anti-HIV-1 antibodies. Secondary to possible false positives, if + results, must be followed by confirmatory test.
2. Western blot – principle method of confirming HIV-1 infection.

2. AIDS – CDC case definition: patients with opportunistic infections (see list below) without evidence of an immunedeficient state or patients who have less than 200 CD4 T-lymphocytes/ml or a CD4 % less than 14%.

AIDS DEFINING ILLNESSES:

Candidiasis of bronchi, trachea, or lungs
Candidiasis, esophageal
Cervical cancer, invasive
Coccidiomycosis, disseminated or extrapulmonary
Cryptococcosis, extrapulmonary
Cryptosporidiosis, chronic intestinal (> 1 month’s duration)
Cytomegalovirus disease (other than liver, spleen, or nodes)
Cytomegalovirus retinitis (with or without loss of vision)
Encephalopathy, HIV-related
Herpes simplex: chronic ulcer(s) (> 1 month duration) or bronchitis, pneumonitis, esophagitis.
Histoplasmosis, disseminated or extrapulmonary
Isosporiasis, chronic intestinal (> 1 month’s duration)
Kaposi’s sarcoma
Lymphoma, immunoblastic (or equivalent term)
Lymphoma, Burkitt’s (or equivalent term)
Lymphoma, primary, of brain
Mycobacterium avium Complex, or M. Kansaii, disseminated or extrapulmonary
Pneumocystis carinii pneumonia
Pneumonia, recurrent-bacterial (> 2 episodes in 12 months)
Progresive multifocal encephalopathy
Salmonella septicemia, recurrent
Toxoplasmosis of brain
Wasting syndrome due to HIV (involuntary weight loss > 10% of baseline + chronic diarrhea [> 2 loose stools/day > 30 days) or chronic weakness and documented enigmatic fever > 30 days)

V. Surrogate Markers

Widely used to determine the stage and progression of disease.

A. CD4 count – indicates degree of immunosupression. Widely used as an indicator for therapeutic interventions including initiation of antiviral therapy and prophylaxis of opportunistic infections. Absolute count widely variable from time to time and can be affected by time of day or the presence of an acute infection. CD4% tend to vary less.

Absolute CD4 count = total WBC X % lymphocyte X CD4 %

C. Viral load – best marker for predicting disease progression. The higher the viral burden of a patient the worst clinical prognosis of the patient. A consensus panel recommends using viral load in all patients to guide initiation of therapy, changes in therapy and development of drug resistance. Two assays commercially available: Amplicor RT-PCR and branch chain DNA assay. Although they provide identical information the results are not interchangeable.

 

 

VI. Clinical Course of HIV Infection

HIV infection is a progressive disease. Typically the patients progress from acute infection to an asymptomatic stage through a progressive lymphadenopathy and finally to full blown AIDS. The time course varies widely from patient to patient, but the average life-expectancy from time of seroconversion is estimated to be 10 years.

A. Stages of HIV Disease

• Viral transmission
• Acute retroviral syndrome
• Seroconversion
• Clinical latent period with or without persistent generalized lymphadenopathy (PGL)
• Early symptomatic HIV infection (AIDS-Related Complex)
• AIDS as defined by the CDC

B. Correlation of HIV Complications with CD4 Cell Count

CD4 cell count	Infectious	Non-infectious
>500/ml	Acute retroviral syndrome	(PGL)
200-500/ml	bacterial pneumonia pulmonary TB thrush candida espophagitis Herpes zoster	Kaposi’s sarcoma cervical cancer ITP
<200/ml	P. carinii pneumonia disseminated/chronic herpes simplex Toxoplasmosis Cryptosporidiosis Disseminated histoplasmosis and Coccidiomycosis Extrapulmonary TB	wasting syndrome peripheral neuropathy CNS lymphoma HIV-assosiated dementia
<50ml	Cytomegalovirus Disseminated M. avium Complex

 VII Management of HIV Disease

A. Early Intervention

1. Early interventions

1. Disease detection: PPD skin test, serologic testing for other diseases (toxoplasmosis, syphilis, hepatitis), pelvic exam and pap smear.
2. Baseline laboratory tests: help determine immune, hematologic, renal and hepatic status – CBC, chemistries, G-6PD level, CD4/%, viral load.
3. Immunizations: symptomatic patients have a suboptimal response to vaccines. Therefore, all vaccines should be given as early in the course of HIV as possible. For the most part, HIV-infected patients should not receive live virus or live bacteria vaccines.

Influenza: annual vaccination is recommended
Pneumococcal: revaccination is recommended every 5 years
Haemophilus B influenza: use controversial.
Hepatitis B: recommended in patients with no evidence of exposure
Tetanus-Difteria: recommended every 10 years
MMR: can be considered (live virus vaccine)

2. Approaches for antiviral therapy

1. Monotherapy: no longer recommended due to poor efficacy and rapid development of resistance.
2. Combination therapy: STANDARD OF CARE (3 vs. 4 agents). Optimal combination varies from patient to patient.
3. Sequential therapy: this approach predispose to rapid emergence of antiviral resistance. Whenever combination therapy is use all agents should be added simultaneously.

3. Potential sites of antiviral activity (see virus life cycle)

1. Penetration, uncoating
2. Reverse transcription – current target of reverse transcriptase agents
3. Integration
4. Transcription and translation
5. Assembly – current target of protease inhibitors
6. Budding and release

4. Potential benefits of antiretroviral therapy

1. Improve survival
2. Slow disease progression
3. Improve quality of life and functional status
4. Reduce incidence and severity of opportunistic infections.

5. Potential problems of antiretroviral therapy

1. resistance
2. toxicities
3. costly
4. drug-drug interactions
5. adherence and life-long treatment

F. Monitoring

1. viral load – obtain 2 baseline measurements at least 2 weeks apart, then at 1 month after start or change of therapy. A change of at least 0.5 log (3 fold) is considered significant. The goal of therapy is to suppress viral load as low as possible (ideally to undetectable levels).
2. CD4 count – obtain 1 baseline reading with viral load, then repeat every 3 months or hand in hand with viral loads.
3. Development of opportunistic infections or other HIV-related complications

G. Indications for initiating therapy

Clinical category	CD4 count and viral load	Recommendation
Symptomatic - AIDS, thrush or Unexplained fever	regardless of value	treat
Asymptomatic	CD4 < 500/ml or Viral load > 10,000-20,000	treatment should be offered.
Asymptomatic	CD4 > 500 and Viral load < 10,000 – 20,000	Many experts would delay therapy and observe; however, some experts would treat.*

 

* Treatment should be considered for all subjects with detectable HIV RNA who request therapy and are committed to lifelong therapy.

If therapy is deferred viral load and CD4 count should be reevaluated every 3-6 months.

 

H. Options for initial therapy;

One choice each from column A and column B. Drugs are listed in random, not priority , order:

Column A	Column B
Indinavir	AZT + DDI
Nelfinavir	d4T + DDI
Ritonavir	AZT + ddC
Saquinavir-SGC	AZT + 3TC
Ritonavir + saquinavir SGC or HGC	d4T + 3TC
Efavirenz

Alternatives: less likely to provide sustained viral supression.

Nevirapine or delavirdine + any combination in column B

Not recommended:
Column B
Saquinavir HGC + any combination in column B
All monotherapies
D4T + AZT (antagonistic combination)
ddC + DDI (overlapping toxicities and lack of clinical data)

I. Antiretroviral agents

1. Reversetranscriptase inhibitors:
   Nucleoside reverse transcriptase inhibitors (NRTI)
   MOA: inhibits the reverse transcriptase enzyme by incorporation into viral DNA and thereby early chain termination occurs.

• Must take two tablets in order to obtain the full benefit from the buffer system needed for absorption. Need to be taken on empty stomach. Buffer system might impair absorption of other medications, thus, recommended to separate from other medications. Total daily dose can be taken once daily.
• Comments: combination product of AZT 300 mg and 3TC 150 mg available (combivir tablets)

2. Non-nucleoside reverse transcriptase inhibitors (NNRTI’s)

MOA: Bind directly to the active site of the reverse transcriptase enzyme, subsequently preventing the conversion of RNA to DNA.

 

Generic name	Nevirapine	Delavirdine	Efavirenz
Brand name	Virammune	Rescriptor	Sustiva
Formulation	200 mg tablets	100 mg tablets	200 mg, 100 mg, 50 mg capsules
Adult Dosing	200 mg qd x14 days then 200 mg bid	400 mg tid (tablets can be mixed with water to produce slurry)	600 mg q hs
Elimination	80 % liver metabolized	>80% liver metabolized	Liver metabolized
Effect on CYP	Induces CYP 3A	Inhibits CYP 3A4 and CYPD26	Induces CYP 3A4 Inhibits CYP 2C9, 2C19
Adverse effects	Rash (30%), SJS reported, increases transaminases	Rash, SJS reported, increases transaminases	Dizziness, insomnia, hallucinations, confusion, rash, SJS reported Contraindicated in pregnancy

 

3.Protease inhibitors

MOA: prevent cleavage of protein precursors that are necessary for HIV infection of new cells.

 

Generic name	Indinavir	Ritonavir	Saquinavir HGC		SaquinavirSGC	Nelfinavir
Brand name	Crixivan	Norvir	Invirase	Fortovase		Viracept
formulations	200 mg, 400 mg capsules	100 mg capsules* , 80 mg/ml solution	200 mg capsules (hard gel)	200 mg capsules (soft gel)		250 mg caplets
Adult dosing	800 mg q 8hr	600 mg bid, requires dose escalation over 2 weeks	600 mg tid	1200 mg tid		750 mg tid or 1250 mg bid
Food requirements	Empty stomach or low fat meal	Administer with Food	High fat meal	High caloric meal		Administer with food
Metabolism	CYP 3A4	CYP 3A3, 2D6	CYP 3A4	CYP 3A4		CYP 3A4
Effect on CYP	Inhibits CYP 3A4	Inhibits CYP 3A4, 2D6, 2C9, 2C19 Induces CYP 1A2, 3A	Inhibits CYP 3A4	Inhibits CYP 3A4		Inhibits CYP 3A4
Storage	Room temperature on original container	Refrigerate capsules, room temperature for oral solution	Room temperature	Refrigerate, capsules stable for up to 1 week at room temperature		Room temperature
Adverse effects	Nephrolithiasis, hyper-bilirubinemia, GI	GI: nausea, vomiting, diarrhea, anorexia, dry mouth, Circumoral paresthesias, hepatitis, increase triglycerides,	GI: nausea, diarrhea Headache Elevated transamisase enzymes	GI: nausea, diarrhea Headache Elevated transamisase enzymes		Diarrhea, abdominal pain, asthenia, Elevated transamisase enzymes

 

*Production of norvir capsules is temporarily discontinued secondary to crystallization problems. Suggestions to improve the taste of the oral solution are available at http:/hivinsite.ucsf.edu/topics/research-advances/2098.3del.html.

New onset diabetes mellitus, or exacerbation of prior diabetes, has been reported in patients using protease inhibitors. The incidence is estimated to be < 5%. Insulin resistance has been found in these patients. In most cases, is not associated with glucose intolerance, or clinical DM. Careful monitoring or adjustment in medications, may be necessary.

Lipid abnormalities have also been reported. The abnormalities include: increased fasting triglyceride concentrations, elevated concentrations of free fatty acids, increased de novo lipogenesis, increased lipolysis and lipid disposal despite hypertriglyceridemia. The optimal management of lipid abnormalities on these patients is still to be determined.

A lipodistrophy disorder or body composition alterations have been reported with all protease inhibitors. Although the description resembles that of Cushing’s disease, serum cortisol levels are typically normal. The following is a list of body composition abnormalities described:

1. increase abdominal girth
2. decreased skinfold thickness in the arms, legs, and face
3. decrease nasolabial and cheek fat pads
4. buffalo hump
5. enlarged supraclavicular fat pads
6. bilateral symmetrical lipomatosis
7. breast enlargement in women

 

To learn more on lipid abnormalities and protease inhibitors go to http://www.healthcg.com/hiv/treatment/lipidupdate/

Double protease inhibitors and NNRTI- protease inhibitors combinations.

Due to complex metabolism of these agents when using them in combinations, dose adjustments are necessary. These combinations are commonly used as salvage regimens and seldom used as initial regimens.

 

	Ritonavir (RTV)	Indinavir (IND)	Nelfinavir (NFV)	Nevirapine (NVP)	Efavirenz (EFV)
Ritonavir		­ IND levels dose: RTV 400mg BID + IND 400 mg BID	­ NFV levels dose: RTV 400mg BID + NFV 500-750 mg BID	No significant interaction. No dose adjustment	No significant interaction. No dose adjustment
Indinavir			­ IND levels no dose recommendations available	¯ IND levels ­ IND dose to 1gm q 8 hr	¯ IND levels ­ IND dose to 1gm q 8 hr
Nelfinavir				No significant interaction. No dose adjustment	No significant interaction. No dose adjustment
Saquinavir (SQV)	­ SQV levels dose: RTV 400mg BID + IND 400 mg BID	Antagonistic in-vitro do not use together	­ SQV levels dose EITHER: NFV 750 mg TID + SQV SGC 800 mg TID or NFV 1250 mg BID + SQV SGC 1gm BID	Decrease SQV levels do not combine	Decrease SQV levels do not combine
Delavirdine (DLV)	No significant interaction. No dose adjustment	­ IND levels ¯ IND dose to 600mg Q 8hr	­ SQV levels, no dose recommendations available	NNRTI’s combinations are not recommended	NNRTI’s combinations are not recommended

Potentially serious drug interactions with protease inhibitors and NNRTI’s
This table reflects the effect of the antiviral on the AUC of the other medication unless otherwise specified.

*protease inhibitors can increase levels of anticonvulsants, anticonvulsants can decrease levels of proteaase inhibitors and NNRTI’s agents in ITALICS coadministration with the antiviral is contraindicated when coadminitatiering rifabutin and indinavir or nelfinavir the dose of rifabutin should be 150 mg daily.

For additional drug-drug interactions information go to: http://www.healthcg.com/hiv/treatment/interactions/

This is an interactive site were you can enter the drug regimen and obtain a drug-drug interactions report.

    4.Miscellaneous agents

Hydroxyurea (HU, hydrea, Droxia)

Interferes with the reduction of ribonucleotides to deoxyribonucleotides. HU works by depleting intracellular dNTP pools, thereby making the virus select nucleoside analogues. At a dose of 500 mg bid has been shown to potentiate the antiviral effect of DDI. In theory it should be eefctive with other NRTI’s. Main side effect is bone marrow supression (leukopenia, anemia, thrombocytopenia). Avoid using in pregnancy and with AZT (overlapping toxicities). It can be poorly tolerated in patients with advanced HIV infection. In addition, might decrease CD4 response of antiviral agents.

 

    5. Investigational agents:

These agents are expected to be FDA approved in the next year. All are available through expanded access programs.
Adefovir dipivoxil 60 mg q day.
nucleotide reverse transcriptase inhibitor with brad spectrum antiviral activity against retroviruses, herepesvirises, and hepadnaviruses (hepatitis B). Can cause Fanconi-like syndrome. Coadministration of L-carnitine is recommended. Amprenavir (Agenerase) 1200 mg BID
Protease inhibitor. Most common side effects include diarrhea, nausea, vomiting, rash and paresthesias.

Previous	Next	Syllabus
The College of Pharmacy		UICPHARM@uic.edu
The University of Illinois at Chicago		Last modified: Dec 30, 1998