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Chapter 36: Anti-viral Agents
Viral Structure and Life Cycle
Implication for Chemotherapeutic
Intervention
Virus consists of nuclei acid surrounded by protein and in some cases an outer-membrane.
By contrast with cells, viruses do not have ribosomes or enzyme, but are obligate intracellular parasites relying on the host for replication.
Viral genomic nucleic acid encode for proteins required for nucleic acid replication and packaging: i.e. producing new virus.
Viral genome size extends from one to 200 genes
Single-stranded
Double-stranded DNA genome
Sngle-strand sense (positive-strand)
Single-strand or segmented antisense (negative-strand)
Double-strange segmented RNA genome
Single stranded RNA sense forms can be directly translated to protein
Viral nucleic acid:
Associated with one or more nucleoproteins
Usually enclosed in a capsid (protein shell consisting of repeating capsomers)
Capsids containing nucleic acids are called nucleocapsids.
Capsomer assembly results in multiaxis symmetry (icosahedral: spheres with 2, 3 and 5 symmetrical axes or helical (2 symmetrical axes)
Some viruses are comprised by the neucleocapsids, while others also have viral envelops comprised of both host cell components and viral-encoded glycoproteins
Enveloped viruses have tegument proteins filling the space between the capsid and the envelop.
Enveloped viruses are sensitive to nonionic detergents and solvents, whereas nucleocapsid viruses are more resistant.
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© Linda M. Stannard, 1995, used with permission
Rotaviruses infect the lining of the intestines and cause diarrhea, particularly in children
Classification of Human Pathogenic Virus
Nucleic acid composition
Nucleocapsid size and symmetry
Presence or absence of a viral envelope
Cell Surface: Viral Interaction
Examples: Adsorption: Interaction of virus with cell surface receptors
Poliovirus capsis protein: cell plasma membrane immunoglobulin superfamily protein
Influenze virus envelope hemagglutinin protein: sialic acid
Human immunodeficiency virus (HIV) envelope glycoproteins: CD4 and chemokine receptors
Herpes simplex virus (HSV) envelope glycoproteins: heparan sulfate and to a tumor necrosis factor receptor
Ebstein-Barr virus (EBV) glycoprotein: B lymphocyte complement receptor CD21
Penetration-Fusion
Viral penetration, dependent upon cellular metabolism and changes in cellular cytoskeleton and membrane structure, is accompanied by uncoating.
Fusion results in intermingling of viral envelop lipids and proteins with cellular membrane lipids and proteins
In some cases viral proteins that mediate adsorption are different that those that are required for fusion.
Adsorption often triggers aggregation of membrane receptor target protein to the virus: cell surface interation site.
Target receptor aggregation initiates changes in membrane properties that leads to internalization.
The aggregated receptor-viral complex may be internalized by endocytosis involving clathrin-coated pits.
Mechanism by which many viruses enter the cell: endocytosis
Influenza Virus
Adenoviruses
Herpesviruses
Wang, F and Kieff, E., Medical Virology, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1065-1066.
Gene Expression and Viral Replication
Uncoated, the virus releases its nucleic acids and proteins into the host cytoplasm.
Viral nuclei acid and structural proteins are synthesized with resultant viral nucleic acids and proteins assembled into virions.
Most RNA viruses replicate their genome and assemble viral constitents in the host cytoplasm.
Most DNA viruses replicate their nucleic acid and make nucleocapsid complexes in the host nucleus.
Positive Strand (sense strand) RNA Viruses
Released into host cytoplasm without accompanying enzymes.
Viral genomic RNA is translated by host cell ribosomes forming a polyprotein that consists of most or all viral proteins.
Polyprotein protease components cleave viral RNA polymerase and other viral proteins from the polyprotein.
Antigenomic RNA is first transcribed from the genomic RNA template.
Viral polymerase then makes positive strand (sense strand) genomes and mRNAs from the antigenomic RNA.
Positive strand (sense strand) viral RNA is encapidated in the host cell cytoplasm.
Examples of Positive Strand RNA Viruses
Poliovirus
Coxsackievirus
Echovirus
Enterovirus
Rhinovirus
Rhinoviruses (Picornaviridae): small, non-enveloped single-stranded RNA virus.
Grows preferentially at 33 - 34oC., temperature of human nasal passages, rather than at 37oC, the temperature of the respiratory tract.
One to two day incubation
A major cause of common-cold: rhino viruses are isolated in about 15% to 40% of adults with common-cold symptoms.
Spread by direct contact with infected secretions, usually airborn droplets
Exposure to cold temperatures, fatigue, sleep-deprivation not associated with increased rates of rhinoviral illness.
World-wide distribution; nearly all adults have circulating neutralizing antibodies to multiple serotypes
Symptoms: common cold, i.e. rhinorrhea, sneezing, nasal congestion, sore throat; lasts four to nine days
Not major cause of lower respiratory disease in children, although bronchitis and bronchial pneumonia occurances have been noted.
Rhinoviral infections: exacerbations of asthma and COPD in adults
Treatment: usually not necessary due to mild nature of infection
Effective prophylaxis of rhinovirus infections by interferon intranasal sparay
Vaccination approach under study; difficulty in vaccine efficacy may be related to the large number of serotypes.
Reduction in transmission rates: hand washing and environmental decontamination.
Hepatitis A virus (Dienstag, J.L, Isselbacher, K. J. Acute Viral Hepatitis, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1677-1689.)
nonenveloped RNA virus: (picornavirus family)
virion contains four capsid polypeptics (VP1 to VP4), cleaved posttranslationally from the polyprotein viral genomic product
one month incubation period
Hepatic replication site--virus can be detected in bile, stools, and blood also
Early antibody response: IgM mediated and lasts for several months
In recovery, anti-HAV of the IgG class is dominant and this antibody remains detectable indefinitely.
Neutralizing IgG anti-HAV present in immune globulin is protective against HAV infection.
Agent is transmitted by fecal-oral route almost exclusively.
Children, young adult age preference
Mild in severity, often subclinical; jaundice
Excellent prognosis
Iactivated vaccine for prophylaxis;
No treatment
All most all previously healthy individual will completely recover from HAV
A small number of patients will experience relapsing hepatitis weeks to months after recovery from acute illness
Relapses may include jaundice, fecal excretion of HAV and aminotransferase elevations.
Recent epidemiologic foci of HAV: child-care centers, neonatal ICUs, promiscuous homosexual men and i.v. drug users.
Norwalk agent
Hepatitis E virus
Rubella virus
Eastern equine encephalitis virus
Western equine encephalitis virus
Yellow fever virus
Dengue virus
St. Louis encephalitis virus
Hepatitis C virus
Hepatitis G virus
Negative Strand (Antisense) RNA viruses
Released into cytoplasm accompanied by viral RNA polymerase.
Most such viruses replicate entirely in host cell cytoplasm.
Viral RNA polymerase trascribes mRNAs and antigenomic RNA which serves as the template for genomic RNA replication.
mRNAs code for viral RNA polymerase and related factors and for structural protein
An exception, influenza virus consists of segmented negative strand RNA that is transcribed in the host nucleus.
Examples of Negative Strand RNA Viruses (From Table 182-1: Wang, F and Kieff, E., Medical Virology, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1066.)
Vesicular stomatitis virus
Rabies Virus
Marburg Virus
Ebola virus
Parainfluenza virus
Respiratory syncytial virus (Dolin,, R., DNA and RNA Respiratory Viruses, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1102-1103.)
Croup--lower respiratory disease in young children
Paramyxoviridae family; Pneumonvirus species.
Enveloped virus replication results in neighboring cell fusion into large multinucleated syncytia
Single stranded RNA genome coding for 10 v irus proteins; helical nucleocapsia surrounded by a lipid envelope containing G (attachment) and F (fusion) glycoproteins
Major respiratory pathogen of young children--most important causes of lower respiratory disease in infants Associated with severe bronchiolitis or pneumonia with bronchiolar epithelia necrosis
In children: 25% to 40%: lower respiratory tract involvement; rhinorrhea, fever, cough wheezing: 1 -2 week recovery time for mild disease
Severe illness is characterized by tachypnea and dyspnea and ultimately hypnoxia;
Predisposing factors to severe disease: prematurity, congential heart disease, bronchopulmonary dysplasia, immunosuppression, nephrotic syndrome (37% motality in infants with congenital heart disease)
Treatment: symptomatic relief for upper respiratory tract involvement; for lower respiratory tract infection: respiratory therapy (hydration, suctioning, humidified oxygen, antibronchospastic drugs; with severe hypoxia, intubation and ventialation;
Aerosolized ribavirin is beneficial in infants (improvement of blood-gas abnormalities).
Newcastle disease virus
Rubeola (measles) virus (Gershan, A., Measles (Rubeola) , In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1123-1125.)
Highly contagious, acute respiratory disease; Paramyxoviridae: spherical virion; inner capsid composed of coiled, helical RNA with three proteins.
Relatively rare disease due to an efficacious live, attenuated measles vaccine program in developed nations.
In the U.S. measles mini-epidemics and major epidemics in developing countries result in continued childhood morbidity and mortality
Virus transmitted by respiratory secretions, aerosols; Contagious 1 or 2 days before symptoms and until 4 days after appears of rash.
Prodomal period: 2 - 4 day period of respiratory symptoms--malaise, cough, conjunctivitis, nasal discharge, fever (to 105oF)
Kiplik's spots (1- 2 mm blue-white spots on a bright red background, buccal mucosa, along seond molars--these spots not associated with any other infections)
Erythematous, nonpruritic, maculopapular rash--form hairlin to trunk and limb;
lymphadenophathy, diarrhea, vomiting, splenomegaly: common;
abnormal chest x-ray due to respiratory tract invasion.
Illness lasts about 10 days
Adult disease: more severe, ie.e. higher fever, more prominent rash, more complications
Respiratory, CNS and GI complications:
Respiratory: laryngitis, croup, bronchitis, otitis media (most common icomplication in young children); pneumonia (usually viral, but secondary bacterial infection may occur--streptococci, pneumococci, staphylococci)
CNS: rare; may include encephalitis; in immunocompromised patients, a fatal encephalitis may occur in one to six months.
GI: gastroenteritis, hepatitis, appendicitis.
Treatment
Treatment: mainly supportive:
Otitis media and pneumonia should be treated with antibiotics;
Encephalitis: requires monitioring of ICP
High doses of vitamin A are helpful in severe or potentially severe measles, particularly in children under two years of age
Ribavirin: effective against measles virus in vitro and may be considered in management of immunocompromised patients.
Mumps virus
Hanta Virus
California encephalitis virus
Sandfly fever virus
Lymphocytic choriomeningitis virus
Lassa fever virus
South American hemorrhagic fever virus
Rotavirus
Reovirus
Colorado tick fever virus
Influenza A, B, and C viruses
Most DNA viruses must be translocated to the host cell nucleus in order for viral DNA transcrition by cellular RNA polymerase II.
Viral mRNA synthesis and processing are dependent on host cell systems.
Examples
Herpesvirus nucleocapsids are transported (microtubule-dependent) to host cell nuclear pores where viral DNA with viral tegument protein are introduced into the nucleus.
Viral tegument protein activates transcription of immediate-early genes.
In herpesvirus, immediate-early gene protein product turn on viral early-gene transcription.
Viral DNA synthesis is dependent on early gene encoded protein and early gene products turn on late-gene transcription.
Late-gene transcription is dependent on DNA replication (inhibitors of DNA replication stop late-gene transcription).
Unique mechanisms for DNA replication is associated with each DNA virus family.
Herpesvirus DNA: "rolling-circle" mechanism; Herpesviruses encode their own polymerase and other proteins that increase nucleotide precursor pools.
Adenovirus genomes are both linear in the virion and are replicated into linear (complementary copies) by viral DNA polymerase with an initiator protein complex.
Double-straned circular papovavirus is replicated into circular DNA progeny by cellular DNA enzymes.
Papovaviruses (papillomaviruses) may integrate into host chromosomes;
Development of cervical cancer may be due to overexpresion of viral proteins with excessive cellular growth stimulation.
Poxviruses are unique DNA viruses because they replicate cytoplasmically
Pox virions have encoded transcription factors, RNA polyerase, enzymes for RNA capping and polyadenylation.
More Complex Viral Genomes (Retroviruses and Lentiviruses)
Retroviruses and Lentiviruses: enveloped RNA viruses with
diploid sense-strand genomes
Reverse transcriptase
Integrase enzymes
These viruses reverse-transcribe their genomic RNA into partially duplicated DNA duplex copies then integrate their viral DNA into host cell genomic DNA for viral replication.
Viral mRNAs and genomic RNA are transcribed from a single, integrated proviral promotor.
Examples
Human T cell leukemia virus (HTLV, Type I & II) are retroviruses that caues tropical spastic paraparesis and adult T cell leukemia.
HTLV transcripts included both full-length genomic transcripts and spliced transcripts which regulate transcription and RNA processing.
Human immunodifficiency virus (HIV types I and II) are lentiviruses that are responsible for AIDS and milder immunodeficiency.
HIV have a larger number of spliced viral transcripts (compared to HTLV retrovirus) encoding regulatory proteins Tat, Rev, Nef, Vpr, Vpu, and Vif.
All viral transcripts and proteins are typically expressed in HTLV-or HIV-infected cells.
Both HTLV and HIV are assembled near host cell plasma membrane. Nucleocapsid consists of two copies of a full genomic transcript, cellular tRNA and proteins derived from viral Gag protein.
Nucleocapsid: enveloped at host-cell plasma membrane sites previously modified by viral glycoprotein insertion.
Enveloped virus with incomplete doublestrand circular DNA genome
After host-cell cytoplasmic entry, viral polymerase completes viral DNA genome synthesis.
Hepatitis B genome is expressed in the host-cell nucleus with viral mRNAs transcribed by cellular RNA polymerase II.
Packaging of progeny virus occurs in the cytoplasm-- where viral RNA, associated with viral RNA polymerase with reverse transcriptase activity, is reversed transcribed into partially double-strand DNA (completing the process)
Wang, F and Kieff, E., Medical Virology, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1066-1068.
Viral Assembly and Release from the Host Cell (Wang, F and Kieff, E., Medical Virology, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1068.)
Nucleic acids from RNA viruses and poxviruses form nucleocapsids in the host cell's cytoplasm.
DNA viruses, except poxviruses, assemble their nucleocapsids in host cell nuclei.
Release from the cell is often associated with virus acquiring their envelope by budding through host cell plasma membranes.
Herpes virus acquire its envelope by budding through the nuclear membrane.
Release mechanisms, some quite complex, differs between viruses.
Nonenveloped nucleocapsid viruses are released only when the host cell dies and loses its cellular structural integrity.
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Safrin, S. and Chambers, H. F Antiviral Agents, in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 788-801. |
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Hayden, F.G., Antimicrobial Agents: Antiviral Agents, In Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.1191-1217 |
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Wang, F and Kieff, E., Medical Virology, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1065-1072. |
Clinical Manifestations and Pharmacological Management of HIV
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Opportunistic Viral Infections
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Three general stages of HIV infection:
Acute phase
Prolonged asymptomatic phase
Advanced disease
These stages may be categorized on the basis of indices of immunodeficiency.
stage I: CD4 T cell count > 500/ micro-liter
stage II: CD4 T cell count 200 -- 500/micro-liter
stage III (advanced): CD4 T cell count <200 per micro-liter
Opportunistic infections associate with stage III (neurological deficits and Kaposi's sarcoma not as strictly related to the degree of immunodeficiency.
Disease classification schemes:
CDC: mainly based on clinical condition.
Walter Reed system based on markers of immunological status (CD4 T cell counts and status of cutaneous hypersensitivity reactions)
Three to six weeks after infection, about 50% -- 70%of individuals present with an acute syndrome.
Typical clinical findings associated with plasma viremia and p24 antigenemia:
Symptoms similar to acute infectious mononucleosis.
Duration: one to several weeks, decreasing as the immune response evolves.
General symptoms include: fever, pharyngitis, lymphadenopathy, headache, retroorbital pain, arthralgias, myalgias, lethargy, malaise, anorexia, weight loss, nausea, vomiting, diarrhea.
Neurologic presentations: meningitis, encephalitis, peripheral neuropathy,myelopathy.
Dermatologic presentations: mucocutaneous ulceration, erythematous macropapular rash.
Occasional opportunistic infections noted during this phase due to reduced CD4 T cell number and T cell functional suppression.
During the acute phase, total lymphocytes and subsets (CD4 and CD8) are reduced. Later CD8 levels increase above normal. Ultimately, total circulating CD8 lymphocytes either remain elevated or return to normal; however, CD4 T cells usually remain somewhat below normal.
Lymphadenopathy: 70% frequency.
After the acute phase, CD4 T cell levels usually remain stable for sometime before progressively declining.
About 10% of patients, even in the absence of symptoms, exhibit rapid immunological deterioration.
Duration of clinical latency: approximately 10 years.
Active viral replication usually continues during this time, possibly in memory T cells even with current HAART protocols. Memory T cells may represent a long-term reservoir.
Rate of disease progression directly correlates with HIV RNA levels.
Individuals with higher HIV RNA levels progress to symptomatic disease more rapidly than those with lower levels.
Some patients (long-term nonprogressors) show minimal decline in CD4 T cell levels over time and have very low HIV RNA concentration.
Other patients remain asymptomatic although their CD4 T cell levels have declined to very low levels.
in these individuals opportunistic infection may be the first presenting symptom.
During the asymptomatic phase,the rate of CD4 T cell loss is about fifty cells / micro--liter / year.
CD4 T cell counts below about 200/micro-liter places the patient at risk for both opportunistic infections and neoplasms.
Early presentations may be related to minor opportunistic infections.
Early Presentations include
Thrush
Oral hairy leukoplakia
Shingles
Generalized lymphadenopathy
Rhrombocytopenia
Recurrent herpes complex
Aphthous ulcers
Condyloma acuminata
Molluscum contagiosum
Generalized lymphadenopathy
Defined as the presence of enlarged lymph nodes (> 1 cm)
Present in two or more extrainguinal sites for more than three months with no other apparent cause
Often earliest symptom of HIV infection after primary infection.
Nodes: discrete, freely movable.
May be seen at any stage of immune dysfunction.
Subsequent decrease in lymph node size may suggest disease progression.
Late in the disease, differential diagnosis includes the following:
Lymphoma
Mycobacterial infection
Toxoplasmosis
Systemic fungal infection
Bacillary angiomatosis
Oral Lesions: thrush, oral hairy leukoplakia, aphthous ulcers: common during this phase of HIV infection
Thrush (Candida infection) -- probably due to Epstein-Barr virus -- suggests somewhat advanced immunological deficit, with T cell counts < 300 per microliter. About 60% of patients in one study who exhibited thrush developed AIDS within one year.
Oral hairy leukoplakia: filamentous white lesion (lateral tongue borders); responds to acyclovir (Zovirax) therapy.
Aphthous ulcers of the posterior oropharynx: common, painful, and may interfere with swallowing -- topical anesthetics may be helpful (short duration); thalidomide also helpful -- suggesting cytokine involvement.
Herpes Zoster: seen in about 10% to 20% of HIV patients
Reactivation of Varicella-Zoster Virus (VZV) consistent with slight immune function decline.
may also be seen in early phase
HIV thrombocytopenia may be due to direct action of the virus on megakaryocytes.
For HIV patients with CD4 T cell accounts < 400 per microliter -- thrombocytopenia frequency is about 10%.
Platelet counts typically remain above 50,000 per microliter
Presenting features: gum bleeding, easy bruisability
Bone marrow examination to rule out other causes (drug toxicity, mycobacterial infection, fungal infection, lymphoma)
Therapeutic interventions:
high-dose IV immunoglobulin (IVIG)
glucocorticoids
Most effective treatment: antiretroviral drugs
Even in the absence of thrombocytopenia, zidovudine (Retrovir, AZT, azidothymidine) significantly increases platelet count.
Zidovudine (AZT)
Zidovudine (azidothymidine, AZT):
Activation by phosphorylation to the 5'-triphosphate derivative; phosphorylated by three cellular kinases;
Active drug is a competitive inhibitor of deoxythymidine triphosphate;
Active drug also chain-terminates proviral DNA synthesis.
Activity (in vitro) against: HIV-1, HIV-2, human T cell lymphotrophic viruses;
Weaker activity: hepatitis B virus, Epstein-Barr virus.
Resistance: reverse transcriptase gene mutations;
Resistance more frequent in advanced HIV infection;
Mutations at certain codons associated with 100-fold reduction in viral susceptibility to zidovudine.
Multiple mutations result in additive loss of drug susceptibility.
Oral and IV formulations availablesignificant first pass effect results in a bioavailability of about 65%.
Hepatic disease (cirrhosis) reduces the clearance significantly and requires dosage adjustment.
Renal disease may also require dosage adjustment.
Zidovudine: Clinical Use
Zidovudine inhibits HIV-1 replication and may decrease of the rate of disease progression and may prolong survival.
Effective in treating: HIV encephalopathy; HIV thrombocytopenia;
Effective in prevention of mother to newborn transmission of HIV.
Combination of zidovudine with other agents, including additional reverse transcriptase inhibitor or protease inhibitor appears to enhance antiviral activity while decreasing development of resistance.
ZDV is beneficial for AIDS patients-- associated with prolonged survival and decreasesin frequency and severity of opportunistic infections.
ZDV was also shown beneficial in clinical trials involving patients with less severe disease, including patients with early symptomatic disease or asymptomatic patients with CD4 counts < 500 per ml.
ZDV monotherapy is inferior to its use in combination with other antiretroviral drugs.
Possibly due to the development of resistance, ZDV clinical efficacy diminishes after 12-18 months.
The rationale for ZDV administration in combination with other agents is that such combinations may diminish or modify the emergence of resistant viral strains.
Zidovudine: Adverse reactions
most common: myelosuppression (anemia, neutropenia) -- myelosuppression may be worse is the zidovudine is administered with other drugs that the also cause bone marrow suppression
Transient adverse reactions, resolving with continued use, include GI intolerance, headache, insomnia.
Less frequent side effects: thrombocytopenia, myopathy, acute cholestatic hepatitis:
High-dose zidovudine therapy may cause CNS effects: confusion, anxiety,tremulousness.
Zidovudine: Drug-Drug Interactions
Zidovudine dosage adjustment required if coadministered with drugs that inhibit hepatic glucuronidation (and probenecid, naproxen, phenytoin, beta-lactam antibiotics, phenobarbital, ethinyl estradiol)
Increase zidovudine toxicity may also be caused by concurrent administration of drugs that are hepatically metabolized (acetaminophen, cimetadine, methadone, sulfonamides, benzodiazepines)
Zidovudine administration may decrease levels of the anti-epileptic drug phenytoin -- requiring serum phenytoin level monitoring.
Treatment of choice: combination antiretroviral drugs, including zidovudine (Retrovir, AZT, azidothymidine)
Neurological Manifestations of HIV Infection
CNS manifestation of HIV-infection: significant morbidity in a high percentage of HIV patients.
Primary: direct effect of HIV infection.
Secondary: sequelae of opportunistic infections.
Roxoplasmosis
Cryptococcus
Cytomegalovirus (CMV)
HTLV-1
Mycobacterium tuberculosis
Progressive multifocal leukoencephalopathy
Syphilis
Primary CNS lymphoma
Categories of neurological effects: inflammatory, demyelinating, degenerative
AIDS-defining neurological disorder: AIDS dementia (HIV encephalopathy)
CNS pathology:
Direct effect on glial cells and macrophages
Secondary effects due to neurotoxin release and possibly release of cytokines such as TGF-beta, IL-6, TNF alpha, IL-1 beta.
Based on abnormal CSF findings, most (> 90%) of HIV patients have some CMS involvement.
CNS HIV infection does not necessarily result in clinically-relevant neurologic symptoms.
Not seen in the very late stages of HIV disease
In acute primary infection,symptoms: headache, photophobia, occasionally encephalitis
CNS findings: elevated protein, lymphocytic pleocytosis.
Cranial nerve involvement: usually VII (and occasionally V and/or VIII).
Most likely an immune-mediated disease.
Also called HIV-associated dementia or AIDS dementia complex.
Generally occurs late in HIV infection.
Major feature is decline in cognitive abilities -- symptoms that, at least initially, could suggest situational depression or fatigue
Dementia may be accompanied by some motor and behavioral abnormalities.
Motor dysfunction: unsteady gait, tremor, poor balance; Advanced manifestations include incontinence (bowel and/or bladder).
Behavioral difficulties: apathy, agitation, mild mania, possible progression in some cases to a vegetative state.
HIV encephalopathy: rarely the initial AIDS-defining presentations (3%).
Ultimately significant HIV dementia develops and about 25% of all patients.
Autopsy analysis indicates > 80% of HIV patients have histologic evidence of CNS disease
Basis of HIV encephalopathy: probably due to direct viral effects.
HIV identified in patient's brains
Main CNS viral reservoirs: macrophages, micro-glial cells and multinucleated giant cells.
Primary involvement is in subcortical regions, similar to the involvement profile seen in Parkinson's disease and Huntington's disease, and dissimilar to that seen in Alzheimer's disease.
No specific treatment at present for HIV encephalopathy;some reports have indicated that antiretroviral drugs may be beneficial.
Improvement in neuropsychiatric tests (Mini-Mental Status Examination) associated with either zidovudine (Retrovir, AZT, azidothymidine) or didanosine (Videx, ddI).
Didanosine (ddI)
Synthetic analog of deoxyadenosine
Phosphorylated active derivative competitively inhibits HIV reverse transcriptase and also interferes with viral replication by chain termination.
Mutation responsible for ddI resistance may restore zidovudine susceptibility but may lead to cross-resistance with zalcitabine.
Oral administration. Elimination by glomerular filtration and tubular secretion.
Dosage adjustment may be required with low creatinine clearance.
DDI: effective in slowing HIV disease progression
Major clinical adverse effect:dose-dependent pancreatitis (risk factors for pancreatitis included alcoholism and hypertriglyceridemia)
Coadministration of ddI with fluoroquinones or tetracycline: low antibiotic serum levels due chelation.
Other adverse effects: peripheral neuropathy, hepatic toxicity, hematocytopenias, CNS toxicity (headache, irritability)
DDI: increased uric acid may cause gout.
Patients with HIV encephalopathy: increased sensitivity to adverse effects of antipsychotic drugs -- such patients must be managed carefully, if antipsychotic medication is to be employed for symptomatic treatment.
Myelopathy occurs at about one-fifth of AIDS patients.
Myelopathy may be part of a generalized HIV encephalopathy.
Three main types of spinal cord disease have been reported in HIV patients.
Vacuolar encephalopathy (similar to subacute combined cord degeneration, seen also in pernicious anemia.
Subacute onset
Gait disturbances [ataxia, spasticity]
Dorsal column disease: pure sensory ataxia
Sensory:parathesias, dysethesias of the lower extremities
Most spinal cord syndromes do not respond to antiviral drug therapy, in contrast to improvement in cognitive function seen following antiviral treatment in patients with HIV encephalopathy.
Polyradiculopathy due to cytomegalovirus (CMV), observed late in HIV infection; associated with lower extremity and sacral parathesia, areflexia, ascending sensory loss, urinary retention, difficulty in walking -- condition responds rapidly to treatment with ganciclovir or foscarnet .
Ganciclovir
Requires tri-phosphorylation for activation
Competitively inhibits viral DNA polymerase
In CMV-infected cells: first phosphorylation step catalyzed by viral specific protein kinase
In HSV-infected cells: first phosphorylation step catalyzed by thymidine kinase
Ganciclovir has activity against: HSV, VZV, CMV, and EBV
Activity against CMV much greater than that of acyclovir
Ganciclovir resistance due to either DNA polymerase mutations or protein kinase mutation
IV and oral route of administration
renal clearance varies in a manner proportional to creatinine clearance
IV ganciclovir indicated for CMV retinitis in HIV patients.
Reduces CMV disease associated with organ transplantation
IV ganciclovir indicated for CMV pneumonitis in patients with compromised immune systems. Also used in other CMV-associated disease, including esophagogastrointestinal infection, hepatitis and "wasting" illness
IV ganciclovir may be used to treat CMV colitis and esophagitis
Oral ganciclovir may be used to prevent and/or in CMV disease in AIDS patients and for maintenance therapy of CMV retinitis
Intraocular ganciclovir -- (intraocular implantation or intravitreal administration) may be used to treat CMV retinitis.
Ganciclovir: Adverse Reactions
Most common: myelosuppression, notably neutropenia: bone marrow suppression limits this drug's use in many patients.
Myelosuppression additive in patients receiving both ganciclovir and zidovudine
Oral route administration less likely to produce myelosuppression than IV route
Unusual CNS toxicity may include headache, seizures, altered mental status
Foscarnet
Inhibits viral DNA polymerase, RNA. polymerase, HIV reverse transcriptase. Phosphorylation step not required for drug activation.
In vitro activity against HSV, VZV, HIV, hepatitis B. virus, HHV-6,Epstein-Barr virus, and CMV.
Foscarnet resistance: DNA polymerase gene point mutation, typically following prolonged administration; mutations may also occur in HIV-1 reverse transcriptase
Only available by IV route of administration.
Clearance: primarily renal; dosage adjustment required based on creatinine clearance.
Foscarnet: Clinical Use
CMV retinitis, acyclovir-resistant HSV;
Foscarnet is as effective as ganciclovir in treating CMV retinitis in patients with AIDS; however, patients survived longer, perhaps because of foscarnet's anti-HIV activity.
Foscarnet superior to vidarabine in treatment of acyclovir-resistant human simplex viral infections
Forcarnet: Adverse Reactions
Significant renal side effects: real insufficiency, hypocalcemia, hypercalcemia, hypophosphatemia, hyperphosphatemia, hypomagnesemia (these effects are due to foscarnet's ability to bind divalent ions).
Lack of hematologic abnormalities allows foscarnet use in combination with myelosuppressive agents such as zidovudine.
Slow infusion rates and saline hydration protect against nephrotoxicity and electrolyte imbalances.
Genital ulcerations
CNS toxicities: headache, seizures, hallucinations
Coadministration with pentamidine increases hypocalcemia and renal toxic
Causes of myopathy in HIV:
HIV itself
Aidovudine (AZT)
Generalized wasting syndrome
Severe myopathy is associated with both inflammatory and noninflammatory processes.
Substantial muscle loss has been reported after long-term zidovudine treatment.
This adverse effect of zidovudine may be due to interference with mitocondrial polymerase function
Muscle loss due to zidovudine is reversible upon discontinuation of the drug.
Fauci, A.S. and Lane, H.C., Human Immunodeficiency Virus (HIV) Disease: AIDS and Related Disorders:. In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1818-1852
Opportunistic Infection and Treatment
(Check other materials for more current information)
Opportunistic infections: complication of advanced HIV disease (CD4 T cells less than 200 per microliter.
Major opportunistic infections include:
Pneumocystis carinii
Cytomegalovirus (CMV)
Mycobacterium avium
About 80% of AIDS patients die as a result of an opportunistic infection.
Toxoplasma gondii second most common cause of secondary CNS infections in AIDS patients (about 40 percent of all CNS infections)
Accounts for over 50% of CNS mass lesions.
Responsible for about 3% of first seizures.
Toxoplasmosis present is about 15% of HIV patients.
Usually a late complication of HIV disease.
Most common clinical presentation:
Fever
Headache
Focal neurologic deficits (90% of patients)
Diagnosis usually based on MRI (preferred) or double-dose contrast computed tomography.
Definitive diagnosis: brain biopsy.
Typically biopsy will not be performed (because of perioperative morbidity) unless patient is unresponsive to treatment. Treatment is initiated based on imaging and seropositivity.
Standard treatment: combination therapy with pyrimethamine and sulfadiazine
Response rate: 90% -- Relapse rate within six months-about 50%.
Therapeutic complications with Pyrimethamine (Daraprim) and sulfadiazine combination:
Leukopenia -- main side effect
Dosages of myelosuppressive antiviral agents, such as zidovudine (Retrovir, AZT, azidothymidine) or ganciclovir (DHPG, Cytovene)r, may have to be reduced.
Fever
Rash
Thrombocytopenia
Renal failure, secondary to sulfadiazine crystalluria.
Side effects are common (45% -- 70%).
Alternative therapy:
Clindamycin (Cleocin) and pyrimethamine (Daraprim): almost as effective as pyrimethamine (Daraprim) and sulfadiazine.
Atovaquone (Mepron) and pyrimethamine (Daraprim)
Azithromycin (Zythromax) plus rifabutin (Mycobutin) plus pyrimethamine (Daraprim).
Atovaquone: broad anti-protozoal activity; effective alternative therapy for patients who have been unresponsive or who have significant adverse reactions to standard therapy.
Patients receiving and trimethoprim/sulfamethoxazole or dapsone and pyrimethamine for Pneumocystis carinii prophylaxis, also are decreased risk for toxoplasmosis.
Adverse effects associated with drugs used to treat toxoplasmosis are sufficiently serious to make those drugs (perhaps with the exception of atovaquone) questionable choices for prophylaxis
Diarrhea in HIV:
Causative agents --
Cryptospiridia
Microsporidia
Isospora belli
Cryptospiridium:common cause of diarrhea: in HIV diarrhea may be self-limited or intermittent in early stages of disease, but may be in severe and life-threatening in advanced immunodeficiency.
Approximately 1% risk of cryptosporidosis per year, if CD4 T cell counts < 300/microliter.
Watery stools: up to several liters per day in volume.
Diarrhea accompanied by crampy abdominal pain -- about one-quarter of patients experienced nausea and / or vomiting.
Lactose intolerance and malabsorption may accompanying Cryptospiridium GI infection.
Diagnosis: in -- stool examination.
No effective treatment known:symptomatic management only.
Microsporidia: most common cause -- Enterocytozoon bieneusi
Symptoms similar to Cryptospiridium infection.
Extraintestinal localizations: muscle, liver, eye (by contrast to Cryptospiridium)
Diagnosis: definitive by electron microscopy; organism identifiable by light microscopy.
No effective treatment known:symptomatic management only.
Isospora belli:coccidian parasite -- most commonly a cause of diarrhea in Carribean and African patients.
Identical symptoms to Cryptospiridia.
Effectively treated with trimethoprim-sulfamethoxazole (Bactrim)
Fauci, A.S. and Lane, H.C., Human Immunodeficiency Virus (HIV) Disease: AIDS and Related Disorders:. In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1818-1852
Leading cause of death in HIV patients.
Most common opportunistic bacterial infection (In the United States): Mycobacterium avium complex (MAC)
Many different infections due to Mycobacterium.
Overview
Mycobacterial infections are a therapeutic challenge
Slow growth characteristic results in relative resistance to antibiotic therapy. Antibiotic activity is usually directly depend on the rate of cell division
Myobacterial cell wall is relatively impermeable to drugs.
Many mycobacterial organisms are intracellular (residing in macrophages, for example)
Single drug treatment of mycobacterial infections readily promotes development of resistance
Combination therapy over an extended period of time is required for effective treatment.
Mycobacterial infections include those caused by Mycobacterium tuberculosis, M bovis, atypical myocacterial infections, and M. leprae (leprosy)
Drugs to Treat Mycobacterial Infections
First Line Drugs (Tuberculosis) (in order of preference)
Second Line Drugs
Amikacin
Aminosalicylic Acid
Capreomycin
Ciprofloxacin
Clofazimine
Cycloserine
Ethionamide
Ofloxacin
Rifabutin
Entry: gastrointestinal and respiratory tract.
MAC infection:-- late complication of HIV; CD4 T cell counts < 100 per microliter.
With prophylaxis, CD4 T cell counts at MAC diagnosis: < 10 per microliter.
HIV patients with MAC infection: medium survival of about 6 to 10 months. (Indicative of late stage).
Most common clinical presentations: weight loss, night sweats, fever.
85% of HIV patients with MAC infection are mycobacteremic.
Liver involvement common; abnormal chest radiographs, lymphadenopathy, abdominal pain, diarrhea
Pharmacological treatment of choice: clarithromycin and ethambutol.
A third agent may be added: rifabutin (Mycobutin), rifampin (Rimactane), clofazimine, ciprofloxacin (Cipro), or amikacin (Amikin)
In advanced HIV infection,bacteremia and death is delayed by use of:
Rifabutin (Mycobutin)(see d4T cells < 75 to 100 per microliter)
Clarithromycin (Biaxin) or azithromycin (Zythromax) may provide better or prophylaxis in patients with CD4 T cell counts < 75 per microliter.
A single agent macrolide for prophylaxis may now be preferred to rifabutin.
Non-Mycobacterial Infections in HIV
Non-mycobacterial infections are leading cause of death in HIV.
Clinical presentations: respiratory tract infection, sepsis, gastroenteritis.
Common bacterial infections in HIV:
Streptococcus pneumoniae
Haemophilus influenzae
(six fold increase in pneumococcal pneumonia incidence in HIV patients;100-fold increase in pneumococcal bacteremia) -- accordingly, HIV patients should receive pneumococcal polysaccharide vaccination.
About one-third of HIV patients' bacteremia is due to Staphylococcus aureus.
Other bacterial infections seen in HIV:
Salmonella
Shigella
Campylobacter
Bartonella
Treponoma pallidum (syphilis)
Most common presentation: condyloma lata (secondary syphilis)
Fauci, A.S. and Lane, H.C., Human Immunodeficiency Virus (HIV) Disease: AIDS and Related Disorders:. In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1831-1835.
About 5% of AIDS patients have active tuberculosis.
In HIV patients with a positive purified protein derivative (PPD) skin- test, re-activation rates are about 7 to 10% per year.
Tuberculosis results in a more rapid progression of HIV infection.
HIV viremia is increased during tuberculosis infection.
HIV viremia decreases back to baseline following successful treatment.
By contrast to Mycobacterium avium complex (MAC), which occurs relatively late in the course of HIV disease, tuberculosis is among the earlier signs of HIV infection.
Symptomatology:
Relatively high CD4 T cell counts: fever, call, dyspnea on exertion, positive chest x-ray (cavitary apical disease of the upper lobes)
Relatively low CD4T cell counts: Disseminated disease -- diffuse/lower lobe, bilateral reticulonodular infiltrates, pleural effusions, hilar and/or mediastinal adenopathy. Involvement may extend to:
Brain
bone
Meninges
GI tract
Lymph nodes (especially cervical)
In patients with low CD4T cell counts -- 60% to 80% of patients have pulmonary disease; 30% to 40% and extrapulmonary disease.
Tuberculosis Treatment in HIV Patients
Tuberculosis is curable in HIV patients.
Isoniazid (INH) and rifampin (Rimactane) are first-line drugs
MDR tuberculosis (multidrug resistance) is presently decreasing in incidence.
Pneumocystis carinii Pneumonia
Clinical Features
"The symptoms of P. carinii pneumonia (PCP) include dyspnea, non-productive cough, and fever.
Chest radiography demonstrates bilateral infiltrates.
Extrapulmonary lesions occur in a minority (<3%) of patients, involving most frequently the lymph nodes, spleen, liver and bone marrow.
Typically, in untreated PCP increasing pulmonary involvement leads to death"-CDC
"The specific diagnosis is based on identification of P. carinii in bronchopulmonary secretions obtained as induced sputum or broncho-alveolar lavage (BAL) material.
In situations where these two techniques cannot be used, transbronchial biopsy or open lung biopsy may prove necessary.
Microscopic identification of P.carinii trophozoites and cysts is performed with stains that demonstrate either the nuclei of trophozoites and intracystic stages (such as Giemsa) or the cyst walls (such as the silver stains).
In addition, immunofluorescence microscopy using monoclonal antibodies can identify the organisms with higher sensitivity than conventional microscopy."-CDC
Pneumocystis carinii trophozoites in broncho-alveolar lavage (BAL) material
Pneumocystis carinii cysts:B: 3 cysts in bronchoalveolar material, Giemsa stain
Cysts in lung tissue, silver stain
Pneumocystis carinii cysts in broncho-alveolar lavage material; silver stain
Pneumocystis carinii (P. carinii): common HIV infection -declining incidence.
P. carinii pneumonia (PCP): AIDS-defining illness in about 20% of HIV patients.
About 50% of HIV patients will contract PCP pneumonia at least once.
PCP pneumonia, because of HIV, is now a growing cause of community acquired pneumonia.
Risk of PCP pneumonia increases as CD4 T cell counts decline.
Patients with CD4 T cell accounts less than 200/microliter have a significantly higher likelihood of contracting PCP.
With prophylaxis against Pneumocystis carinii, PCP is now occurring when the median CD4 T cell count is about 36/microliter.
PCP definitive diagnosis requires and demonstration of trophozoite or cyst form of the organism in samples from sputum, bronchoalveolar lavage or opened lung biopsy.
Standard therapy: trimethoprim-sulfamethoxazole (Bactrim) [IV and oral formulation]
High incidence of side effects (about 50 % -- 65%) in HIV patient population.
Rash, fever, leukopenia, thrombocytopenia, and hepatitis
More serious hypersensitivity reactions possible including Stevens-Johnson syndrome
Possibly advisable not to prescribe zidovudine or ganciclovir, because of cumulative myelotoxic effects.
In patients unable to tolerate trimethoprim/sulfamethoxazole, pentamidine isethionate may be used (parenteral administration only)
Slow administration required to avoid cardiovascular adverse effects.
Compared to trimethoprim/sulfamethoxazole, pentamidine is associated with more adverse side effects including:
Nephrotoxicity [dosage reduction necessary]
Pancreatitis [requires discontinuation of pentamidine]
Hyper- or hypo-glycemia. [Probably secondary to pancreatic damage]
Trimethoprim/dapsone (oral)
Clindamycin (Cleocin)/primaquine (oral and parenteral)
Macrolides and clindamycin block movement of peptidyl tRNA from acceptor to donor site.
As a result, the next, incoming tRNA cannot bind to the still occupied acceptor site.
Protein synthesis stops.
Atovaquone (oral only)
Trimetrexate/leucovorin (oral and parenteral)
The combination of trimethoprim/dapsone is comparable in effectiveness to trimethoprim/sulfamethoxazole, with fewer toxicities
Pneumocystis prophylaxis its central in management of HIV-infected patients.
Pneumocystis prophylaxis is indicated when:
Previous PCP infection has occurred
Patient's CD4 T cell level < 200 per microliter
Presence of unexplained fever (> 100o F)
History of oropharyngeal candidiasis.
Preferred medication for prophylaxis: trimethoprim-sulfamethoxazole (Bactrim)
Aerosolized pentamidine (Pentam) was associated with increased jeopardy of recurrence
Aerosolized pentamidine use is associated with increased likelihood of disseminated pneumocystosis.
Combination of dapsone, pyrimethamine, and leucovorin may be the alternative for patients intolerant of trimethoprim (generic) sulfamethoxazole (Gantanol); aerosolized pentamidine (Pentam) remains an option.
Candida infections: the most common fungal infections in HIV patients.
Often occur early in HIV disease.
May signify onset of clinical manifestation of immunodeficiency.
Generally easy to control
Range of infections:
Oral cavity (thrush): white, exudate on posterior oropharynx.
In late stages of HIV infection (see for T cell accounts less than 100 per microliter):
Candida infections: esophagus, lungs, bronchi, trachea -- -- indicative of severe immunodeficiency.
Esophagitis, not responsive to therapy directed at Candida,may be due to an other causes, such as, cytomegalovirus infection, HSV, Kaposi sarcoma, lymphoma
Oral or vaginal Candida: topical nystatin (Mycostatin) or clotrimazole (Mycelex) troches.
In severe cases: systemic therapy-- ketoconazole (Nizoral) or fluconazole (Diflucan)
Fluconazole (Diflucan) may be preferable (ketoconazole (Nizoral)e may be less well absorbed in patients with high gastric pH)
Another option for management of severe cases: IV amphotericin B (Fungizone, Amphotec), then oral fluconazole (Diflucan).
Leading cause of meningitis in HIV patients.
Cryptococcus neoformans, a fungus: -- life threatening infection in 6% to 12% of AIDS patients.
Generally occurs with advanced disease (CD4 T cell counts < 100 per microliter)
Cryptococcus neoformans enters the body through the respiratory tract, but the infection sites are generally the brain and meninges.[CNS infection -- 67% to 85%]
Patients present with subacute meningioencephalitis
Patients, in addition to meningitis, may present with cryptococcoma.
Common symptoms:
Rever (frequency: 100%)
Altered mental status
Headache
Meningeal signs
Pulmonary manifestation: 40% of patients with CNS infection
Common symptoms:
Fever
Cough
Dyspnea
Definitive diagnosis: organism culture from spinal fluid, blood, bone marrow, sputum, or tissue
Cryptococcal Infections: Treatment
Therapy: initiated immediately when antigen or culture tests our positive for cryptococcal infection
Standard therapy in HIV patients:amphotericin B (Fungizone, Amphotec) in combination with flucytosine (Ancobon)..
Due to neutropenia, more than half of patients will not be able to receive the full course of flucytosine (Ancobon) treatment.
Since over 50 percent of HIV patients will suffer a relapse, following amphotericin B (Fungizone, Amphotec) treatment, patients should be maintained on fluconazole (Diflucan) indefinitely.
Fluconazole (Diflucan) is sometimes used as prophylaxis against candidal and cryptococcal infections when CD4 T cell count < 100 per microliter.
Most commonly seen:in regions where Histoplasma capsulatum is endemic. (Mississippi and Ohio River Valley).
For these geographic reasons, there are about 0. 5% of histoplasmosis-AIDS cases in the United States overall.
Generally a late manifestation of HIV (median CD4T cell count for patients with histoplasmosis -- 33 per microliter); occasionally, histoplasmosis is the first presenting clinical indication.
Histoplasma capsulatum:may present initially as a pulmonary infection,disseminated disease is the most common clinical presentation in HIV.
Clinical presentations:
Fever
Weight loss
Lymphadenopathy
Hepatosplenomegaly
Bone marrow involvement (33%):
Thrombocytopenia
Neutropenia
Anemia
Abnormal chest x-ray (50% of patients: diffuse interstitial infiltrate or diffuse small nodules)
Diagnosis: organism culture from blood, bone marrow, or tissue.
Treatment: initially --amphotericin B (Fungizone, Amphotec): maintenance -- amphotericin B (Fungizone, Amphotec) or oral itraconazole (Sporanox).
Opportunistic Viral Infections
Significant problem throughout the course of HIV infection.
Viral infections of special concern:
Cytomegalovirus (CMV)
Herpes simplex virus
Varicella zoster virus
Epstein-Barr virus
In HIV, the clinical problem is the re-activation of latent CMV.
Clinical presentations:
Fenerally late in HIV disease (CD4 T cell count < 50 per microliter)
Retinitis
Perhaps the most devastating manifestation
Progressive, painless loss of vision
Usually bilateral; diagnosis: direct clinical assessment by an experienced ophthalmologist
Retinal appearance:perivascular hemorrhage and exudate.
Necrotic inflammatory process: reversible vision loss
Esophagitis
Presentations: chest pain (substernal); odynophagia (pain on swallowing)
Diagnosis: endoscopy -- usually reveals distal esophageal bolster
Colitis
Frequency:5% to 10% of AIDS patients.
Clinical presentations:
Diarrhea
Abdominal pain
Weight loss
Anorexia
Diagnosis: endoscopy -- usually reveals multiple mucosal ulcerations.
Barium enema may be appear normal; consequently, HIV patients with CMV colitis may suffer abdominal perforation and bacteremia.
Some other CMV manifestations in HIV patients:
Pneumonia
Ascending myelitis
Subacute polyneuropathy
Three major drugs for treatment of systemic CMV infection: Ganciclovir (DHPG, Cytovene), Cidofovir, Foscarnet
Ganciclovir (DHPG, Cytovene) and cidofovir (Vistide): available as ocular implants.
Ganciclovir
Overview
Requires tri-phosphorylation for activation
Competitively inhibits viral DNA polymerase
In CMV-infected cells: first phosphorylation step catalyzed by viral specific protein kinase
In HSV-infected cells: first phosphorylation step catalyzed by thymidine kinase
Ganciclovir has activity against: HSV, VZV, CMV, and EBV
Activity against CMV much greater than that of acyclovir
Ganciclovir resistance due to either DNA polymerase mutations or protein kinase mutation
IV and oral route of administration
renal clearance varies in a manner proportional to creatinine clearance
IV ganciclovir indicated for CMV retinitis in HIV patients.
Reduces CMV disease associated with organ transplantation
IV ganciclovir indicated for CMV pneumonitis in patients with compromised immune systems. Also used in other CMV-associated disease, including esophagogastrointestinal infection, hepatitis and "wasting" illness
IV ganciclovir may be used to treat CMV colitis and esophagitis
Oral ganciclovir may be used to prevent and/or in CMV disease in AIDS patients and for maintenance therapy of CMV retinitis
Intraocular ganciclovir -- (intraocular implantation or intravitreal administration) may be used to treat CMV retinitis
Ganciclovir: Adverse Reactions
Most common: myelosuppression, notably neutropenia: bone marrow suppression limits this drug's use in many patients.
Myelosuppression additive in patients receiving both ganciclovir and zidovudine
Oral route administration less likely to produce myelosuppression than IV route
Unusual CNS toxicity may include headache, seizures, altered mental status
Cidofovir
in vitro activity against HSV-1, HSV-to, VZV, CMV, EBV, adenovirus, human herpes virus strain 6 (HHV-6) and human papilloma virus.
Cidofovir phosphorylation to the active diphosphate form is viral independent.
IV cidofovir: effective in treating CMV retinitis.
Topical 1 % cidofovir may be useful in treating genital warts and for treating mucocutaneous herpes simplex infection.
Cleared by the kidney -- dosage modification required in real failure
Nephrotoxicity: major does limiting side effect for IV route of administration.
Nephrotoxicity may be prevented by administration of oral probenecid (prevents tubular secretion) and adequate saline hydration
Drug resistance: DNA polymerase gene mutation
Foscarnet:
Overview
Inhibits viral DNA polymerase, RNA. polymerase, HIV reverse transcriptase. Phosphorylation step not required for drug activation.
In vitro activity against HSV, VZV, HIV, hepatitis B. virus, HHV-6,Epstein-Barr virus, and CMV.
Foscarnet resistance: DNA polymerase gene point mutation, typically following prolonged administration; mutations may also occur in HIV-1 reverse transcriptase
Only available by IV route of administration.
Clearance: primarily renal; dosage adjustment required based on creatinine clearance.
Foscarnet: Clinical Use
CMV retinitis, acyclovir-resistant HSV;
Foscarnet is as effective as ganciclovir in treating CMV retinitis in patients with AIDS; however, patients survived longer, perhaps because of foscarnet's anti-HIV activity.
foscarnet superior to vidarabine in treatment of acyclovir-resistant human simplex viral infections
Forcarnet: Adverse Reactions
Significant renal side effects: real insufficiency, hypocalcemia, hypercalcemia, hypophosphatemia, hyperphosphatemia, hypomagnesemia (these effects are due to foscarnet's ability to bind divalent ions).
Lack of hematologic abnormalities allows foscarnet use in combination with myelosuppressive agents such as zidovudine.
Slow infusion rates and saline hydration protect against nephrotoxicity and electrolyte imbalances.
Genital ulcerations
CNS toxicities: headache, seizures, hallucinations
Coadministration with pentamidine increases hypocalcemia and renal toxicity
Retinitis: --Classic appearance is yellow exudates sheathing the retinal blood vessels, and areas of focal hemorrhage
Initial response rates: 80% to 90% following ganciclovir or foscarnet. [Ganciclovir-easier to administer for initial therapy]
Ganciclovir (DHPG, Cytovene): high incidence of bone marrow suppression -- may not be given in combination with zidovudine or trimethoprim/sulfamethoxazole.
Foscarnet (Foscavir): high incidence of renal/electrolyte disorders
Maintenance therapy is required following initial response -- note relapse rates are very high.
Oral ganciclovir is licensed for CMV prophylaxis -- oral ganciclovir delays the development of CMV disease
In patients without renal dysfunction, patients treated with foscarnet (Foscavir)exhibited slightly longer survival then those treated with ganciclovir (DHPG, Cytovene). (Perhaps because foscarnet has activity against HIV as well as CMV)
One common protocol involves initial treatment with ganciclovir and maintenance treatment with foscarnet
Ganciclovir (DHPG, Cytovene)-resistant strains would be treated with either cidofovir or foscarnet
Cidofovir (Vistide)-- less potent, however easier to administer
Cidofovir (Vistide) side effects: leukopenia, weakness, nausea, diarrhea, decreased intraocular pressure
Herpes Simplex Virus Infection
Associated with orolabial, genital, perianal lesions.
Frequency and severity of infections increase as CD4 T cell count decreases.
HSV may also cause esophagitis, manifested at multiple small ulcers.
HSV and VZV rarely cause a widespread, bilateral necrotizing retinitis: acute retinal necrosis syndrome.--characterized by kerititis, pain, iritis.
Severe or recurrent HSV: acyclovir (Zovirax)
Acyclovir: Mechanism of Action
Acyclic guanosine derivative: clinical activity --herpes simplex virus -1,-2, Varicella-zoster virus.
In vitro activity against Epstein-Barr virus, cytomegalovirus, human herpes virus-6
requires three phosphorylation steps:
First to the monophosphate (requires viral kinase); Viral kinase requirement provides selectivity for infected cells.
Selected activation results in triphosphate accumulation only in infected cells.
Acyclovir triphosphate accumulates in infected cells and inhibits viral DNA synthesis by: competitive inhibition of dGTP for the viral DNA polymerase and by binding to the DNA template and resulting in chain termination after incorporation into viral DNA
In HSV (Human Simplex Virus) or VZV (Varicella-zoster virus):
Alteration in viral thymidine kinase or viral DNA polymerase
Deficiency in thymidine kinase activity (cross resistance with valacyclovir, famcyclovir, and ganciclovir)
Other antiviral agents that do not depend on viral kinases and which would not the exhibit cross resistance: foscarnet, cidofovir, or trifluridine.
Acyclovir: oral, IV, topical; cleared primarily by glomerular filtration and tubular secretion. Half life varies enormously dependent on renal function. Drug tissue levels are from 50 percent to 100 percent of serum levels
Clinical Uses and Consideration
Most widespread use: treatment of primary infection and recurrence of genital and labial herpes; shortens symptom duration; viral shedding time; time to lesion resolution.
Failure of treatment to reduce the frequency of recurrences suggests that acyclovir does not eliminate latent infection.
IV acyclovir: treatment of choice for herpes simplex encephalitis and neonatal HSV infection
VZV -- less susceptible to acyclovir therapy then HSV
IV acyclovir in immunocompromised patients reduces likelihood of cutaneous and visceral dissemination.
Adverse Reactions: generally few side effects, and occasional nausea, diarrhea, headache; no evidence of terratogenicity; most frequently encountered toxicity -- renal dysfunction; occasional CNS affects (tremors, lethargy).
Alternative: famciclovir (Famvir)
Rapidly converted to penciclovir following oral administration and first-pass effect.
Penciclovir, the active form of the drug, is similar to acyclovir.
Antiviral activity against HSV-1,HSV-2,VZV, EBV, and hepatitis B.
Drug activation requires a viral thymidine kinase.
Inhibition of DNA synthesis results from competitive inhibition of viral DNA polymerase.
Penciclovir triphosphate, the active drug form, achieves a higher intracellular concentration than acyclovir triphosphate. Cross resistance seen between famcyclovir and acyclovir.
Oral administration only. Clearance is by renal mechanisms.
Clinical use: recurrent genital herpes, herpes zoster infection
Adverse reactions: infrequent headache diarrhea and nausea.
Valacyclovir (Valtrex), Although effective for recurrent herpes simplex in HIV, valacyclovir should be avoided because of reported fatal cases of thrombotic thrombocytopenic purpura
Rapidly converted to acyclovir after oral administration
Achieves 3 to 5 times higher serum levels then with acyclovir (similar serum levels to IV acyclovir administration).
Mechanism of action, resistance profile, and pharmacokinetics: identical to that seen with acyclovir.
Used in treatment of patients with recurrent genital herpes or herpes zoster. May be administered with less frequency then acyclovir, a possible benefit.
Generally well tolerated; low incidence of nausea diarrhea and headache.
HIV patients receiving high-dosage valacyclovir (eight grams per day):
GI disturbances
Fatal thrombotic microangiopathies (thrombocytopenic purpura and hemolytic uremic syndrome).
Valacyclovir probably should not be given to immunocompromised patients, including HIV patients.
Herpes strains resistant to acyclovir are increasingly common; these resistant strains are also resistant to ganciclovir -- sensitivity to foscarnet usually remains.
Varicella zoster virus: (chickenpox); latent in dorsal root ganglia after initial infection.
Shingles occur or upon reactivation.
Shingles in a patient under 50 years of age may suggest immunodeficiency, including HIV.
Shingles is an early indication of HIV-induced immunodeficiency.
Clinical presentation:
VZV infection in HIV is usually confined to the skin
Acute retinal necrosis syndrome: rarely seen, associated with trigeminal shingles.
Primary infection (not recurrent) may be fatal -- should be aggressively treated with acyclovir (Zovirax) and hyperimmuune globulin.
If shingles are treated, lesions may resolve more quickly
Treatment options: high-dose oral or IV acyclovir (Zovirax) or oral famciclovir (Famvir); acyclovir (Zovirax)-resistant strains-- foscarnet (Foscavir)
Epstein-Barr virus: a cause of infectious mononucleosis-- a common infection in HIV patients.
May play a role in causing oral hairy leukoplakia (white lesions-- lateral aspect of the tongue and adjacent buccal mucosa --sometimes confused with candidiasis, but lesions cannot be removed by scraping).
May be associated with lymphoma.
Other Herpes Viral Infections in Humans
Human herpesvirus 8 (HHV-8): associated with Kaposi's sarcoma lesions and body cavity lymphoma in HIV patients -- no specific treatment
Human herpesvirus 6:causes exanthem subitum in infants(remittant fever lasting three days, followed by crisis then a few hours later by a rash on the trunk)
JC virus infection: human papovarvirus --causes progressive multifocal leukoencephalopathy (PML); important opportunistic pathogen in AIDS patients.
Demyelinating disease, beginning as subcortical white matter foci; eventually cerebral hemispheres, cerebellum, and brain stem involvement.
Protracted clinical course: multifocal neurological deficits:
Ataxia, hemiparesis, visual field defects, aphasia, sensory defects.
Possible Treatment: intrathecal cytosine arabinoside; no consistently effective treatment presently available (1997)
Human Papilloma virus: common in HIV patients (about two times more common than in general population)
Virus is associated with epidural dysplasia.
Hepatitis viruses:
Nearly all of HIV-infected individuals show evidence of hepatitis B infection.
Co-infection with hepatitis C and/or D is common;
Presence of HIV infection may slightly worsen hepatic disease;
Patients with HIV infection may respond more poorly to IFN-alpha therapy for hepatitis B then non-HIV patients.
Fauci, A.S. and Lane, H.C., Human Immunodeficiency Virus (HIV) Disease: AIDS and Related Disorders:. In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., andBraunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1831-1837.
Significant contributors to morbidity and mortality in HIV.
Kaposi sarcoma
Lymphoma
Intraepithelial dysplasia of the cervix and anus
Multicentric neoplasm: multiple vascular nodules -- skin, mucous membranes, viscera.
Minor to extensive involvement.
A sexually transmitted to factor appears to play a significant role in Kaposi sarcoma development. (HHV 8 maybe this viral cofactor)
Almost exclusively associated with homosexual men. With the decline of HIV infection rates in this population, the rate of appearance of Kaposi sarcoma has also declined.
Can be an early manifestation of HIV infection (normal CD4 T cell counts)
With better management of opportunistic infections, Kaposi's sarcoma is now appearing as a late manifestation of HIV infection
ay result from cytokine dysregulation.
Characteristics of tumor.
Vascular in nature
Dolor: reddish to purple to brown (bruise-like)
Size: few mm -- several cm
Skin
"Kaposi's sarcoma is a malignant neoplasm of the blood vessels.
Grossly, it resembles an angiosarcoma.
However, the actual primary cell of origin is unknown.
It is characterized grossly as a raised purple mass, as seen on the arm of this patient.
Its incidence has increased in the past two decades due to the AIDS epidemic.
Thirty percent of AIDS patients have Kaposi's sarcoma".
Courtesy of The Urbana Atlas of Pathology,University of Illinois College of Medicine at Urbana-Champaign,Legends by Patricia J. O'Morchoe, M.D. Images from material collected by Donald R. Thursh, M.D. and Dr. P. J. O'Morchoe,Concept, design and implementation by Allan H. Levy, M.D., with the assistance of Ms. Jill Conway. Technical assistance by Ms. Dedra Williams and Ms. Tara Ramanathan. (used by permission)
Lymph nodes
Gastrointestinal tract
Lung
Spleen
The large erythematous patches on the surface of this spleen are areas of Kaposi's sarcoma.
Courtesy of The Urbana Atlas of Pathology,University of Illinois College of Medicine at Urbana-Champaign,Legends by Patricia J. O'Morchoe, M.D. Images from material collected by Donald R. Thursh, M.D. and Dr. P. J. O'Morchoe,Concept, design and implementation by Allan H. Levy, M.D., with the assistance of Ms. Jill Conway. Technical assistance by Ms. Dedra Williams and Ms. Tara Ramanathan. (used by permission)
Since less than 10% of AIDS patients with Kaposi sarcoma die of malignancy -- death from opportunistic infection is much more common, treatment that suppresses immune function should be avoided.
Treatment is palliative, not associated with enhanced survival.
Circumstances for Treatment:
Cosmetic problems; significant discomfort --
Localized irradiation (HIV patients are especially sensitive to radiation therapy side effects)
Intralesional vinblastine
Cryotherapy (if possible)
Large number of lesions:
single agent chemotherapy
Etoposide (VP-16,VePe-sid)
Vinblastine (Velban)
Oxorubicin (Adriamycin)
Bleomycin (Blenoxane)
IFN-alpha
The most important predictor of therapeutic response to single agent chemotherapy is CD4 T cell count.
In life-threatening cases, combination therapy is indicated: drug combinations include --
low dose doxorubicin (Adriamycin), bleomycin (Blenoxane), and vinblastine (Velban).
About 6% of HIV patients develop lymphoma (approximately and 120-fold increase over the incidence in the general population)
Late manifestation of HIV-- CD4 T cell count < 200 per microliter
As HIV patients live longer because of improved antiretroviral treatment, better management and prophylaxis of opportunistic infections, lymphomas may appear more frequently.
Three major lymphoma types occur in HIV infected patients:
Grade III or IV immunoblastic lymphoma
Burkitt's lymphoma
Primary CNS lymphoma
Most (90%) are B-cell phenotype; about half contain Epstein-Barr viral DNAImmunoblastic lymphoma
Accounts for about 60% of lymphoma seen in HIV
More common in older patients
Generally high-grade
Burkitt's lymphoma (small noncleaved cell lymphoma)
Accounts for about 20% of lymphoma seen in HIV.
Age-group: 10 to 19 years of age.
Frequency in HIV population: about 1000-fold higher than in the general population.
About 50% of HIV-Burkitt's lymphoma contain Epstein-Barr viral genome (and African Burkitt's lymphoma -- 97% contain Epstein-Barr)
Primary CNS lymphoma
Accounts for about 20 percent of lymphoma in HIV.
Most primary CNS lymphomas are positive for Epstein-Barr.
CNS lymphoma in HIV patients-- associated with advanced disease (CD4 T cell count less than 40 per microliter)
Focal neurological deficits including headaches, seizures, cranial nerve involvement.
Clinical presentations: varied
focal seizures -- rapidly growing mass lesions
At least 80% of HIV lymphoma patients present with:
Extranodal disease (including gastrointestinal sites, 25%) and
Night sweats and than in
Fever
Weight loss
Low response rates and high incidence of opportunistic infections were associated with standard intensive therapeutic approaches -- now largely abandoned
Median survival for patients treated with intensive protocols: 4-6 months. (Note these patients usually have relatively advanced HIV disease with low CD4 T cell counts)
Low-dose protocols are presently being evaluated.
Primary CNS lymphoma:
Often unsuccessful
Palliative approaches:
Radiation
Glucocorticoids
Intraepithelial Dysplasis of the Cervix or Anus
Complication of HIV infection
Human papilloma virus-associated condition -- intraepithelial neoplasia -- invasive cancer.
As HIV patients live longer, and increased incidence of these diseases may be expected.
All HIV patients: periodic pelvic/rectal examination to detect cellular dysplasia.
Fauci, A.S. and Lane, H.C., Human Immunodeficiency Virus (HIV) Disease: AIDS and Related Disorders:. In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., andBraunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1837-1840.
Antiviral Treatment Strategies (Consult more current information)
Withhold antiretroviral treatment until CD4 T cell counts < 500 per microliter. This approach should only be followed if there is good reason to believe that the patient will not be compliant with the multidrug regimen. Current HIV treatment guidelines suggest that treatments which will reduce viral loads should be offered to patients as early as possible {within the above constraint. However, long-term serious side effects associated with current highly active antiretroviral combination therapy has resulted in reevaluation of the optimal treatment approach. The reader should consult the most recent CDC guidelines concerning HIV therapeutic options.
Initiate treatment with:
2 nucleosides plus 1 protease inhibitor
2 nucleosides plus 1 non-nucleoside
2 nucleosides plus ritonavir (Norvir) plus another protease inhibitor
Chosen approach would be retained until disease progression, defined by CD4 T cell counts below 200 per microliter.
New treatment protocol implemented at this time, probably including one or two new nucleosides plus a protease inhibitor.
Most current analysis of clinical trials suggest that more aggressive, early treatment is likely the more beneficial approach.
Immune-based treatment
IFN-alpha
Bone marrow transplantation with lymphocytes transfer
Thymic implantation
Active immunotherapy: e.g. envelope vaccines
Passive immunotherapy: inactivated anti-HIV and antisera, HIV-specific monoclonal antibodies, interleukin2 administration.
Fauci, A.S. and Lane, H.C., Human Immunodeficiency Virus (HIV) Disease: AIDS and Related Disorders:. In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., and Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1845-1854.
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Prophylaxis Against Secondary Infection
Prevention of secondary infection: important in survival in quality of life for HIV patients
Pneumocystis carinii infection: prophylaxis if CD4 T cell count falls below 200 per microliter or CD4 percentage decreases below 15 percent.
PCP prophylaxis: trimethoprim-sulfamethoxazole (Bactrim).(also provides protection against toxoplasmosis and certain bacterial infections)
Alternative PCP prophylaxis: dapsone/p pyrimethamine (Daraprim), clindamycin (Cleocin)/ primaquine
in patients intolerant of the above protocols, aerosolized pentamidine (Pentam)
Mycobacterium avium complex (MAC): extremely common infection; typically seen when CD4 T cell counts < 100 per microliter:
MAC prophylaxis: rifabutin (Mycobutin)
Alternative MAC prophylaxis: clarithromycin (Biaxin), azithromycin (Zythromax)(probably better than rifabutin (Mycobutin))
Fauci, A.S. and Lane, H.C., Human Immunodeficiency Virus (HIV) Disease: AIDS and Related Disorders:. In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., andBraunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1845-1854
Antiviral Therapy for HIV Infected Patients
(MMWR 1998: 47 RR-3: 38-78)
From The Johns Hopkins Report,based on the recommendation of the Department of Health and Human Services/Kaiser Family Foundation as of April 1998] Updated information (http://www.hivatis.org and http://www.cdc.gov); Updated: "Drugs for HIV Infection", The Medical Letter, volume 42 (issue 1069), Jan. 10, 2000--check for more current information in this rapidly changing area:
Antiretroviral Treatment
Indication for Antiviral Treatment
Clinical category: -- Acute HIV or < 6 months after seroconversion
All CD4T cell counts and HIV RNA levels
Recommendation: Treat
Highly active anti-retroviral treatment (HAART) in which three or four agents are combined use the standard of care for managing human immunodeficiency virus infection.
These protocols involving three or four drugs, using combination, can:
Decrease viral replication
Improve immunologic status and
Prolong life
Basis of treatment:
Suppression of initial burst of viral replication, decreasing the magnitude of virus dissemination through the body
Decrease the severity of acute disease
Potentially alter the initial viral"set-point",which may affect the rate of disease progression
Possible reduction in rate of viral mutation due to suppression of viral replication.
Clinical category:-- Symptomatic (thrush, unexplained fever,AIDS)
All CD4 T cell counts and HIV RNA levels
Recommendation: treat
Clinical category: -- Asymptomatic:
CD4 T cell count < 500 per microliter or HIV RNA >10,000 (bDNA) or > 20,000 (RT -- PCR
Recommendation: Treat (consideration given based on prognosis for disease-free survival time and willingness of patient to accept therapy)
Clinical category: -- Asymptomatic:
CD4CD4 T cell counts > 500 per microliter and HIV RNA < 10,000 (bDNA) or less than 20,000 (RT-PCR)
Recommendation: Treat:
Rationale: Reduction of patient viral load, improved immunological status, prolongation of life
Effective therapy requires rigorous compliance in taking medication.
Treatment Protocol (January, 2000)--check CDC for more current information
Drugs of choice for Adult HIV infection:
Protocol I
Two nucleosides + 1 protease inhibitor
Zdovudine (Retrovir, AZT, azidothymidine) plus lamivudine (Epivir, 3TC) Or
Zidovudine (Retrovir, AZT, azidothymidine) plus didanosine (Videx, ddI) Or
Stavudine (Zerit, d4T) plus lamivudine (Epivir, 3TC) Or
Stavudine (Zerit, d4T) plus didanosine (Videx, ddI) Or
Zidovudine (Retrovir, AZT, azidothymidine) plus zalcitabine (Hivid, ddc)
And
Nelfinavir (Viracept) or saquinavir (Fortovase) soft gel capsules, or amprenavir (Agenerase) or ritonavir (Norvir, less commonly used due to adverse effects)
Protocol II
Two nucleosides plus 1 non-nucleoside
Zidovudine (Retrovir, AZT, azidothymidine) plus lamivudine (Epivir, 3TC) Or
Zidovudine (Retrovir, AZT, azidothymidine) plus didanosine (Videx, ddI) Or
Stavudine (Zerit, d4T) plus lamivudine (Epivir, 3TC) Or
Stavudine (Zerit, d4T) plus didanosine (Videx, ddI) Or
Zidovudine (Retrovir, AZT, azidothymidine) plus zalcitabine (Hivid, ddc)
And
Efavirenz (EFV; Sustiva): preferred
Nevirapine (Viramune)-more adverse side effects
Nevirapine (Viramune) & delaviridine (Rescriptor) require more doses
Note: combining efavirenz (EFV; Sustiva) and nevirapine (Viramune) with protease inhibitors require increasing the dosage of the protease inhibitor
Protocol III
Two nucleosides plus ritonavir (Norvir) plus another protease inhibitor
Zidovudine (Retrovir, AZT, azidothymidine) plus lamivudine (Epivir, 3TC) Or
zidovudine (Retrovir, AZT, azidothymidine) plus didanosine (Videx, ddI) Or
Stavudine (Zerit, d4T) plus lamivudine (Epivir, 3TC) Or
Stavudine (Zerit, d4T) plus didanosine (Videx, ddI) Or
Zidovudine (Retrovir, AZT, azidothymidine) plus zalcitabine (Hivid, ddc)
And
Ritonavir (Norvir) (usually given in doses of 100-400 mg bid, when given in combination with another protease inhibitor)
And
Efavirenz (EFV; Sustiva): preferred
Nevirapine (Viramune)-more adverse side effects
Nevirapine (Viramune) & delaviridine (Rescriptor) require more doses
Note: combining efavirenz (EFV; Sustiva) and nevirapine (Viramune) with protease inhibitors require increasing the dosage of the protease inhibitor
"Drugs for HIV Infection", The Medical Letter, volume 42 (issue 1069), Jan. 10, 2000, Published by The Medical Letter, Inc., 1000 Main Street, New Rochelle, New York, 10801; Fauci, A.S. and Lane, H.C., Human Immunodeficiency Virus (HIV) Disease: AIDS and Related Disorders:. In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 1818-1852
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