Mariela Diaz-Linares, Pharm.D.
Spring 1998
Opportunistic Infections in HIV-Infected Patients
Mariela Diaz-Linares, Pharm.D.
Spring 1998
Opportunistic Infections in
HIV-Infected Patients
Goals and Objectives:
By the end of this lecture the student should be able to:
1. Identify AIDS-Defining Illnesses as defined by the Center for Disease Control (CDC).
2. Describe the clinical presentation of Pneumocystis carinii pneumonia, Disseminated Mycobacterium avium Complex, Cryptococcal meningitis and Toxoplasmosis, genital and anorectal herpes, varicella zoster and CMV retinitis.
3. Devise a therapeutic plan for each of the following opportunistic infections: PCP, DMAC, Toxoplasmosis, Candidiasis and Cryptococcus, herpes, V. zoster and CMV retinitis.
4. Recognize adverse effects and drug interactions of agents used for the treatment and prevention of opportunistic infections
Selected readings:
Applied Therapeutics: The Clinical Use of Drugs. Sith Edition, 1995
Chapter 68. Human Immunodeficiency Virus (HIV) Infection. Pages 68-1 - 68-48
Pharmacotherapy: A Pathophysiologic Approach. 3rd Edition, 1996
Chapter 117 Principles and Management of the acquired immunodeficiency syndrome. Pages 2353-2386.
USPHS/IDSA. 1997 USPHS/IDSA Guidelines for the prevention of opportunistic infections in persons infected with Human Immunodeficiency Virus. MMWR 1997;46/No. RR-12.
Serious opportunistic infections occur most often in the late stages of HIV disease. The risk of developing certain opportunistic infections has been closely associated to the CD4 count. The vast majority of deaths in HIV-infected patients are due to an opportunistic infection. The high incidence of occurrence and mortality associated with these infections has lead to recent research regarding the prevention and treatment of these infections in a desperate attempt to improve mortality and improve quality of life. However, the relatively high occurrence of drug toxicities and drug interactions hampers our ability to effectively and safely manage opportunistic infections.
III. MANAGEMENT OF SPECIFIC OPPORTUNISTIC INFECTIONS
A. Pneumocystis carinii
Since the recognition of AIDS, Pneumocystis carinii pneumonia (PCP) has been the most frequent AIDS-defining diagnosis in the United States. However, the relative frequency of PCP is decreasing presumably as a result of prophylaxis and antiviral therapy.
The lung is the most important target organ of Pneumocystis carinii. Although rare, other sites of infection have been reported including skin, liver, kidney, lymph nodes, CNS, spleen and heart.
1. Clinical Manifestations
- fever, cough, weight loss, and malaise
- insidious and prolonged onset (weeks to months)
- Labs: decreased PO2, elevated LDH
- CXR: bilateral interstitial infiltrates (may be normal in early stages)
2. Diagnosis
-direct diagnosis: can only be made by identification of the organism in the sputum
-induced sputum - positive in 60-70%
-bronchoalveolar lavage (BAL) - diagnostic in 95-99% of cases
-transbronchial biopsy - sensitivity approaches 97%
-open lung biopsy - 99% sensitive. This method is reserved as a last resort.
-indirect diagnosis: can be made on the basis of clinical presentation, chest x-ray, and arterial blood gas.
-disease severity can be determined by PO2:
Mild: PO2 > 70mmhg
Moderate/Severe PO2 < 70mmhg
3. Factors Associated with Poor Prognosis
-severe hypoxemia
-prolonged symptoms
-extensive radiographic involvement
-need for mechanical ventilation
4. Treatment All HIV(+) patients with confirmed PCP should be treated. Choice of therapy will depend on severity of disease and ability to tolerate certain medication. The optimal duration of therapy is unclear, but 14-21 days is generally recommended.
FIRST CHOICE
TMP/SMZ is the drug of choice for the treatment of PCP, however, greater than 50% of the HIV-infected population is intolerant to TMP/SMZ.
Dose: 15-20mg/kg/day (based on TMP component) IVPB for moderate to severe disease (PO2 < 70mmhg) or PO for mild disease (PO2 > 70mmhg) divided into 3 to 4 doses.
Adverse reactions occur in over 60% of AIDS patients. They include rash, fever, leukopenia, anemia, thrombocytopenia, nausea, vomiting, elevated serum creatinine, elevated liver function tests. Most side-effects are dose dependent.
ALTERNATIVE CHOICES
These choices have been shown to be effective in the treatment of PCP, but recent data suggests that none is be as effective as TMP/SMZ.
Pentamidine is the second most widely used therapy for moderate- severe PCP.
Dose: 4mg/kg/day given by slow intravenous infusion over 60-90 minutes. Intramuscular injections are possible but are associated with sterile abscesses. There is no oral form.
Adverse reactions also occur frequently in this patient population, in fact, many clinicians avoid this drug due to the high incidence of serious toxicities. Hypotension and thrombophlebitis can occur during infusion. Acute side-effects include nephrotoxicity, hypoglycemia, fever, leukopenia, pancreatitis. The dysglycemias can occur days to weeks after therapy and insulin-dependent diabetes may develop months after therapy.
Clindamycin + Primaquine can be used as an alternative for mild to moderate disease In mild disease both drugs can be given orally and in moderate disease clindamycin should be given intravenously.
Dose:
Clindamycin 450mg every 6 hours PO or 600mg IVPB every 6 hours
Primaquine 15-30mg ( of the base) PO Daily
Adverse reactions include diarrhea, rash and anemia.
Dapsone + Trimethoprim
Dose: Dapsone 100mg PO daily
Trimethoprim 20mg/kg/day in 4 divided doses
Adverse reactions include hemolytic anemia (patients with G6PD deficiency), leukopenia, rash, nausea, and vomiting.
Atovaquone was approved in 1992 for the treatment of mild to moderate PCP only. Initially, the drug was available as a 250mg tablet with extremely poor bioavailability which was improved three fold when administered with high fat meals. Recently, it was made available as a suspension with improved bioavailability no longer requiring coadministration of high fat meals.
Dose: Suspension Form: 750mg/5ml PO BID
Adverse reactions include rash, elevated LFTs, nausea, vomiting, diarrhea and headaches.
Trimetrexate approved for use in patients with severe disease and who are refractory or intolerant to other therapies. It is inferior to TMP/SMZ when used as initial therapy. Its use is limited by severe toxicities and it must be used with leucovorin during and for 3 days after discontinuation of therapy.
Dose: 45mg/M2 IV infusion over 60-90 minutes daily, Leucovorin: 20mg/M2 PO or IV q 6 hours
Adverse reactions include severe bone marrow suppression, renal and hepatic impairment, and oral and GI ulcerations.
ADJUNCTIVE THERAPY
Corticosteroids is standard of care for all patients with an initial room air PO2 < 70 mmhg. Steroids should be added to therapy within 24-72 hours of presentation. Steroids added early in the course may reduce respiratory failure, deterioration of oxygenation and mortality.
Consensus Report Recommends the following regimen:
Days 1-5 Prednisone 40mg PO BID
Days 6-10 Prednisone 40mg PO daily
Days 11-21 Prednisone 20mg PO daily
In patients who can not take PO prednisone, parenteral methylprednisolone may be substituted.
5. Prophylaxis of PCP
Primary Prophylaxis is indicated for patients who have no prior history of PCP but have a CD4 count <200 or CD4 % <20%, or patients with unexplained fever > 2 weeks or oral thrush.
Secondary Prophylaxis is indicated for all patients who have had at least one episode of PCP.
TMP/SMZ: has been shown to be the most effective agent. It also has the added advantage of being inexpensive and having activity against other organisms such as toxoplasmosis and bacteria.
Dose: 1 DS tablet Daily (less frequent and lower doses may also be effective)
Dapsone: not as effective as TMP/SMZ, but has similar advantages including activity against toxoplasmosis and it is inexpensive. Should be considered as the second choice agent for prophylaxis.
Dose: 50-100mg Daily (less frequent dosing has also been studied)
Aerosolized Pentamidine: not as effective as TMP/SMZ, but is as effective as dapsone. Disadvantages include narrow spectrum of activity, high cost, potential for spreading of TB and potential occupational hazard for health care workers. This form of prophylaxis should only be considered in patients who do not tolerate TMP/SMZ or dapsone. Breakthrough apical PCP can occur. A common adverse evnt during administration is bronchospasm.
Dose: 300mg via nebulizer once every month
B. Candidiasis
Oral and esophageal candidiasis occur frequently in patients with HIV disease. Esophageal candidiasis can become very severe causing a great deal of pain and an inability to swallow food, drinks or medication. The role of prophylaxis has yet to be determined. In female patients recurrent vaginal candidiasis is a common ocurrence.
Treatment
Nystatin suspension 100,000 to 1,500,000 units "swish and swallow" every 4-6 hours
-this form of topical treatment has not been found to be very effective in this patient population due to inadequate contact time, poor taste and frequency.
Clotrimazole troche 10mg orally 5X daily
-when used correctly this topical treatment can be effective, particularly in mild cases of thrush. Patients must be instructed to dissolve the troche in their mouth.
Disadvantages include frequency of dosing and taste.
Ketoconazole 200-400mg Daily
-absorption problems in patients with achlorhydria
-drug interactions
Fluconazole 100-200mg orally Daily x 1 week resistance has been reported
For severe cases or cases unresponsive to fluconazole consider:
Itraconazole Suspension 100mg orally BID x 1 week
Amphotericin oral solution : 100mg/ml 1ml(swish as long as possible then swallow) x 2 weeks.
Amphotericin IV used in severe cases of esophagitis
C. Cryptococcus neoformans meningitis
1. Clinical Manifestations
- insidious onset
- mild symptoms include headache, nausea, dizziness,somnolence
- severe symptoms include mental status changes, seizures, coma
- with cranial nerve involvement there may be facial numbness and visual changes
2. Diagnosis
- Lumbar puncture for examination of CSF: decreased glucose, increased protein and WBCs, may be normal in AIDS patients
- India Ink Smear of CSF is + in 80% of patients
- Cultures of CSF or Blood
- Cryptococcal antigen is present in > 90% of cases
3. Treatment
Amphotericin B remains first line of therapy. It has been associated with decreased mortality in the first two weeks of therapy due to an earlier microbiologic response. May be used alone or in combination with 5-flucytosine, however, patients seldom tolerate the 5-FC due to severe bone marrow suppression. Most experts reccommmend combination therapy to start with since this is associated with a faster rate of CSF sterilization. Optimal duration of acute therapy is 8 to 10 weeks total, followed by life-long maintenance therapy.
Dose: 0.4-0.7mg/kg/day or 1.0mg/kg every other day IV +/- 5-FC 25mg-37.5mg/kg four times daily. Therapy should be continued for a minimum of two weeks or until 15 mg/kg and sterile CSF.
Adverse reactions include nephrotoxicity, electrolyte imbalance, anemia, infusion related toxicities and if 5-FC is used severe bone marrow suppression and GI intolerance. 5-FC Bone marrow supression correlates with blood levels, therapeutic drug monitoring is recommended.
Fluconazole may have a role in the treatment of cryptococcal meningitis in AIDS patients who are intolerant or refractory to Amphotericin B. Fluconazole is recommended for the completion of acute treatment after a 2 week course of ampho B (for a total of at least 8 weeks).
Dose: 400mg PO daily for 8 to 10 weeks
Adverse reactions include nausea, vomiting and hepatotoxicity
4. Maintenance Therapy 50% of all cases relapse in 6 months
Fluconazole 200mg daily, doses up to 400 mg daily are sometimes required to prevent relapse.
Amphotericin B 0.6-1mg/kg IV 1-3x/week
Itraconazole 400 mg daily can be an alternative in patients with suspected fluconazole resistance.
D. Mycobacterium avium Complex (MAC)
MAC is the most common mycobacterial infection in AIDS patients. It causes disseminated disease in 25-50% of patients with AIDS. It is primarily seen in patients with very advanced disease (CD4 < 75) and it is associated with a high mortality.
1. Clinical Manifestations
- insidious onset
- non-specific symptoms include fever, night sweats, diarrhea, abdominal pain, nausea, and vomiting
- non-specific signs include, anemia, elevated alk phos, weight loss, lymphadenopathy and hepatosplenomegaly.
2. Diagnosis
- positive blood culture
- identification from tissue biopsy (ie. bone marrow, liver, lymph node)
3. Treatment
Until recently no therapy was thought to be effective, however, recent studies suggest not only the potential of acute therapy to improve survival but that there is the potential to prevent this disease. Any treatment regimen should include at least two drugs and every regimen should include a macrolide as specified below:
Clarithromycin 500mg BID
or
Azithromycin 500mg daily
Plus one or more of the agents listed below
the following two have been shown to be most effective
Ethambutol 15mg/kg daily
Rifabutin 300mg daily
_____________________________________________
Ciprofloxacin 750mg BID
Amikacin 10-15mg/kg IV/IM daily (inconvenient ROA, toxic)
Clofazamine 100-200mg daily, has been demonstrated not to be effective in the treatment of MAC disease and should not be used. Exceptions may include patients with macrolide resistance.
Clarithromycin in a dose of 1000 mg BID is associated with decreased survival. This higher dose should not be used in the treatment on MAC disease.
Therapy should continue for the lifetime of the patient. These agents all have a potential for drug-drug interactions and adverse reactions that students should become familiar with.
4. Prophylaxis
Recently, the CDC revised its recommendations to state prophylaxis is recommended in patients with a CD4 count of < 50/mm3.
Clarithromycin 500mg BID
Azithromycin 1200mg q week
The macrolides are the prefered agents for prophylaxis. Both agents have comparable in efficacy. In addition, they have demonstrated to confer protection against respiratory bacterial infections.
Common side effects include diarrhea, nausea, metalic taste.
In patient who are intolerant to the macrolides Rifabutin 300mg/day can be considered as an alternative agent.
Rifabutin is associated with numerous adverse effects including neutropenia, rash, GI intolerance and discolored urine. It also has similar drug interactions to rifampin. Caution must be used when prescribed with Protease Inhibitors. The use of rifabutin could result in the development of resistance rifampin in persons who have active TB. This condition should be excluded prior to initiate rifabutin prophylaxis.
E. Toxoplasmosis
Reactivation of prior latent infection with Toxoplasma gondii is the most common cause of encephalitis in AIDS patients. If left untreated, the mortality rate approaches 100%. Treatment of acute toxoplasmosis is associated with response rates of 65 to 90%. Unfortunately, greater than 50% of patients treated for this disease experience severe drug toxicities requiring discontinuation of therapy. Primary therapy of toxoplasmosis must be followed by life-long suppressive therapy, since relapse rates without continued therapy nears 100%.
1. Clinical Manifestation
- mild nonspecific: fever, malaise, weakness
- mental status changes, visual changes, seizures, coma, hemiparesis
2. Diagnosis
- CT scan consistent with multiple ring enhancing lesions and mild to moderate edema
- MRI helpful when CT scan doesn't reveal changes
- CSF fluid: no or few WBCs, normal glucose, elevated protein
3. Treatment
First Line Therapy:
Pyrimethamine 100-200mg PO X 1, then 50-75mg PO Daily
Plus
Sulfadiazine 1-2Gm PO every 6 hours
Plus
Leucovorin (folinic acid) 5-10mg PO Daily
Initial response is expected in 2-3 weeks, however, therapy with full doses should be continued for 4 to 6 weeks after resolution of signs and symptoms. This regimen provides prophylaxis against PCP in addition to Toxoplasmosis supression.
Alternative Therapy: (for patients with Sulfa Allergies)
Pyrimethamine (see above)
plus
Clindamycin 600mg PO or IV every 6 hours
doses as high as 1200 mg IV Q 6 hours have been used, the benefit of higher doses is unclear
plus
Leucovorin (see above)
Adverse reactions associated with pyrimethamine include dose-dependent thrombocytopenia, granulocytopenia and megaloblastic anemia. Sulfadiazine has been associated with rash, neutropenia, nephritis and elevated transaminases.
4. Suppressive Therapy
Pyrimethamine 25-50mg daily + Sulfadiazine 1gm every 6 hours + Leucovorin 5-10mg daily
or
Pyrimethamine 25-50mg daily + Clindamycin 300-600mg every 6 hours + Leucovorin 5-10mg daily
For patients intolerant to either regimen:
Azithromycin 600 mg/day or dapsone 100 mg/day or atovaquone 750 mg q 8-12 hours in combination with pyrimethamine and leucovorin (doses as above)can be considered for supressive therapy. The clinical efficacy of these regimens has not been demonstrated in clinical trials.
5. Primary prophylaxis
Primary prophylaxis is recommended in patients with CD4 count less < 100/mm3 and toxoplasma IgG antibodies.
TMP/SMZ is the agent preferred prophylactic agent. If the patient can’t tolerate TMP/SMZ alternative regimens include: dapsone 50 mg daily + pyrimethamine 50 mg once weekly + leucovorin 25 mg once weekly or dapsone 200 mg + pyrimethamine 75 mg + leucovorin 25 mg all administered once weekly.
Prophylactic monotherapy with dapsone, pyrimethamine, azithromycin, clarithromycin, or atovaquone can not be recommended at this point. Aerosolized pentamidine does to confer protection against toxoplasmosis.
F. Herpes Simplex Virus
Herpes simplex virus types 1 and 2 (HSV-1, HSV-2) can cause disease in both normal and immunocompromised patients and are responsible for significant morbidity in AIDS patients. Most adult patients with AIDS have been infected with one or both HSV types at some point prior to the development of AIDS. Thus, these patients are not usually at risk of developing primary disease. However, AIDS patients remain at risk for significant disease due to reactivation of latent virus. When latent HSV reactivates it can cause severe recurrent HSV disease with prolonged viral shedding. The prevalence of HSV infection in is higher in the AIDS population due to the common risk factor for transmission of HSV and HIV. Serologic studies have revealed that up to 77% of HIV-infected patients have been previously infected with HSV.
A. Clinical Presentation
B. Diagnosis
-viral cultures - is the "Gold Standard"
-antigen detection by direct fluorescent antibody (DFA)
-clinical signs and symptoms
C. Treatment
The prompt administration of antiviral therapy reduces mortality and risk of serious complications.
1. Acyclovir - is the antiviral agent of choice for HSV
The drug may be administered either PO or IV. The optimal route of administration, dosage and duration depend on site and severity of infection.
a. Pharmacology
- absorption is slow and incomplete
- distributed into all tissues
- excreted renally (requires dose reductions in patients with renal dysfxn)
b. Adverse Reactions
- IV administration may be associated with phlebitis, irritation at the site of injection and renal dysfunction( due to crystallization in renal tubules).
- PO has been associated with mild nausea and vomiting, headaches and rash.
- Overall, this drug is very well tolerated
c. Dosing Regimens
- Mucocutaneous Herpes (genital, anorectal)
- Mild cases: 200mg PO 5x daily x 10 days or until lesions crust, Alternative dosing 400 mg tid
- Severe cases: 5mg/kg IV q 8 hrs x 7 days or 800 mg PO 5x/day
- Prophylaxis: 400mg PO BID or TID, indicated in patients with recurrent episodes (> 5 per year)
- note: breakthrough infection does not necessarily imply resistance
2. Alternative Therapy
Famciclovir 250mg PO BID x 5 Days - (indicated for treatment of recurrent episodes only)
Valacyclovir 500mg PO BID x 5 days - (indicated treatment of recurrent infection in immunocompetent patients)
3. Treatment of Acyclovir-Resistant Herpes
Acyclovir resistant herpes are deficient in thymidine kinase; thus little value in using valacyclovir or famciclovir.
Drug of choice: Foscarnet 40mg/kg IV TID x 7 21 days depending on response.
G. Varicella-Zoster Virus (VZV)
Fortunately, primary VZV infection is usually a childhood disease, thus, most adult patients with AIDS have been previously infected with VZV. AIDS patients, on the other hand, are at greater risk than the general population for developing recurrent disease. For AIDS patients who have never been exposed to VZV, primary infection can be very serious and life-threatening.
A. Clinical Presentation
- most often a recurrent infection
- radicular pain followed by localized or segmented rash covering 1-3 dermatomes
- widespread cutaneous or visceral dissemination may occur
- visceral dissemination to the lung, liver or CNS can be life-threatening
B. Treatment of VZV
Early recognition and treatment (within 72 hrs) is essential in preventing postherpetic neuralgia and other complications. Many patients can be treated with oral agents.
1. Acyclovir - Drug of Choice
primary infection: 10mg/kg/IV q 8 hours x 7 days or until lesions crust or 800mg PO 5X daily
recurrent infection localized: treat as above
recurrent disseminated: 10mg/kg IV q 8 hours x 7 days
2. Famciclovir 500mg PO TID x 7 days or until lesions crust
Indicated for primary or recurrent localized only
3. Valacyclovir 1gm PO TID x 7days, only for immunocompetent patients
4. Treatment of acyclovir-resistant vzv
Foscarnet 40mg/kg IV q 8 hours
H. Cytomegalovirus (CMV)
Infection with CMV is extremely common in patients with advanced AIDS. It can result in several clinical illnesses, including retinitis, pneumonia, colitis, esophagitis and encephalitis. Retinitis occurs most often (in up to 40% of AIDS patients) while gastrointestinal infection occurs less frequently (5-10%). Viremia will eventually develop in the majority of patients, but not all patients will develop clinical disease as a result of positive blood or urine cultures. Therefore, detection of disease should be made by tissue biopsy or histologic evidence of damage caused by the virus.
1. Chorioretinitis
This is the most common site of CMV infection in AIDS patients. It Can present as a unilateral or a bilateral infection characterized hemorrhagic lesions. This disease can progress rapidly and cause partial or total blindness. Relapse after initial therapy is very common requiring life-long maintenance therapy.
2. Treatment
Treatment of CMV retinitis is primarily limited to two drugs, although recently, a third drug was approved. Treatment of acute infection must be administered IV (induction). Maintenance therapy is life-long and can be administered in a variety of ways including IV, PO, intravitreal and ocular implants. Treatment is not a cure it only suppresses the virus.
1.Ganciclovir (Cytovene)
a. Pharmacology
-absorption is poor
-distributed widely (variable distribution to the eye)
-eliminated renally (requires dosage adjustments)
b. Adverse effects
-myelosuppression - neutropenia occurs in 25-40% of patients often requiring dose adjustments, discontinuation (switch to other agent) or concomitant treatment with GCSF. Consider discontinuing other myelosuppressive drugs (i.e. AZT, TMP/SMZ) if allowable.
-others include: liver function abnormalities, fever, nausea, seizures
c. Dosing Regimens
Induction Therapy:
5mg/kg IV q 12 x 14-21 days or until clinical improvement
Maintenance Therapy: (life-long)
IV: 5mg/kg q day : This route provides systemic protection. Disadvantages include sytemic toxicities, line sepsis, daily infusions, central line.
PO: 1000 mg TID with food (oral GCV is associated with a risk of a more rapid rate of progression to retinitis) Advantages include systemic protection and no need for central line.
Intravitreal injections: 200-1600mcg q week (higher conc. at site of infection, may be associated with risk of opthalmitis and other ocular complications, offers no systemic protection)
Ocular implants: 1mcg/hr replace q 6 months (associated with the longest time to progression of disease; however it offers no systemic protection and the other eye remains at risk. Also, associated with surgical complications and infections. The combination of the implants and oral ganciclovir is currently under research as a option to provide systemic coverage while delivering high concentrations of drug to the eye.
d. Resistance to ganciclovir has been reported. In these cases foscarnet must be used.
2. Foscarnet (Foscavir)
a. Pharmacology
- poorly absorbed (not available as oral agent)
- widely distributed
- renally eliminated
b. Adverse effects
-renal insufficiency is the most serious side-effect
adequate hydration is required and dosage adjustments according to crcl
-others include: nausea, headache, tremor, phlebitis, hypokalemia, hypomagnesemia, hypocalcemia and hypophosphatemia.
c. Dosing Regimens
Induction Therapy:
60mg/kg IVPB q 8hrs or 90mg/kg q 12 hrs 14-21 days
Maintenance Therapy: (life-long)
90-120mg/kg IVPB q day
intravitreal injections: 1200-2400 mcg q week
d. Monitor serum creatinine and electrolytes carefully. Adjust doses based on renal function and adjust dose accordingly. Discontinue other nephrtoxic drugs if possible. Replace electrolytes aggressively in order to avoid complications (i.e. seizures).
3. Combination ganciclovir and foscarnet
This combination should be reserved for patients with refractory disease. When compared to either ganciclovir alone or foscarnet alone the combination was significantly superior in delaying disease progression and there were no differences in side-effects. However, there was a noticeable decrease in quality of life due to the numerous and duration of infusions
Dose: Ganciclovir 5mg/kg daily IVPB + foscarnet 90mg/kg daily IVPB
4. Cidofovir (vistide)
This is the newest of the CMV agents and although it offers an alternative for patients who can't tolerate ganciclovir or foscarnet it should be reserved as a third line agent. Cidofovir offers the advantage of every other week dosing, however, it is extremely nephrotoxic and must be used with caution in all patients particularly those with pre-existing renal dysfunction or on concomitant nephrotoxic drugs. In order to avoid or minimize nephrotoxicity the patients must be adequately hydrated prior to each dose. Additionally, patients must take probenecid prior to and after each dose of cidofovir.
Induction therapy:
5mg/kg infused over 1 hour weekly x 2 weeks
Maintenance therapy:
5mg/kg infused over 1 hour every 2 weeks
Three hours prior to each infusion the patient should receive 1L of normal saline and 2 gm of probenecid (oral). During infusion another liter of normal saline should be infused. Two hours and 8 hours after the end of the infusion give 1g of probenecid. This protocol needs to be follow carefully to avoid the nephrotoxicity associated with this product. Some experts recommend another liter of normal saline 24 hours after the end of the infusion secondary to the long half-life of this compound.
Prior to each dose of cidofovir serum creatinine, urine protein, and neutrophil count must be monitored closely and the drug should be dose adjusted or discontinued if any abnormalities.
Caution: Patients who are being swithced from foscarnet require an adequate washout period prior to starting cidofovir.
5. Prophylaxis
Prophylaxis of CMV retinitis is controversial. Two major placebo controlled trials have shown contradicting results. Although, oral ganciclovir was recently approved for this indication in patients with CD4 < 50 most experts hesitate to use it due the controversial data, the risk for adverse events and the extremely high cost of this modality.
HV is a 37 year old African American female who recently was diagnosed with HIV. Today she returns to clinic for routine follow-up of initial laboratory tests.
PMH:
FH: Non-contributory
SH:
Allergies: NKDA
Medications:
PE:
Pertinent baseline laboratories:
Questions:
1. Should HV start antiretroviral therapy?
2. Which antiretroviral regimen should be started on a drug navie patient like HV?
3. When HV should return to clinic to evaluate her response to therapy?
4. What other interventions can be done for HV?
Answers:
1. Should HV start antiretroviral therapy?
Yes. Although HV is currently asymptomatic with a CD4 cell count of 350 cell/mm3 her viral load is high enough to warrant treatment.
2. Which antiretroviral regimen should be started on a drug naive patient like HV?
The goal of therapy should be to decrease plasma viral load to undetectable levels. The preferred regimen to accomplish this consist of 2 nucleoside analogues reverse transcriptase inhibitors (NRTI's) and one potent protease inhibitor (PI) e.g. AZT/3TC/Indinavir. The use of monotherapy should be avoided for all patients. Combination therapy with 2 NRTI's may provide undetectable viral load measurements in selected patients, but the initial viral suppression is not sustained in the majority of these patients.
3. When HV should return to clinic to evaluate her response to therapy?
A 4 week period is considered an adequate time to evaluate clinical response using viral load. A 0.5-log decrease in viral load is considered a significant reduction. In HV this will be a viral load measurement of approximately 9500 copies/ml. If HV viral load has not significantly decreased questions regarding efficacy of the regimen, adherence ( to schedule and food requirements), and adequate handling of sample should be raised. Maximal antiviral effect of a regimen is seen at approximately 12 weeks, thus, if HV viral load is not undetectable by current assay at this visit she can continue her current regimen and another viral load measurement should be obtained after completing 3-4 months of therapy. Other laboratory tests to monitor include: CD4 cell count, chemistries including liver function test, amylase and glucose, complete blood count with differential. Once maximal viral suppression has been achieved HV CD4 and viral load should be reevaluated every 3-4 months to evaluate durability of antiviral effect.
4. What other interventions can be done for HV?
HV CD4 cell count is greater than 200 cells/mm3 thus, she has a low risk for developing. Other interventions that can be done for HV include: pelvic exam and PAP smear, tuberculosis skin testing and immunization against pneumococcal disease and influenza virus during influenza season.
28 y/o Hispanic female with history of injection drug use and prostitution. Diagnosed with AIDS in 1994 when she presented with PCP. Today she presents to the clinic with c/o weight loss, diarrhea, fever, chills and generalized weakness for greater than 2 weeks. She reports full compliance with her medication.
She failed her last appointment 1 month ago.
PMH: PCP x 1 episode, Recurrent genital herpes
Allergies: none
Current Medication:
Labs: (from months ago when she started indinavir)
CD4=40, CD4%=3, HIV-RNA 125,OOO copies/ml
WBC 3.0 (ANC=700), Hct=35, plt 350
Chemistry and liver profile are only significant for elevated alkaline phosphatase (2x uln) and
albumin of 2.0.
WT: 110 lbs VS: are normal
PE: significant only for abdominal tenderness and profound weight loss
Working Diagnosis: Mycobacterium Avium Complex (MAC)
Questions
1. List at least 4 factors that led to the current diagnosis. (Include signs/symptoms and labs)
2List at 2 factors that could be contributing to this patients low WBC.
3.How could a more definitive diagnosis of MAC be made?
4. Recommend a plan for the treatment of MAC in this patient. (include drug(s), doses, route of administration and duration of therapy) Briefly discuss the rational for your plan.
Case#2 answers
1. List at least 4 factors that led to the current diagnosis. (Include signs/symptoms and labs)
weight loss, fever, anemia, elevated alkaline phosphatase
2.List at 2 factors that could be contributing to this patients low WBC.
Drug related (azt , rifabutin or bactrim) or HIV disease related
3. How could a more definitive diagnosis of MAC be made?
Blood culture
4. Recommend a plan for the treatment of MAC in this patient. (include drug(s), doses, route of administration and duration of therapy) Briefly discuss the rational for your plan.
First d/c rifabutin, then start:
Clarithromycin 500mg BID PO
plus
Ethambutol 15mg/kg q day PO
Therapy is for life
Combination therapy is most effective. Prefer not to use rifabutin in this patient due to potential drug-interaction with protease inhibitor and she developed the disease while receiving rifabutin.. Three-drug regimen usually not necessary.
5. List at least 4 agents that have the potential for drug- interactions with protease inhibitors. (not necessarily pertaining to this case) (4 pts)
rifabutin, rifampin, nevirapine --decrease AUC of protease inhibitors resulting in sub-therapeutic levels terfenadine, astemizole, cisapride, triazolam, midazolam, etc -- metabolism of these drugs may be inhibited by the protease inhibitors resulting in potentially dangerous levels.
Basic Explanation of Significant Viral Load Changes
A change of > 0.5 log represents a significant change. A 0.5 log decrease is equivalent to a 3 fold decrease.
Measurement copies/ml Power 10x LOG Fold/log decrease based on 100,000 100,000 1 x 105 5 logs 10,000 1 x 104 4 logs 10 fold (1 log) 1,000 1 x 103 3 logs 100 fold (2 log) 100 1 x 102 2 logs 1000 fold (3 log) 10 1 x 101 1 logs 10,000 fold (4 log)
i.e. If the viral load falls from 100,000 copies/ml to 10,000 copies/ml , this is a 1 log decrease which is equivalent to a 10 fold decrease.
Table of examples ( It is best to think in terms of fold changes)
Baseline HIV-RNA Follow-up HIV-RNA Fold Change Significant yes or no 150,000 50,000 3 fold decrease yes 20,000 10,000 2 fold decrease no 10,000 30,000 3 fold increase yes 500,000 900,000 1.8 fold increase no 10,000 14,000 1.4 fold increase no 100,000 25,000 4 fold decrease yes
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