Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiviral Drugs

  • Anti-viral drugs with activity against HIV (Human Immunodeficiency Virus)

    • HIV-1 Pathophysiology/Pathogenesis

      • Symptoms of HIV Disease

        • Introduction

          • During the extended time course of HIV infection, clinical symptoms may appear at any point.

          • However, the range of diseases appears correlated with the CD4⁺ T cell count.

            • The more serious HIV infection complications are usually noted in individuals with CD4⁺ T cell counts <200 μ/L.

          • An AIDS diagnosis can be established in a patient with HIV infection combined with the CD4⁺ T cell count < 200 μ/L or in a patient presenting with one of the HIV-associated diseases representative of significant cell-mediated immunity dysfunction, described as category "C".

          • Category C:  AIDS Surveillance Case Definition^2,9 [MMWR 43(No. RR-17) December 18, 1992. [MMRW:  Morbidity and Mortality Weekly Report; http://www.cdc.gov/mmwr/ ]

            Bronchial, tracheal or lung Candidiasis	Esophageal Candidiasis	Invasive cervical cancer	Coccidioidomycosis (disseminated or extrapulmonary)
            Cryptosporidiosis (chronic intestinal, >1 months duration)	Cytomegalovirus disease (other than liver, spleen, or nodes)	Cytomegalovirus retinitis (vision loss)	Encephalopathy (HSV-related)
            Herpes simplex (chronic ulcer(s); >1 months duration); bronchitis, pneumonia or esophagitis	Histoplasmosis(disseminated or extrapulmonary)	Isosporiasis (chronic intestinal, >1 months duration)	Kaposi's sarcoma
            Burkitt's lymphoma	Lymphoma, primary (brain)	Mycobacterium avium complex or M. kansasii, (disseminated or extrapulmonary)	Mycobacterium tuberculosis, any site
            Pneumocystis jirovecii pneumonia	Pneumonia (recurrent)	Progressive multifocal leukoencephalopathy	Salmonella septicemia, recurrent
            	Brain Toxoplasmosis	HIV wasting syndrome

        •  Presentations of patients with HIV disease have been evolving, given that patients are living longer, mainly as a result of improved antiretroviral medications, combinations of these drugs and use of drugs for prophylaxis of opportunistic infections.² 

          • As a consequence, presentation of typical "AIDS-defining" disease continues but has been joined by non-AIDS diseases such as non-AIDS related cancers along with cardiovascular, renal, and hepatic dysfunction.

          • Diseases affecting HIV patients receiving cART (HAART) are exhibiting mainly non-AIDS presentation.

          • Presently, less than half of deaths among AIDS patients occur due to an AIDS defining illness.

          • A principal element in managing HIV disease symptomatology/complications is based on using cART to control HIV replication on one hand and adding primary (and secondary) prophylaxis to limit opportunistic infections on the other.² 

             

            • Opportunistic infection pathogens in HIV: Abbreviated, partial listing (for complete listing see ref. 2, Table 189-10; NIH/CDC/IDSA 2009 Guidelines for the Prevention of Opportunistic Infections in Persons Infected with HIV)

              Pathogen	Indications	First Choice(s)	Alternatives
              Pneumocystic jiroveci (Pneumocystis pneumonia, PCP)	CD4+ T cell count <200/μL or Oropharyngeal candidiasis or Prior PCP infection	Trimthoprim/sulfamethoxazole (TMP/SMX)	Dapsone or Dapsone + Pyrimethamine + Leucovorin
              Mycobacterium turberculosis
              Isoniazid sensitive	Skin test > 5 mm or Prior Positive test without pretreatment or Close contact with a case of active pulmonary TB	Isoniazid + pyridoxine	Rifabutin or Rifampin
              Isoniazid resistant	Same with high likelihood of exposure to isoniazid-resistant TB	Rifabutin or rifampin
              Multidrug resistant	Same with high likelihood of exposure to isoniazid-resistant TB	Consult local public health authorities
              Mycobacterium-avium complex	CD4+ T cell count , 50/μL	Azithromycin or Clarithromycin	Rifabutin or Azithromycin
              	Prior documented disseminated disease	Clarithromycin + Ethambutol +/- Rifabutin	Azithromycin + Ethambutol  + Rifabutin
              Toxoplasma gondii	TOXO IgG antibody positive and CD4+ T cell count <100/μL	TMP/SMX	Various combinations
              	Prior toxoplasmic encephalitis and CD4+ T cell count <200/μL	Sulfadiazine + Pyrimethamine + Leucovorin	Clindamycin + Pyrimethamine + Leucovorin
              Varicella zoster virus	Significant chickenpox exposure or shingles in a patient with no history of immunization or prior exposure to either	Varicella zoster immune globulin, IM, within 96 h of exposure	Acyclovir
              Cryptococcus neoformans	Prior documented disease	Fluconazole	Itraconazole
              Histoplasma capsulatum	Prior document disease or CD4+ T cell count <250/μL and high risk	Itraconazole	Fluconazole
              Coccidioides immitis	Prior documented disease or positive serology and CD4+ T cell count < 250/μL if from a disease endemic area	Fluconazole	Itraconazole
              Cytomegalovirus	Prior end-organ disease	Valganciclovir or Gangciclovir (sustained release) + Valganciclovir	Cidofovir IV + Probenecid or Fomivirsen intravitreal or Foscarnet
              Penicillium marneffei	Prior documented disease	Itraconazole
              Salmonella species	Prior bacteremia	Ciprofloxacin
              Bartonella	Prior infection	Doxycycline or Azithromycin or Clarithromycin

               

      • Pulmonary Disease:

        • Pulmonary disease is a frequent complication of HIV infection, with the most common manifestation being pneumonia.

          • Three of the 10 most frequently encountered AIDS-defining diseases are represented by recurrent bacterial pneumonia, tuberculosis and pneumonia due to the fungus Pneumocystis jirovecii.²

        • Prior to the development of the highly active, combination antivirals (cART; HAART), nearly 65% of AIDS patients exhibited pulmonary disease. The most common cause was Pneumocystis jirovecii (PCP).⁹  

          • Other frequently encountered causes included pulmonary disease due to:⁹ 

            • Other fungi, bacteria

            • Mycobacterium tuberculosis and

            • Mycobacterium avian complex (MAC).

          • By contrast, viral pneumonia secondary to cytomegalovirus (CMV) infection was uncommon even though a 100% incidence of prior infection could be demonstrated.

        • Since the development of the highly active antiretroviral combinations (cART), along with immune system reconstitution, fewer cases of opportunistic infections are reported, allowing for discontinuation of primary and secondary Pneumocystis jirovecii (PCP) prophylaxis in some cases.⁹  

          • Also, the likelihood of pulmonary Kaposi's sarcoma appears to be in decline.

        • On the other hand, bacterial pneumonia, often caused by Streptococcus pneumoniae and non-Hodgkin's lymphoma have become increasingly likely.⁹

        • Acute bronchitis is commonly observed in all HIV infection stages, with the most severe cases, as expected, observed in patients with the lower CD4+ T cell counts.²

          • Sinusitis presentation includes fever, nasal congestion as well as headache, with the definitive diagnosis depending on CT or MRI imaging.²

            • Sinuses most likely affected are maxillary, although sinusitis may be noted in ethmoid, sphenoid and frontal sinuses as well.

            • Radiographic improvement is both quicker and more easily confirmed in patients receiving antimicrobial medication.

              • High incidence of sinusitis in HIV population may be due to an increased infection frequency with encapsulated organisms including Haemophilus influenzae and Streptococcus pneumoniae.

              • In patients with low CD4 + T cell counts mucormycosis sinus infections may be observed.

                • Mucormycosis is a fungal infection caused by fungi in the order Mucorales.¹⁰  

                  • Mature sporangium of a Mucor sp. fungus¹⁴ 

                    CDC/George LK Mature sporangium of a Mucor sp. fungus. "This photomicrograph reveals a mature sporangium of a Absidia sp. fungus. "Mucor is a common indoor mold, and is among the fungi that cause the group of infections known as zygomycosis, also known as mucormycosis). "The infection typically involves the rhino-facial-cranial area, lungs, GI tract, skin, or less commonly other organ system"

                  • Mucormycosis often involves sinuses, brain or lungs with biopsy specimens of involved tissue being more reliable than swabs for diagnosis.¹¹

                  • Should a mucormycosis diagnosis be established, amphotericin B administration is likely the appropriate intervention, given the rapid spread/high mortality rate of the disease.¹²

                  • In addition to AIDS, other predisposing factors include diabetes, malignant, renal failure, lymphomas, organ transplant, long-term corticosteroid therapy and immunosuppressive therapy and others.¹³

              • In cases involving HIV patients, sinus mucormycosis appears to progress more slowly.

                • In this presentation, local debridement along with local + systemic amphoteracin B represent effective treatment.^2,12

          • Pneumocystis pneumonia (Pneumocystis jirovecii, PCP), independent of the substantial reduction in incidence, following both administration of prophylactic drugs in addition to highly active antiretroviral regimens (cART, HAART), pneumocystis pneumonia remains the single most common pneumonia caused in HIV patients with HIV infection in the United States.²

            • It is a likely etiologic agent in about one fourth of pneumonia cases in individuals with HIV, corresponding to an incidence of 2-3 cases per 100 person-years.

            • Importantly, about half of cases of HIV-associated PCP are found in individuals unaware of their HIV status.²

            • The highest risk of PCP pneumonia is in those patients previously experiencing PCP pneumonia and who have a CD4+ T cell count of <200/μl.

              • Nearly 80% of PCP patients have CD4+ T cell count of less than 100/μl.

              • Overall about 95% of HIV patients with CD4+ T cell count exhibit values <200/μl.

            • PCP pneumonia may occur in patients who experience night sweats, recurrent fever and unexplained weight loss; furthermore patients with CD4+ T cell counts less than 200/μl are candidates for PCP prophylaxis.

            • It is important to emphasize that in those patients with known HIV infection receiving both prophylaxis and cART (HAART) the incidence of PCP pneumonia approaches 0.²

              • In the United States, currently, primary PCP occurs with the median CD4+ T cell count of only 36/ul.

          • Clinical presentation of PCP pneumonia include fever with cough (nonproductive typically).

            • Complaints of a characteristic retrosternal chest pain, worse on inspiration, and described as "sharp or burning."²

            • Early diagnostic information concerning presentation of HIV patients with respiratory complaints should consider patient's risk factors, degree of immunosuppression and chest radiography.⁹ 

              • Often the clinical presentation of lung disease accompanying HIV infection may be nonspecific⁹ .

                • In addition to fever and cough, shortness of breath, exertional dyspnea, hemoptysis, weight loss and night sweats represent expectable signs and symptoms.

                  • These presentations occuring in the subacute or chronic setting correspond to an increased likelihood for a PCP (Pneumocystis jirovecci), disseminated tuberculosis or fungal disease or Kaposi's sarcoma diagnosis.

                    • Focal airspace consolidation is consistent with Kaposi sarcoma, bacterial pneumonia, cryptococcosis, legionellosis as well as Mycoplasma pneumoniae infection.

                    • Hilar and mediastinal adenopathy may indicate tuberculosis, Mycobacterium avium complex, Kaposi's sarcoma and non-Hodgkin's lymphoma.

                    • Pleural effusions may suggest a finding of Kaposi's sarcoma, empyema, tuberculosis and non-Hodgkin's lymphoma.

                  • Even with the normal radiograph, PCP and tuberculosis should be considered in patients with respiratory complaints.⁹

              •  

                Chest X-ray of a patient with PCP (Pneumocystis jirovecii)

                CDC/User InvictaHOB Lung X-ray of a patient shows infection with Pneumocystis jirovecii. http://commons.wikimedia.org/wiki/File:PCPxray.jpg http://history.nih.gov/NIHInOwnWords/docs/page_38c.html

              •  

                CT scan:  PCP Pneumonia

                Sharma S CT scan illustrating bilateral scattered opacities, with some ground glass adjacent, typical of Pneumocystis pneumonia (PCP). LIFE (Leading International Fungal Education):  Pneumocystis Pneumonia http://www.life-worldwide.org/fungal-diseases/pneumocystis-pneumonia

          • HIV patients with Pneumocystis jirovecii infection may present with otic involvement, as a primary infection, showing a polyploid mass associated with the external auditory canal.² 

            • HIV patients receiving aerosolized pentamidine for PCP prophylaxis may exhibit a number of extra pulmonary Pneumocystis jirovecii manifestations.² 

            • These extrapulmonary effects include:

              • Ophthalmic choroid lesions

                • A number of choroidal lesion cases have been described in AIDS patients.¹⁵ 

                  • These cases reported bilateral, scattered, yellow-white choroid lesions.

                  • One case was thought to be a presumed extension of cryptococcal meningitis into the optic nerve and choroid.

                    • However, the remaining cases (six patients) had Pneumocystis pneumonia at some time during the course of the disease and were receiving aerosolized pentamidine treatment.

                    • Mycobacterial infection was also noted in five of the six patients.

                  • The clinical course for each of the seven cases, summarized in case reports, exhibited similar appearances but different outcomes.¹⁵ 

                    • Ophthalmic choroid lesions¹⁵

                      "Scattered lesions with one under the fovea and flame haemorrhages at the disc margin with several cotton-wool spots and haemorrhages. Attribution:  Figure 1:  Case 6 A from reference 15

              • Necrotizing vasculitis (similar to Burger's disease)

              • Bone marrow hypoplasia

                • Generally, HIV-related bone marrow abnormalities in adults involved hypocellularity, myelodysplasia and poor marrow recovery.¹⁶ 

                  • Most hematological pathologies in HIV-infected individuals are classified as blood cytopenias.

                  • Neutropenia and anemia are thought to occur as a result of inadequate production due to HIV-mediated suppression.

                    • Suppression may be caused by the presence of abnormal cytokines as well as through alteration of the bone marrow microenvironment.

                    • In the case of thrombocytopenia, immune system induced platelet destruction along with inadequate production appear responsible.

                    • Other causes of hematological abnormalities include drugs, malignancies, nutritional deficiencies as well as secondary opportunistic infections.¹⁶ 

                • A recent study considered bone marrow abnormalities in children, focusing on three clinical cases.¹⁶ 

                  • The first clinical case considered a seven-year-old boy with pulmonary tuberculosis, anemia, thrombocytopenia and bone marrow examination revealing hypoplastic marrow and an absence of megakaryocytes.

                  • The second child was a 3 1/2-year-old girl with both severe anemia and dyserythropoiesis.

                  • The third individual was a seven-year-old boy with splenic abscesses and pancytopenia. Bone marrow examination in this case revealed myelofibrosis with increased plasma cells.¹⁶ 

              • Intestinal obstruction.

            • Various other organ involvement has been described.²

 

References

Flexner C Antiretroviral Agents and Treatment of HIV Infection, Chapter 59  in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th edition (Brunton LL Chabner BA Knollmann BC, eds; Brunton LL, ed; Blumenthal DK  Murri N Hilal-Dandan R, assoc eds, Knollmann BC, consulting ed, on-line edition) The McGraw-Hill Companies, 2011. Fauci AS Lane HC Chapter 189, Human Immunodeficiency Virus Disease:  AIDS and Related Disorders, in Harrison's Online   (Dan L. Longo, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, J. Larry Jameson, Joseph Loscalzo, Eds.),  Harrison's Principles of Internal Medicine, 18th edition, The McGraw-Hill Companies, Inc. 2012. Longo DL Fauci AS  188, The Human Retroviruses, in Harrison's Online   (Dan L. Longo, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, J. Larry Jameson, Joseph Loscalzo, Eds.),  Harrison's Principles of Internal Medicine, 18th edition, The McGraw-Hill Companies, Inc. 2012. Safrin S Antiviral Agents, Chapter 49 in Basic & Clinical Pharmacology, 12 e (Katzung BG Masters SB Trevor AJ) The McGraw-Hill Companies, 2012 (on-line edition). Cochrane A Retroviruses Chapter 28 in Fundaments of Molecular Virology, 2e, Acheson NH, ed., John Wiley & Sons pp 342-353 2011. Cochrane A Human Immunodeficiency Virus Chapter 29  in Fundaments of Molecular Virology, 2e, Acheson NH, ed., John Wiley & Sons pp 354-364 2011. Ryan KJ, Ray C. Chapter 18. Retroviruses: Human T-Lymphotropic Virus, Human Immunodeficiency Virus, and Acquired Immunodeficiency Syndrome. In: Ryan KJ, Ray C. eds. Sherris Medical Microbiology (Part editor, Ahmad N Ray CG Drew WL), 5e. New York, NY: McGraw-Hill; 2010. Butel JS Chapter 44:  AIDS and Lentiviruses (Brooks FG, Carroll KC Butel JS Morse SA, Mietzner TA in Jawetz, Melnick & Adelberg's Medical Microbiology, 26th edition), 2013, on-line edition. Segreti J Chapter 40.  Pulmonary Complications of HIV Disease in Current Diagnosis & Treatment in Pulmonary Medicine (Hanley ME Welsh CH, eds). The McGraw-Hill Companies, Inc. 2003. on-line edition. James WD Berger TG Dirk M Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. 326, 10th edtion (2006) Murcomycosis MedlinePlus, A service of the U.S. National Library of Medicine (NIH) http://www.nlm.nih.gov/medlineplus/ency/article/000649.htm CDC (Centers for Disease Control and Prevention) Mucormycosis:  Treatment and Outcome. http://www.cdc.gov/fungal/diseases/mucormycosis/treatment.html Nancy F Crum-Cianflone, MD MPH. eMedicine. http://emedicine.medscape.com/article/222551-overview Updated Apr 2, 2013. CDC/George LK Mature sporangium of a Mucor sp. fungus. http://commons.wikimedia.org/wiki/File:Mature_sporangium_of_a_Mucor_sp._fungus.jpg Rosenblatt MA Cunningham C Teich S Friedman AH  Choroidal lesions in paties with AIDS Brit J of Ophthmol 74:  610-614 1990. Shah I Murthy A Bone marrow abnormalities in HIV infected children, report of three cases and review of the literature. J Res Med Sci 19(2), 181-183, Feb. 2014. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3999606/

 

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