Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiviral Drugs

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

    • HIV-1 Pathophysiology/Pathogenesis:  HIV Disease Presentations

      • Pulmonary Disease (continued)

        • Bacterial Pneumonia

          • Bacterial pneumonia is in HIV positive individuals, occurring with a frequency of about one case per 100 person-years.² 

            • As noted below, HIV patients may be especially susceptible to infections with "encapsulated" microorganisms as S. Pneumoniae and H. influenzae account for most cases in AIDS patients.

              • This tendency may be related to B cell dysfunction and/or neutrophil dysfunction secondary to HIV infection.² 

              • S. Pneumoniae (pneumococcal) may be the earliest serious infection associated with HIV and S. pneumoniae may present as:

                • Pneumonia

                • Sinusitis and/or

                • Bacteremia.²

              • If untreated, patients with HIV infection have a sixfold increase in pneumococcal pneumonia incidence and a 100-fold increase in incidence of pneumococcal bacteremia.²

              • Furthermore, pneumococcal disease may present even in individuals with "relatively" intact immune systems.²

                • For example, associated with a first episode of pneumococcal pneumonia was a CD4⁺ T cell count of about 300/μl.

                  • As a result of high risk of pneumococcal disease, HIV patients should be considered candidates for immunization using pneumococcal polysaccharide, as a recommended prophylactic measure.

                  • Such immunization appears most effective when patient CD4⁺ T cell count is >200/μl.

                    • Repeat immunization appears appropriate, perhaps every five years.²

          • Diagnosis of bacterial pneumonia depends on certain presentations including:

            • Sudden onset of fever

            • Sputum production

            • Cough

            • Dyspnea and

            • Chest pain.¹⁰ 

          • Lobar or segmental infiltration demonstrated by chest x-ray supports the diagnosis.¹⁰ 

          • Diagnosis is facilitated by sputum Gram stain/culture and blood culture results.

          • Empirical therapy may be appropriate for common pathogens.

          • Generally, bacterial pneumonia is more common in HIV-positive individuals than in seronegative control subjects.¹⁰

            • The likelihood of bacterial pneumonia tends to increase as CD4⁺ T cell lymphocyte counts decrease.

            • The pneumonia risk appears higher for injection drug users compared to that seen in men who have had sex with men.

            • Cigarette smoking confers a higher pneumonia risk both for HIV-patients and for non-HIV individuals.

              • The incidence of bacterial pneumonia is decreased by about 50% when patients stop smoking.²

            • HIV patients developing pneumonia exhibit a 400% higher mortality compared with individuals not developing the disease.

            • Use of trimethoprim/sulfamethoxazole (TMP/SMX), as prophylaxis, reduces the likelihood of pneumonia development.

              • Probably the most common pathogen responsible for bacterial pneumonia in this setting is Streptococcus pneumoniae (S pneumoniae) followed by Haemophilus influenzae.¹⁰

                • Stretptococcus pneumoniae in spinal fluid¹¹

                  Content Provider: CDC/Mitchell MS (Public Domain, USGOV-HHS-CDC) Stretptococcus pneumoniae in spinal fluid (FA stain [digitally colorized]. (1964) http://commons.wikimedia.org/wiki/File:Pneumococcus_CDC_PHIL_ID1003.jpg

                •  

                  Haemophilus influenzae:  Gram negative coccobacilli of a sputum sample¹²

                  Galindo BJ Haemophilus influenzae:  Gram negative coccobacilli of a sputum sample. (2005) http://commons.wikimedia.org/wiki/File:Haemophilus_influenzae_Gram.JPG

          • Bacteremia, secondary to bacterial pneumonia, is more likely to occur in HIV positive patients than in seronegative individuals.¹⁰ 

            • Pulmonary function decline over the long-term that are more common following bacterial pneumonia in HIV patients include:¹⁰

              • Permanent reduction in forest expiratory volume (FEV1)

              • Forced vital capacity (FVC)

              • FEV1/FVC

              • Carbon monoxide diffusing capacity.¹⁰

        • Tuberculosis²  

          • "TB Culture"¹³

            CDC/Kubica G TB Culture "This is a close-up of a Mycobacterium tuberculosis culture revealing this organism's colonial morphology. "Note the colorless rough surface, which are typical morphologic characteristics seen in Mycobacterium tuberculosis colonial growth. "Macroscopic examination of colonial growth patterns is still one of the ways microorganisms are often identified." http://commons.wikimedia.org/wiki/File:TB_Culture.jpg

          • Mycobacterium tuberculosis is more common now as a result of the HIV epidemic.²  

            • About one-third of all AIDS-related deaths, worldwide, are associated with tuberculosis (TB).

              • In the United States TB is the primary cause of death for about 10%-15% of HIV-infected patients.

                • "TB and HIV Co-infection, 2012"¹⁴

                  Harrington RD, M.D. Medical Director Harborview Medical Center HIV Clinic; Director of the UW Center for AIDS Research Clinical Research Core and Associate Section Chief of Infectious Diseases at Harborview medical Center. https://www.youtube.com/watch?v=z-6yfEBbKDY Other Presentation from the Northwest AIDS Education and Training Center: http://depts.washington.edu/nwaetc/echo/pres/#

          • Untreated TB increases the rapidity of HIV progression.

          • Active TB is associated with an increase in plasma HIV RNA and by contrast HIV RNA levels are reduced with successful TB treatment.²

            • By contrast to infection with atypical mycobacteria such as Mycobacterium avium complex (MAC), active TB tends to develop early in the course of HIV infection, representing an early clinical sign of HIV.

          • Clinical presentations of TB in HIV-infected patients vary in a manner reflecting CD4⁺ T cell count.²  

            • For example, patients with higher CD4⁺ T cell counts show a more typical pattern of pulmonary reactivation: fever,

              • Cough

              • Dyspnea on exertion

              • Weight loss

              • Night sweats a

              • Chest x-ray showing cavitary apical disease (upper lobes).

            • On the other hand, patients with lower CD4⁺ T cell counts may more commonly present with disseminated disease.²  

              • In that case chest x-ray may indicate diffuse or lower lobe bilateral reticular nodular infiltrates, pleural effusions, and hilar and/or mediastinal adenopathy.

              • Infection in bone, brain, G.I. tract, meninges, cervical lymph nodes and viscera may also be found.

            • Patients with HIV infection may have both advanced HIV and active TB, while not presenting evidence of clinical disease.²

              • Accordingly, TB screening should be an element in initial HIV patient evaluation.

                • In the HIV setting, therapy is generally the same as for the HIV-negative individual.

                  • For pharmacokinetic interaction reasons, rifabutin should be substituted for rifampicin patients receiving HIV protease inhibitors or nonnucleoside reverse transcriptase inhibitors.

              • Initiation of cART (HAART) and/or anti-TB treatment may induce immune reconstitution inflammatory syndrome (IRIS) which can cause clinical deterioration.

                • This reaction may be most likely observed in individuals in which both anti-HIV and anti-TB treatment are initiated concurrently.

                  • Accordingly, TB treatment may be implemented first followed 2-8 weeks later by cART (in the antiretroviral-naïve patient).

            • Effective active TB prevention may be possible by: ²

              • Effective investigation for evidence of latent or active TB

              • HIV-positive patients receiving a PPD (Purified Protein Derivative) tuberculosis test, or

              • IFN-gamma release assay.

                • In individual with anergy (an inability to mount a delayed-type hypersensitivity response to skin test antigens) dependence on a PPD skin test is inappropriate.

                  • These tests depend on the patient being able to exhibit an immune response to M tuberculosis.

                    • Patients with CD4⁺ T cell counts <200 cells/μl may be unable to generate a positive response.²