Nonnucleoside Reverse Transcriptase Inhibitors

The class of NNRTIs is a chemically heterogeneous group of compounds that are entirely unrelated to nucleosides. They inhibit HIV replication at the same stage as nucleoside analogues, but they noncompetitively bind directly to the active site of reverse transcriptase (122). (See Fig. 2.2 for the site of action.) These drugs are not substrates for the reverse transcriptase enzyme and are not incorporated into the developing viral DNA chain. They are also active in their native state and do not...

Ii

Dates for smallpox and rabies vaccines are for the first published results of vaccine usage. Remaining dates are for FDA approval of vaccine. was approved by the U.S. Food and Drug Administration (FDA) in 1998, it was taken off the market after a few months due to a relatively small but statistically significant increase in the number of infants developing intussusception. Therefore, the medical-legal environment in the United States forced the removal of a vaccine from the market that could...

Conclusion

As the population of HIV-infected individuals increases, the need for better access to antiretroviral therapy becomes more critical. In countries where HAART is available, however, the role of the physician has expanded from therapy of HIV and associated opportunistic infections to include the adverse effects of antiret-roviral therapy, drug resistance, and noncompliance. Not only will it be necessary to be aware of these limitations of HAART, it will also be necessary to be knowledgeable of...

Introduction

Public health measures should always be the first line of defense against viral infections and should include clean drinking water, proper sewage disposal, vector control, testing of blood and blood products, nonsharing of needles, hand washing and use of disposable gloves, and safer sex condom usage abstinence (Fig. 1.1). Global travel has made the rapid implementation of these measures paramount. The rapid spread of the SARS (severe acute respiratory syndrome) corornavirus and avian influenza...

Hyperparathyroidism osteopenia and bone pain

Ritonavir has been implicated in in vitro studies in which ritonavir, nelfinavir, and indinavir have an effect on vitamin D metabolism and differentiation of osteo-cytes (239). Extreme bone pain has been reported, possibly as an idiosyncratic reaction to ritonavir (240). Calcium inhibition has been reported by others and may result in children on ritanovir experiencing impaired growth (241,242). Drug interactions. Ritonavir is associated with numerous drug interactions and adverse effects,...

Info

Fig. 2.15 Trade names, structure, and uses of Ritonavir. Fig. 2.15 Trade names, structure, and uses of Ritonavir. prolonged survival in these patients, although earlier intervention would likely have been much more effective. Coad-ministration of ritonavir with amprenavir results in a synergistic relationship between the two (231). Indinavir and ritonavir combinations have improved pharmacokinetic properties with twice-daily dosing with food (232). Ritonavir is taken orally as a capsule or in...

Human Immunodeficiency Virus

Antriretroviral drugs are used primarily to treat the patients with HIV infection which has become a major global scourge with little relief in sight for developing nations. The virus is transmitted through exposure to infected semen, cervical or vaginal secretions, or infected blood. Intravenous drug users who share contaminated needles are most at risk for contracting HIV. Unprotected sex between partners is a worldwide cause of transmission. Children born to HIV-infected women contract the...

Hiv Protease Inhibitors

The PIs were introduced in 1995 as a promising new category of antiretrovirals that work by a different mechanism than the reverse transcriptase inhibitors (192). These compounds block a separate virus-specific enzyme known as HIV protease. Mechanism of action. Inhibition of the protease enzyme prevents the cleavage of viral polyproteins in the final stage of viral protein processing (See Fig. 2.2 for site of action.). Without the HIV protease activity, mature HIV virions cannot be assembled...

Dyspepsia

New-onset diabetes mellitus and hyperglycemia have been reported with all of the PI drugs (207). Liver disease. Saquinavir may be more potent in patients with liver disease because of slower removal of medicine from the body. Dosage adjustments may be necessary Coadministration with terfenadine, cisapide, triaz-olam, midazolam, or ergot derivatives. Coadministra-tion with terfenadine, cisapride, triazolam, midazolam, or ergot derivatives may cause potentially serious...

Hemolytic anemia Reported rarely

Indinavir therapy is associated with a 6-25 incidence of asymptomatic, unconjugated hyperbilirubinemia (257,258). Mechanistic studies in rats indicate that hyperbilirubinemia is due to indinavir-mediated impairment of bilirubin-conjugating activity (259). Gilbert's syndrome. Gilbert's syndrome is a benign, inherited condition of deficient bilirubin conjugation, occurring in 5 to 10 of the general population. Gilbert's genotype is associated with a 50 reduction in...

Myopathy or myositis

The most common cutaneous manifestation of AZT use is longitudinal melony-chia which is usually noted after 2-6 weeks of therapy (53). The color of the affected nails has been described as dark bluish or brownish. Other dermatologic manifestations. Skin pigmentation, nonspecific macules and papules, pruritis, and urticaria are rarely reported. Psoriasis. Patients with HIV infection may develop psoriasis which is very difficult to treat using conventional therapy. An...

Zidovudine [AZT Retrovir

Zidovudine is the most extensively studied drug of all the anti-retrovirals. It is no longer used as monotherapy, except in parts of the world where other antiretroviral drugs are not available. It has been widely prescribed by practitioners after early studies revealed improved survival rates and delayed declines in CD4 counts in patients with HIV infection 36-38 . As a result of monotherapy with zidovudine, resistant HIV strains have developed, which have limited the efficacy of this...

Nucleotide Reverse Transcriptase Inhibitors Tenofovir Disoproxil Fumerate Viread

Tenofovir is a nucleotide analog reverse transcriptase inhibitor. The best-known nucleotide analogues are the antivirals, ade-fovir Hepsera and cidofovir Vistide , used for the treatment of hepatitis B and cytomegalovirus infections. Adefovir was discontinued as an HIV therapy due to proximal renal tubular dysfunction. See Fig. 2.13 for names, structure, and approved uses of tenofovir. It is FDA-approved for the treatment of HIV infection in combination with other anti-HIV therapies. The...

Didanosine [ddl Videx

Didanosine ddI is indicated for patients with HIV who are either unable to tolerate zidovudine or those who have became refractory to its effects. The structure, brand names, and approved usage of didanosine areshown in Fig. 2.4. In 1993, a partially randomized study compared zidovudine alone versus different combination regimens of zidovudine and didanosine. The results showed more sustained increases in CD4-positive cell counts and more frequent decreases in plasma HIV-1 RNA titers among all...

Neutropenia

Alopecia, erythema, macules, papules, pruritis, and urticaria have been seen rarely with lamivudine 65 . Pediatric patients. In pediatric clinical trials, 14 of children on monotherapy and 15 of those on combination therapy with lamivudine developed pancreatitis. Mucocutaneous manifestations. When mucocutaneous manifestations are seen with Combivir, there appears to be an equal chance that zidovudine or lamivudine may be responsible. Lamivudine resistance. One of the...

Zalcitabine [ddC Hivid

Zalcitabine ddC , another synthetic nucleoside analogue, has minimal efficacy when used alone, but is useful for combination therapy in HIV patients. The structure, brand names, and approved usage for zalcitabine are shown in Fig. 2.6. Zalcitab-ine is a reverse transcriptase inhibitor. It is indicated, along with zidovudine, for patients with deteriorating HIV infection according to both clinical and immunological parameters CD4 lt 300 ml . The oral dosage is 0.75 three times daily. Most...

Investigational Drugs

At the time of this writing, there are 23 new antiretroviral agents under current development and study. Five nucleoside analogues, six NNRTIs and seven PIs show promise based on early study results. New classes of antiretroviral drugs are currently under investigation, with possible alternative mechanisms for effective therapy against HIV. Zintevir AR177 is the main compound under development as an integrase inhibitor 313 . In vitro, this compound is a potent inhibitor of the HIV integrase...