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 disease during pregnancy through cross-contamination with the mother's body secretions or blood during delivery, or during breast-feeding.

When initially infected, patients usually have normal CD4 cell numbers, a low viral load, and an immunological response that indicates a prevalence of Th 1 lymphocytes. With advanced infection, CD4 levels fall, viral loads rise, and Th 2 lymphocytes are predominant. The Th 2 lymphocytes enhance humoral immunity and produce IL-4, IL-5, IL-10, and allergic responses. As CD4 levels fall, patients are bombarded with a variety of organisms as immunological responses decline. Many patients develop previously "rare" diseases due to viruses, bacteria, parasites, and fungi as well as neoplastic and other noninfectious disorders.

Interventions for HIV. Mechanistic analyses of the replication of HIV infection within a patient have revealed several

Table 2.1 Adverse Effects and Drug Interactions of Antiretroviral Agents

Antiretroviral drug

Mucocutaneous side effects

Nondermatologic side effects

Concomitant drugs to avoid

Zidovudine Longitudinal melonychia; skin AZT pigmentation, macules, papules, pruritis, urticaria

Didanosine Erythema, macules, papules; oral ddl and esophageal ulcers; Ofuji papuloerythroderma

Stavudine Erythema, macules, papules;

D4T esophageal ulcers

Zalcitabine Macules, papules, oral ulcers, ddc esophageal ulcers

Lamivudine Alopecia, erythema, macules, 3TC papules, pruritis, urticaria

Bone marrow suppression (anemia, neutropenia); gastrointestinal upset (nausea); neuropathy, hepatotoxicity, myopathy, myositis Pancreatitis; peripheral neuropathy; fever; malaise

Peripheral neuropathy; lactic acidosis; hepatomegaly with steatosis

Peripheral neuropathy, severe pancreatitis, severe lactic acidosis, severe hepatomegaly with steatosis

Peripheral neuropathy, nausea/ vomiting, anorexia, headache, malaise, neutropenia, pancreatitis

Any that suppress bone marrow

Any that cause pancreatitis; quinolone antibiotics and azole antifungals must not be given within 2 hours before or within 6 hours after ddl Same as for AZT

Cimetidine, metoclopramide, A1 and Mg OH antacid preparations; probenacid

Any that cause pancreatitis

Abacavir Hypersensitivity reaction;

ABC macules, papules, urticaria

Emtricitabine Hyperpigmentation

Nevirapine Erythematous macules and NVP papular eruption; Stevens-

Johnson syndrome

Delavirdine Erythematous macular and DLV papular exanthem +/- pruritis;

Stevens-Johnson syndrome, erythema multiforme

Hypersensitivity reaction; Fever, fatigue, malaise, nausea, vomiting, diarrhea, abdominal pain, arthralgias, cough, dyspnea Headache, abdominal pain, diarrhea, nausea, vomiting, fatigue

Hepatic reaction

Alcohol

Fever, arthralgias

Ketoconazole and oral contraceptives, dose adjustments for other drugs metabolized by cytochrome P450 system (especially isozyme (CYP3A) (e.g. protease inhibitors and rifampin)

Drugs metabolized by CYP3A pathway (clarithomycin, cisopride, terfenadine, astemazole, warfarin, protease inhibitors, certain benzodiazepines, certain calcium channel blockers, certain anticonvulsants and antimycobacterial agents, high fat meals, antacids, certain H2-receptor antagonists

Table 2.2 (Continued)

Antiretroviral drug

Mucocutaneous side effects

Nondermatologic side effects

Concomitant drugs to avoid

Efavirenz EFV

Tenofovir

Saquinavir SQV

Ritonavir RTV

Morbilliform or macular and papular eruptions; Less common: blistering, desquamation, ulceration; Rare: Stevens-Johnson syndrome; erythema mutliforme

Fat redistribution, wasting appearance, protease pouch, buffalo hump, crix belly

Macules, papules and others listed under SQV

Central nervous system or psychiatric symptoms: dizziness, somnolence, insomnia, confusion, impaired concentration, amnesia, agitation, euphoria, hallucinations, abnormal dreaming, abnormal thinking Nausea, vomiting, diarrhea, flatulence, osteopenia, lipodystrophy, renal toxicity Lipodystrophy syndrome, hyperlipidemia, hyperglycemia, probable coronary artery disease, new onset diabetes mellitus, diarrhea, nausea, abdominal discomfort, dyspepsia

Nausea/vomiting, fever, diarrhea, circumoral paresthesias, peripheral paresthesias, taste perversion, hepatitis, hypermenorrhea and others listed under SQV

Drugs metabolized by CYP3A pathway: astemizole, cisapride, midazolam, triazalam, clarithromycin, ergot derivatives, rifampin, phénobarbital

Any that decrease renal function

Vitamin A supplements; drugs metabolized by CYP3A enzymes; terfenadine, cisapride, triazolam, midazolam, ergot derivatives

Drugs metabolized by cytochrome P450 system (e.g., astemizole; certain antiarrythmics as quinidine, amiodarone, encainide, flecainide; certain sedative/ hypnotics as diazepam and flurazepam) as well as others listed under SQV

Indinavir IDV

Nelfinavir NFV

Amprenavir APV

Lopinavir

Erythematous macules and papules, dry skin, alopecia, paronychia, pyogenic granulomas and others listed under SQV; rare: Stevens-Johnson syndrome Same as listed under SQV

Macules and papules +/- pruritis; Rare: Stevens-Johnson syndrome; others as listed under SQV As listed under SQV

Fosamprenavir "Rash" 1% develop Stevens-GW 433908 Johnson syndrome

Atazanavir BMS-232632 Enfuviritide ENF, T-20

Injection site reactions

Nephrolithiasis, renal insufficiency or renal failure; pharyngitis, gastrointestinal upset, anemia, hepatitis and other listed under SQV and RTV

Diarrhea and other as listed under SQV and RTV Perioral paraesthesias, diarrhea, headache, nausea/vomiting and others listed under SQV and RTV Diarrhea and others listed under SQV and RTV Nausea, diarrhea

Diarrhea, jaundice

Allergic reactions, pain or numbness in feet or legs, decreased appetite, weakness, constipation, pancreatitits

Same as listed under SQV and RTV

Same as listed under SQV and RTV

As listed under SQV and RTV

As listed under SQV and RTV

Sulfonamide, lovastatin, simavastatin, triazolam, midazolam, ergot-based drugs, cisapride, pimozole

Iron Cycle Diagram

Fig. 2.2 Sites of action of antiretroviral drugs. Nucleoside, nucle-otide and non-nucleoside reverse transcriptase (RT) inhibitors act at the same step in the replication of HIV. Nucleoside analogues, when phosphorylated, competitively inhibit RT by acting as an alternative substrate for the enzyme. Non-nucleoside analogues do not require phosphorylation but noncompetitively bind directly to the active site of RT. Protease inhibitors prevent the cleavage of viral polyproteins in the final stage of viral protein processing, thus preventing the assembly of mature HIV virions. Fusion inhibitors prevent binding to the surface of the cell and subsequent infection of the cell.

Fig. 2.2 Sites of action of antiretroviral drugs. Nucleoside, nucle-otide and non-nucleoside reverse transcriptase (RT) inhibitors act at the same step in the replication of HIV. Nucleoside analogues, when phosphorylated, competitively inhibit RT by acting as an alternative substrate for the enzyme. Non-nucleoside analogues do not require phosphorylation but noncompetitively bind directly to the active site of RT. Protease inhibitors prevent the cleavage of viral polyproteins in the final stage of viral protein processing, thus preventing the assembly of mature HIV virions. Fusion inhibitors prevent binding to the surface of the cell and subsequent infection of the cell.

avenues for therapy. These include inhibitors that are active during the binding, fusion, and entry of the viral capsid into the cell. Then, during RNA replication, reverse transcriptase drugs interfere with RNA replication. Viral integrase drugs (of which there are none approved at this writing) interfere with entry into the nucleus. Another potential, but not yet having any approved drugs, target would be the viral zinc-finger nucleocapsid proteins. Finally, viral protease inhibitors attack the virus as it leaves the cell to infect other cells. (See Fig. 2.2)

Treatments for HIV. There is no known "cure" for HIV disease. The initial regimen programs for HIV began with nucleoside reverse transcriptase inhibitors (NRTIs) in 1987 and therapy was with one drug, zidovudine Over time, it became obvious that as HIV replicated, it also mutated. This meant that therapy began to fail. Progress (rising CD4+ counts and lowered HIV RNA levels) began to unravel. Other drugs, administered individually, were no better. However, combinations of antiret-roviral drugs provided a "cocktail" that attacked the virus at multiple points (12). This HAART became the standard of care in 1996 in developed countries where insurance or government health care pays for the nearly $20,000 bill for drugs prescribed for a patient each year. In developing countries, however, mono-therapy may be the only option, if any antiretroviral therapy is available. Figures 2.1 and 2.2 illustrate the available therapies that can be used in HAART and their sites of action.

Typically HAART consists of two nucleoside analogues and a protease inhibitor (PI) or a non-nucleoside reverse tran-scriptase inhibitor (NNRTI). Today there is an armada of anti-retrovirals in the arsenal with many more being developed (Fig. 2.2). Nucleotide and nucleoside reverse transcriptase inhibitors, PIs, and NNRTIs have been joined by fusion inhibitors. Selecting the appropriate therapy, however, is no longer a simple matter.

There have been several suggested therapy cocktails consisting of three or even four antiretrovirals taken concurrently. The "original combination therapy" called for two NRTIs administered with one NNRTI or a PI. (13,14)

Recent studies indicate that a combination of three anti-virals appears most efficacious and that efavirenz, lamivu-dine, and zidovudine provide the best combination for patients receiving their first HIV medication. At this time, lamivudine and zidovudine are available as a combination pill (Com-bivir®). This combination drug, administered with efavirenz, means patients take only three pills/day with a concomitant increase in patient compliance.

If resistance is detected, the patient and doctor must consider other antiretroviral drugs as alternative therapy. The options may appear numerous, but many factors enter into the picture. Once resistance occurs, other related drugs may demonstrate cross-resistance. Allergies to one drug usually transfer to other drugs in the same category. Concomitant non-antiretroviral drugs also must be considered. For example, prescribing a drug known to cause hepatic toxicity might prove to be risky to a patient with any type of hepatitis. Likewise, any drug that affects liver metabolism must be used with extreme care if given along with other agents metabolized by the liver.

Controversy still exists regarding the optimal time to initiate therapy due to the cost of treatment, the side effects, and the difficulty with compliance which results in potential resistance. Newly revised guidelines on treating adults and adolescents with HIV and AIDS provide suggestions for regimens that are more definitive. The guidelines were prepared by the Panel on Clinical Practices for Treatment of HIV Infection, convened by the Department of Health and Human Services. For the first time, the guidelines include lists of "preferred" and "alternative" regimens. These lists are available at http://aidsinfo.nih.gov; the document also lists regimens or components that should never be offered.

The preferred regimen based on NNRTIs calls for a combination of efavirenz, lamivudine, and zidovudine, tenofovir or stavudine, except for women who are pregnant or may become pregnant. Patients on this regimen take three to five pills per day.

The preferred regimen based on PIs calls for a combina-tioin of lopinavir/ritonavir (coformulated as Kaletra®) together with lamivudine and either zidovudine or stavudine. Patients on this regimen take 8 to 10 pills per day.

Triple NRTI regimens should be used only when an NNRTI- or PI-based regimen cannot be used as first-line therapy. The panel's preferred triple-NRTI regimen calls for a combination of abacavir, lamivudine, and either zidovudine or stavudine. Patients on this regimen take two to six pills per day. Regimens listed as "alternative" in the guidelines, however, may actually be the preferred regimen for a specific patient.

The panel listed 12 regimens or components that should never be offered. Several, including monotherapy and dual nucleoside therapy, had been listed as contraindicated in previous versions of the guidelines. The newly listed contraindicated regimens are a three-NRTI regimen with abacavir, tenofovir, and lamivudine (because of early virologic nonresponse); a three-NRTI regimen with didanosine, tenofovir, and lamivu-dine (because of a high rate of virologic failure); the combination of didanosine and stavudine (because of a high incidence of toxicities, including several deaths); the combination of atazanavir and indinavir (both of which can cause high-grade hyperbiliru-binemia and jaundice); and emtricitabine plus lamivudine as a two-NRTI backbone (since both drugs have similar resistance profiles and minimal additive antiviral activity).

The guidelines found at www.hivatis.org recommend initiation of treatment for all HIV-infected persons who have symptoms of HIV infection, a rapidly declining CD4 count, a CD4 count <200-350 cells/mm3, or a viral load >30,000 RNA copies/ml (bDNA assay) or 55,000 RNA copies ml (RT-PCR assay) (regardless of the CD4 count) (15).

Guidelines are less established for pediatric patients, but it is generally recommended that therapy be initiated in children with clinical symptoms of HIV infection or evidence of immunosuppression, regardless of viral load. However, any child with HIV RNA levels >100,000 copies/ml is at a high risk for mortality, and antiretroviral therapy should be started. Others recommended starting therapy in children at HIV RNA levels >10,000-20,000 copies/ml. Zidovudine (AZT) monotherapy is indicated only for infants of indeterminate HIV status during the first six weeks of life to prevent perinatal HIV transmission (16).

Even combination therapy has many side effects that HIV-infected persons must tolerate. Side effects and the required number of pills to be taken daily affect patient compliance. Even missing 5% of one's pills may put a patient at risk for drug resistance. These factors have led to the development of more potent and safer antiretroviral agents. Although resistance is less likely with HAART than with monotherapy, it remains a problem.

Combination therapies. To address the need for fewer pills, pharmaceutical companies have begun to market combination therapies. Three of these are currently marketed. Zidovudine and lamivudine are marketed as Combivir. A combination of abacavir, zidovudine, and lamivudine is marketed as Trizivir®. Lopinavir, which was approved only as a combination drug with ritonavir, is marketed in this combination as Kaletra.

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