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Chapter 93Chapter 93

Antiviral Agents II: Drugs for HIV Antiviral Agents II: Drugs for HIV Infection and Related Opportunistic Infection and Related Opportunistic

InfectionsInfections

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Drugs for HIV Infection and Related Drugs for HIV Infection and Related Opportunistic InfectionsOpportunistic Infections

Human immunodeficiency virus is a retrovirus Human immunodeficiency virus is a retrovirus (HIV-1 and HIV-2)(HIV-1 and HIV-2)

HIV has RNA as genetic materialHIV has RNA as genetic material Uses reverse transcriptase to convert RNA Uses reverse transcriptase to convert RNA

into DNA and integrase to Insert its DNA into into DNA and integrase to Insert its DNA into oursours

Target cells: CD4 T cells (helper Target cells: CD4 T cells (helper lymphocytes)lymphocytes)

Transmission Transmission – – blood and body fluidsblood and body fluids Virus present in all body fluidsVirus present in all body fluids

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Human Immunodeficiency VirusHuman Immunodeficiency Virus

Promotes immunodeficiency by killing CD4 T Promotes immunodeficiency by killing CD4 T lymphocyteslymphocytes

Difference between HIV and AIDSDifference between HIV and AIDS Global epidemicGlobal epidemic Standard antiretroviral therapy (ART)Standard antiretroviral therapy (ART)

Reduced AIDS deaths by 72%Reduced AIDS deaths by 72% HAART – highly active antiretroviral therapyHAART – highly active antiretroviral therapy

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Fig. 93-1. Structure of the human immunodeficiency virus.Note that HIV has two single strands of RNA, and that each strand is associated with a moleculeof reverse transcriptase. (gp 41 = glycoprotein 41, gp120 = glycoprotein 120.)

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Fig. 93-2. Replication cycle of the human immunodeficiency virus.See text for description of events. (CCR5 = CCR5 co-receptor, CD4 = CD4 receptor, CXCR4 = CXCR4 co-receptor, dsDNA = double-stranded DNA, gp120 = glycoprotein 120, mRNA = messenger RNA, ssDNA = single-stranded DNA, ssRNA = single-stranded RNA.)

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Classification of Antiretroviral DrugsClassification of Antiretroviral Drugs

Five types of antiretroviral drugsFive types of antiretroviral drugs Inhibit enzymes required for HIVInhibit enzymes required for HIV

Reverse transcriptase inhibitorsReverse transcriptase inhibitors Integrase inhibitorsIntegrase inhibitors Protease inhibitorsProtease inhibitors

Block viral entry into cellsBlock viral entry into cells Fusion inhibitorsFusion inhibitors CCR5 antagonistsCCR5 antagonists

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Nucleoside Reverse Transcriptase Nucleoside Reverse Transcriptase Inhibitors (NRTIs)Inhibitors (NRTIs)

Zidovudine (Retrovir)Zidovudine (Retrovir) Inhibits HIV replication by suppressing synthesis Inhibits HIV replication by suppressing synthesis

of viral DNAof viral DNA Adverse effectsAdverse effects

Anemia and neutropeniaAnemia and neutropenia Lactic acidosis/hepatic steatosis (rare)Lactic acidosis/hepatic steatosis (rare) Gastrointestinal effectsGastrointestinal effects CNS reactionsCNS reactions

Drug interactionsDrug interactions

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Non-Nucleoside Reverse Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)Transcriptase Inhibitors (NNRTIs)

Differ from the NRTIs in structure and Differ from the NRTIs in structure and mechanism of actionmechanism of action

NNRTIs bind to the active center of reverse NNRTIs bind to the active center of reverse transcriptase and cause direct inhibitiontranscriptase and cause direct inhibition

Active as they are administeredActive as they are administered See Table 93-4See Table 93-4

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Non-Nucleoside Reverse Transcriptase Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)Inhibitors (NNRTIs)

Efavirenz (Sustiva)Efavirenz (Sustiva) Nevirapine (Viramune)Nevirapine (Viramune) Delavirdine (Rescriptor)Delavirdine (Rescriptor) Etravirine (Intelence)Etravirine (Intelence)

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NNRTIsNNRTIs

Efavirenz (Sustiva)Efavirenz (Sustiva) Preferred agent for treating HIVPreferred agent for treating HIV

Only NNRTI recommended for first-line Only NNRTI recommended for first-line therapy for HIV infectiontherapy for HIV infection

Drug interactionsDrug interactions Adverse effectsAdverse effects

TeratogenicityTeratogenicity Transient adverse CNS effects in 50% of patientsTransient adverse CNS effects in 50% of patients RashRash

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Protease InhibitorsProtease Inhibitors

Among the most effective antiretroviral drugs Among the most effective antiretroviral drugs availableavailable

Used in combination with NRTIs – can reduce Used in combination with NRTIs – can reduce viral load to an undetectable levelviral load to an undetectable level

ResistanceResistance Drug interactionsDrug interactions

P450 inhibitorsP450 inhibitors P450 inducersP450 inducers P450 substratesP450 substrates Herb interactionsHerb interactions

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Protease InhibitorsProtease Inhibitors

Adverse effectsAdverse effects Hyperglycemia/diabetesHyperglycemia/diabetes Fat malredistributionFat malredistribution HyperlipidemiaHyperlipidemia Reduced bone densityReduced bone density HepatotoxicityHepatotoxicity Increased bleeding in hemophiliacsIncreased bleeding in hemophiliacs Reduced bone mineral densityReduced bone mineral density Elevation of serum transaminaseElevation of serum transaminase

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Protease InhibitorsProtease Inhibitors

Lopinavir/ritonavir (Kaletra)Lopinavir/ritonavir (Kaletra) Ritonavir (Norvir)Ritonavir (Norvir) Indinavir (Crixivan)Indinavir (Crixivan) Saquinavir (Invirase, Fortovase)Saquinavir (Invirase, Fortovase) Nelfinavir (Viracept)Nelfinavir (Viracept) Amprenavir (Agenerase)Amprenavir (Agenerase)

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Protease InhibitorsProtease Inhibitors

Fosamprenavir (Lexiva)Fosamprenavir (Lexiva) Atazanavir (Reyataz)Atazanavir (Reyataz) Tipranavir (plus Ritonavir)Tipranavir (plus Ritonavir) Darunavir (plus Ritonavir)Darunavir (plus Ritonavir)

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HIV Integrase Strand Transfer HIV Integrase Strand Transfer InhibitorsInhibitors

Raltegravir (Isentress) approved in 2007Raltegravir (Isentress) approved in 2007 First and only member of this new class of First and only member of this new class of

antiretroviral drugsantiretroviral drugs Adverse side effectsAdverse side effects

Diarrhea, nausea, fatigue, headache, and itchingDiarrhea, nausea, fatigue, headache, and itching FDA Pregnancy Risk Category CFDA Pregnancy Risk Category C

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Enfuvirtide (Fuzeon)Enfuvirtide (Fuzeon)

HIV fusion inhibitorHIV fusion inhibitor Widely known as T-20Widely known as T-20 First and only HIV fusion inhibitorFirst and only HIV fusion inhibitor Blocks entry of HIV into CD4 T cellsBlocks entry of HIV into CD4 T cells BID subQ dosing costs $20,000 a year BID subQ dosing costs $20,000 a year Adverse effectsAdverse effects

Injection site reactions, pneumonia, and Injection site reactions, pneumonia, and hypersensitivity reactions hypersensitivity reactions

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Maraviroc (Selzentry)Maraviroc (Selzentry)

CCR5 antagonistCCR5 antagonist Approved in 2007Approved in 2007 Indicated only for combined use with other Indicated only for combined use with other

antiretroviral drugs in treatment-experienced antiretroviral drugs in treatment-experienced adults infected with CCR5-tropic HIV-1 strains adults infected with CCR5-tropic HIV-1 strains that are resistant to multiple drugsthat are resistant to multiple drugs

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Laboratory Monitoring for HIV Laboratory Monitoring for HIV Infection and Drug Therapy Infection and Drug Therapy

Viral load (plasma HIV RNA)Viral load (plasma HIV RNA) Best measurement for predicting clinical outcomeBest measurement for predicting clinical outcome

CD4 T-cell countsCD4 T-cell counts

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HIV Treatment in PregnancyHIV Treatment in Pregnancy

Same principles that guide antiretroviral Same principles that guide antiretroviral therapy in nonpregnant adultstherapy in nonpregnant adults

Mother-to-child transmission HIVMother-to-child transmission HIV Occurs primarily during labor and deliveryOccurs primarily during labor and delivery Risk for transmission can be greatly reduced by Risk for transmission can be greatly reduced by

ART, which minimizes maternal viral loadART, which minimizes maternal viral load The same general principles also apply to The same general principles also apply to

childrenchildren

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TreatmentTreatment

Prophylactic drugs can reduce the risk for Prophylactic drugs can reduce the risk for infection after accidental exposureinfection after accidental exposure

Advanced HIV disease may need Advanced HIV disease may need prophylactic antibiotics because of decreased prophylactic antibiotics because of decreased CD4 T cell countsCD4 T cell counts

PCP most common opportunistic infectionPCP most common opportunistic infection Trimethoprim plus sulfamethoxazoleTrimethoprim plus sulfamethoxazole