Quick reference guide to antiretrovirals

Author: Malte Schütz, MD
Quick Reference Guide to Antiretrovirals
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Guide to Antiretroviral Agents
Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and Nucleotide RTIs (NtRTIs)
Comments and Common Side Effects
About 4% hypersensitivity reaction: fever, malaise, possible rash, GI, respiratory. Resolves within 2 days after discontinuation. DO NOT RECHALLENGE. Also: rash alone without hypersensitivity. Peripheral neuropathy in 15%, rare pancreatitis; avoid alcohol. OK to take at same time as other antiretrovirals that can be taken on an empty stomach. Older chewable tablet formulation has additional restrictions. Generally well tolerated. Active against HBV. Peripheral neuropathy (1%-4% in early studies; 24% in expanded access Peripheral neuropathy in 17%-31% of trial participants; oral ulcers. Used rarely due to toxicity, inconvenient dosing, and questions regarding efficacy. Initial nausea, headache, fatigue, anemia, neutropenia, neuropathy, Combination tablet containing ZDV 300 mg and 3TC 150 mg. Combination tablet containing ZDV 300 mg, 3TC 150 mg, and ABC 300 mg. Generally well tolerated. Active against HBV. Significant interaction with ddI Protease Inhibitors (PIs)
Comments and Common Side Effects
Kidney stones in 6%-8%: good hydration essential. Occasional nausea and GI upset. Store in original container which contains desiccant; without this, IDV is stable for only about 3 days. GI side effects common but mild. Hyperlipidemias. Nausea, diarrhea, numb lips; occasional hepatitis. Hyperlipidemias. Store capsules in refrigerator. Stable at room temperature for up to 1 month. Used at lower dosages as Soft gel formulation with improved absorption. Long-term storage (6 cap) 3x/d with fatty food (>28 g) * in refrigerator. Stable at room temperature for 3 mo. Hard gel formulation with poor absorption. Bioequivalent to Fortovase when combined with RTV. Smaller tablet size and easier * Frequently dosed with ritonavir to simplify administration and raise drug levels. See Drug-Drug Combinations section for details. Guide to Antiretroviral Agents (Cont.)
Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Comments and Common Side Effects
Transient rash. P450 3A4 inhibitor. 600 mg twice daily dosing being studied. Coadministration with gastric acid lowering agents decreases absorption. Initial dizziness, insomnia, transient rash, P450 3A4 inducer; avoid Transient rash, hepatitis à monitor LFTs. P450 3A4 inducer. Once-daily dosing recommendation based on limited clinical data. Ribonucleotide Reductase Inhibitors
Comments and Common Side Effects
Bone marrow suppression, aphthous ulcers, hair loss, peripheral neuropathy, hepatotoxicity. Augments ddI and d4T and their toxicities. No direct antiviral effect. Drug-Drug Combinations
This table gives an overview of current knowledge of drug-drug combinations. The Abbreviations
NRTIs are not listed since they do not require dose adjustments when combined. In contrast, PIs and NNRTIs tend to have complex metabolism and in combinations affect each other’s drug levels and potency. The knowledge on these combinations is still evolving, and few formal dose modification recommendations are available. Caution and close monitoring are advised. Treating physicians should verify all information with an AIDS specialist and check * Comments on each combination are given below. Lopinavir/
Tenofovir/didanosine interaction
Tenofovir increases ddI (EC) Cmax by +49% itonavir
2 hours. When coadministered with food the effect is enhanced (Cmax +64%; AUC +60%). Indinavir
Studies evaluating dose reduction of ddI are in Contraindicated Combinations
ZDV + d4T combination is antagonistic in vivo ddI and ddC should not be combined due to increased risk of peripheral neuropathy IDV + SQV combination is antagonistic in vitro and in practice extremely difficult to dose Comments on Drug-Drug Combinations
NVP decreases IDV levels by 30%. (IDV decrease is most pronounced in patients with a high IDV level within the IDV & NVP
interpatient variability of IDV levels). Consider IDV dosage increase, eg, 1 000 mg every 8 hours (5th CROI, 1998). The addition of RTV can prevent this interaction (see #23). LPV/RTV &
Decrease in LPV Cmin by 35% -40% and AUC by 20%-25%; considered not significant in patients naive to PIs. If PI resistance suspected, consider LPV dose increase to 533/133 mg (4 cap) 2x/d (Abbott data, 2000). Steady-state studies indicate no significant changes in NVP or NVP levels, suggesting standard doses of each (5th NFV & NVP
NVP decreases RTV levels by 11%, not requiring dose adjustment. SQV-hard gel AUC decreased by 27%, which is of concern as SQV-hard gel by itself reaches marginal levels only. SQV & NVP
No effect on NVP level. No data on nevirapine and SQV-soft gel formulation. Decrease in EFV AUC by 22% and EFV Cmin by 36%; NVP levels unchanged; dose increase of EFV to 800 mg 1x/d NVP & EFV
being discussed, but no safety data are available for this dose (7th CROI, 2000). Decrease in APV Cmax by 36%, AUC by 39%, and Cmin by 43% (5th CROI, 1998). See comments 22 and 25 below APV & EFV
EFV decreases IDV AUC by 31% and Cmax by 16%; consider dose increase to IDV 1000 mg every 8 hours (ICAAC, IDV & EFV
1998). The addition of RTV can prevent this interaction (see #23) LPV/RTV &
Decrease in LPV Cmin by 35%-40% and AUC by 20%-25%; considered not significant in patients naive to PIs. If PI resistance suspected, consider LPV dose increase to 533/133 mg (4 cap) 2x/d (Abbott data, 2000). EFV increases NFV level by 20%. No change in EFV level. Clinical efficacy documented in several studies with 10 NFV & EFV
standard dose of both drugs (6th CROI, 1999). EFV increases RTV AUC by 18% and Cmax by 24%. No dose adjustment for EFV necessary. Consider dose 11 RTV & EFV
reduction of RTV. Monitor LFTs (ICAAC, 1998). See comment 21 for further dosing options. EFV decreases SQV-S AUC by 62% and Cmax by 50%. Avoid combination with SQV as sole PI (ICAAC, 1998). See 12 SQV & EFV
DLV increases APV Cmax/AUC/Cmin by 1.3-fold/4-fold/6-fold, respectively (Glasgow, 2000). APV decreases DLV 13 APV & DLV
Compared with IDV 800 mg 3x/d alone, IDV 400 or 600 mg with DLV 400 mg 3x/d leads to increase in IDV Cmin of 140% and 400% respectively. IDV 1200 mg with DLV 600 mg 2x/d with food increases IDV Cmin/AUC/Cmax by 14 IDV & DLV
0%/+40%/+70%. Consider dosing IDV 600 mg with DLV 400 mg 3x/d, or IDV 1200 mg with DLV 600 mg 2x/d with or without food (ICAAC, 1999, Glasgow, 2000). 15 NFV & DLV
Increase in NFV levels by 113%. 40% decrease in DLV AUC (Pharmacia & Upjohn data 8/98). DLV increases RTV levels by 70%. May merit RTV dose reduction, eg, 400 mg 2x/d. Limited data (5th CROI, 1998, 16 RTV & DLV
DLV dosed 400 mg 3x/d or 600 mg 2x/d decreases SQV clearance by 63%, resulting in increase in SQV 17 SQV & DLV
AUC/Cmin/Cmax. Dose of SQV 1400 mg 2x/d or 1000 mg 3x/d with DLV 600 mg 2x/d or 400 mg 3x/d being evaluated (7th CROI, 2000). Decrease in APV Cmax/AUC/Cmin by 37%/32%/14%, respectively, and increase in SQV Cmax by +21%, but 18 APV & SQV
decrease of SQV AUC by 19% and Cmin by 48% (Geneva, 1998). Triple interaction SQV/RTV/APV currently being studied. LPV/RTV &
SQV 1000 mg 2x/d with standard-dose LPV showed sustained SQV levels equivalent to dosing of SQV/RTV 1000/100 mg 2x/d and unchanged LPV levels with good viral efficacy (Pharmacology Workshop, 2002). NFV increases SQV-S levels 3-fold or higher. Consider dosage of NFV 750 mg + SQV-S 800 mg 3x/d, or NFV 1250 20 NFV & SQV
mg + SQV-S 1200 mg 2x/d (under study) (6th CROI, 1999). RTV increases SQV levels 3-fold or higher. Good results from studies of 400 mg 2x/d for each drug. No food effect of this combination. Addition of EFV to RTV/SQV 400 mg 2x/d does not significantly change levels (7th CROI, 2000; RTV, SQV &
ICAAC, 2001). SQV 1000 mg/RTV 100 mg 2x/d results in similar SQV levels. Once-daily SQV/RTV (1600/100 mg) with food showed good clinical efficacy (IC AAC, 2001). Soft-gel or hard-gel caps appear bioequivalent in all dosage combinations with RTV (9th CROI, 2002; Pharmacology Workshop, 2002). RTV increases APV levels significantly, ie, APV 1200 mg with RTV 200 mg 2x/d increases APV Cmax/AUC/Cmin by +33%/+131%/+680%. The addition of EFV 600 mg 1x/d to this combination results in Cmax -9%, AUC +8% and APV, RTV &
Cmin +27% (Falloon, 1999; Lamotte, 2000). APV decreases RTV Cmin 3 -fold compared with RTV Cmin in RTV/IDV or RTV/SQV combinations, which may affect the levels of other PIs added to APV/RTV combination (Pharmacology Workshop, 2001). FDA-approved dose: APV/RTV 600/100 mg 2x/d or 1200/200 m g 1x/d. Comments on Drug-Drug Combinations (Cont.)
RTV increases IDV AUC up to +480%. Compared with IDV alone, 400 mg of both drugs 2x/d leads to same IDV peak and higher trough levels and acts as true dual-PI combo. No reports of nephrolithiasis in this combination. 23 IDV & RTV
IDV/RTV 800/100 mg or 800/200 mg 2x/d augments IDV to higher peak and trough levels without antiviral activity of RTV. No significant food effect on IDV absorption with either dose combination. Other dose combinations under study (6th CROI, 1999). The addition of NVP or EFV to IDV/RTV does not significantly lower IDV levels (ICAAC, 2001). Addition of RTV to LPV/r increases LPV concentration. Studies in progress. RTV Cmin is 3 -fold lower in LPV/RTV LPV/RTV &
combination compared with 100 mg RTV 2x/d in IDV/RTV or SQV/RTV combination (Pharmacology Workshop, RTV increases level of NFV and NFV M8 metabolite. NFV/RTV 2000/200 mg 1x/d increases combined NFV + M8 Cmin/AUC/Cmax by 50% compared with NFV 1250 mg 2x/d in HIV neg. volunteers Rashes noted (Pharmacology 25 NFV & RTV
Workshop, 2001). RTV 400 mg with NFV 500 mg or 750 mg 2x/d results in NFV AUC equivalent to standard dose. Higher dose results in higher AUC of M8, but also lower RTV level. Limited clinical data (6th CROI, 1999). Full dose of APV+NFV results in decrease in APV Cmax by -14%, but increase in AUC by +46% and Cmin by +235%. APV, NFV &
No significant effect on NFV levels. The addition of EFV 600 mg 1x/d resulted in same APV Cmax and AUC and mild reduction of Cmin by -14%. Consider dosing APV/NFV or APV/NFV/EFV at full dose of each drug (7th CROI, 2000). NFV increases IDV level by 51%; IDV does not affect NFV level. NFV/IDV 1250/1200 mg 2x/d with a low-fat snack on 27 IDV & NFV
em pty stomach shows good drug levels and clinical efficacy (6th CROI, 1999). LPV/RTV &
Limited data from single-dose PK suggests unchanged NFV AUC, but increase in NFV Cmin and M8 metabolite. Coadministration of APV 450-750 mg with standard dose LPV/ RTV 2x/d results in significant decrease of APV Cmin LPV/RTV &
by 220-420% and trend to lower LPV Cmin, compared with APV/RTV 100 mg or LPV/RTV alone from historical controls. Additional RTV 100 mg 2x/d did not compensate for this interaction (Pharmacology Workshop, 2001). Interaction confirmed by additional studies (ICAAC , 2001; 9th CROI, 2002). LPV/RTV &
Single-dose PK show increase in IDV level; IDV dose reduction suggested (Abbott data, 2000). Small case series reported IDV 800 mg or 600 mg 2x/d with standard-dose LPV/RTV (Pharmacology Workshop, 2002). Increase in APV Cmax/AUC/Cmin by +18%/+32%/+25%, respectively, and decrease in IDV Cmax by -22%, AUC by - 31 APV & IDV
38% and Cmin by -27% (GlaxoWellcome data, 1999). Guide to Antiretroviral Resistance Mutations
These tables give an overview of mutations associated with resistance to antiretrovirals. Interaction between mutations is complex and cannot be fully represented in a concise table format; thus, use of interpretation software is strongly recommended (eg, the Stanford algorithm available at http://hivdb.stanford.edu/hiv/ -- click "Mutation list analysis"). The table below reflects data published by the International AIDS Society--USA on November 24, 2001, available at http://www.iasusa.org/resistance_mutations/index.html and may aid in the interpretation of genotypic analysis results. Results of genotypic testing always indicate mutations in the majority virus population only (>20%). Mutations caused by previous antiretrovirals may only be present in minority virus populations and may thus not be detected, but may re-emerge if the drug(s) in question is resumed. Thus, any mutations reported by previous genotypic testing of a given patient should be taken into account when deciding on future treatment. Nucleoside and Nucleotide Reverse Transcriptase Inhibitors
A mutation at codon 75 has been associated with d4T resistance in vitro
* Multi-NRTI resistance: the 151 complex
** Multi-NRTI resistance: the 69 insertion complex
*** Nucleoside-associated mutations (NAMs) associated with cross-resistance among NRTIs except 3TC, and cross-resistance with tenofovir (if 4 or
more are present). These are also indicated in parentheses in the rows for specific NRTIs affected
Nonnucleoside Reverse Transcriptase Inhibitors
* Either of these mutations is associated with substantially reduced efficacy of all currently available NNRTIs ** Accumulation of 2 or more of these mutations can be associated with cross-resistance to all currently available NNRTIs Protease Inhibitors
Note: Underlined mutations are primary resistance mutations for that agent; other mutations are secondary resistance mutations. Mutations have not yet been categorized as primary or secondary for lopinavir/ritonavir * Only the presence of multiple mutations is associated with diminished response to lopinavir/ritonavir ** Accumulation of 4-5 or more of these mutations will probably cause multi-PI resistance Legal disclaimer: This guide has been developed solely as an educational resource for healthcare professionals. The information presented here
represents the views of the author only and not Medscape, Inc. These materials may discuss uses and dosages for therapeutic products that have not
been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic
product discussed.
Medscape, Inc, 2002. Online version: http://hiv.medscape.com/updates/quickguide

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