Quick Reference Guide to Antiretrovirals

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February 11, 2002

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Guide to Antiretroviral Agents

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and Nucleotide RTIs (NtRTIs)

Generic Brand Dose Comments and Common Side Effects
Abacavir (ABC) Ziagen 300 mg 2x/d About 4% hypersensitivity reaction: fever, malaise, possible rash, GI, respiratory. Resolves within 2 days after discontinuation. DO NOT RECHALLENGE. Also: rash alone without hypersensitivity.
Didanosine (ddI) Videx EC 400-mg capsule 1x/d on empty stomach (>60 kg body weight) Peripheral neuropathy in 15%, rare pancreatitis; avoid alcohol. OK to take Videx EC at same time as other antiretrovirals that can be taken on an empty stomach. Older chewable tablet formulation has additional restrictions.
Lamivudine (3TC) Epivir 150 mg 2x/d Generally well tolerated. Active against HBV.
Stavudine (d4T) Zerit 40 mg 2x/d (>60 kg body weight) Peripheral neuropathy (1%-4% in early studies; 24% in expanded access patients with CD4+ counts <50).
Zalcitabine (ddC) Hivid 0.375-0.75 mg 3x/d Peripheral neuropathy in 17%-31% of trial participants; oral ulcers. Used rarely due to toxicity, inconvenient dosing, and questions regarding efficacy.
Zidovudine (ZDV, AZT) Retrovir 300 mg 2x/d Initial nausea, headache, fatigue, anemia, neutropenia, neuropathy, myopathy.
ZDV + 3TC Combivir 1 tablet 2x/d Combination tablet containing 300 mg of ZDV and 150 mg of 3TC.
ZDV + 3TC + ABC Trizivir 1 tablet 2x/d Combination tablet containing 300 mg of ZDV, 150 mg of 3TC, and 300 mg of abacavir.
Tenofovir Viread 300 mg 1x/d with food Generally well tolerated. Active against HBV. Significant interaction with ddI (see Drug-Drug Combinations below).

 

Protease Inhibitors (PIs)

Generic Brand Dose Comments and Common Side Effects
Amprenavir Agenerase 1200 mg (8 cap) 2x/d, or 600 mg with RTV 100 mg 2x/d, or 1200 mg with RTV 200 mg 1x/d * Rash (20%), diarrhea, nausea
Indinavir Crixivan 800 mg (2 cap) every 8 hours on empty stomach or with snack containing <2 g of fat * 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.
Lopinavir/
Ritonavir
Kaletra Coformulated lopinavir 400 mg + ritonavir 100 mg (3 cap) 2x/d with food GI side effects common but mild. Hyperlipidemia.
Nelfinavir Viracept 1250 mg (5 tab) 2x/d or 750 mg (3 tab) 3x/d with food Diarrhea common; occasional nausea
Ritonavir Norvir 600 mg (6 cap) 2x/d; start with 300 mg 2x/d and increase to full dose over 14 days Nausea, diarrhea, numb lips; occasional hepatitis; hyperlipidemia. Store capsules in refrigerator. Stable at room temperature for up to 1 month. Used at lower dosages as pharmacokinetic enhancer of other protease inhibitors.
Saquinavir soft gel cap Fortovase 1600 mg (8 cap) 2x/d or 1200 mg (6 cap) 3x/d with fat-containing food (>28 g) * Soft gel formulation with improved absorption. Long-term storage in refrigerator. Stable at room temperature for 3 months.
Saquinavir hard gel cap Invirase Used in combination with ritonavir Hard gel formulation with poor absorption. Bioequivalent to Fortovase when combined with RTV. Smaller tablet size and easier storage than Fortovase.

* Frequently dosed with ritonavir to simplify administration and raise drug levels. See Drug-Drug Combinations section for details.

Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Generic Brand Dose Comments and Common Side Effects
Delavirdine Rescriptor 400 mg (2 tab) 3x/d Transient rash. P450 3A4 inhibitor. 600 mg twice daily dosing being studied. Coadministration with agents that lower gastric acid decreases absorption.
Efavirenz Sustiva 600 mg (1 tab) 1x/d initially at bedtime Initial dizziness, insomnia, transient rash, P450 3A4 inducer; avoid clarithromycin coadministration.
Nevirapine Viramune 200 mg (1 tab) 1x/d for 2 weeks, then 200 mg 2x/d or 400 mg 1x/d Transient rash, hepatitis; thus, monitor LFTs. P450 3A4 inducer. Once-daily dosing recommendation based on limited clinical data.

 

Ribonucleotide Reductase Inhibitors

Generic Brand Dose Comments and Common Side Effects
Hydroxyurea (not FDA-approved for HIV therapy) Hydrea 500 mg 2x/d Bone marrow suppression, aphthous ulcers, hair loss, peripheral neuropathy, hepatotoxicity. Augments ddI and d4T and their toxicities. No direct antiviral effect. Used rarely due to reported toxicity.

 

Drug-Drug Combinations

This table gives an overview of current knowledge of drug-drug combinations. The 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 any dose adjustments with a pharmacist.
* Comments on each combination are given below.

Abbreviations

RTV Ritonavir NVP Nevirapine
IDV Indinavir DLV Delavirdine
NFV Nelfinavir EFV Efavirenz
APV Amprenavir ADV Adefovir
LPV Lopinavir TNV Tenofovir
SQV Saquinavir (Fortovase, Invirase)

  APV IDV LPV/RTV NFV RTV SQV DLV EFV
NVP No data IDV [1] LPV [2] No significant interaction [3] No significant interaction [4] SQV [5] No data EFV [6]
EFV APV [7] IDV [8] LPV [9] No significant interaction [10] Modest in both [11] SQV level; do not combine [12] No data  
DLV APV [13] IDV [14] No data NFV [15] RTV [16] SQV [17]  
SQV APV;
SQV [18]
Antagonistic in vitro (in one lab) SQV-S [19] SQV-S [12] SQV [21]  
RTV APV;
RTV [22]
IDV [23] RTV [24] NFV [25]  
NFV APV [26] IDV [27] NFV [28]   Tenofovir/didanosine interaction

Tenofovir increases ddI (EC) Cmax by +49% and AUC by +46% when doses separated by 2 hours. When coadministered with food the effect is enhanced (Cmax +64%; AUC +60%). Studies evaluating dose reduction of ddI are in progress.

LPV/RTV APV;
LPV [29]
IDV [30]  
IDV APV;
IDV [31]
 

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

1 IDV & NVP NVP decreases IDV levels by 30%. (IDV decrease is most pronounced in patients with a high IDV level within the interpatient variability of IDV levels). Consider IDV dosage increase, eg, 1000 mg every 8 hours (5th CROI, 1998). The addition of RTV can prevent this interaction (see #23).
2 LPV/RTV & NVP 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).
3 NFV & NVP Steady-state studies indicate no significant changes in NVP or NVP levels, suggesting standard doses of each (5th CROI, 1998).
4 RTV & NVP NVP decreases RTV levels by 11%, not requiring dose adjustment.
5 SQV & NVP SQV-hard gel AUC decreased by 27%, which is of concern as SQV-hard gel by itself reaches marginal levels only. No effect on NVP level. No data on nevirapine and SQV-soft gel formulation.
6 NVP & EFV Decrease in EFV AUC by 22% and EFV Cmin by 36%; NVP levels unchanged; dose increase of EFV to 800 mg 1x/d being discussed, but no safety data are available for this dose (7th CROI, 2000).
7 APV & EFV Decrease in APV Cmax by 36%, AUC by 39%, and Cmin by 43% (5th CROI, 1998). See comments 22 and 25 below for dosing options.
8 IDV & EFV EFV decreases IDV AUC by 31% and Cmax by 16%; consider dose increase to IDV 1000 mg every 8 hours (ICAAC, 1998). The addition of RTV can prevent this interaction (see #23).
9 LPV/RTV & EFV 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).
10 NFV & EFV EFV increases NFV level by 20%. No change in EFV level. Clinical efficacy documented in several studies with standard dose of both drugs (6th CROI, 1999) .
11 RTV & EFV EFV increases RTV AUC by 18% and Cmax by 24%. No dose adjustment for EFV necessary. Consider dose reduction of RTV. Monitor LFTs (ICAAC, 1998). See comment 21 for further dosing options.
12 SQV & EFV EFV decreases SQV-S AUC by 62% and Cmax by 50%. Avoid combination with SQV as sole PI (ICAAC 1998). See comment 21 for further dosing options.
13 APV & DLV DLV increases APV Cmax/AUC/Cmin by 1.3-fold/4-fold/6-fold, respectively (Glasgow, 2000). APV decreases DLV levels.
14 IDV & 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 0%/+40%/+70%, respectively. 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).
16 RTV & DLV DLV increases RTV levels by 70%. May merit RTV dose reduction, eg, 400 mg twice daily. Limited data only (5th CROI, 1998, Pharmacia & Upjohn data 8/98).
17 SQV & DLV DLV dosed 400 mg 3x/d or 600 mg 2x/d decreases SQV clearance by 63%, resulting in increase in SQV 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).
18 APV & SQV Decrease in APV Cmax/AUC/Cmin by 37%/32%/14%, respectively, and increase in SQV Cmax by +21%, but decrease of SQV AUC by 19% and Cmin by 48% (Geneva, 1998). Triple interaction SQV/RTV/APV currently being studied.
19 LPV/RTV & SQV 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).
20 NFV & SQV NFV increases SQV-S levels 3-fold or higher. Consider dosage of NFV 750 mg + SQV-S 800 mg 3x/d, or NFV 1250 mg + SQV-S 1200 mg 2x/d (under study) (6th CROI, 1999).
21 RTV, SQV & EFV 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; 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 (ICAAC, 2001). Soft-gel or hard-gel caps appear bioequivalent in all dosage combinations with RTV (9th CROI, 2002; Pharmacology Workshop, 2002).
22 APV, RTV & EFV 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 Cmin +27% (Falloon, 1999; Lamotte, 2000). APV decreases RTV Cmin 3-fold compared with RTV Cmin in RTV/IDV or RTV/SQV, which may affect levels of other PIs added to APV/RTV (Pharmacology Workshop, 2001). FDA-approved dose: APV/RTV 600/100 mg 2x/d or 1200/200 mg 1x/d.
23 IDV & RTV 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. 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).
24 LPV/RTV & RTV Addition of RTV to LPV/r increases LPV concentration. Studies in progress. RTV Cmin is 3-fold lower in LPV/RTV combination compared with 100 mg RTV 2x/d in IDV/RTV or SQV/RTV combination (Pharmacology Workshop, 2001).
25 NFV & RTV 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 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).
26 APV, NFV & EFV Full dose of APV+NFV results in decrease in APV Cmax by -14%, but increase in AUC by +46% and Cmin by +235%. 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).
27 IDV & NFV NFV increases IDV level by 51%; IDV does not affect NFV level. NFV 1250 mg with IDV 1200 mg 2x/d with a low-fat snack on empty stomach shows good drug levels and clinical efficacy (6th CROI, 1999).
28 LPV/RTV & NFV Limited data from single-dose PK suggests unchanged NFV AUC, but increase in NFV Cmin and M8 metabolite.
29 LPV/RTV & APV Coadministration of APV 450-750mg with standard dose LPV/r 2x/d results in significant decrease of APV Cmin by 220-420% and trend to lower LPV Cmin, compared to APV/RTV 100mg or LPV/r 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).
30 LPV/RTV & IDV 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).
31 APV & IDV Increase in APV Cmax/AUC/Cmin by 18%/32%/25%, respectively, and decrease in IDV Cmax by 22%, AUC by 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

ZDV 41       67   70    
ddI (41)     65 (67)   (70) 74  
ddC (41)     65 (67) 69 (70) 74  
d4T† 41       67   70    
3TC   44              
ABC 41     65 67   70 74  
TNV (41)     65 (67) 69 (70)    
MDR*     62           75
MDR** 41   62   67 SS 70    
MDR*** 41       67   70    
ZDV             210 215 219
ddI           184 (210) (215) (219)
ddC           184 (210) (215) (219)
d4T†             210 215 219
3TC       118   184      
ABC   115       184 210 215 219
TNV             (210) (215) (219)
MDR* 77   116   151        
MDR**             210 215 219
MDR***             210 215 219

† 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 (NNRTIs)

DLV   103     181         236
EFV 100 103   108 181 188 190 225    
NVP 100 103 106 108 181 188 190      
MDR*   103       188        
MDR** 100   106   181   190   230  

* 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 (PIs)

APV 10       32     46 47   50   54     73     84   90
IDV 10 20 24   32   36 46         54   71 73 77 82 84   90
LPV/RTV* 10 20 24   32 33   46 47   50 53 54 63 71 73   82 84   90
NFV 10     30     36 46             71   77 82 84 88 90
RTV 10 20     32 33 36 46         54   71   77 82 84   90
SQV 10                 48     54   71 73 77 82 84   90
MDR** 10             46         54         82 84   90

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

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