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05 AIDS

HIV Treatment Strategy

On this page --

Strategic Overview

Some of the material you find here is from the Clinical Guidelines* page of the Journal of the American Medical Association (JAMA) website.

Before you read on, there are two important things you need to know about this web page --

  1. This isn't medical advice you are reading. There is no substitute for getting your medical advice from a doctor who specializes in treating HIV Disease. Think of this material as doing your homework before you see your doctor.
  2. This web page was last updated in late-1998. Medical advances may have made some or all of this information obsolete. 

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When To Start Treatment          

Most of the treatment recommendations are based on two blood tests --

JAMA articles recommend * offering treatment to those --

  1. with symptoms of very recent HIV infection. These symptoms -- called acute HIV syndrom -- are often described as "flu-like."
  2. within six months of becomming HIV-positive.
  3. with any opportunistic infections.
  4. with
  5. any other HIV-positive person based on

Other issues involved in the decision to start treatment include --

In addition to the basic therapy, the Clinical Guidelines page includes recommendations for preventing HIV transmission --

  1. Pregnant HIV-positive women*. The U.S. Public Health Service recommends AZT (Retrovir®) to help keep the baby from getting HIV.
  2. Occupational exposure* includes health care workers stuck by a contaminated needle. The U.S. Public Health Service recommends a 2 or 3 drug combination -- including drugs effective with the strain involved in the accident. See "Recommended Drugs" below.
  3. Nonoccupational HIV exposure* includes--

    The U.S. Public Health cannot definitively recommend for or against antiretroviral agents in these situations because of the lack of efficacy data on the use of antiretroviral agents in preventing HIV transmission after possible nonoccupational exposure.

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HIV-fighting Drugs      

Monotherapy

For a long time, treating HIV with drugs meant starting with AZT. When that stopped working -- because the virus figured a way around the drug -- the doctor would switch you to another drug. When treated like this, AZT always fails after a short period of time.

Do not let a doctor do this to you. If your doctor prescribes a single anti-HIV drug for you, get a different doctor.

Using a single drug is called "monotherapy." Never just take a single drug to fight HIV.

The days of monotherapy are gone. We now have lots of scientific evidence that show using 2 or 3 drugs at the same time works better than monotherapy.

   

The Drug List

ÆGIS keeps a  list of drugs approved for use in the United States. That list is a bit more technical than the information here. See, also, Quick Reference Guide to Antiretrovirals* by Malte Shutz, M.D.

There are currently three major classes of anti-HIV drugs in the arsenal:

  1. Nucleoside Reverse Transcriptase Inhibitors, also called "NRTIs" or "Nukes"
  2. Non-nucleoside Reverse Transriptase Inhibitors, also called "NNRTIs" or "non-Nukes" and
  3. Protease Inhibitors, or "PIs"

They are summarized in the tables below.

Nukes

Characteristics of Nucleoside Reverse Transcriptase Inhibitors

Generic Name Zidovudine  (AZT) Didanosine (ddI) Zalcitabine  (ddC) Stavudine (d4T) Lamivudine (3TC)
Brand Name Retrovir Videx HIVID® Zerit Epivir
Dosing
Recommendations		 200 mg tid or
300 mg bid or with
3TC as Combivir, 1 bid		 Tablets
>60 kg: 200 mg bid
<60 kg: 125 mg bid		 0.75 mg tid 60kg: 40 mg bid
<60 kg: 30 mg bid		 150 mg bid
<50 kg: 2 mg/kg bid
or with ZDV as
Combivir 1 bid
86%
Adverse Events

Bone marrow suppression: anemia, neutropenia

Subjective complaints: GI intolerance, headache, insomnia, asthenia

Lactic acidosis with hepatic steatosis is a rare but potentially life-threatening toxicity with the use of all NRTIs.

Pancreatitis

Peripheral neuropathy

Nausea

Diarrhea

Lactic acidosis with hepatic steatosis is a rare but potentially life-threatening toxicity with the use of all NRTIs.

Peripheral neuropathy

Stomatitis (throat swelling)

Lactic acidosis with hepatic steatosis is a rare but potentially life-threatening toxicity with the use of all NRTIs.

Peripheral neuropathy

Lactic acidosis with hepatic steatosis is a rare but potentially life-threatening toxicity with the use of all NRTIs.

(minimal toxicity)

Lactic acidosis with hepatic steatosis is a rare but potentially life-threatening toxicity with the use of all NRTIs.
Official Website
 		 Glaxowellcome www.bms.com www.roche-hiv.com www.bms.com Glaxowellcome

Non-Nukes

Characteristics of Non-Nucleoside Reverse Transcriptase Inhibitors

Generic Name Nevirapine Delavirdine efavirenz
Trade Name Viramune® Rescriptor® Sustiva&trade;
Form 200 mg tabs 100 mg tabs 50 mg, 100 mg, or 200 mg capsules
Dosing
Recommendations		 200 mg po qd x 14 days,
then 200 mg po bid		 400 mg po tid
(Four 100 mg tabs in > 3 oz water
to produce slurry		 600 mg po qHS
Drug interactions Induces cytochrome p450 enzymes. The following drugs have suspected interactions that require careful monitoring if co-administered with nevirapine: rifampin, rifabutin, oral contraceptives, protease inhibitors, triazolam and midazolam. Inhibits cytochrome p450 enzymes. Not recommended for concurrent use: terfenadine, astermizole, alprazolam, midazolam, cisapride, rifabutin, rifampin, triazolam, ergot derivatives, amphetamines, nifedipine, anticonvulsants (phenytoin, carbamazepine, phenobarbitol)

Delavirdine increases levels of clarithromycin, dapsone, quinidine, warfarin, indinavir, saquinavir.

Antacids or didanosine: separate delavirdine administration by 1 hour or more.

 Mixed induce/inhibitor of cytochrome p450 A4 enzymes; concentrations of concomitant drugs can be increased or decreased depending upon specific enzyme pathway involved.

Not recommended for concurrent with astemizole, cisapride, midazolam, triazolam, or ergot derivatives. Efavirenz decreases levels of indinavir (31%), saquinavir (62%) and increases levels of nelfinavir (20%) and ritonavir (18%).

Other potentially significant drug interactions requiring careful monitoring when co-administered with efavirenz include: warfarin, clarithromycin, rifabutin, rifampin, and ethinyl estradiol. Enzyme inducers such as rifampin, rifabutin, phenobarbital, and phenytoin would be expected to decrease efavirenz concentrations.

Adverse Events

Rash1

Increased transaminase levels

Hepatitis

Rash1

Headaches

Rash1

Central nervous systems symptoms2

Increase transaminase levels

False positive cannabinoid test

Teratogenic in monkeys3
Official Website
 		 http://hiv.roxane.com http://www.pnuaids.com http://www.sustiva.com
  2. Severe rash may occur in up to 5% of patients; cases of Stevens-Johnson Syndrome have been reported.
  3. May include dizziness, somnolence, insomnia, abnormal dreams, confusion, abnormal thinking, impaired concentration, amnesia, agitation, depersonalization, hallucinations, and euphoria. The overall frequency of any of these symptoms associated with use of efavirenz was 52% compared with 26% in controls; 2.6% of those on efavirenz discontinued the drug due to these symptoms.
  4. No data are available regarding teratogenicity of other NNRTIs in non-human primates.

PIs

Characteristics of Protease Inhibitors
Generic Name Indinavir Ritonavir Nelfinavir
Saquinavir
Trade Name Crixivan® NorvirTM Viracept® Invirase® Fortovase®
Form 200, 400 mg caps 100 mg caps
600 mg/7.5 ml po solution		 250 mg tablets 200 mg caps 200 mg caps
Dosing
Recommendations		 800 mg q8h
Take 1 hr before or 2 hrs after meals; may take with skim milk or low fat meal		 600 mg q12h*
Take with food if possible		 Adult: 750 mg (three tablets) t.i.d. Take with meal or light snack.

Children 2 to 13 years: Dose instructions will be given by doctor. Take with meal or light snack.

 600 mg TID*
Take with large meal		 1,200 mg TID
Take with large meal
Storage Room temperature Refrigerate capsules; refrigeration for oral solution is preferrd but not required if used within 30 days Room temperature away from sources of moisture. Room temperature Refrigerate or store at room temperature (up to 3 mos.)
Adverse Effects

Nephrolithiasis

GI intolerance

Nausea

Lab: Increased indirect bilirubinemia (inconsequential)

Headache

Asthenia

Blurred vision

Dizziness

Rash

Metallic taste

Thrombocytopenia (causes abnormal bleeding/bruising)

Hyperglycemia****

GI intolerance

Nausea

Vomiting

Diarrhea

Paresthesias -- circumoral and extremities

Hepatitis

Asthenia

Taste perversion

LAB: Triglycerides increase >200%

LAB: Transaminase elevation, elevated CPK and uric acid

Hyperglycemia****

Diarrhea

Abdominal pain

Asthenia

Nausea

Flatulence

Rash

GI intolerance

Nausea

Diarrhea

Headache

Elevated transaminase enzymes

Hyperglycemia****

GI intolerance

Nausea

Diarrhea

Abdominal pain

Dyspepsia

Headache

Elevated transaminase enzymes

Hyperglycemia****
Drug Interactions Inhibits cytochrome P450 (less than ritonavir)

Not recommended for concurrent use: rifampin, terferadine, astemizole, cisapride, triazolam, midazolam, ergot alkaloids

Indinavir levels increased by: ketoconazole***, delavirdine, nelfinivir

Indinavir levels reduced by: rifampin, rifabutin, grapefruit juice, nevirapine

Didanosine: reduces indinavir absorption unless taken >2 hours apart.

 Inhibits cytochrome P450 (potent inhibitor)

Ritonavir increases levels of multiple drugs that are not recommended for concurrent use**

Didanosine: may cause reduced absorption of both drugs; should be taken >2 hours apart

Ritonavir decreases levels of ethinyl estradiol, theophylline, sulfamethoxazole and zidovudine

Retonavir increases levels of clarithromycin and desipramine

 Inhibits cytochrome P450 (less than ritonavir)

Nelfinavir levels reduced by rifampin, rifabutin

Contraindicated for concurrent use: triazolam, midazolam, ergot alkaloids, terfenadine, astemizole, cisapride.

Nelfinavir decreases level of ethinyl estradiol and norethindrone

Nelfinavir increases levels of rifabutin, saquinavir, and indinavir

Not recommended for concurrent use: rifampin

 Inhibits cytochrome P450

Saquinavir levels increased by ritonavir, ketoconazole, grapefruit juice, nelfinavir, delavirdine

Saquinavir levels reduced by: rifampin, rifabutin and possibly the following: phenobarbital, phenytoin, dexamethasone and carbamezepine, nevirapine

Not recommended for concurrent use: rifampin, rifabutin, terfenadine, astermizole, cisapride, ergot alkaloids, triazolam, midazolam

 Inhibits cytochrome P450

Saquinavir levels increased by ritonavir, ketoconazole, grapefruit juice, nelfinavir, delavirdine

Saquinavir levels reduced by: rifampin, rifabutin and possibly the following: phenobarbital, phenytoin, dexamethasone and carbamezepine, nevirapine

Not recommended for concurrent use: rifampin, rifabutin, terfenadine, astermizole, cisapride, ergot alkaloids, triazolam, midazolam
Official Website
 		 www.crixivan.com www.norvir.com www.agouron.com www.roche-hiv.com www.roche-hiv.com

PI Notes
* Dose escalation for Ritonavir: Day 1-2: 300 mg bid; day 3-5: 400 mg bid; day 6-13: 500 mg bid; day 14: 600 mg bid. Combination treatment regimen with Saquinavir (400-600 mg po bid) plus Ritonavir (400-600 mg po bid).
** Drugs contraindicated for concurrent use with Ritonavir: amiodarone (Cordarone), astemizole (Hismanal), bapridil (Vascar), bupropion (Wellbutin), cisapride (Propulsid), clorazepate (Tranxene), clozapine (Clozaril), diazepam (Valium), encainide (Enkaid), estazolam (ProSam), flecainide (Tambocor), flurazepam (Dalmane), meperidine (Demerol), midazolam (Versed), piroxicam (Feldene), propoxyphene (Darvon), propafenone (Rythmol), quinidine, rifabutin, terfenadine (Seldane), triazolam (Halcion), zolpidem (Ambien), ergot alkaloids.
*** Decrease indinavir to 600 mg q8h
**** Cases of new onset hyperglycemia have been reported in association with the use of all protease inhibitors (ref. 48-50).

   

Drug Combinations

Here are the combinations with the biggest track records. This list is based on current government recommendations. It has been described as a "work in progress" by some authorities. Your doctor may have another combination that may work just fine.

Recommended Antiretroviral Agents for Treatment of Established HIV Infection
Preferred Strong evidence of clinical benefit and/or sustained suppression of plasma viral load (2,42,43)
One choice each from column A and column B(note 1). Drugs are listed in random, not priority, order:
Column A Column B
Indinavir (AI) ZDV + ddI (AI)
Nelfinavir (AII) d4T + ddI (AII)
Ritonavir (AI) ZDV + ddC (AI)
Saquinavir-SGC (AII) ZDV + 3TC(note 6) (AI)   
Ritonavir + Saquinavir (BII) SGC or HGC(note 2) d4T + 3TC(note 6) (AII)
Efavirenz (AII)  
Alternative Less likely to provide sustained virus suppression, or data inadequate (44,45).
  • Nevirapine or delavirdine + 2 NRTIs (Column B, above) (note 3) (BII)
Not Generally Recommended Strong evidence of clinical benefit but initial virus suppression is not sustained in most patients (46-49)
  • 2 NRTIs (Column B, above) (CI)
  • Saquinavir-HGC + 2 NRTIs (Column B, above)(note 7) (CI)
Not Recommended Evidence against use, virologically undesirable, or overlapping toxicities...
Notes
  2. Virologic data and clinical experience with saquinavir-SGC (Fortovase) are limited in comparison with other protease inhibitors.

  3. Use of ritonavir 400 mg b.i.d. with saquinavir-SGC (Fortovase) 400 mg b.i.d. results in similar drug exposure and antiretroviral activity as when using 400 mg b.i.d. of saquinavir-SGC (Invirase) in combination with ritonavir. However, this combination with Fortovase has not been extensively studied and gastrointestinal toxicity may be greater when using Fortovase.

  4. The combination of any of the 3 available NNRTIs + 2 NRTIs can suppress viremia to undetectable levels in the majority of patients remaining on treatment for > 28 weeks. An efavirenz- containing regimen has been shown to compare favorably to a PI-containing regimen with regard to suppression of viremia through 36 weeks; such head-to-head comparative trials have not been performed with nevirapine or delavirdine. Of note, use of efavirenz, nevirapine or delavirdine may result in resistance that precludes efficacy of any other member of this drug class.
  5. This combination of NRTIs is not recommended based on lack of clinical data using the combination and/or overlapping toxicities.
  6. Zidovudine monotherapy may be considered for prophylactic use in pregnant women with low viral load and high CD4 T cell counts to prevent perinatal transmission, as discussed under "Considerations in the Pregnant Woman."

  7. High level resistance to 3TC develops within 2-4 weeks in partially suppressive regimens; optimal use is in 3-drug antiretroviral combinations that reduce viral load to undetectable levels.

  8. Use of saquinavir-HGC (Invirase) is generally not recommended, except in combination with ritonavir.

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AZT is mentioned in most of the combination therapies. It's been around the longest.

Some folks with HIV refuse to take AZT because of side-effects or fears of long-term toxicity. However, AZT crosses the blood/brain barrier better than any of the other drugs.

In addition to infecting your blood stream, HIV gets into your central nervous system (i.e., brain). It's important to include a drug that get into the brain, and AZT does that better than any of the other drugs currently approved. (NOTE: Your mileage may vary.)

   

Changing Treatment

When To Change

There are five times when you should consider changing to another mix of anti-HIV drugs --

  1. treatment failure. Your drugs aren't working if --
  2. side-effects, including toxicity. Many side-effects are minor. Others go away after you've taken a drug for awhile. A few side-effects are truly nasty and indicate a change in treatment strategy.
  3. discipline. If you have trouble sticking to the rules about taking a drug, you may need to switch. Rules generally involve when you can and cannot eat food.
  4. drug interactions. For example, ritonavir has a huge list of drugs that can't be taken while you are taking ritonavir. If you absolutely must be taking one of those drugs, you need to change to something other than ritonavir.
  5. better is available. For example, if you are only taking AZT ("monotherapy"), you should get onto one of the 2 or 3 drug combinations.
    Guidelines for Changing an Antiretroviral Regimen for Suspected Drug Fail    

  • Criteria for changing therapy includes: Inadequate reduction in plasma viral load after initiation of therapy, re-appearance of virus after suppression to undetectable, significant increases in viral load, and declining CD4+ T cells.
  • When the decision to change therapy is based on viral load determination, it is preferable to confirm with a second viral load test.
  • It is important to distinguish between the need to change a regimen due to drug tolerance and the inability to comply with the regimen, versus failure to achieve the goal of sustained viral suppression. Single agents can be changed or dose reduced in the event of drug tolerance.
  • In general, one should not change a single drug or add a single drug to a failing regimen. It is important to use at least two new drugs and preferable to use an entirely new regimen with at least three new drugs.
  • It is important to recognize that many patients have limited options for new regimens. In some of these cases the rational approach will be to continue the prior regimen if partial viral suppression was achieved.
  • The decision to change therapy and the choice of a new regimen requires that the physician have considerable expertise in the care of people living with HIV. Physicians who are less experienced in the care of persons with HIV infection are strongly encouraged to obtain assistance through consultation with, or referral to, a physician with considerable expertise in the care of HIV-infected patients.

 

   

Changing Drugs

Studies show you will get better results if you change all or most of the drugs you are currently taking. If you need to change one of your drugs, it's almost always better to do a big switch -- changing all of the drugs you are currently taking. It's less potent just to add one new drug to the mix. See Possible Regimens for Patients Who Have Failed Antiretroviral Therapy: A Work in Progress*

The guidelines for changing your antiretroviral treatment are summarized in Table XIV* of the Guidelines for the Use of Antiretroviral Agents in HIV Infected Adults and Adolescents.

The most common drug combinations are listed above.

   

When to STOP Treatment

Sometimes a person with very advanced AIDS will have quality of life issues that suggest stopping an intense drug regimin. However, some of the new protease inhibitors have many of these "late stage" patients up and around -- mowing the grass, for instance.

A news item in January, 1997, indicated that those on multiple drug combinations will have to stay on them for a long time. One person -- who had no detectable viral activity for some time -- volunteered to stop taking the drugs. The virus kicked back in quickly, indicating that it has a hiding place in the body that scientists haven't yet discovered.

   

Other Resources and Information

Official U.S. Government Recommendations

Summer, 1998. The Department of Health and Human Services (U.S.) is preparing a treatment strategy document.

For those who have never taken anti-HIV drugs, these are the recommendations --

For those already taking anti-HIV drugs, a draft of the document warns against changing one or two of the drugs. If you need to change drugs, change them -- don't just add a drug.

The document also warns HIV patients to get treatment from a specialist. Here is a quote from a draft of the document: "Where possible, the treatment of HIV-infected patients should be directed by a physician with extensive experience in the care of these patients." Studies show your survival rate goes up when you are treated by an HIV specialist.

Source: HHS Guidelines for the Use of Antiretroviral Agents in HIV Infected Adults and Adolescents* - June 17, 1998.

   

This information is designed to support, not replace, the relationship that exists between you and your doctor.
©1998. AEGIS.