Living with HIV

Advanced HIV Discussion Topics

Created and funded by Roger Spitzer, MD. Updated 07/24/2004

Resistance to Antiretroviral Therapy
One of the lessons we have learned from the failure of single drug therapy for HIV is that the virus quickly develops resistance to antiviral agents when given the opportunity. This means that the drug will no longer inhibit the reproduction of HIV at normal doses, allowing for continued destruction of CD4 lymphocytes and progression to AIDS and death. This occurs by the process of mutation, whereby the genetic code of HIV changes to produce enzymes that are not affected by the various antiretroviral agents. HIV may need one or several mutations to create high level resistance to a specific drug, but when tens of millions of viruses are produced in the body every day, this can happen within a matter of weeks or months. Once resistance has developed to a single drug, adding a second drug usually leads to development of resistance to the new drug as well. Not every single virus will carry all the resistance mutations, but those that do are to reproduce even when the drug is present.
The biggest problem with resistance is that HIV doesn't forget. In most cases, once resistance has developed, it persists even if the offending drug is no longer used. Additionally, the virus becomes cross-resistant to similar drugs. As an example, strains of HIV resistant to Norvir are also resistant to Crixivan and usually Fortovase as well. The only effective means of preventing resistance is to suppress viral load to undetectable levels. Even at viral loads of 500, there is enough viral reproduction for clinically important resistance to develop.

Development of Antiretroviral Resistance from Poor Adherence
At baseline viral load is high and quickly drops to undetectable levels with treatment. Although there are some resistant viruses at baseline, there are not enough to cause problems. During periods of poor adherence to the medication regimen, HIV begins multiplying again, with resistant virus gaining a competive advantage. Eventually, enough resistance develops that the virus can continue multiplying even in the presence of antiretroviral drugs, with resistant viruses predominating. Most experts feel that for successful treatment, at least 95% of medication doses must be taken on schedule.

The treatment implications of viral resistance are as follows: 1) We should initiate therapy with multiple drugs in order to suppress the viral load to undetectable levels. 2) There is no place for single drug therapy or sequential therapy (adding drugs one at a time) in the current therapy of HIV. 3) If the viral load is increasing on the current drug regimen and the patient is taking all of the medication, we should change at least two of the drugs at a time, preferably to drugs with little cross-resistance. 4) It is critical that all antiretroviral medication be taken all the time, as prescribed. Even brief periods with subtherapeutic drug levels may allow resistance to develop. (see figure above) 5) Those who have been heavily treated with various antiretroviral agents without complete viral supression may have had so much resistance develop that no regimen using currently available drugs will be able to get the viral load down to undetectable levels.

Combination Therapy
As explained above, we normally try to use combinations of 3 or more antiretroviral agents to try to acheive supression of viral load to undetectable levels. This is termed Highly Active Antiretroviral Therapy (HAART). There are currently 4 classes of antiretroviral agents. The nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) mimic thymine, adenine, cytosine or guanine, normal components of DNA, and cause disruption of HIV's ability to create new DNA. The non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind to HIV's reverse transcriptase enzyme and also block formation of new DNA. The protease inhibitors (PIs) block the protease enzyme and prevent viral RNA from being packaged properly, resulting in a defective viral particle. There is also extensive research on the use of Interferon and Interleukin-2, natural substances which augment the body's ability to fight viruses, fusion inhibitors (T-20) and drugs that block HIV's integrase enzyme.

Antiretroviral Medication Classes
Nucleoside Reverse Transcriptase Inhibitors Nucleotide Reverse Transcriptase Inhibitors Non-Nucleoside Reverse Transcriptase Inhibitors

Protease Inhibitors

Fusion Inhibitors
Thymidine Analogs Nonthymidine Analogs Guanosine Analogs
Retrovir Epivir Ziagen Viread Rescriptor Crixivan Fuzeon
Zerit Hivid amdoxovir(DAPD)*   Viramune Fortovase T1249*
  Videx     Sustiva Norvir  
  Emtriva(FTC)     emivirine* Viracept  
  lodenosine(FddA)*     Calanolide A* Kaletra  
  dOTC*     capravirine* Agenerase  
* Investigational drugs in development

Examples of successful regimens would be Retrovir/Epivir/Kaletra, Retrovir/Epivir/Ziagen or Viread/Epivir/Viramune. Combinations such as Retrovir/Zerit would not be advisable, as both drugs act at the same site. Norvir is often combined with most of the other protease inhibitors because Norvir raises the blood levels of the other PIs, allowing lower doses (and less side effects) with both drugs.

HIV Genotyping and Phenotyping
HIV genotyping is a new test that attempts to determine to which drugs a particular strain of HIV is likely to be resistant. The test is done using DNA amplification techniques in order to identify genetic mutations that have been associated with resistance. Since several mutations are usually needed to produce clinically significant resistance and the actual interaction of the immune system and multi-drug regimens are difficult to predict, the results of the genotype assay are not always accurate in predicting a response (or lack of it) to therapy. Additionally, since hundreds of slightly different genotypes are in circulation at any given time, these assays often miss less common mutants (sampling errors). The most accurate test is to try a drug regimen and then check the response with a viral load assay. The genotype assay helps to guide the initial selection of drugs in salvage regimens and has been shown to improve success rates when used for this purpose. Phenotype assays actually grow HIV in a test tube in the presence of various antiretroviral agents, which gives a more direct measure of susceptibility to various drugs. This test is also subject to sampling errors.

Lipodystrophy/ Lipoatrophy Syndrome
One of the unfortunate long term side effects of antiretroviral therapy is the lipodystrophy/lipoatrophy syndrome. When this occurs, there is a redistribution of fat on the body. The first signs are usually loss of fat on the arms and legs (the veins become more prominent) and fat accumulation in the abdomen. Later one can get accumulation of fat on the back of the neck (a hump) and loss of fat in the cheeks. This does not seem to have any medical consequences but is unappealing cosmetically. Physicians first thought this was caused by the protease inhibitors, but currently Retrovir, Zerit and Videx seem to be the drugs most responsible for this syndrome. The exact mechanism is not known and there is no good treatment. Growth hormone injections have shown some benefits and regular excercise seems to help. Plastic surgery can also help with more severe cases by removing fat pads behind the neck or by collagen injections to fill out the cheeks. Surgical correction tends to be temporary, however. Stopping or changing medications usually keeps it from getting worse, but reversal of lipodystroophy changes is usually mild at best.

Prophylaxis against Opportunistic Infections
Prophylaxis means taking medication or treatment to prevent the development of certain diseases. When discussing HIV, primary prophylaxis is used to prevent an infection in the first place, whereas secondary prophylaxis is used to describe treatment aimed at preventing a recurrence of an infection one has already had. Secondary prophylaxis is often used to describe long term suppressive treatment of incurable infections, such as Toxoplasmosis, in addition to prevention of new infections, such as with Pneumocystis. The following table lists the more common drugs used for prophylaxis, with the first line agent shown first. The CD4 count used to determine when prophylaxis is started should be the lowest sustained level you have had. If your CD4 count has a sustained rise to a level above where prophylaxis is recommended, you may be able to stop certain prophylactic medications on the advice of your physician.

Prophylaxis of Opportunistic Infections
Infection  When to Start Prophylaxis  Primary Prophylaxis  Secondary Prophylaxis 
  Oral Candidiasis CD4< 200    Fluconazole (D)    Fluconazole (C)
   Itraconazole (D)    Itraconazole (C)
Cryptococcosis CD4< 50    Fluconazole (C)    Fluconazole (A)
     Amphotericin B (A)
Cytomegalovirus Retinitis CD4<  50    Oral Ganciclovir (C)    
 Herpes simplex Any CD4 count    Acyclovir (D)    Acyclovir (A)
       Famciclovir (A)
 Mycobacterium avium
Complex (MAC)
CD4< 50    Clarithromycin (A)    Clarithromycin/ Ethambutol
   Azithromycin (A)    Azithromycin/ Ethambutol
   Rifabutin (B)  
 Mycobacterium tuberculosis (TB) PPD (TB skin test) over 5 mm.    Isoniazid for 9 months(A)    none
   Rifampin/ Pyrazinamide
   for 2 months (A)
Pneumococcal Pneumonia HIV positive and CD4 > 200    Pneumovax (B)  
 Pneumocystis carinii
Pneumonia (PCP)
CD4< 200    TMP/SMX*(A)    TMP/SMX*(A)
   Dapsone (B)    Dapsone (B)
   Aerosolized Pentamidine (B)    Aerosolized Pentamidine (B)
   Atovaquone(B)    Atovaquone(B)
Toxoplasmosis CD4< 100    TMP/SMX* (A)    Pyrimethamine/Sulfa (A)
   Pyrimethamine/Dapsone (B)    Pyrimethamine/Clindamycin(B)
     (A)-Strongly recommended
     (B)-Moderate evidence for benefit, generally recommended
     (C)-Inadequate evidence to recommend for or against use
     (D)-Not recommended
     *TMP/SMX- Trimethoprim/Sulfamethoxazole

Recommendations from USPHS/IDSA Prevention of Opportunistic Infections Working Group
MMWR Morb Mortal Wkly Rep. 1999;48(RR-10):1-66
here to get the full version in Acrobat format

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