New Drug Holds Hope for HIV-Positive Patients Who are Multiple-Drug Resistant

Modern HIV treatment is, compared to what was available in the 1980's and 1990's, highly effective. It is so effective that doctors and nurses now usually spend less time explaining the side effects of the medications used to control the virus, and more time persuading patients to stay on needed medications despite the fact they feel good. A minority of HIV patients, however, experience multiple-drug resistance, a phenomenon that greatly complicates their care.

What is Multiple-Drug Resistance?

Drug resistance is the failure of a medication that previously controlled an infection to continue to control that infection. Multiple-drug resistance is a condition in which more than one medication to control the same infection that once worked becomes ineffective.

The human immunodeficiency virus HIV multiplies at a very rapid rate. Unlike more complex organisms, it does not have proteins that correct errors in its DNA. Some of these mutations will enable HIV to produce new and different enzymes.

The drugs that are used to treat HIV target the enzymes that the virus needs to attach to T-cells and then to multiply inside them. There are drugs that target reverse transcriptase, integrase, protease, and gp41. If a mutation causes slight changes in these enzymes so that they still function for the virus but they do not respond to drugs, then the virus is able to resist the drug.

How Do HIV+ People Acquire Drug-Resistant HIV?

The more viruses there are in the bloodstream of an HIV+ person, the more opportunities there are for genetic mutations and the resulting drug resistance. The golden rule of prevention of drug-resistant HIV is very simple: Keep viral load (the number of copies of the virus per ml of blood) as low as possible. To keep viral load as low as possible, it is critically important that:

• No doses of medication are ever skipped. When the concentrations of a needed medicine in the bloodstream go down, viral load and mutations go up.
• HIV patients can never pick and choose prescription medications. That's because the doctor chooses the cocktail of drugs carefully to avoid interactions. For instance, For example, if the nucleoside/nucleotide reverse transcriptase inhibitor Viread (tenofovir) is combined with the protease inhibitor Revataz (atazanavir), blood levels of Reyataz can fall to dangerously low levels. This is why the protease inhibitor Norvir (ritonavir), which boosts Reyataz levels in the bloodstream, must be taken when Viread is also prescribed. Taking one medication and missing another may make a third medication less effective.
• Medication must be absorbed into the digestive tract. If vomiting and diarrhea are a problem, the doctor has to know. Some medications have to be taken with or without food to be absorbed properly.
• The doctor has to know all the drugs, legal and illegal, the patient is taking. Some drugs have to be activated by the liver. Other drugs are broken down by the liver. The doctor needs to know if there is something that makes a medication ineffective, or overly effective, due to the liver's total burden of processing drugs.

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Viral load isn't the only factor in acquiring drug-resistance. HIV patients who have unprotected sex may acquire drug-resistant strains of the virus from their partners. HIV-negative people who have unprotected sex while on Truvada sometimes are infected with a strain that is resistant to the prophylactic drug, and assuming they are OK they don't get treatment before the virus mutates into resistant forms. Even in the HIV window period, before the virus is even detectable, it can mutate to evade drug treatment.

How Can HIV+ People Know They Have Become Multiple-Drug Resistant? What Can They Do?

There are several indicators that HIV has mutated to a multiple-drug resistant form, or a HIV+ person has been infected with a new strain of the virus that is multiple-drug resistant:

• Viral load goes from undetectable to detectable. A single "blip" in viral load numbers, however, does not mean that the virus has become drug-resistant.
• Viral load fails to become undetectable during the first few months of taking a new treatment regimen.
• Viral load keeps on rising despite taking all the prescribed medications at the right time.

It's helpful to know whether you have been exposed to drug-resistant HIV as soon as you know you have the virus. Doctors can test for drug-resistance very early on, although there is always a possibility that you can have both drug-resistant HIV and a "wild type" unmutated HIV. The wild type HIV can force the mutated HIV to go into hiding, only to have it come out of hiding when drugs have brought the "normal" HIV under control.

There are two principle kinds of drug-resistance testing, genotypic and phenotypic. In genotypic testing, a lab looks for genes that indicate that certain drugs won't work. Sometimes a single gene in HIV is a sign that a specific drug won't work. If the HIV in the blood drawn from the patient has a gene called M184V, the doctor knows that the HIV is resistant to Epivir and Emtriva and it probably won't help to try those drugs. For other medications, there may be a complex pattern of genetic mutations that predict resistance, particularly resistance to protease inhibitors and nucleoside/nucleotide reverse transcriptase inhibitors. Doctors are gaining experience in using gene testing to predict resistance to these drugs, but the method is not perfect.

Genotypic testing takes one to two weeks. A second method called phenotypic resistance testing exposes the patient's virus to actual medications and measures changes in viral load in the laboratory. This method is much more precise, but it take three to six weeks to get results.

All of this testing points doctors to first-, second-, third-, and later choices for fighting the virus. A new HIV drug, however, may entirely bypass the whole problem of multiple-drug resistance. Current HIV medications attack the virus. The new experimental medication called ibalizumab, under development by TaiMed Biologics, consists of genetically engineered antibodies. These antibodies interact directly with T-cells rather than with the virus. When these monoclonal (genetically engineered) antibodies come in contact with the receptor sites that can receive HIV, they lock out the virus and keep the cell from becoming infected.

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There have been reports about ibalizumab since 2010. However, it has finally passed two clinical trials and is finally ready for large-scale testing. If the medication works in the third stage trial as well as in the first, HIV+ people will have a treatment that is taken twice a week rather than several times a day, doesn't depend on absorption through the digestive tract, isn't processed by enzymes in the liver and therefore not subject to most drug interactions, and to which HIV cannot become resistant. The FDA is treating it as an orphan drug, not really needed by people who respond to other therapies, but experts estimate that as many as 5 percent of all HIV+ people will be able to get it with medical insurance upon successful completion of the clinical trial. The majority of HIV patients, experts say, are doing fine, but this new treatment may be what is needed for those who are not. This new drug won't be an HIV cure, but it may be the next best thing.