Viral Resistance: How It May Affect Treatment Options
Although the use of triple and quadruple drug combinations for HIV infection has dramatically changed the course of the disease in many persons with HIV/AIDS in the last two years, the appearance of new therapeutic approaches has also created new challenges from the clinical point of view.
One of the new concerns is viral resistance to the drugs currently used and how it may affect future treatment options for thousands of people living with HIV now taking drug combinations. This is an important matter for all people with HIV, but in particular, for those previously exposed to monotherapy or double-nucleoside therapy, and those failing combinations that include protease inhibitors.
HIV is a virus that replicates at a very high rate, and consequently the virus produces mutations at a rate of one new mutation for each replication cycle. A mutation is just a change in one of the many proteins (amino acids) that form the genetic material of the virus. This process occurs independently of the drug treatment. In other words, the type of virus you have (called wild type) mutates constantly regardless of whether you are taking HIV medications. The force that drives mutations appearing is the level of viral load.
Current triple and quadruple combinations may reduce viral replication to very low levels. We do not know for sure how low the level should be in order to avoid mutations appearing, although it is now estimated that those people with HIV who can sustain a viral load under 50 copies have a high chance to avoid these mutants that are resistant to medication. The more mutations the virus develops the more chances it has to produce ones that will avoid destruction by the current medications. This mutant virus that escapes destruction is not as well fit as the wild type (original) virus, but it is still able to replicate and damage the immune system.
Adherence is the cornerstone to a successful antiviral treatment, because a person who does not take the medications as prescribed will have peaks of viral replication in between doses; eventually this will lead to the appearance of a mutant virus that can escape the drug's antiviral action. Lack of compliance with the prescribed regimen is the leading viral resistance suspect, but it may also happen for other reasons, such as: 1) sub-optimal combination (either a of lack of access to medications or because the person has added new drugs to a failing regimen); 2) some people metabolize the drugs at a faster rate and therefore eliminate the drug from their bodies before it reaches full antiviral activity; 3) interactions with other medications, or in some cases with alcohol or recreational drugs, may also affect the metabolism of antiviral medications; and 4) some people have previously received monotherapy or double combination of some of the drugs included in a treatment (particularly nucleosides analogues).
Compliance, interaction with other medications, and treatment with previously used agents can be managed by educating both the person with HIV and the physician (although this can be done only in the setting of very good, personalized medical care that is out of reach for most people now covered by HMOs or receiving care at inner cities clinics). The issue of rapid metabolism of antiviral medication will eventually be resolved with the development of rapid testing technology that already exists but is very expensive and time consuming, and is only available in research.
Drug Resistance and Treatment Options
It can be said that substantial and sustained viral increase during combination therapy is, in most cases, the result of drug resistance; the qualifiers here -- substantial and sustained -- are not clearly defined. A variation of 0.50 log or more in viral load from the lower level achieved is considered a biological variation of the virus and does not imply the appearance of viral resistance. If the viral load increases within this parameter, it is important not to stop the treatment but to repeat the test within two weeks to verify if the variation was due to the appearance of resistant virus.
If the increase of viral load is higher than 0.5 log, federal guidelines suggest changing the combination to a new set of drugs not previously used. However, this is easier said than done since in many cases the person has used a variety of medications before and the virus may be resistant to some or all drugs that were previously used. Although we now have 11 approved antiviral drugs, and the number of their potential combinations is very high, in practice the options most people have are limited due to drug interactions, previous treatment and side effects. There are now two types of tests that can help determine the resistance pattern of the virus: genotypic testing determines the most prevalent mutations in the sample analyzed, and phenotypic testing measures the actual sensitivity of the virus to different antiviral dosages. Both tests have serious utility limitations.
Genotypic testing is now available but is not financially accessible to everyone. Sometimes the cost is reimbursed by insurance companies or from some U.S. laboratories. Conceptually, phenotypic testing is more reliable as it clearly indicates if the virus is sensitive to a specific drug (an antiviral drug still may be effective even in the presence of the mutation related to resistance to the same drug). Phenotypic testing is available only in some research centers. It has limitations because it is unclear as to which one of the several techniques for phenotyping is the most appropriate. It's important that tests be used only while the person is still on the failing regimen. This is because once a treatment is suspended, the specific resistant mutations tend to be replaced very rapidly by wild type virus, and if the plasma sample is obtained after the individual stopped treatment the results will not accurately indicate real resistance. The jury is still out on whether using resistance tests in clinical treatments is valid. For people who have already used many drugs, genotypic testing is very limited. Chances are that the person will not show genotype mutations to the drugs previously used, although resistance to these drugs will probably appear if the person is treated with the same medication. In these cases, phenotypic testing can provide a more accurate picture of the virus' sensitivity to different drugs.
One important point to consider is time's effect on resistance. The short and medium time consequences concerning viral resistance are not well understood. In the long term, it is obvious that mutant strains of the virus will produce the same level of immune suppression that characterizes AIDS, but long term usually means years. We know from recent studies that a substantial decrease in viral load (1 log or more) results in clinical benefits that seem to be out of proportion with the reduction in viral activity. The virus may be as virulent as before, but a substantial reduction in viral load seems to allow the person's immune system to bounce back. On the bright side, we may say that even if a person does not obtain viral replication control (defined here as becoming undetectable using the under 50 copies test), he or she still may gain substantial clinical benefits if the viral load from his or her pretreatment level reduces significantly (a significant reduction would be at least 1.50 log).