Mellors' presentation entitled "Management of Antiretroviral Treatment Failure" (Abstract 615), focused on effective salvage therapies for people in whom antiretroviral therapy did not maintain suppression of HIV. According to Mellors, no greater challenge faces HIV researchers than the management of treatment failure. He defined treatment failure as the inability of a drug regimen to achieve or maintain viral load under 50 copies. Even though suppression of viral load to below 50 copies is associated with the most durable viral suppression, not every patient can get there. No single regimen will give us a suppression of HIV.
Factors that may prohibit individuals from achieving and sustaining a viral load below 50 copies include the person's current T-cell count and viral load, prior treatment experience, the likely cause of treatment failure (drug resistance, non-adherence, suboptimal drug potency), and the number of drugs that are actually working, based on resistance testing.
But why do some regimens work and others don't? According to Mellors, some regimens just aren't strong enough to achieve viral suppression, but some people may be taking them because they have nothing else to take. Also, drug concentrations may not be high enough because of incomplete drug adherence, negative drug-to-drug interactions, and the clearance of the drug within a particular person (pharmacokinetics). And finally, a person's reaction to side effects may reduce adherence and possibly discontinuation of that drug.
Mellors offers that drug resistance is part of the problem with Highly Active Antiretroviral Therapy (HAART) in reducing viral load to below 50 copies. Viral resistance or cross resistance from other drugs is a large reason why many people infected with HIV may not benefit from HAART. With fair certainty, genotypic tests can determine mutations which occur with one drug and may possibly confer cross resistance to another drug within the same class. This will allow physicians and people with HIV disease to "weed out" the drugs which don't work and continue using the ones which do. If a mutation known as "103" occurs while using an NNRTI (Sustiva, Viramune and others), this usually denotes cross resistance to all drugs within this class. Therefore, using this drug in a highly effective combination is very important.
"Re-suppressing" the viral load to below 400 only occurs in 30 percent to 40 percent of people who have used antiretrovirals before and even less frequently in people who have used NNRTIs before. Only 7 percent of people who had used an NNRTI and had a viral load above 40,000 had sustained suppression, according to the CNA 2007 study which assessed responses from 99 treatment-experienced people (44 percent NNRTIs, 60 percent protease inhibitors with three or four previous PI regimens, and 72 percent NRTI). Mellors also offered some guidelines for salvage therapy:
Mellors also cited reason for optimism, since there are many new "second generation" protease inhibitors (ABT-378, tipranavir), NNRTIs (A1549, DPC 951 and 963), NRTIs (DAPD and dOTC), nucleotide analogs (tenofovir), and anti-fusion inhibitors (T-20 and T-1249). Although adefovir has many problems, there is another drug within the same class which may offer some hope. Tenofovir (PMPA) can achieve a viral load reduction of more than 1 log, and is active against the multi-drug resistant mutation 151. This offers hope to people who have this mutation (151) which renders all NRTIs (such as AZT, Zerit, etc.) and adefovir, useless. Unlike adefovir, Tenofovir isn't nephrotoxic (poisonous to the kidneys).
For people who have no other options, "mega-HAART" may be useful. This is a regimen which may contain up to eight different drugs from all classes of antiretrovirals. While a person's initial reaction may appear good, problems can arise: drug-to-drug interactions, intolerance of the drugs which may lead to selective adherence, numerous side effects, and not really knowing which drug is active and which aren't.
Mellors said that future clinical trials will have to be better designed. Genotyping participants will make it easier to determine whether or not the drug regimen they are on is working, and if viral load suppression is not achieved quickly, individuals can be moved to a new regimen.
Ernie Rodriguez is a treatment advocate in AIDS Project Los Angeles' Treatment Education Program. He can be reached by calling (323) 993-1486 or by e-mail at firstname.lastname@example.org.