November 17, 2002
In clinical practice does the therapy work long-term? The answer is a resounding yes. Most treated patients will maintain an undetectable viral load. Failure of a drug regimen due to virological failure is now surprisingly uncommon, with individuals more likely to change therapy due to the development or the risk of development of toxicities or in an attempt to make adherence easier by prescribing simpler regimens. In the Swiss cohort, only 10 percent of patients remain on the same therapy at five years, with 20 percent of individuals changing therapies at least once, but few because of virological failure.
Despite a considerable amount of clinical trial and cohort data, the question of which drugs are the best with which to start therapy remains unclear. Although data suggests that it may be more effective to commence therapy with an NNRTI-based therapy than a protease inhibitor-based therapy, much of the present data compares a non-nucleoside with a non-ritonavir (RTV, Norvir)-boosted protease inhibitor. The majority of patients now receiving a protease inhibitor will receive a ritonavir-based protease inhibitor (50 percent of the Swiss cohort are receiving such therapy), and this may lead to protease inhibitors performing as well or even out-performing NNRTIs. The choice of which nucleoside backbone is the best remains unclear, with little data available regarding the differences in efficacy and the majority of doctors and patients choosing their nucleoside therapies based on the risk of both short-term and long-term toxicity. Therefore the use of AZT (zidovudine, Retrovir) and 3TC (lamivudine, Epivir) has remained constant, while the use of abacavir (ABC, Ziagen) has become more common, and the use of d4T (stavudine, Zerit) less so due to the implications of its probable association with the lipodystrophic syndrome. Tenofovir is increasingly used due to its safety profile in individuals both naive to therapy and those who have developed resistance. Tenofovir has been associated with a lower incidence of raised cholesterol and triglycerides and less mitochondrial-associated toxicity than d4T in the Gilead 903 study.
The major problem with protease inhibitors has been the relatively high tablet load, and the toxicity profile, especially lipodystrophy, hypercholesterolaemia and hypertriglyceridaemia. Atazanavir, which is a new protease inhibitor, has the advantage of less negative effect on cholesterol levels. However, its place in HIV therapy has yet to be determined, and it remains unclear whether a lower incidence of hypercholesterolaemia will be associated with less lipodystrophy in clinical practice.
The newest class of drugs to be used -- fusion inhibitors, namely T-20 -- works by stopping HIV from entering cells by preventing cell/virus fusion. T-20 has been shown to be effective in individuals who are resistant to other classes of antiretrovirals. But it needs to be injected twice daily, which although tolerable in the short term, may be more difficult in long-term therapy. In addition, T-20 has been shown to be of most use in individuals who have other effective antiviral agents available for them to use, based on resistance testing. Therefore, its true use in a very late salvage regimen remains unclear, particularly with the known dangers of adding a single drug to a failing regimen.
Due to the long-term toxicities and adherence problems associated with HIV therapy, many individuals have studied the possibility of occasional breaks from therapy (i.e., structured treatment interruptions [STIs]). Although there have been many studies on STIs, their benefit remain unclear, although several trials of STI are still ongoing. STIs may be of benefit in those treated at the time of acute seroconversion, with some individuals being able to maintain an undetectable viral load after repeated STIs without the need for therapy. In addition, in individuals who have a multi-resistant virus, an STI would remove drug pressure to keep the resistant virus, thus allowing a return to wild-type virus with a greater benefit when therapy is restarted. This was recently shown to be of benefit in the French GIGA HAART study where individuals who were given a STI followed by GIGA HAART (i.e., multiple drug therapies from all three available classes) had more of an antiviral benefit than those who did not receive an STI prior to initiation of treatment. However, a catastrophic fall in CD4 count could occur in people undergoing STIs which would put them at risk for the development of new opportunistic infections or tumors.