November 17, 2002
The use of highly active antiviral therapy (HAART) has clearly revolutionized the treatment of HIV disease and both patients and physicians have been enjoying reductions in morbidity and mortality. The best choice of initial antiretroviral therapy remains unclear. However, physicians are increasingly choosing simpler regimens with either a non-nucleoside (NNRTI) in association with two nucleoside analogues (NRTIs) or triple-nucleoside therapy. Protease inhibitors -- due to the recognition of increased long-term toxicity and often high tablet load -- are kept in reserve for patients who fail their initial treatments. However, despite the relative ease of non-nucleoside- and triple nucleoside-based therapy, both are also associated with toxicities, both in the short term and increasingly in the long term. At the present time, we have six nucleosides, a nucleotide (tenofovir [TDF, Viread]), three non-nucleosides and six protease inhibitors to choose from. In the coming months this choice will be expanded to include a new protease inhibitor (atazanavir [Zrivada]), and a novel class of drugs -- the fusion inhibitors, namely T-20 (enfuvirtide, Fuzeon).
In this session Dr. Bernard Hirschel of Geneva, Switzerland summarized antiviral therapy in the year 2002. Dr. Hirschel introduced this session with the encouraging news that in the developed world, individuals with HIV are no longer dying of HIV-associated disease so long as highly active antiretroviral therapy is commenced correctly. In the Swiss cohort study, the risk of death in individuals starting antiviral therapy is no greater than in an age-matched cohort of HIV-negative individuals. Although this is encouraging for individuals living with HIV, it also is slightly daunting in that individuals will need to take antiretroviral therapies for life, and therefore may be facing more than 40 years of continuous drug treatment based on our current understanding of HIV disease.
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.
In summary, HIV treatment works, which is good news for everyone affected by HIV. However, whether individuals can tolerate long-term therapy with increasing reports of long-term toxicity and associated adherence problems remains unclear. Although newer therapies are becoming available, their true role in HIV therapy still remains unclear.
Little new data was presented in this session. This overview really stated that the available antiviral therapy works, with virological failure secondary to lack of efficacy of the drugs becoming increasingly uncommon. Newer therapies may allow individuals the choice of less toxic and easier-to-adhere-to agents. Perhaps most important from this session was the understanding that physicians must now concentrate not on the power of specific drugs, but on drugs that will improve the quality of patients' lives.