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Treatments for HIV have advanced rapidly over the past decade. Andrew Phillips and colleagues argue that we should re-evaluate the timing of treatment in the light of new knowledge
Opinions on when patients with HIV should start antiretroviral therapy have differed widely.1 2 3 4 A definitive answer has proved elusive in the absence of a randomised trial. Treatment guidelines have cited data from observational cohorts and have generally concluded that treatment should first be considered as the CD4 count falls below 350×106/l, less than half of the average normal concentration in uninfected people,5 but certainly started before the level has reached 200×106/l.6 7 Recent research means that we should re-evaluate whether this position remains justified. Before doing this it is important to be clear on the reasons for reaching the position in the first place.
Antiretroviral therapy clearly reduces the risk of AIDS related diseases, even in those with a relatively high CD4 count. A large joint cohort analysis shows a decreased rate of AIDS after starting antiretroviral therapy, even in those with CD4 counts above 350×106/l (figure(figure).8 So what have been the reasons for delaying?
Firstly, many antiretroviral drugs are inconvenient to take and are associated with unpleasant effects including nausea, diarrhoea, headache, and central nervous system toxicity. They may also cause occasional life threatening adverse effects such as hypersensitivity reactions, acute hepatitis, lactic acidosis, and pancreatitis.9 Furthermore, long term use of antiretroviral therapy has been linked with increased risk of myocardial infarction.10 If therapy can safely be delayed most patients would prefer to wait.
Secondly, the absolute risk of AIDS related diseases has been felt to be sufficiently low at CD4 counts above 250×106/l that delay can be considered, given the disadvantages of treatment. Tables that provide the six month risk of AIDS for a person with a given CD4 count, viral load, and age6 11 indicate that a 35 year old with CD4 count 350×106/l and viral load 30000 copies/ml has an estimated 1.6% risk of an AIDS disease, for example.11 While this risk would be reduced by antiretroviral therapy, many clinicians and patients have not considered it sufficiently high to warrant initiation of therapy.
Thirdly, treatment of HIV has developed rapidly over the past 15-20 years. Patients' responses to antiretroviral therapy have improved,12 13 14 partly because of better adherence as a result of reduced toxicity, more convenient regimens, and adherence support. Furthermore, drugs with longer half lives that are more forgiving of poor adherence have become available. Understanding of resistance has also improved, as has the availability of drugs to use when extensive resistance is present.
Given this ongoing improvement it has made sense to delay antiretroviral therapy. For example, a patient starting therapy in 1996 might have been put on a regimen containing either full dose ritonavir (associated with severe gastrointestinal adverse effects) or hard gel saquinavir (associated with a high rate of resistance). If he or she had been able to wait until 1999 then a regimen of combivir and efavirenz could have been started, which has proved durable success and is still widely used. In addition, it was feared that starting antiretroviral therapy too early could lead to premature exhaustion of all available treatment options because of resistance.
Estimates of the risks of developing AIDS have not changed,11 but the context in which we are weighing up the risk has altered. We have started to appreciate, albeit with experience only of relatively short term use, that antiretroviral therapy may permit close to a normal lifespan. Given this perspective, the 1.6% six month risk of AIDS for a person with CD4 count 350×106/l and viral load of 30000 copies/ml discussed above begins to not look so low. Further reminder of the risks at CD4 counts above 200-250×106/l has come from recent results of the strategies for management of antiretroviral therapy (SMART) study (box). This compared episodic antiretroviral therapy guided by CD4 count with continuous antiretroviral therapy and found a significantly increased risk of disease progression in those on episodic therapy despite the fact that almost all participants had CD4 counts above 200×106/l throughout the trial.15 Cohort studies have also shown a continuum of decreased risk with higher CD4 counts, even in the 200-500×106/l range, in patients who both have and have not received antiretroviral therapy.11 16
Our understanding of drug toxicities has also improved recently. The increased risk of myocardial infarction with antiretroviral therapy is now better understood and seems to be associated with protease inhibitors not non-nucleoside reverse transcriptase inhibitors and at least partly related to lipid changes with these regimens.17 As such, the threat can be better managed clinically in individual patients. Similarly, lipodystrophy has been a major concern and reason for delaying antiretroviral therapy.18 19 The lipoatrophy component, for example, is now known to be related to thymidine analogues19 20 and can thus be better avoided. In addition, the SMART trial unexpectedly showed that patients who had interrupted antiretroviral therapy had significantly increased risk of a combined endpoint of myocardial infarction, stroke, liver cirrhosis, and renal failure compared with those on continuous treatment.16 It had been hypothesised that reduced use of antiretroviral therapy would lower the risk of such conditions. Furthermore, recent findings from the data collection on adverse event of anti-HIV drugs (DAD) study have shown that risk of death from liver disease and of “non-AIDS” cancers are increased at lower CD4 counts, with differences even between those in the 200-350×106/l and >350×106/l categories.21 SMART also confirms that differences in CD4 count within this range translate into differences in risk of deaths from what had been thought of as non-HIV related causes. Finally, in SMART interrupted therapy had no benefits on quality of life.22
The third reason for delaying was to wait for improvements in drugs and adherence support. Again, recent data have weakened this argument for delay. Recent cohort analyses have shown that the initial response to antiretroviral therapy has improved substantially and now tends towards a plateau.12 13 14 Viral load responses are now generally so good that there may be relatively little scope for further improvement. In one study, the percentage of patients with initial virological failure dropped from 23% in 1996 to 8% in 2002.12
A related reason for delaying antiretroviral therapy was the concern over accumulation of drug resistance and exhaustion of drug options. Although we observe an appreciable rate of appearance of resistance mutations over time among patients taking antiretroviral therapy, the rate of accumulation of resistance to the three main classes seems slow.23 Even if one or two regimens have failed, new drugs are likely to become available soon that are active against a virus which is resistant to current drugs.24
In the light of this re-evaluation, when should a patient start antiretroviral therapy? Delaying treatment until the CD4 count has fallen below 300-350×106/l carries risks that it seems clear will not be balanced or outweighed by any short or longer term mortality risks from immediate therapy. We therefore suggest that guidelines should now recommend starting treatment at around 350×106/l, so long as the patient is ready. For patients with higher CD4 counts the risk-benefit balance remains uncertain, and we need an international randomised trial in patients with a CD4 count above 500×106/l comparing immediate treatment with deferral of treatment until the count reaches 350×106/l. The increased stability of HIV treatment now makes such a trial possible and would enable us to evaluate the risk of non-AIDS related diseases, which SMART suggested might also be increased in those not taking antiretroviral treatment, as well as of the risk of developing AIDS (box).
Treatment, of course, depends on availability of the drugs. Patients and doctors in settings where the newer less toxic and more convenient regimens are not an option may still prefer to carry the risks and wait until these become available. In settings where antiretroviral therapy availability is severely limited, the priority for initiation should continue to be those with the greatest level of immunodeficiency, where the clinical benefits are greatest.
Competing interests: All authors have at some point received funding (personally or for research) from one or more companies producing drugs for HIV.
Contributors and sources: All authors have worked in HIV infection for many years and are involved in design, coordination, and analysis of large randomised trials and observational studies of people with HIV. BGG is chair of the British HIV Association treatment guidelines committee, which ANP was also a member of. NC and JDL are members of the executive committee of the European AIDS Clinical Society.