Treatment of HIV Disease - the evidence

Dr Brian Gazzard MA MD FRCP Chelsea & Westminister Hospital, London

As yet evidence-based medicine gives an only imperfect picture of the optimum treatment for HIV-infected individuals. Too many compounds with anti-HIV activity exist to test all possible combinations using randomised controlled clinical trials. Doctors and people living with HIV disease have become reluctant to enter such studies as they believe being involved in long-term control trials limits their therapeutic options.

Unfortunately, many of the randomised clinical controlled trials have been generated in response to the need for drug licensing rather than to clarify important therapeutic issues. The Federal Drug administration has already decided that future HIV drugs should be licensed on the basis of surrogate marker studies using both CD4 count and plasma HIV viral load.

However, data available so far does not indicate that these surrogate markers meet all the criteria set down by Prentis. 1 They are good prognostic markers, and responses to treatment would be expected to influence outcome biologically. However, they do not explain a substantial proportion of the treatment effect, both grossly under- and overestimating the likely efficacy of individual treatments.

Thus it would seem reasonable, for the moment, that drugs with anti-HIV activity should be licensed on the basis of falls in plasma HIV viral load and rises in CD4 count, but whether comparisons can be made between different treatments, particularly when reviewing drugs that act at different sites of the replication cycle (eg, nucleosides and protease inhibitors), remains problematic

Monotherapy

Randomised controlled clinical trials do show that single drug therapy (zidovudine [ACT]) prolongs life in symptomatic infection 2 but another study showed that this treatment had no effect on long-term outcome when given earlier rather than in late disease. 3 A meta-analysis of currently available AZT monotherapy studies has demonstrated that early treatment has a transient benefit in delaying clinical events that is lost in long-term studies.

Dual therapy

Perhaps the randomised controlled clinical trials with greatest impact have been those that have shown that dual therapy is better than AZT monotherapy. 4-6 Three studies have looked at AZT/didinosine (DDI) and AZT/zalcitabine (DDC) combinations, which appear to be equally effective. A Glaxo Wellcome-sponsored study also showed that the addition of lamivudine (3TC) to AZT monotherapy or to AZT/DDI or AZT/DDC combinations improved clinical outcome, at least in the short term. 7

Triple therapy

Further studies demonstrated that protease inhibitors contained in triple therapy combinations - ie, AZT/3TC/indinavir - delayed clinical events, as compared with dual nucleoside regimes (AZT/3TC), in a group of patients with advanced disease who had at least three month's previous AZT monotherapy experience. 8 Another study published so far in only abstract form demonstrated that a triple therapy regimen containing ACT, 3TC and saquinavir in the form of hard gelatin capsules was superior to dual therapy combinations in a group of naïve patients. 9

Optimum treatment of HIV
While these randomised clinical controlled trials may provide the best quality of evidence, they leave many unanswered questions in terms of the optimum treatment of HIV.

No study has addressed the issue of the optimum time to begin treatment . In the USA this tends to be started in any individual with a viral load over 10,000 copies per ml, irrespective of CD4 count. In Europe more notice is taken of the CD4 count in deciding when to start treatment. The benefit of early as compared with later treatment urgently needs a strategic randomised clinical study, but there appears to be few prospects of this taking place in the near future.

When the decision has been made to start treatment, the issue of the optimum initial treatment remains undetermined. It is clear from surrogate marker studies that dual nucleoside analogues plus a protease inhibitor have a more pronounced initial effect on plasma HIV viral load that is better sustained than the effects of dual nucleoside therapy alone. This supports the two studies that have been published showing improved clinical outcome with such triple therapy regimens. 8,9

Another study showed that two nucleosides, (AZT/DDI) plus a non-nucleoside reverse transcriptase inhibitor (NNRTI) (nevirapine) had an impressive effect on surrogate markers but was not powered to demonstrate effects on clinical events. 10 It is likely, but not certain, that this effect is best in those with moderate plasma HIV viral loads (less than 50,000 copies per ml), and direct comparisons of an initial regimen containing an NNRTI with those containing a protease inhibitor have not been performed.

Many influential workers believe that powerful initial therapy is the best way to get HIV infection under control and that, if sequential therapy with less effective agents is tried, each response to different drugs will be poorer than the last. Although this idea that response of treatment-naïve patients is superior to those of treatment-experienced patients is widespread, definitive evidence is lacking.

Conclusion

It is not possible to give definitive advice about the best treatment for HIV infection at present. It would seem common sense that the treatment should begin before the development of irreversible immune damage , although nobody knows when this occurs. AZT/3TC/indinavir undoubtedly has the best randomised clinical control trial evidence and surrogate marker data suggest its effectiveness as initial treatment, although it is likely that other protease inhibitors or other nucleoside combinations would prove equally effective.

Dual nucleoside analogue therapy is less likely to be effective both in terms of drops in viral load and short-term clinical outcome and should be reserved for individuals who recognise that they may be poorly compliant and for those who believe that a sequential approach to therapy, reserving both NNRTIs and protease inhibitors for later treatment, is a sensible approach.

As some of the most impressive results using protease inhibitors have been achieved in those with relatively late disease and those who have failed previous therapy, this view is reinforced by the difficulty in adhering to some proteinase inhibitor regimens. These drugs have a number of long-term and short-term side effects, some of which are emerging only recently. Some believe that those with modest plasma viral loads (less than 50,000 copies per ml) should be started before therapy on a double nucleoside/NNRTI combination.

It is extremely important that established facts about HIV treatment should be separated from conjecture, however well informed by opinion leaders, as otherwise this will prevent important research that will finally establish the optimum therapy for HIV.