HIV and AIDS: gap between biology and reality in AIDS
Andrew Carr, David A Cooper The theme of the 1998 World AIDS Conference was "Bridging the gap". As well as highlighting appalling inequalities between developed and developing nations, the meeting was sobered by the evident gap between HIV therapy based on biological plausibility ("treat hard and early") and therapy based on "real world" factors including potency, adherence, and long-term side-effects. Early combination therapy trials led to widespread recommendations that triple therapy (one protease inhibitor and two nucleoside analogue reverse transcriptase inhibitors) be standard care for most patients (CD4 counts <500 cells/mm3 and/or plasma HIV RNA>10 000 copies/mL). Triple therapy reduces mortality and new opportunistic illnesses, and can also reverse established opportunistic diseases by improving specific immune responses that probably do not, however, eradicate opportunistic pathogens. Triple therapy data prompted speculation that the therapy might eradicate HIV. Despite 2 years' undetectable viraemia with triple therapy in some patients, however, HIV can be cultured from latently infected CD4+ lymphocytes, cells that may have a lifespan of years. This suggests that HIV eradication is not possible with current therapy, and that therapy, at least in its current form, must be lifelong. Complete adherence to triple therapy is unusual, which is not surprising if one is prescribed up to four doses and 20 pills daily for life, to be taken with or without food, and given the therapy's potential and often chronic toxicities (for example, nausea, diarrhoea, renal calculi, headaches). Individuals taking less than 80% of their antiretrovirals had worse virological outcomes over relatively short follow-up. Simpler, less toxic maintenance therapy after 6 months' fully suppressive induction therapy led to rapid virological failure in many patients. Much enthusiasm for triple therapy has derived from on-treatment analyses showing up to 90% clearance of plasma viraemia. Intent-to-treat analyses, however, showed that perhaps only 60% of patients have undetectable viraemia after 1 year of standard triple therapy. It is unclear whether failure is more a function of non-adherence, toxicity, or inadequate potency, and there are minimal efficacy data beyond 18 months. Five-drug therapy appears to suppress viraemia more effectively, but at the risk of greater toxicity and adherence problems. Lastly, a syndrome of lipodystrophy (peripheral fat wasting and/or central fat accumulation), hyperlipidaemia, insulin resistance, and type II diabetes develops with short-term protease inhibitor therapy (fat changes reported by 50% of patients after only 10 months). Lipodystrophy was also reported in a few patients not receiving protease inhibitors, and so the impact of HIV disease and other drugs needs study. Case reports of cardiac ischaemia followed; the long-term cardiovascular risks need clarification and raise uncertainty over the use of protease inhibitors in early HIV disease. Despite biological plausibility, studies of protease inhibitors which evaluate survival benefit have not yet been carried out. The post-1996 AIDS conference hype that "combination therapy including a protease inhibitor will make HIV a chronic, manageable disease just like diabetes" came back to haunt us. Nevertheless, there are promising prospects. Non-nucleoside and newer nucleoside analogue reverse transcriptase inhibitors provide more convenient, and perhaps equipotent, options as third drugs of triple-therapy regimens. Such regimens are used increasingly in early disease, but again long-term safety and efficacy studies are incomplete. In 1999, biological strategies for eradication of latently infected cells will be tested. Clinical trials testing strategies such as what to start with and when to start will commence. Drug development will focus on better-tolerated, once-daily drugs; new classes of antiretrovirals are unlikely to appear soon. To bridge the gap between biological plausibility and reality, patients need regimens that are more potent, easier to take, and less toxic.
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