|What We Used to Think||What We Think Now||What We Hope to Find in the Future|
|Initial therapy with NNRTI- and PI-based regimens, as well as triple NRTIs, could provide reasonably similar results.||Lopinavir/ritonavir- and efavirenz-based regimens have emerged as leading choices as the anchor of a first regimen.
Clinical trials have indicated that triple-NRTI therapy is not as effective as efavirenz-containing regimens. Triple-NRTI combinations that do not include a thymidine analogue appear to be dramatically less effective than ZDV/3TC/ABC.
|The specific role of atazanavir (particularly when boosted with ritonavir) as first-line therapy.
Will novel triple-NRTI combinations perform better than ZDV/3TC/ABC? Or is the issue the use of drugs from a single ART class?
An ongoing ACTG study comparing efavirenz and lopinavir/ritonavir will likely clarify the merits and pitfalls of each of these preferred regimens.
|"Hit hard and early" should succumb to a more cautious "hit hard and later" approach.||There is increasing comfort with initiation of HIV therapy at a CD4 cell count of 350/uL. Some data suggest there are advantages to starting treatment at 350 and higher.||As HIV therapies become less toxic, will the benefits of ART at CD4 cell counts above 350/uL become more apparent, leading to a shift back toward early therapy?|
|Efavirenz CNS toxicity is a major limiting factor in use of this drug.||Close monitoring of subjects receiving efavirenz demonstrates that the side effects are short lived (less than four weeks) and limited to the known adverse effects ascribed to the drug. In clinical trials, treatment discontinuation rates are low.||Longer term follow-up may provide further insights on cumulative toxicity, if any exists.|
|The lipid changes associated with HIV therapy may increase risk of cardiovascular disease, but the extent of the risk is not known.||Several studies demonstrate that the risk appears, at this point, to be very low.
AdvertisementHowever, some studies do indicate increasing rates of cardiovascular disease among antiretroviral-receiving patients. Overall the benefits of therapy far outweigh this risk.||Longitudinal follow-up of large cohorts will continue to generate information concerning risk.|
|Protease inhibitors cause a rise in lipids that increase the risk of cardiovascular disease.||HIV therapy alone is not the sole cause of lipid disorders. HIV infection itself perturbs lipid levels. This effect is partially reversed by antiretroviral therapy, which raises lipids to levels consistent with those that existed prior to HIV infection.||How will aggressive lipid management, increasingly being adopted into standard HIV practice, impact future cardiovascular disease risk?
Is the reversal of HIV infection-induced changes in lipids by ART seen also in women, African Americans and other populations?
|Atazanavir is a protease inhibitor with a lipid- and glucose-friendly profile but is less potent than other agents in the class.||The combination of atazanavir with low-dose ritonavir has been shown to increase the potency of this agent without significant cost to its favorable effect on metabolic parameters.||Further study of the use of ritonavir-boosted atazanavir, particularly its durability and salvage potential, are needed.|
|Once resistance develops to an antiretroviral it loses its effectiveness.||Resistance mutations do confer reduced viral susceptibility to an agent, but in the case of NRTIs some antiviral effect may remain. The subsequent impact of resistance on viral fitness may be protective against rapid CD4 cell decline and full viral rebound.||Can reductions in viral fitness accompanying NRTI resistance be exploited as a management strategy?|
|Antiretroviral resistance may be transmitted to others. Evidence of resistance fades over time making it difficult to detect years later.||Resistance is transmittable. One out of 10 newly diagnosed individuals have evidence of major ART mutations. Even after being infected for more than a year, patients show evidence of resistance.||Will resistance testing prior to starting therapy prove to be a clinically effective and cost-effective approach?|
|Fusion inhibitors would be nice.||The first fusion inhibitor has been approved, but stand in line and have your cash ready. Enfuvirtide works and is better tolerated than expected.||Can enough enfuvirtide be made to satisfy the need? Will the drug find a role beyond salvage (early therapy, post exposure prophylaxis)? Does enfuvirtide lead to immunologic changes that predispose someone to pneumonia?|
|Baseline CD4 cell count and viral load predict HIV disease progression.||Disease progression may actually be best predicted by the change in CD4 and viral load months after therapy starts.||Does a patient's six-month response need to be evaluated with the aim of manipulating therapy to optimize effect? Is this feasible given limitations of currently available ARTs?|
|Once-daily therapy would be nice.||Once-daily therapy is nice. More options for once-a-day dosing exist. Most believe this will increase antiretroviral adherence.||Is adherence to and efficacy of once-daily therapy improved? For whom is once-daily therapy not advisable?|