A case for earlier initiation of HAART, or still a need for caution?

Initiating HIV treatment at a CD4 cell count above 350 cells/mm³ with newer anti-HIV drugs would reduce illness and death caused by HIV, limit treatment side-effects, be cost-effective, and reduce the onward transmission of HIV, according to four US HIV doctors writing in the December 1^st edition of Clinical Infectious Diseases.

However, an alternative viewpoint written by two American HIV clinicians published in the same edition of the journal rebuts each of these arguments and concludes that there is little evidence that there is any benefit from starting HAART at a higher CD4 cell count, and that significant risks of toxicities and resistance remain even with newer antiretroviral drugs.

When HAART first became available US doctors adopted a ‘hit hard, hit early’ approach, advocating the aggressive treatment of HIV in individuals with CD4 cell counts as high as 500 cells/mm³. Treatment guidelines have adopted an increasingly cautions approach since then. HIV treatment guidelines in the US, UK and Europe currently recommend that HAART should be started before an individual’s CD4 cell count falls below 200 cells/mm³ and that there is no survival benefit, but a greater risk of side-effects and resistance, if treatment is initiated at a higher CD4 cell count.

Arguments for starting HAART at higher CD4 cell counts

Dr Scott Holmberg of the US Center for Disease Control, and HIV clinicians Dr Frank Palella, Dr Kenneth Lichtenstein and Dr Diane Havlir express concern that “the therapy initiation pendulum has swung too far in the direction of later initiation - at a CD4 cell count near 200 cells/mm³ - rather than earlier initiation – at a CD4 cell count of above 350 cells/mm³. They argue that:

• Guidelines recommending that later initiation of therapy rely on “a few short-term, sometimes unpublished cross-sectional analyses of observational cohort or clinical trial data. They add that the few studies which have compared patients who started HAART at higher and lower CD4 cell count found that patients who commenced HAART with higher CD4 cell counts had significantly lower mortality. However, they do not mention that attempts to set up large `when to start` trials during the mid-1990s were thwarted by the widespread adoption of early treatment on the basis of a few small, short-term clinical trials.
• Patients starting HAART at higher CD4 cell counts are more likely to have a durable virological response to therapy and achieve and sustain a viral load below 50 copies/ml.
• The risk of opportunistic infections is smaller in patients who start HAART with a CD4 cell count above 350 cells/mm³.
• Starting HAART at a higher CD4 cell count means that treatment can be safely interrupted later.

They also maintain that arguments in favour of delaying HAART concerning toxicity and resistance are no longer valid because of the favourable side-effect and resistance profiles of newer antiretroviral drugs. They argue that:

• Newer HIV drugs are less toxic.
• Patients are more likely to get side-effects such as lipodystrophy, loss of bone density and peripheral neuropathy if they start treatment with a low CD4 cell count.
• Patients coinfected with hepatitis C virus are more likely to experience liver fibrosis if they start treatment with more advanced suppression.
• Resistance is less of a concern given the expanding number of anti-HIV drugs and classes.
• As adherence to newer HAART regimens is easier, resistance is actually less likely to develop than with earlier antiretroviral drugs.

Health economic and public health arguments are also advanced as supporting the earlier initiation of HAART as:

• Starting HAART at lower CD4 cell counts costs almost twice as much as initiating antiretroviral therapy in individuals with a CD4 cell above 500 cells/mm³.
• There is cost-benefit in terms of quality adjusted life years for patients who start HAART earlier.
• Starting HAART earlier would reduce sexual transmission of HIV by reducing viral load and the shedding of HIV in sexual fluids.

Current guidelines reflect need for caution

Responding to these arguments HIV clinicians Dr Cal Cohen and Dr Brian Boyle note that although there are uncertainties about the optimum time to start HAART, studies have shown that patients who commence antiretroviral therapy with low CD4 cell counts experience “significant immunologic recovery…and impressive ability of the recovered immune system to restore control of preexisting opportunistic infections, as demonstrated by the CD4 cell count, even after the cessation of secondary prophylaxis.”

Regarding the higher incidence of lipodystrophy in patients who start HAART with lower CD4 cell counts, they note that “this finding…is almost certainly dependent upon the HAART regimen used.” Indeed, they refer to evidence from the Gilead 903 study which showed “low rates of lipodystrophy and other toxicities” despite 39% of individuals enrolled in the study having a CD4 cell count below 200 cells/mm³.

Other concerns about side-effects also remain. Even though newer protease inhibitors do not appear to cause the lipid abnormalities of early drugs in this class, the authors note that the DAD study found an increased risk of cardiovascular events even after controlling for lipid profiles. The authors also note “reductions in bone density, increases in insulin resistance, and a small but still present risk of lipodystrophy” even with the newer less-toxic drugs and regimens.

Resistance also remains a significant concern. Due to their long-term side-effects profile and ease of adherence NNRTI-based regimens are the first choice anti-HIV treatment combination. However, failure of this regimen is likely to leave an individual with resistance to two classes of antiretroviral drugs.

Arguments concerning long-term preservation of therapeutic options are also considered by Cohen and Boyle. They note that “a significant number of patients with a nadir CD4 cell count of 200 – 350 cells/mm³ also have significant durations of treatment interruption – up to six months or even longer – before treatment is started again on the basis of agreed treatment criteria.”

In addition, although starting treatment at a higher CD4 cell count may allow longer treatment interruptions, it is not clear if this would, over time, actually mean that less time is spent on treatment.

Cohen and Boyle also note that it's unclear if starting and maintaining HIV treatment is a better or worse strategy than approaches based on CD4 cell count, where treatment is started when indicated by treatment guidelines and interrupted once it rises above a determined level, and subsequently restarted once it falls again, or for clinical reasons. This approach is being investigated in the international SMART study which is currently recruiting.

Cohen and Boyle conclude that there despite the availability of new anti-HIV drugs there is no evidence that HAART should be started earlier. “There remain potential disadvantages to doing so, including risks of antiretroviral toxicity and emergence of resistance, and, in a field anchored by evidence-based medicine, there is limited evidence of its advantages.”