HAART interspersed with relatively long periods of treatment interruption may become the future standard of care for certain people living with HIV, according to the authors of a paper published in the December 1st issue of Clinical Infectious Diseases (now available online).
Ironically, whilst most of the world struggles to find ways to get people with HIV onto HAART, treatment interruption has become a hot topic in well-resourced countries, as resistance and the long-term toxicities of HAART become more of an issue in the management of HIV disease.
Investigators from Johns Hopkins University School of Medicine and the University of Texas performed a "strictly observational" study of treatment interruption (TI) in 105 attendees of the Johns Hopkins HIV clinic in Baltimore who stopped HAART - either at their doctor's suggestion or with their doctor's approval - with the intention of resuming therapy after clinical disease progression or when CD4 cell counts decreased or HIV plasma viral load increased to an undefined level, based on decisions from the individual's doctor. Information regarding interruption and resumption of therapy, as well as CD4, viral load and lipodystrophy-related data, were all obtained from medical records, with clarification from the doctors themselves when necessary.
Three outcomes were investigated: time to treatment reinitiation (TR), rate of change in CD4 cell count per year after TI, and estimated time between TI and reaching a CD4 count of 200 cells/mm3. Individuals were classified as either nonresumers (n=60, 57%) or resumers (n=45, 43%), depending on whether they had resumed HAART by the time the authors had written the paper (April 2003). The study had no fixed end, and the average length of time that nonresumers had been off therapy was 10 months, with a mean CD4 count of 500 cells/mm3 and a mean HIV RNA level of 46,000 copies/mL in April 2003.
In contrast, resumers were off therapy for an average of only four months. As a group, their mean CD4 count before resuming was 305 cells/mm3, and their mean HIV RNA levels were 164,000 copies/mL. Reasons for resuming HAART, which were not mutually exclusive, included: increasing viral load (n=8); decreasing CD4 cell count (n=11), or both (n=15); patient preference (n=2); symptomatic rebound viraemia (n=3); and treatment of hepatitis B coinfection (n=1). No clinical disease progression was seen.
The majority of individuals who resumed HAART achieved virus suppression similar to their pre-TI level, with 2 out of 15 not achieving their prior
The investigators went on to analyse the data using Kaplan-Meier curves to estimate time off HAART based on CD4 count and viral load at HAART initiation. Unsurprisingly, they found that the relative hazard (RH) of restarting therapy sooner than those with more than 500 CD4 cells was highest in those with less than 200 CD4 cells (RH=4.4), compared to those with 200-350 CD4 cells (RH=2.9) and 351-500 CD4 cells (RH=1.6). Similar findings were seen according to viral load, with those whose pre-treatment viral load was over 5 log10 copies/mL almost six times more likely to resume treatment than those with a viral load between 4 and 4.49 log10 copies/mL.
Interestingly, of the 32 individuals with some evidence of lipodystrophy, 17 (53%) had some improvement, either by patient report, clinician assessment or both. Additionally, four of seven individuals with hyperglycaemia and 24 of 35 with high blood lipids experienced (non-defined) improvement during the TI.
The authors suggest - perhaps rather prematurely given the small numbers involved in this observational study, and given that previous pulse therapy data show conflicting results(see news stories below) - that these results "have implications for the pulse therapy strategy, in which the goal of therapy is to maintain the CD4 cell count above a predetermined threshold using cycles of therapy followed by prolonged TIs. There may be a subset of patients - presumably, those with relatively low virus load set points and good CD4 cell count responses to HAART - who will be able to discontinue therapy for prolonged periods of time."
They do concede, however, that those with high pre-treatment viral loads and low CD4 counts, as well as those individuals who do not have substantial rises in CD4 counts on HAART, will not be able to follow this strategy, which excludes the majority of people currently on HAART.
Further information on this website
Should treatment breaks be guided by CD4? Study suggests yes - news story, September 2003
High-dose pulsed therapy - the future for structured treatment breaks? - news story , July 2003
Week on, week off treatment strategy buried at Paris conference - news story, July 2003
Long cycle treatment breaks unsafe and do not lessen side-effects or improve CD4 count or viral load - news story, July 2003
Structured treatment interruptions - overview
Treatment interruptions - factsheet
Tarwater PM et al. Prolonged Treatment Interruption after Immunologic Response to Highly Active Antiretroviral Therapy Clinical Infectious Diseases 37: 1541-8, 2003.