Nearly 13% of individuals taking HAART in a major observational cohort have experienced the failure of all of the three main classes of antiretroviral drugs, according to a study published in the December 1st edition of The Journal of Infectious Diseases. The investigators from the EuroSIDA study group found that individuals who had experienced the failure of all the three main classes of anti-HIV drugs were significantly more likely to experience disease progression or death.
Relatively little is known about the incidence of triple class failure and how long it takes for triple class failure to develop after commencing HAART. Therefore, investigators from the EuroSIDA cohort conducted an observational longitudinal study involving 3496 treatment-experienced and treatment-naïve individuals from 72 treatment centres in Europe, Israel and Argentina. Their aims were to:
- Describe the time to triple class treatment failure.
- Describe the prevalence and incidence of triple class treatment failure.
- Summarise the clinical outcome of patients with triple class failure.
The investigators noted that virological failure of a class of antiretrovirals could be caused by intolerance rather than resistance. Although triple class failure could often be considered a surrogate marker for resistance in most cases, other causes of treatment failure could not be ruled out.
Individuals were enrolled from 1994 to 2001 with follow-up provided until the end of 2002.
Virological failure to a drug class was defined as having occurred when all tests showed a viral load above 1000 copies/ml for a total of four or more months after starting therapy with the class of antiretrovirals.
Just under 64% of patients (2230) had received either antiretroviral monotherapy or dual therapy before starting HAART. At baseline, these treatment-experienced had significantly lower median viral loads (p
A median of 16 viral load measurements were taken from treatment experienced patients and thirteen for treatment naïve individuals. The median interval between each viral load test was three months.
Investigators had a total of 9542 person years of follow up for treatment-experienced patients available for analysis and 4726 person years of follow up for treatment-naïve patients.
Treatment-experienced patients had been taking antiretroviral therapy for a median of 34 months prior to starting HAART, 58% of individuals had received both monotherapy and dual therapy, and the median number of anti-HIV drugs taken at baseline by treatment-experienced patients was three. Over 47% of treatment-experienced patients did commence any new nucleoside analogues when they started HAART.
During follow-up a total of 1816 patients (51.9% of the study population) took drugs from all the three main antiretroviral classes. In total 445 patients (12.7%) experienced the failure of all three classes, including 370 (16.6%) of patients who were treatment- experienced at baseline and 75 (5.9%) of individuals who were treatment naïve.
The overall incidence of triple class resistance was 3.9 cases per 100 patient years of follow-up amongst treatment-experienced patients and 1.9 cases per 100 patient years amongst treatment-naïve patients.
Incidence amongst treatment-naïve patients increased from 1 case per 100 patient years during the first two years of follow-up to 3.3 cases per 100 patient years after five years of follow-up, almost exactly the same as the 3.4 cases per 100 patient years seen in treatment-experienced patients at this time point.
After adjusting for baseline CD4 cell count and viral load, the risk of developing triple class failure increased by 43% per year of HAART for treatment-naïve patients. Amongst treatment-experienced patients, after adjusting for baseline CD4 cell count and viral load, the total of new nucleosides started, and total exposure to nucleosides, the risk of developing triple class failure decreased by 71% during the first two years of HAART.
Amongst the treatment-naïve patients there was no statistically significant relationship between triple class failure and the year HAART was started, HIV risk category, coinfection with hepatitis B or C virus, CD4 cell count at baseline or the availability of resistance testing. The only factor associated with triple class failure was viral load at baseline with each log increase in viral load increasing the risk of triple class failure by 55% (p = 0.011).
For treatment-experienced patients the investigators failed to find a statistically significant relationship between the year HAART was started, the number of nucleosides taken before HAART, prior antiretroviral regimen, and the availability of resistance tests. However, they did find a statistically significant relationship between the risk of triple class failure and injecting drug use (p = 0.48), and viral load prior to starting HAART (p
The incidence of new AIDS defining events and death increased with each additional class of antiretroviral drugs failed. The incidence of new AIDS or death was 2.7 per 100 patient years in patients with no resistance, 3.7 per 100 patient years amongst patients with resistance to one or two classes of antiretrovirals, and 5 cases per 100 patient years amongst patients with triple class resistance (p 3, for whom the risk of AIDS or death increased by 47% per class of antiretroviral drugs failed (p = 0.006).
“By 2003, one in 20 treatment-naïve and one in six treatment-experienced patients from the EuroSIDA study who started receiving HAART experienced triple class failure”, write the investigators. They add, “the incidence of triple class failure was considerably lower among treatment naïve patients but increased with increasing time since starting HAART.”
The investigators draw attention to the implications of triple class failure for both patients and HIV clinics. “For the individual, this may lead to a poorer prognosis and to potential transmission of resistant virus to others. For the clinics, it may lead to increased cost due to more-intensive diagnostic tests, the use of more-expensive drugs such as enfurvirtide, and the use of more drugs in each regimen.”
The increased incidence of triple class failure amongst treatment-naïve patients is attributed by the investigators to poor adherence to the early HAART regimens which were often difficult to take, and differences in early treatment guidelines. They conclude by calling for further research into the “long-term consequences of triple class failure on the durability of HAART and on the reduction in clinical disease progression and how best to manage this situation.”
Mocroft A et al. Time to virological failure of three classes of antiretrovirals after initiation of highly active antiretroviral therapy: results from the EuroSIDA study group. J Infect Dis 190: 1947 – 46, 2004.