Patients staying on first-line HIV treatment combinations for longer

The introduction of the fixed-dose NRTI combination pills Kivexa (abacavir and 3TC, called Epzicom in the US) and Truvada (tenofovir and FTC) in summer 2004 “ushered in a new treatment era for antiretroviral-naïve patients initiating antiretroviral therapy”, write American researchers in the October 1^st edition of AIDS. After the introduction of these combination pills, the investigators found that the amount of time patients remained on first-line treatment increased significantly.

Ease of dosing and improved tolerability were identified by the researchers as the main reasons why patients were able to remain on their treatment for longer.

There is now extremely robust evidence that antiretroviral therapy can significantly improve the prognosis of HIV-positive individuals. Based on knowledge of currently available treatment, once a patient has started HIV therapy it is necessary for him/her to remain on such treatment for life. Although the arsenal of available anti-HIV drugs has increased in recent years, it is important the best possible use is made of the 20 or so drugs available for prescription.

First-line antiretroviral therapy provides the best chance of long-term HIV suppression, and it is important that patients taking such therapy are provided with tolerable and effective drugs.

Researchers at the University of Birmingham in Alabama, one of the largest HIV treatment centres in the southern United States, found that the median duration of first-line antiretroviral therapy between 1996 and 2001 was a little over one and a half years. Early HIV treatment combinations, available in this period, relied on drugs with significant side-effects, that had to be taken in large numbers up to three times a day.

But in more recent years, powerful anti-HIV drugs have become available with fewer side-effects, and requiring only once-daily dosing. A key breakthrough was the licensing in the US in August 2004 of two fixed-dose once-daily nucleoside reverse transcriptase inhibitor (NRTI) pills, Epzicom (Kivexa in Europe), and Truvada.

Investigators wished to see if the introduction of these pills was associated with an increase in the amount of time patients were able to remain on their first-line antiretroviral treatment.

They therefore designed a retrospective study involving 542 patients who started HIV treatment between January 2000 and July 2007. These patients were divided into two groups: those who initiated therapy before July 31^st 2004, and those who started treatment from August 2004 (when the new fixed-dose pills became available) onwards.

Overall, two-thirds of patients were taking treatment that involved three pills or fewer each day, and 85% of patients were taking a fixed-dose NRTI pill. There was a marked increase in the proportion of patients taking once-daily treatment from just 12% in 2000 to 82% in 2007, and the proportion of patients taking a fixed-dose NRTI also increased over this time period from 77% to 95%.

Use of abacavir or tenofovir as part of an antiretroviral regimen increased from just 6% in the earlier period to 85% for therapy started after August 2004. The increase in the use of these drugs was paralleled by a steep decline in the use of AZT (77% to 14%). The researchers also noted increases in the use of ritonavir-boosted protease inhibitors (from 7% to 23%), NNRTIs (68% to 72%), and the disappearance of triple NRTI therapy (16% to 0%), a strategy shown to involve a high risk of viral rebound and resistance.

Furthermore, the investigators also found that there was a significant decline in the number of patients who stopped treatment within 90 days of initiating therapy with their first antiretroviral regimen (14% to 6%, p

Overall, median duration of treatment with first-line antiretroviral therapy increased from 780 days between 2000 and July 2004 to 1043 days from August 2004 onwards.

Investigators then looked at how long patients were able to stay on their first treatment combination according to its complexity and composition. On average, patients remained on treatment requiring a dose of three or fewer pills a day for 1218 days, compared to just 340 days for pills consisting of six pills or more per dose. Patients taking once-daily treatment stayed on their first combination for 1253 days compared to 712 days for patients taking twice-daily treatment. Combinations including abacavir or tenofovir were much more durable (median 1253 days) than those including d4T or ddI, and patients stayed on NNRTI-based treatment (median 1132 days) for longer than treatment based on a boosted protease inhibitor (median 1043 days).

A series of statistical analyses were then performed by the investigators. They found that, after controlling for patient characteristics, those who initiated therapy before August 2004 were 44% more likely to stop treatment than those who started treatment after the introduction of Epzicom and Truvada (HR = 1.44, 95% CI 1.03 – 2.02).

But when the investigators included dosing frequency in this model, they found that this difference disappeared, but that twice-daily treatment was associated with a 92% increase in the risk of treatment discontinuation compared to once-daily therapy (HR = 1.92, 95% CI 1.29 – 2.88).

Next the researchers looked at the composition of treatment, and this showed that treatment based on anything other than an NNRTI was associated with a greater risk of stopping treatment (for example, boosted protease inhibitor HR = 1.57, 95% CI 1.02 – 4.26). Use of d4T or AZT increased the risk of treatment discontinuation by 116% compared to abacavir or tenofovir (HR = 2.16 95% CI 1.09 – 4.26).

The investigators note that their study has a number of limitations, not least its small sample size and single-centre design. Furthermore, the investigators do not specify the maximum duration of of therapy for patients taking the most modern antiretroviral regimens, nor do the provide details of the reasons driving treatment changes.

“In treatment-naïve patients starting antiretroviral therapy, contemporary intial regimes are more durable than those initiated prior to 2004”, write the inverstigators. Lower pill burden, less frequent dosing, and greater tolerability are offered as likely explanations.

They add, “the enhanced durability of more modern regimens is encouraging in light of recent data highlighting the importance of uninterrupted antiretroviral therapy”.