Better than expected 'real world' benefits seen in highly treatment-experienced patients on atazanavir

'Real world' experience from a Spanish HIV clinic has found that once-daily boosted atazanavir (Reyataz) in combination with a once-daily nucleoside backbone resulted in a "deeper than expected" reduction in viral load in a small group of heavily pre-treated patients after 48 weeks. The prospective data, published as a letter in the June edition of the Journal of Acquired Immune Deficiency Syndromes, suggest that once-daily atazanavir-based antiretroviral therapy may be a viable option for HIV-positive individuals with extensive prior antiretroviral experience.

In Europe, atazanavir boosted with ritonavir (Norvir) - at a dose of 300/100mg once daily - has been approved for use in both treatment-naive and treatment-experienced patients since 2004. Approval was based on the results of several studies sponsored by atazanavir's manufacturer, Bristol Myers Squib (BMS).

However, whilst BMS's 045 study found that boosted atazanavir was as effective as Kaletra (lopinavir/ritonavir) in reducing viral load and increasing CD4 cell counts in treatment-experienced patients up to 96 weeks, around two-thirds of the study's participants had fewer than four primary protease mutations.

In addition, nearly half of the participants had less than four primary nucleoside analogue mutations, implying that a large minority had the opportunity to assemble a dual nucleoside analogue backbone that was active.

Further analysis of the 045 study found that patients with four or more baseline protease mutations had a better response to Kaletra than to atazanavir, and no response was seen to atazanavir in those with five or more protease mutations.

However, since the 045 study found that atazanavir was better tolerated than Kaletra (at least in its soft-gel formulation, which will be discontinued once the Kaletra tablet has been approved in Europe), and resulted in a better lipid profile, it could potentially be a viable protease inhibitor for treatment-experienced patients with adherence and/or tolerability issues.

Investigators from an HIV clinic in Madrid evaluated the efficacy and safety of what they term once-daily "atazanavir-based rescue regimens" in 56 consecutive patients treated between March 2003 and September 2004. The nucleoside background combination was similar to the 045 study, with two-thirds on tenofovir (Viread) and ddI (Videx EC).

This was an extremely heavily pre-treated patient population (71% male, 65% former injection drug users) who had already taken between seven and fourteen (median ten) prior regimens, comprising a median of nine prior drugs (range 5-12). Most (91%) had previously failed treatment with at least one protease inhibitor (PI), and 69% had received two or more PIs. The cohort had a median of five protease mutations (interquartile range 4 - 8) and ten nucleoside mutations (interquartile range 5 - 15) prior to starting atazanavir-based therapy.

At baseline their median viral load was 19,950 copies/ml (range, 2,500 - 80,000 copies/ml). Almost half (48%) had interrupted therapy prior to starting atazanavir-based therapy due to a "lack of virologic response with prior regimens," write the investigators. Their median time on prior treatment was around four years, and 61% were also coinfected with hepatitis C virus, suggesting that adherence and/or tolerability had been problematic in the past.

After 48 weeks, 48% achieved a viral load of less than 50 copies/ml. This appears to compare favourably with 48 week intent-to-treat data from BMS's 045 study where 38% on boosted atazanavir achieved less than 50 copies/ml. However, the Spanish investigators do not say whether their results were based on intent-to-treat or on-treatment analysis, since they write that data from only 46 patients were available for analysis after one year. In these 46 patients, the median viral load decrease over a year was 2.5 log₁₀copies/ml.

The investigators note that despite the fact that the combination of tenofovir and ddI as nucleoside backbone is no longer recommended due to concerns over CD4 declines, "a subsequent increase in CD4 cell counts was observed." After a year, median CD4 cell counts increased by 68 cells/mm³ in the 46 patients available for analysis.

The investigators concede, however, that this was an observational, clinical cohort study with a small number of patients, "and we cannot exclude the possibility that our results were distorted by residual confounding or unmeasured factors."

In addition, they do not report on tolerability and whether there were any discontinuations due to adverse events.

Nevertheless, they conclude that since they found a "deeper than expected" viral load decline after 48 weeks, "even if management of HIV-infected patients who have experienced prior virologic failure is challenging and often not successful, nowadays, pretreated patients in need of rescue therapies can also benefit from simple regimens, at least in the short-term."