Atazanavir (Reyataz) for HIV-1 infection: SMC review

The Scottish Medicines Consortium issued on 7th December, 2008 an advice on the recently approved protease inhibitor Atazanavir (Reyataz)

Atazanavir (Reyataz) is accepted for use within NHS Scotland in antiretroviral treatment naïve HIV-1 infected adults in combination with other antiretroviral medicinal products.
The combination of atazanavir and ritonavir was non-inferior to a standard boosted
protease inhibitor regimen in treatment naïve HIV patients. The combined regimen was associated with lower incidences of diarrhoea and lipid adverse-effects and a higher incidence of hyperbilirubinaemia in this patient population.

This is an excerpt of the detailed advice on atazanavir:

Indication

Use in antiretroviral treatment naïve HIV-1 infected adults in combination with other antiretroviral medicinal products.

Dosing information

Atazanavir 300mg once daily with ritonavir 100mg once daily.

Therapy should be initiated by a physician experienced in the management of HIV infection.
Product availability date
20 June 2008

Summary of evidence on comparative efficacy

Atazanavir (ATV, Reyataz) was accepted for restricted use within NHS Scotland in September 2004 for the treatment of HIV-1 infected, antiretroviral treatment experienced adults, in combination with other antiretroviral medicinal products in those patients who do not require concomitant statin use. The current submission aims to broaden this indication to include HIV-1 infected antiretroviral treatment naïve adults.

This indication is supported by 48-week data from a 96-week randomised open-label, multi-centre clinical study conducted in antiretroviral-naïve patients aged 18 years and older with qualifying plasma HIV RNA ≥5,000 copies/mL (c/mL) at screening, to assess the efficacy and safety of ATV plus ritonavir (ATV/RTV, 300mg/100mg once daily) compared to lopinavir plus ritonavir (LPV/RTV, 400mg/100mg twice daily), both in combination with the nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir (TDF, 300mg) and emtricitabine (FTC, 200mg) administered once daily. Patients included in the study were prohibited from taking antiretroviral therapy during the 30 days before screening or for one week or more at any time (although certain exceptions were permitted). Patients were excluded from the study if they had proven or suspected acute hepatitis in the 30 days prior to study entry or a calculated creatinine clearance (CrCl) <60mL/min.

The primary efficacy endpoint was the proportion of patients with HIV RNA <50c/mL at week 48. The secondary efficacy endpoints were the proportion of patients with HIV RNA <400c/mL at week 48, time to loss of virologic response (TLOVR) (which defines the number of responders at week 48 as patients with confirmed HIV RNA <50c/mL through week 48 without intervening virologic rebound or treatment discontinuation; failure in this analysis included patients with virologic rebound and those that discontinued therapy, never responded or were never treated), the reduction of log10 HIV RNA from baseline through week 48, the change in CD4 cell count from baseline through week 48, and the antiretroviral resistance profiles of patients experiencing virologic failure. Efficacy endpoints were evaluated by treatment regimen for as-randomised patients. The principal analysis of the primary endpoint was based on the Confirmed Virologic Response (CVR) Non-Completer = Failure (NC=F; intention-to-treat [ITT]) definition of response. Supportive analyses used the CVR Non-Completer = Missing (NC=M), TLOVR and Virologic Response – Observed Cases (VR-OC) definitions of response. Treatment regimens were compared using the difference in proportions (ATV/RTV minus LPV/RTV) and 95% confidence interval (CI) based on a stratified normal approximation. The ATV/RTV regimen was determined to be similar (non-inferior) to the LPV/RTV regimen if the lower confidence limit for the difference in proportions was greater than -10%.

Of 1,057 patients enrolled in the study, 883 patients were randomised to either ATV/RTV (440) or LPV/RTV (443). Five randomised patients were never treated (two in the ATV/RTV group and three in the LPV/RTV group) and three patients randomised to LPV/RTV received ATV/RTV for the entire study. Thirty-nine patients (8.9%) in the ATV/RTV group and 58 patients (13%) in the LPV/RTV group discontinued treatment before week 48. Patient demographics and baseline characteristics were not significantly different between the two groups.

Non-inferiority of the ATV/RTV regimen to the LPV/RTV regimen was demonstrated for the proportion of patients with HIV RNA <50c/mL at week 48. The lower confidence limit was within the pre-specified boundary of -10%. The non-inferiority was further supported by analyses of HIV RNA <400c/mL at week 48. Both regimens achieved ≥3.0 log10 HIV RNA reduction from baseline and were comparable for mean increases from baseline in CD4 cell count at week 48. Hazard ratio estimates for TLOVR and 95% CI were 0.93 (0.71 to 1.23) for HIV RNA <50c/mL and 0.78 (0.56 to 1.09) for HIV RNA <400c/mL.

When considering the primary efficacy outcome, 343/440 patients (78%) in the ATV/RTV group were classified as responders without virologic rebound compared to 338/443 patients (76%) in the LPV/RTV group. Virologic failure for the HIV RNA <50c/mL outcome using CVR (NC=F) was the most frequent reason for lack of response on both regimens (14% [60/440] and 12% [52/443] in the ATV/RTV and LPV/RTV groups, respectively). Most patients with virologic failure were never suppressed through week 48 (65% [39/60] and 50% [26/52] respectively), while 27% (16/60) and 37% (19/52), respectively experienced rebound.
Other reasons for not being a responder included discontinuation due to adverse events, death, lost to follow-up and poor compliance. The pivotal study described above indicated that the emergence of phenotypic and genotypic resistance to ATV/RTV is a rare event and similar to LPV/RTV. No patient on either regimen, with a wild-type baseline isolate, developed genotypic or phenotypic resistance.

Summary of evidence on comparative safety

Safety data from the pivotal study demonstrated that the pattern of adverse events (AEs) was consistent with the known safety profile of ATV/RTV and LPV/RTV when combined with NRTIs. ATV/RTV demonstrated a significantly better lipid profile compared to LPV/RTV.
Mean percent changes from baseline in fasting lipids (total cholesterol [13% versus 25%], non-HDL cholesterol [8.2% versus 22%] and triglycerides [15% versus 52%]) at week 48 were significantly lower on ATV/RTV than LPV/RTV. Treatment-related hypertriglyceridaemia occurred in 2.3% and 8.5% of patients on ATV/RTV and LPV/RTV, respectively. A total of 2.3% and 7.6% of patients on ATV/RTV and LPV/RTV, respectively, received lipid lowering therapy.

ATV/RTV demonstrates an improved gastrointestinal tolerability profile compared to LPV/RTV. Diarrhoea of any grade was reported in 2.5 times as many patients on LPV/RTV as ATV/RTV (53% versus 21%), whilst only 2.3% of patients on ATV/RTV had grade 2 to 4 diarrhoea (described as mild to moderate) compared to 11% on LPV/RTV. Diarrhoea was reported as a serious adverse event (SAE) in 1.4% of patients on LPV/RTV and <1% of patients on ATV/RTV. Treatment-related diarrhoea (11% versus 46%) and nausea (15% versus 22%) occurred with a lower frequency in the ATV/RTV group than the LPV/RTV group. Four patients (<1%) on LPV/RTV discontinued due to diarrhoea compared to none on ATV/RTV. A total of 5.7% and 13% of patients on ATV/RTV and LPV/RTV, respectively,
received the anti-diarrhoeal therapy, loperamide, through week 48 with the frequency of at least 10%.

Bilirubin-associated disorders constitute a recognised side effect of ATV/RTV which is both benign and reversible and not associated with any hepatocellular toxicity. In the ATV/RTV regimen bilirubin-associated disorders of jaundice, hyperbilirubinaemia and ocular icterus were more common on ATV/RTV than LPV/RTV (any grade; 35% versus 1.1%). Treatment- related jaundice (15% versus <1%), hyperbilirubinaemia (9.5% versus 0%) and ocular icterus (8.4% versus 0%) of any grade occurred with a higher frequency in the ATV/RTV group compared with the LPV/RTV group. Grade 2 to 4 treatment-related hyperbilirubinaemia and jaundice were also higher in the ATV/RTV group (5.9% versus 0% and 3.6% versus 0%, respectively). Patient discontinuation due to jaundice/hyperbilirubinaemia was rare (<1% in the ATV/RTV group and 0% in the LTP/RTV group).

Supportive safety data from a 96-week open-label randomised controlled trial evaluating ATV/RTV (300mg/100mg) once daily versus ATV (400mg) once daily, both combined with lamivudine / stavudine (XR) 300mg/100mg (75mg for patients weighing <60kg) once daily, demonstrated that the overall safety profile of AVT/RTV over 96 weeks was similar to that reported in the pivotal trial over 48 weeks. The main discrepancy relates to the number of patients discontinuing ATV/RTV therapy due to AEs, which was 8.4% (8/95) in the supportive study at both the 48 weeks interim analysis and the 96 weeks end of trial analysis
versus 2.5% (11/441) in the pivotal study at 48 weeks. In the supportive study four patients in the ATV/RTV group discontinued therapy due to hyperbilrubinaemia, one due to jaundice and one due to an increase in blood bilirubin.

Summary of clinical effectiveness issues

The British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2008) indicates that the efficacy outcomes used to assess treatment response in the pivotal study (plasma HIV RNA levels and CD4 cell counts) are proven surrogate markers for HIV disease progression and routinely used as markers of the biological activity of antiretroviral therapy. The CD4 count is considered to be a better indicator of the immediate risk of AIDS-defining diseases than the viral load in those on antiretroviral therapy. However, it should be noted that CD4 count and viral load responses
do not precisely reflect the expected clinical outcome and are not perfect surrogates of the clinical response.

Response rates (HIV RNA <50c/mL at week 48 using CVR) varied across regions but not by race. When considering the mean changes from baseline of CD4 at week 48 on the ATV/RTV regimen, differences of ≥50 cells/mm3 were noted within race (lower mean change for blacks [154 cells/mm3] versus whites [226 cells/mm3]) and region (Africa [170 cells/mm3] versus South America [221 cells/mm3]). With regard to gastrointestinal-related AEs, blacks had the lowest incidence of nausea on the ATV/RTV regimen (5.9%), compared to 17% to 19% in whites, Asians, and other races. As no data were presented to indicate the racial split of HIV infected patients in Scotland, it is unclear whether the results of the pivotal study, where 52% of patients (53% in the ATV/RTV group and 50% in the LPV/RTV group) were classified as non-white, will translate into clinical practice for the Scottish HIV population.
ATV/RTV is the only licensed boosted protease inhibitor (PI) currently dosed once daily and consequently has the lowest bill burden of the PIs. As with the majority of other PIs and unlike LPV/RTV, ATV requires to be taken with food. The BHIVA guidelines note that the interaction of ATV with acid-reducing agents, notably proton-pump inhibitors, is not overcome by ritonavir boosting, and where alternative antacid strategies cannot be used, atazanavir should be avoided.

Additional information: guidelines and protocols

British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy, 2008 (web consultation draft available at www.bhiva.org) recommend that efavirenz should be considered first line in all patients. Boosted PIs should be reserved for specific groups of patients, such as those with primary NRTI and / or non-nucleoside reverse transcriptase inhibitors (NNRTI) resistance, women who wish to become pregnant, and in some patients with psychiatric problems. The guidelines recommend that the HAART standard of care, in treatment naïve patients, is a regimen that consists of NNRTIs (with efavirenz as the recommended agent) and two NRTIs with Truvada(tenofovir plus emtricitabine) or Kivexa (abacavir plus lamivudine) as the recommended agents). For patients who are unsuitable for an NNRTI, the BHIVA guidelines recommend therapy initiation with a boosted PI (LPV/RTV, fosamprenavir/RTV, ATV/RTV and saquinavir/RTV) in combination with two NRTIs.

Source: Scottish Medicines Consortium. Drug Advice: Atazanavir (Reyataz). PDF full text

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