Saquinavir/r non-inferior to Kaletra at week 48 (Gemini study)
Simon Collins, HIV i-Base
The Gemini Study was a 48-week prospective, open-label trial that randomised 337 treatment-naive patients to either saquinavir/r or lopinavir/r, using tenofovir and FTC as background nukes.
Interim 24-week and full 24-week results were presented at the Glasgow 2006 and IAS 2007 conferences respectively, showed very little difference between the two groups. 48-week results were presented at EACS by Sharon Walmsley from the University of Toronto.
337 treatment-naive patients from the US, Canada, France and Thailand were randomised to either saquinavir/ritonavir 1000mg/100mg BID (n=167) or lopinavir/r 400mg/100mg BID, Kaletra capsule formulation (n=170), with tenofovir/FTC as background nucleosides.
39 of these patients were excluded in the per protocol analysis due to not meeting entry criteria (mainly having baseline CD4 counts >350 cells/mm3 or viral load <10,000 copies/mL). Further discontinuations and loss to follow-up in the trial, detailed in Table 1, resulted in only 128 and 135 patients in the saquinavir/r (SQV/r) and lopinavir/r (LPV/r) arms respectively, reaching the week 48 endpoint,
Table 1: Subject discontinuations in Gemini by week 48
|Reason for withdrawal||SQV/r (n = 167)||LPV/r (n = 170)|
|Overall discontinuations, n (%)||39 (23)||35 (21)|
|Safety, n (%)||8 (5)||13 (8)|
|Adverse event =1%, n (%)||5 (3)||12 (7)|
|Death [a] n||3 [b]||1 [c]|
|Non-safety, n (%)||22 (13)||19 (11)|
|Violation of selection criteria at entry||0||2|
|Other protocol violations||1||0|
|Failed to return||12||12|
|Insufficient therapeutic response, n (%)||9 (5)||3 (2)|
[a] 7 total: 3 deaths occurred outside of treatment period in LPV/r group (after withdrawal or during follow-up period): hepatic failure (possibly related to study drug), Burkitts lymphoma, PML [b] Cause of death: victim of crime (remotely related to study drug), drowning, sepsis [c] Cause of death: suicide
This was a non-inferiority study (defined with lower CI threshold of -12%). The primary efficacy endpoint was the percentage of patients with HIV-1 RNA <50 copies/mL at week 48. Secondary efficacy and tolerability endpoints included time course of viral load and CD4 changes and clinical and laboratory side effects, serious side effects and deaths.
Study groups were balanced at baseline: approximately 80% male, median age 37 (range 28-66). Although the median weight 69kg this ranged from 34-131kg, which was reported as reflecting the geographic differences (and presumably HIV-related wasting in some patients). This was an advanced group of patients. Mean viral load was 5.2 log (+0.5 log), with >63% starting at over 100,000 copies/mL. Mean CD4 count was reported as approximately 160 cells/mm3 (+SD 125), with 40% starting with <100 cells/mm3. 24% of the SQV/r arm and 29% of the LPV/r arm had experienced a prior AIDS defining event. Just under 10% of patients were coinfected with hepatitis C.
At week 48, by ITT analysis (missing data=non-response), 64.7% patients in the SQV/r and 63.5% in the LPV/r arm had viral load <50 copies/mL (estimated difference 1.14% [95% CI 9.611.9] p < 0.0119), meeting the predefined definition of non-inferiority for saquinavir/r. There was a similar difference in the per-protocol analysis (3.5% (95% CI 8.115.0), p < 0.0058).
Both groups reported viral load reductions of -3.3 logs at week 48 (p=0.62, NS). Median CD4 increases were similar: +178 (SQV/r) vs +204 (LPV/r), (p=0.33, NS).
More patients failed virologically in the SQV/r arm: 11 (7%) vs 5 (3%), p=0.13 NS, with more patients also having documented poor adherence (6/11 vs 2/5). 5 of the patients in the SQV/r arm compared to 0 in the LPV/r arm were subsequently found to have had undocumented resistance at baseline. The only case of new PI resistance was in a patient using SQV/r.
Side effects, detailed in Table 2, were broadly similar in each group, with slightly less GI disorder reported with SQV/r.
Table 2: Summary of adverse events (all grades)
|SQV/r (n = 163)||LPV/r (n = 168)|
|Total pts with . 1 AE, n (%) Total number of AEs Total number of SAEs||83 (51) 231 32||106 (63) 247 24|
|Individual AEs reported in =3% of participants in either group|
|Total pts with =1 AE Bronchitis Upper respiratory tract||39 (24) 9 (6) 4 (2)||47 (28) 2 (1) 8 (5)|
|Total pts with =1 AE Nausea Vomiting Diarrhea Abdominal pain||27 (17) 10 (6) 10 (6) 11 (7) 3 (2)||45 (27) 15 (9) 10 (6) 24 (14) 5 (3)|
|Total pts with =1 AE Fatigue||20 (12) 8 (5)||16 (10) 6 (4)|
|Total pts with =1 AE Hypertriglyceridemia Anorexia||13 (8) 0 5 (3)||13 (8) 5 (3) 4 (2)|
|Nervous system disorders:|
|Total pts with =1 AE Headache||13 (8) 4 (2)||12 (7) 7 (4)|
|Total pts with =1 AE Depression||10 (6) 4 (2)||13 (8) 5 (3)|
|Musculoskeletal/ connective disorders: Total pts with =1 AE||9 (6)||13 (8)|
|Respiratory/thoracic/mediastinal disorders: Total pts with =1 AE||8 (5)||6 (4)|
|Renal/urinary disorders: Total pts with =1 AE||7 (4)||2 (1)|
|Skin/Subcutaneous Tissue disorders: Total pts with =1 AE||6 (4)||5 (3)|
|Vascular disorders: Total pts with =1 AE||1 (<1)||5 (3)|
The only statistical difference in lipid changes at week 48, favouring the SQV/r arm, were lower increases in triglycerides: +0.16 vs +0.62 mmol/L, (p=0.0022), with no differences for TC, LDL and HDL. However, the SQV/r benefit in TC/HDL ratio seen at week 24 (-0.40 vs -0.07, p=0.02) lost statistical significance by week 48 (-0.27 vs -0.13, p =0.47).
Interventions with lipid lowering drugs (based on NCEP and ACTG guidelines), were warranted for higher number of patients in the SQV/r arm due to increases in LDL, and for more patients in the LPV/r arm due to increases in triglycerides. Lipid lowering drugs were not widely used during the study (n=4 patients in the SQV/r arm and 7 patients in the LPV/r arm).
These results provide support for use of boosted saquinavir in first-line treatment, when a PI is indicated.
It is unclear how the newer Kaletra tablet formulation would effect these results. After the study was enrolled, Kaletra was reformulated to require fewer pills, no refrigeration or diet restrictions, to have better pharmacokinetics and possibly an easier GI side effect profile.
It is disappointing that the improvement in TC:HDL ratio in favour of saquinavir seen at week 24, lost statistical significance by week 48. It will be important to see additional analysis by baseline viral load and CD4 count, and details about incidence of lypodystrophy, and it is disappointing that extended follow-up will not be presented.
Ref: Walmsley S, Ruxrungtham K, Slim J et al. The Gemini Study: Saquinavir/r (SQV/r) vs lopinavir/r (LPV/r) plus emtricitabine/tenofovir (FTC/TDF) as initial therapy in HIV-1 infected patients. Abstract PS1/4.
The presentation is available online: