Included Studies

The evidence for this review was drawn from three randomized controlled trials (RCTs) — LIPO-010 (N = 412), CTR-1011 (N = 404), and Stanley et al. 2014 (N = 54) — each of which compared tesamorelin 2 mg/day (subcutaneous injection) to placebo. Eligible participants in Stanley et al. 2014 also underwent a second randomization process to undergo a hyperinsulinemic euglycemic clamp. LIPO-010 and CTR-1011 comprised a 26-week double-blind (DB) main phase, followed by a 26-week extension phase (the extension phase of CTR-1011 was denoted CTR-1012). In the extension phase, participants who received tesamorelin in the main phase were re-randomized to continue receiving tesamorelin 2 mg/day (T-T group) or switched to placebo (T-P group), whereas all individuals who received placebo in the main phase were assigned to receive tesamorelin (P-T group). The study by Stanley et al. 2014 consisted of a six-month DB treatment phase. The primary efficacy outcome for LIPO-010 and CTR-1011 was the per cent change in VAT at week 26.

In LIPO-010 and CTR-1011, VAT was assessed by a CT scan from a single 5 mm slice obtained at the level of the L4-L5 intervertebral disc space. In LIPO-010 and CTR-1011, relevant secondary efficacy outcomes included patient-reported outcomes (PROs) related to body image, specifically perceived belly size, belly appearance distress, and belly profile. Other relevant efficacy outcomes measured in both trials included waist circumference and QoL. Investigators of CTR-1011 also administered the EuroQol 5-Dimensions (EQ-5D) instrument, a generic measure of health-related quality of life (HRQoL). In Stanley et al. 2014, the co-primary efficacy outcomes were changes in VAT (measured using a single-slice CT at L4) and liver fat (not relevant for this review).

All three trials enrolled participants who were aged 18 to 65 years, HIV-positive, on a stable ART regimen, and had objective evidence of abdominal fat accumulation as follows: waist circumference ≥ 95 cm and waist-to-hip ratio ≥ 0.94 for males, and waist circumference ≥ 94 cm and waist-to-hip ratio ≥ 0.88 for females. In LIPO-010 and CTR-1011, more than half of participants in each treatment group reported taking an ART regimen that included a protease inhibitor (PI), whereas more than a third of participants did so in Stanley et al. 2014. In each trial, at least a third of participants reported taking an ART regimen that included a non-nucleoside reverse transcriptase inhibitor (NNRTI), whereas across all trials, more than 90% of participants reported taking a nucleoside reverse transcriptase inhibitor (NRTI).

Some methodological issues were identified in the trials. First, discussions with the clinical expert consulted by CADTH Common Drug Review (CDR) for the purpose of this review revealed concerns regarding the external validity of the results of the included studies. Specifically, the study populations were different from those normally seen in routine clinical practice in Canada at present with respect to the nature of the current ART. The expert indicated that, in today’s clinical practice, HIV patients are much more likely to receive ART regimens that consist of backbones other than PIs, including integrase strand transfer inhibitors (INSTIs) and NNRTIs. To this end, of the six regimens recommended by the US Department of Health and Human Services to manage ART-naive patients, five are INSTI-based, and one is ritonavir-boosted PI-based. In LIPO-010, the number of participants receiving ART regimens that consist of integrase inhibitors was not reported, whereas less than 5% of participants in CTR-1011 were receiving INSTI-based therapies. In Stanley et al. 2014, the number of participants on integrase inhibitors was unclear, as the authors reported that seven (25.0%) and six (27.3%) individuals in the tesamorelin and placebo group, respectively, were receiving entry inhibitors and integrase inhibitors. Moreover, as a result of the large number of HIV treatments available today, single or multiple substitutions of the various components of an ART regimen can be made to achieve optimal virologic suppression with fewer adverse events, including a substantially reduced risk of the accumulation of visceral fat. Further, the psychometric properties of the instruments used to evaluate body image and QoL in LIPO-010 and CTR-1011 were not clear, which leaves uncertain the degree to which the results are valid and clinically meaningful.

Efficacy

Across all three included studies, tesamorelin was associated with a statistically significantly greater reduction in VAT versus placebo: the least squares (LS) mean differences (95% confidence interval [CI]) for tesamorelin versus placebo were −19.6% (−23.7% to −15.3%) in LIPO-010 at week 26, and −11.7% (−16.2% to −7.1%) in CTR-1011 week 26, and −16.6% (−30.6% to −2.6%) in Stanley et al. 2014 at six months (Table 1). In LIPO-010 and CTR-1011, tesamorelin was associated with a statistically significantly greater reduction in waist circumference at 26 weeks versus placebo, with absolute differences (95% CI) of −1.8 cm (−2.8 cm to −0.9 cm) and −1.3 cm (−2.4 cm to −0.2 cm), respectively. In the same two trials, at week 26, there were no statistically significant differences between treatment groups with respect to change in belly size evaluation, while the effects of tesamorelin versus placebo on change in belly appearance distress and patient-reported belly profile ratings were inconsistent. There were no statistically significant differences between tesamorelin and placebo with respect to changes to the overall (item-wise) QoL score at week 26.

Table 1

Summary of Results (Main Phase).

In the extension phase, continued treatment with tesamorelin (T-T group) was associated with a statistically significantly greater reduction in VAT versus discontinuing treatment with tesamorelin (T-P group) from weeks 26 to 52: LS mean differences (95% CI) were −20.4% (−29.8 to −11.0) and −25.8% (−40.7% to −10.9%) in LIPO-010 and CTR-1012, respectively. For both trials, however, participants in the T-P group experienced increases in VAT by as much as 24.9% over the same time period. Furthermore, from weeks 26 to 52, participants in the T-T group experienced statistically significantly greater improvements in belly appearance distress and patient-reported belly profile versus those in the T-P group, although there were no statistically significant differences between treatment groups with respect to changes in belly size evaluation.

Across the trials, no analyses were conducted to evaluate the impact of waist circumference on the primary efficacy outcome. In LIPO-010, the investigators did not find a statistically significant treatment-by-baseline interaction with respect to the per cent change in VAT at week 26 (P = 0.251). The impact of baseline VAT was not evaluated on the primary efficacy outcome in CTR-1011 and the study by Stanley et al. 2014. In LIPO-010, with respect to the primary efficacy outcome, in one analysis of covariance (ANCOVA) model, neither the NNRTI nor the NNRTI-by-treatment interaction were statistically significant (P = 0.711 and P = 0.392, respectively); in a separate ANCOVA model, neither the ART regimen nor the treatment-by-ART regimen interaction were statistically significant (P = 0.855 and P = 0.962, respectively). In CTR-1011, neither the ART regimen nor the treatment-by-ART regimen interaction were statistically significant (P = 0.213 and P = 0.810 respectively) as they pertained to the primary efficacy outcome.

Harms

Across all three studies, at least 70% of study participants in each trial experienced a treatment-emergent adverse event (AE) at week 26 (Table 1). A greater proportion of participants in Stanley et al. 2014 experienced an AE (tesamorelin: 89.3%; placebo: 95.5%) than those in the main phase of LIPO-010, followed by those in CTR-1011. Approximately 5% more participants receiving tesamorelin (LIPO-010: 82.8%; CTR-1011: 74.1%) experienced an AE than those on placebo (LIPO-010: 75.9%; CTR-1011: 69.8%). There were no deaths in LIPO-010 and Stanley et al., whereas two participants died in CTR-1011, one in each treatment group. Across all three studies, at week 26, a greater percentage of participants receiving tesamorelin reported an injection-site–related AE, myalgia, or fluid retention or edema than those in the placebo group. In LIPO-010, one participant (0.4%) receiving tesamorelin (versus none receiving placebo) developed diabetes mellitus (recorded as a treatment-emergent AE) at week 26. In LIPO-010, a greater percentage of participants receiving tesamorelin versus placebo (2.9% versus 1.5%) developed a malignancy, whereas a smaller percentage of participants receiving tesamorelin in CTR-1011 versus those receiving placebo (0.4% versus 3.2%) developed a malignancy.

In the LIPO-010 extension phase, AEs were observed in 57.8%, 74.7%, and 73.9% of participants in the T-T, P-T, and T-P groups, respectively; the corresponding percentages in CTR-1012 were 73.9%, 57.6%, and 76.7%. Two participants died in the extension phase of LIPO-010: one individual in the T-T group and the other in the P-T group.