Approximately two years have passed since the initial approval of tipranavir (TPV, Aptivus), yet our knowledge of this agent continues to grow through ongoing research. New findings presented at the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2007) provide insight into how to maximize tipranavir's effectiveness, clinical outcomes of tipranavir in women versus men and what patients and clinicians can expect in terms of changes in metabolic parameters produced by tipranavir.
The Importance of Combining Tipranavir With Another Active Agent
Data from several clinical trials -- namely, the TORO trials of enfuvirtide (T-20, Fuzeon), the RESIST studies of tipranavir, the POWER studies of darunavir (TMC114, Prezista) and the MOTIVATE studies of maraviroc -- demonstrate that it is possible to achieve an undetectable viral load (less than 50 copies/mL) in a substantial proportion of patients who are heavily treatment experienced.1-4
The key to doing so is to combine these new agents with at least one other active antiretroviral in the newly designed regimen. In this way, the use of at least two fully active agents creates a high genetic barrier to resistance. Indeed, even the U.S. Department for Health and Human Services (DHHS) guidelines state, "Adding a drug with activity against drug-resistant virus (e.g., a potent ritonavir [RTV, Norvir]-boosted protease inhibitor [PI]) and a drug with a new mechanism of action (e.g., an HIV entry inhibitor) to an optimized background antiviral regimen can provide significant antiretroviral activity."5
To gauge just how well tipranavir supports the DHHS's statement, Raffi and colleagues6 compared the efficacy and safety of tipranavir + ritonavir with or without the addition of enfuvirtide in treatment-experienced patients participating in the RESIST studies. RESIST data from week 48 were used in the analysis after being segregated by patients who took tipranavir + ritonavir with enfuvirtide (170/746; 22.8%) and those who took tipranavir + ritonavir without enfuvirtide (576/746; 77.2%). The data were then assessed by intent-to-treat, non-completer-equals-failure analysis.
A comparison of baseline characteristics between the two groups revealed that patients who received enfuvirtide had more advanced disease compared with patients who did not receive enfuvirtide based on HIV-1 RNA levels, CD4+ cell count and Centers for Disease Control (CDC) class C disease. The former group had also taken more antiretrovirals prior to enrollment. However, all other baseline characteristics were similar between the two groups.
|Baseline Characteristic||Receipt of T-20|
(n = 170)
|No Receipt of T-20|
(n = 576)
|Median age, years (range)||44 (17-67)||42 (17-80)|
|Male, n (%)||152 (89.4)||477 (82.8)|
|White, n (%)||133 (78.2)||438 (76.0)|
|Median HIV-1 RNA, log10 copies/mL||5.06||4.72|
|Median CD4+ cell count, cells/mm3||74||179|
|CDC class C disease, %||65.3||57.8|
|Median number of antiretrovirals previously used (range)|| || |
|5 (1-7)||4 (1-7)|
|"||6 (3-8)||5 (2-8)|
|2 (0-3)||1 (0-3)|
|Median number of IAS protease mutations||11||10|
|NRTI = nucleoside reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor.|
Among the individuals who received enfuvirtide, the majority were taking enfuvirtide for the first time (124/170; 72.9%), whereas a much smaller proportion had previously used enfuvirtide and were recycling the agent for re-use (46/170; 27.1%). Baseline characteristics were generally similar between the enfuvirtide recipients using new versus old enfuvirtide.
Despite the greater treatment experience and more advanced disease among patients who received enfuvirtide, these individuals demonstrated better virologic suppression to levels below 50 copies/mL than did individuals who did not receive enfuvirtide (29.4% vs. 20.7%). Moreover, those patients who received new enfuvirtide demonstrated markedly better virologic suppression below 50 copies/mL than did patients who were recycling old enfuvirtide (37.1% vs. 8.7%). Changes in CD4+ cell count showed similar patterns as virologic suppression: Patients who received enfuvirtide had greater CD4+ cell count increases than patients who did not receive enfuvirtide (+87 vs. +32 cells/mm3), and patients who received new enfuvirtide demonstrated greater CD4+ cell count increases than patients receiving old enfuvirtide (+102 vs. +32 cells/mm3).
Interestingly, median tipranavir trough concentrations in blood plasma measured 10 to 14 hours after dosing were 46% higher in patients who received enfuvirtide compared with those who did not (45.2 vs. 31.0 µM). These increases in tipranavir trough concentrations with versus without concomitant enfuvirtide use were seen in both males (44.3 vs. 29.8 µM) and females (54.5 vs. 40.5 µM), as well as across patients with different body surface areas. Similar increases in the trough concentrations of lopinavir/ritonavir (LPV/r, Kaletra; +23%) and saquinavir (SQV, Invirase; +63%) were also observed among patients who received enfuvirtide versus those who did not. These cumulative data suggest that enfuvirtide may enhance pharmacokinetic exposure to certain PIs, including tipranavir, regardless of patient gender or size. Despite the higher tipranavir trough concentrations in patients receiving enfuvirtide, hepatic safety was not compromised. In fact, liver safety was actually better among patients who did receive enfuvirtide versus those who did not with regard to hepatic adverse events (5.9 vs. 9.3 events per 100 person-years of exposure), grade 3/4 elevations in alanine aminotransferase (ALT) levels (6.5% vs. 12.9%) and grade 3/4 elevations in aspartate aminotransferase (AST) levels (4.1% vs. 8.3%).
Given that patients receiving tipranavir + ritonavir + enfuvirtide experienced better virologic and immunologic outcomes after 48 weeks of treatment compared with patients who did not receive enfuvirtide, it appears that tipranavir upholds the DHHS's recommendation to combine at least two active agents in a patient's salvage regimen to maximize treatment efficacy. The findings from this study also highlight how the widespread introduction of tipranavir, along with other novel agents, into clinical practice has caused a dramatic shift in the goals of therapy for treatment-experienced patients. Previously, the goal of achieving undetectable viral loads was not considered feasible for these individuals. However, given newly available agents such as tipranavir, current guidelines now stress viral load suppression to levels below 50 copies/mL, which preserves immune function and prevents clinical progression.5,7
Tipranavir Packs Just as Powerful a Punch in Women as in Men
Females have long received short shrift when it comes to the clinical analysis of investigational agents. Even though women account for approximately 30% of all new HIV diagnoses in the United States and nearly 18 million women worldwide are living with HIV infection, most HIV clinical trials are underpowered to detect gender differences. This is quite disconcerting given increasing evidence suggesting that women receiving antiretrovirals may experience different efficacy, safety and tolerability issues compared with men.
Sharon Walmsley and colleagues performed a retrospective analysis8 of data from the RESIST trials to evaluate the efficacy and safety of tipranavir + ritonavir and comparator PIs (CPIs) boosted with ritonavir among treatment-experienced women. Pharmacokinetic analyses were also performed to determine if drug exposure levels influenced the safety profile of particular PIs.
The 203 treatment-experienced women participating in the RESIST trials represent only 12.6% of the total population. Eighty-six of these women were randomly assigned to receive a CPI + ritonavir, whereas 117 were assigned to receive tipranavir + ritonavir. All baseline characteristics were generally comparable between men and women participating in RESIST, except that only about 11% of men were black compared with about 23% of women.
A comparison of virologic efficacy among women versus men identified no significant gender differences. By week 48, 25.6% of women and 22.1% of men who received tipranavir + ritonavir had a viral load below 50 copies/mL (odds ratio: 1.15; 95% confidence interval [CI]: 0.71-1.84; P = .5728). The mean change in viral load at week 48 was also comparable between women and men who received tipranavir + ritonavir at -1.46 and -1.30 log10 copies/mL, respectively, after adjustment for PI stratum, use of enfuvirtide and background sensitivity to NRTIs (P = .1890).
In contrast to these findings, women who received tipranavir + ritonavir demonstrated a significantly greater increase in CD4+ cell count compared with men who received tipranavir + ritonavir (+84 vs. +52 cells/mm3; P = .0017). Women also had 17% higher steady-state trough concentrations of tipranavir in blood plasma than did men (adjusted mean values: 45.3 vs. 38.75 µM), but this did not result in any appreciable increase in adverse events in women compared with men. Women did show a slight increase in the rate of adverse events based on person-years of exposure, but this was limited to only grade 1 adverse events; all higher grade adverse events and adverse events resulting in treatment discontinuation were similar between women and men.
|Outcome, Events Per PEY||Women||Men|
|Grade 1 AE||343.4||279.1||225.6||291.3|
|Grade 2 AE||117.5||136.4||119.8||154.2|
|Grade 3 AE||19.9||23.4||22.9||27.5|
|Grade 4 AE||24.2||32.4||29.6||35.4|
|AEs resulting in treatment discontinuation||10.6||11.8||10.3||10.5|
|AE = adverse event; PEY = patient-years of exposure.|
These retrospective findings indicate that the virologic efficacy and safety of tipranavir + ritonavir is comparable in women and men, despite slightly higher tipranavir trough concentrations in the former. Moreover, women appear to experience slightly better immunologic outcomes with tipranavir + ritonavir compared with men. The SPRING study, as the name -- Safety, Efficacy and Pharmacokinetics of Tipranavir Boosted with Low-Dose Ritonavir (500/200 mg) Twice Daily in 400 Racially and Gender Diverse HIV-Positive, Treatment-Experienced Population -- suggests, is a multi-center, open-label, phase 3b trial designed to examine patient outcomes with tipranavir in a racially diverse group of 200 female and 200 male treatment-experienced patients across eight countries in three continents. The results from this study, in combination with the analysis of the RESIST data and findings from other planned studies, should help clinicians better understand gender differences in response to tipranavir in treatment-experienced patients.
Effects of Tipranavir on Body Composition and Metabolic Parameters
Many PIs have been associated with lipoatrophy, accumulation of central fat, insulin resistance and type 2 diabetes mellitus,9,10 but these data have mostly come from case reports, cross-sectional studies or short studies conducted in healthy HIV-uninfected volunteers. To better assess the effects of select PIs on body composition and metabolic parameters using prospective data, Carr and colleagues performed a metabolic sub-study11 based on data from Study BI 1182.33, a randomized trial that prospectively compared the efficacy and safety of tipranavir + ritonavir versus lopinavir/ritonavir in treatment-naive individuals over 48 weeks.
The sub-study included 140 treatment-naive individuals who were randomly assigned to receive tipranavir + ritonavir 500/100 mg twice daily (n = 46), tipranavir + ritonavir 500/200 mg twice daily (n = 48) or lopinavir/ritonavir 400/100 mg twice daily (n = 46), all in combination with tenofovir (TDF, Viread) and lamivudine (3TC, Epivir). Lipodystrophy was assessed at screening and week 48 with dual energy X-ray absorptiometry scans, abdominal computed tomography scans and measurement of waist and hip circumferences. Metabolic parameters were assessed somewhat more frequently at weeks 0, 24 and 48. Baseline characteristics were generally well balanced across treatment groups.
The change in limb fat between baseline and week 48 -- the primary study endpoint -- increased for all three treatment groups. Although no significant differences were found between either of the tipranavir + ritonavir groups compared with the lopinavir/ritonavir group, there was a trend toward a greater increase in limb fat in the lopinavir/ritonavir arm versus the tipranavir + ritonavir 500/100-mg arm (P = .072). Trunk fat increased slightly in the lopinavir/ritonavir arm and decreased slightly in the tipranavir + ritonavir arms, and these differences were statistically significant. However, across all arms, the ratio of trunk fat to limb fat was stable, as were changes in waist and hip circumferences. Importantly, visceral adipose tissue (VAT) decreased in all arms, particularly in the tipranavir + ritonavir 500/200-mg arm. The larger increases in body fat observed with lopinavir/ritonavir compared with tipranavir + ritonavir suggest that lopinavir/ritonavir has a more substantial influence on fat metabolism.
|Median Change From Baseline to Week 48||TPV/r|
(n = 46)
(n = 48)
(n = 46)
|P Value for TPV/r|
|P Value for TPV/r|
|Limb fat, kg||+0.41||+0.83||+1.17||.072||.163|
|Arm fat, kg||+0.03||+0.09||+0.16||.04||.29|
|Leg fat, kg||+0.46||+0.63||+0.96||.08||.17|
|Total fat, kg||+0.36||+0.35||+2.18||.03||.07|
|Trunk fat, kg||-0.29||-0.18||+0.76||.02||.02|
Whereas lopinavir/ritonavir appeared to have a greater influence on fat metabolism, tipranavir + ritonavir appeared to have a greater influence on lipid levels. Both tipranavir + ritonavir arms produced significantly greater increases in cholesterol levels compared with lopinavir/ritonavir. Greater increases in triglycerides and lower increases in high-density lipoprotein (HDL) cholesterol were also observed for tipranavir + ritonavir versus lopinavir/ritonavir, but these differences did not reach statistical significance.
|Median Change From Baseline to Week 48, mg/dL||TPV/r|
(n = 46)
(n = 48)
(n = 46)
|P Value for TPV/r|
|P Value for TPV/r|
Within each treatment arm, no significant changes in glucose sensitivity were observed over the treatment period according to glucose and insulin levels at fasting and at two hours after an oral glucose tolerance test and homeostasis model assessment for insulin resistance. Plasma adiponectin levels increased in all arms over 48 weeks, but the increases were significantly greater in the tipranavir + ritonavir arms compared with the lopinavir/ritonavir arm (both P values < .002). The clinical importance of adiponectin increases is not well understood, but the investigators hypothesized that it may reflect a compensatory response to the metabolic effects of the PIs. Plasma leptin levels increased significantly more in the lopinavir/ritonavir arm compared with the tipranavir + ritonavir 500/100-mg arm (+1,168 vs. -38.5 pg/mL; P = .015). As might be expected, changes in limb fat were negatively correlated with adiponectin levels (r = -0.201; P = .025) and positively correlated with leptin levels (r = 0.665; P < .0001).
In sum, 48 weeks of treatment with either tipranavir + ritonavir or lopinavir/ritonavir led to increases in subcutaneous fat, but greater body fat increases were observed with lopinavir/ritonavir, suggesting that this agent bears a stronger influence on fat metabolism. Importantly, tipranavir + ritonavir treatment was not associated with increased insulin resistance or increased VAT, which contrasts with previous studies of other PIs. These findings suggest that tipranavir is not associated with the development of lipodystrophy or insulin resistance in treatment-naive patients.
- Nelson M, Arastéh K, Clotet B, et al. Durable efficacy of enfuvirtide over 48 weeks in heavily treatment-experienced HIV-1-infected patients in the T-20 Versus Optimized Background Regimen Only 1 and 2 clinical trials. J Acquir Immune Defic Syndr. December 1, 2005;40(4):404-412.
- Hicks CB, Cahn P, Cooper DA, et al, on behalf of the RESIST investigator group. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet. August 5, 2006;368(9534):466-475.
- Clotet B, Bellos N, Molina J-M, et al, on behalf of the POWER 1 and 2 study groups. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet. April 7, 2007;369(9568):1169-1178.
- van der Ryst E, Cooper D, Konourina I, et al. Efficacy of maraviroc in combination with at least one other potent new antiretroviral drug: 24-week combined analysis of the MOTIVATE 1 and 2 studies. In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WEPEB115LB.
- Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. U.S. Dept of Health and Human Services; October 10, 2006.
- Raffi F, Battegay M, Rusconi S, Opravil M, Kraft M, Sabo JP. Co-administering tipranavir/r (500/200 mg BID) and enfuvirtide (ENF) in the RESIST studies resulted in superior virological outcomes and a comparable safety profile compared to regimens containing tipranavir/r without enfuvirtide. In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WEPEB045.
- Hammer SM, Saag MS, Schechter M, et al. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel. JAMA. August 16, 2006;296(7):827-843.
- Walmsley S, Squires K, Kraft M, et al. Tipranavir/ritonavir (500/200 mg BID) demonstrated potent and durable virologic responses and a favourable safety profile in HIV-1 positive women participating in RESIST. In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract MOPDB04.
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- Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS. May 7, 1998;12(7):F51-F58.
- Carr A, Cooper DA. Lipodystrophy associated with an HIV-protease inhibitor. N Engl J Med. October 29, 1998;339(18):1296.
- Carr A, Zajdenverg R, Workman C, et al. Effects of tipranavir/r (500/200 or 500/100 mg BID) in comparison with lopinavir/r (400/100 mg BID) on changes in body composition and metabolic parameters in ARV-naive patients over 48 weeks. In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUPEB072.