Enfuvirtide: EFFICACY

In: Drug

10 Jun 2010

In both studies, the addition of enfu-virtide to an optimized regimen provided significant antiretroviral and immunological results through 24 weeks of HIV treatment-experienced patients and those with multidrug-resistant HIV infection. TORO-1 showed a decrease in viral loads of 1.7 log10 in the enfuvir-tide/optimized background regimen group, whereas a decrease of 0.76 log10 was seen in the optimized background regimen only (control) group (P < .001). Changes in CD4 counts in the enfuvir-tide/optimized background regimen group were increased by a median of 76 cells/mm3, whereas controls showed an increase of 32 cells/mm3, respectively (P< .001).

TORO-2 showed similar changes in viral loads, with a decrease of 1.43 log10 for patients receiving the enfuvirtide/ opimized background regimen and a decrease of 0.65 log10 in controls (P < .001). The CD4 count rose by 65 cells/mm3 in the patients receiving the enfuvirtide/optimized background regimen, and the controls experienced an increase of 38 cells/mm3. Analysis of both studies revealed a consistent activity of enfuvirtide across baseline immune cell counts, viral loads, age, race, and gender (Table 2).

Table 2 Outcomes of Randomized Treatment at Week 24 (from Pooled TORO-1 and TORO-2)

Enfuvirtide + Background    Background Regimen (90 mg b.i.d.)        Regimen Outcome                                                 (n = 661)                  (n = 334)

HIV-1 RNA log change from baseline

(log|0 copies/ml)

-1.52

-0.73

CD4 cell count change from baseline

(cells/mm3)

+71

+35

HIV RNA > 1 log below baseline

342 (52%)

86 (26%)

HIV RNA < 400 copies/ml

247 (37%)

54 (|6%)

Discontinued because of adverse reactions

40 (6%)

|2 (4%)

Discontinued because of injection-site reactions

20 (3%)

N/A

Discontinued because of other reasons

36 (5%)

|4 (4%)

Lalezari et al. conducted a clinical trial to study the long-term safety and antiviral activity of enfuvirtide in a multi-center 48-week, noncontrolled, open-label rollover study of 71 HIV-infected adults. Baseline HIV RNA levels were 4.8 log10 copies/ml, and the CD4 count was 134.8 cells/mm3. The results showed a mean -1.33 log10 HIV RNA change within 14 days after initiation of treatment; at week 48, approximately one-third of all patients in the intent-to-treat group maintained significant suppression of plasma HIV RNA of either fewer than 400 copies/ml or more than a 1.0 log10 decline from the baseline values. The mean gain in absolute CD4 count at 48 weeks was 84.9 cells/mm3.

SAFETY

During trials, patients tolerated enfu-virtide well. By far, the most common adverse drug events (ADEs) were reactions at the injection site. At the end of the 24 weeks in TORO-1 and TORO-2, nearly all patients in the enfuvirtide group (98.2%) reported at least one injection-site reaction, with most patients experiencing their first reaction during the first week. About 42% to 49% of patients also reported either mild-to-moderate tenderness and pain without limitation of their usual daily activities. Only 8.7% of these patients had pain or discomfort and needed oral analgesic agents, and none of the patients required hospitalization. Other common signs of injection-site reactions included erythema (87%), induration (84%), and nodules or cysts (82%). eriacta tablets

Other ADEs that were noted during the study were thought to be related to the optimized treatment regimen. The enfuvirtide group included a total of 77.6% of patients who exhibited an ADE other than local injection-site reactions, whereas the control group included a total of 74.5% of patients who also experienced ADEs. ADEs included diarrhea (79%), nausea (72%), fatigue (64%), and vomiting (25%), respectively. Patients also experienced insomnia, headache, dizziness, flatulence, and weight loss (Table 3).

Table 3 Percentage of Patients with Treatment-Emergent Adverse Events Excluding Injection-Site Reactions (from Pooled TORO-1 and TORO-2)

Adverse Event Enfuvirtide + Background    Background Regimen (%)             Regimen (%)(n = 663)             (n = 334)
Peripheral neuropathy 8.9 6.3
Insomnia 11.3 8.7
Depression 8.6 7.2
Anxiety 5.7 3
Cough 7.4 5.4
Sinusitis 6.2 2.1
Influenza 3.9 1.8
Weight loss 6.5 5.1
Myalgia 5 2.4
Constipation 3.9 2.7
Pancreatitis 2.4 0.9
Lymphadenopathy 2.3 0.3

An increased rate of bacterial pneumonia was observed in subjects receiving enfuvirtide, compared with the control arm, but it is unclear whether this increase was related to enfuvirtide per se. Hypersensitivity reactions were associated with enfuvirtide therapy, including rash, fever, nausea and vomiting, chills, rigors, hypotension, and elevated serum liver transaminase levels. These reac­tions may occur upon rechallenge.
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The manufacturer suggests careful monitoring of bacterial pneumonia and hypersensitivity. Results from the phase II 48-week study of the drug’s long-term safety and efficacy suggest that ADEs do not increase with prolonged exposure. Furthermore, enfuvirtide is well tolerated in both adults and children with HIV infection.


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